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Sample records for pick disease of the brain

  1. Brain pathology in Niemann Pick disease type A: insights from the acid sphingomyelinase knockout mice.

    Science.gov (United States)

    Ledesma, Maria Dolores; Prinetti, Alessandro; Sonnino, Sandro; Schuchman, Edward H

    2011-03-01

    Severe neurological involvement characterizes Niemann Pick disease (NPD) type A, an inherited disorder caused by loss of function mutations in the gene encoding acid sphingomyelinase (ASM). Mice lacking ASM, which mimic NPD type A, have provided important insights into the aberrant brain phenotypes induced by ASM deficiency. For example, lipid alterations, including the accumulation of sphingolipids, affect the membranes of different subcellular compartments of neurons and glial cells, leading to anomalies in signalling pathways, neuronal polarization, calcium homeostasis, synaptic plasticity, myelin production or immune response. These findings contribute to our understanding of the overall role of sphingolipids and their metabolic enzymes in brain physiology, and pave the way to design and test new therapeutic strategies for type A NPD and other neurodegenerative disorders. Some of these have already been tested in mice lacking ASM with promising results. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

  2. Brain pathology in Niemann Pick disease type A: Insights from the acid sphingomyelinase knockout mice

    Science.gov (United States)

    Ledesma, Maria Dolores; Prinetti, Alessandro; Sonnino, Sandro; Schuchman, Edward H.

    2010-01-01

    Severe neurological involvement characterizes Niemann Pick disease (NPD) type A, an inherited disorder caused by loss of function mutations in the gene encoding acid sphingomyelinase (ASM). Mice lacking ASM (ASMko), which mimic NPD type A, have provided important insights into the aberrant brain phenotypes induced by ASM deficiency. For example, lipid alterations, including the accumulation of sphingolipids, affect the membranes of different subcellular compartments of neurons and glial cells, leading to anomalies in signalling pathways, neuronal polarization, calcium homeostasis, synaptic plasticity, myelin production or immune response. These findings contribute to our understanding of the overall role of sphingolipids and their metabolic enzymes in brain physiology, and pave the way to design and test new therapeutic strategies for type A NPD and other neurodegenerative disorders. Some of these have already been tested in ASMko mice with promising results. PMID:21214563

  3. Pick disease

    Science.gov (United States)

    ... in behavior Failure to show emotional warmth, concern, empathy, sympathy Inappropriate mood Not caring about events or ... and steadily becomes worse. The person becomes totally disabled early in the course of the disease. Pick ...

  4. Alterations of myelin-specific proteins and sphingolipids characterize the brains of acid sphingomyelinase-deficient mice, an animal model of Niemann-Pick disease type A.

    Science.gov (United States)

    Buccinnà, Barbara; Piccinini, Marco; Prinetti, Alessandro; Scandroglio, Federica; Prioni, Simona; Valsecchi, Manuela; Votta, Barbara; Grifoni, Silvia; Lupino, Elisa; Ramondetti, Cristina; Schuchman, Edward H; Giordana, Maria Teresa; Sonnino, Sandro; Rinaudo, Maria Teresa

    2009-04-01

    Niemann-Pick disease (NPD) type A is a neurodegenerative disorder caused by sphingomyelin (SM) accumulation in lysosomes relying on reduced or absent acid sphingomyelinase (ASM) activity. NPD-A patients develop progressive neurodegeneration including cerebral and cerebellar atrophy, relevant Purkinje cell and myelin deficiency with death within 3 years. ASM'knock-out' (ASMKO) mice, an animal model of NPD-A, develop a phenotype largely mimicking that of NPD-A. The mechanisms underlying myelin formation are poorly documented in ASMKO mice. In this study we determined the content of four myelin-specific proteins, myelin basic protein (MBP), 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), myelin associated glycoprotein (MAG) and proteolipid protein (PLP), and that of myelin-enriched sphingolipids in the brains of ASMKO and wild-type mice in early stages of post-natal (pn) life. Protein and mRNA analysis revealed that in ASMKO mice beginning from 4 post-natal weeks (wk-pn), the expression levels of MAG, CNP, and MBP were below those observed in wild-type mice and the same applied to PLP at 10 wk-pn. Moreover, at 4 wk-pn the expression of SOX10, one of the transcription factors involved in oligodendrocyte development and maintenance was lower in ASMKO mice. Lipid analysis showed that SM and the gangliosides GM3 and GM2 accumulated in the brains of ASMKO mice, as opposed to galactocerebroside and galactosulfocerebroside that, in parallel with the mRNAs of UDP-galactose ceramide galactosyltransferase and galactose-3-O-sulfotransferase 1, the two transferases involved in their synthesis, decreased. Myelin lipid analysis showed a progressive sphingomyelin accumulation in ASMKO mice; noteworthy, of the two sphingomyelin species known to be resolved by TLC, only that with the lower Rf accumulated. The immunohistochemical analysis showed that the reduced expression of myelin specific proteins in ASMKO mice at 10 wk-pn was not restricted to the Purkinje layer of the

  5. New therapies in the management of Niemann-Pick type C disease: clinical utility of miglustat

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    James E Wraith

    2009-11-01

    Full Text Available James E Wraith, Jackie ImrieWillink Biochemical Genetics Unit, Royal Manchester Children’s Hospital, Manchester, UKAbstract: Niemann-Pick disease type C (NP-C is an autosomal recessive disorder characterized by progressive neurological deterioration leading to premature death. The disease is caused by mutations in one of two genes, NPC1 or NPC2, leading to impaired intracellular lipid transport and build-up of lipids in various tissues, particularly the brain. Miglustat (Zavesca®, a reversible inhibitor of glycosphingolipid synthesis, has recently been authorized in the European Union, Brazil and South Korea for the treatment of progressive neurological symptoms in adult and pediatric patients, and represents the first specific treatment for NP-C. Here we review current data on the pharmacology, efficacy, safety and tolerability of miglustat in patients with NP-C, based on findings from a prospective clinical trial, preclinical and retrospective studies, and case reports. Findings demonstrated clinically relevant beneficial effects of miglustat on neurological disease progression in adult, juvenile and pediatric patients with NP-C, particularly those diagnosed in late childhood (6–11 years and in juveniles and adults (12 years and older, compared with those diagnosed in early childhood (younger than 6 years. Miglustat therapy was well-tolerated in all age groups. With the approval of miglustat, treatment of patients with NP-C can now be aimed toward stabilizing neurological disease, which is likely the best attainable therapeutic goal for this disorder.Keywords: Niemann-Pick disease type C, NP-C, miglustat, Zavesca®

  6. Niemann-Pick Disease

    Science.gov (United States)

    ... Disease] National Niemann-Pick Disease Foundation, Inc. National Tay-Sachs and Allied Diseases Association See all related ... Disease] National Niemann-Pick Disease Foundation, Inc. National Tay-Sachs and Allied Diseases Association See all related ...

  7. A case of progressive aphasia without dementia: "temporal" Pick's disease?

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    Scheltens, P; Hazenberg, G J; Lindeboom, J; Valk, J; Wolters, E C

    1990-01-01

    We report a patient who suffered from progressive aphasia for nine years, before developing mild behavioural disturbances. Sequential computed tomography (CT) scanning and magnetic resonance (MRI) imaging showed progressive bilateral temporal atrophy. The case is thought to be a temporal form of Pick's disease, in which isolated progressive aphasia was the only symptom over many years. Images PMID:2303835

  8. The characteristics of neurofibrillary tangles in brains of patients with Niemann-Pick disease type C%C型Niemann-Pick病神经原纤维缠结的形成与特征

    Institute of Scientific and Technical Information of China (English)

    张旻; 降风; 魏佳军; 王雪贞; 王伟; Inez Vincent; 卜碧涛

    2008-01-01

    Objective To describe the spatial and temporal characteristics of neurofibrillary tangles (NFT) in brains of patients with Niemann-Pick disease type C (NPC). Methods In order to analyze formation of NFT in NPC, the brains collected from 17 patients with NPC aged from 7 months to 55 years old were investigated using antibodies against the protein tau and the specific proteins in mitotic phase. Results Typical NFT could be detected in the parahippocampns of a NPC patient as early as at 4 years old. The number of NFT were increasing along with the time. Gradually, the hippocampus and other regions of the temporal lobes and the frontal lobes would be affected with the time. Immunohistochemically, the NFT formed the shape similar to NFT seen in AD brains, without the presence of senile plagues. Interestingly,mitosis-phase markers appeared in the degenerating NPC neurons prior to hyperphesphorylation of tau and formation of NFT. Conclusions The formation of NFT does not result from aging, for there is no close relation between the presence of senile plagues and the formation of NFT. Ectopic activation of cdc2/cyclinB1 kinase complex might be an early event leading to NFT formation. Antagonist of the kinase complex may potentially slow down the formation of NFT.%目的 探讨C型尼曼-皮克病(NPC)脑部神经原纤维缠结(NFT)形成的时相特征.方法 以17例年龄7个月至55岁的NPC患者为研究对象,采用tau蛋白和有丝分裂期相关抗体进行免疫组织化学染色和银染,分析患者脑内NFT形成的特点.结果 最早可在4岁的患者海马旁回发现典型的NFT形成,随年龄增长数量逐渐增多.在形态上与阿尔茨海默病(AD)所见高度相似,但未发现老年斑.在NPC中,有丝分裂期磷酸化表位早于tau蛋白过度磷酸化及NFT形成.结论NFT形成并非老龄化过程的结果 ,且与老年斑的存在与否并无关联.cdc2/cyclinB1可能是NFT形成的关键性早期事件,针对其活性的

  9. Genetics Home Reference: Niemann-Pick disease

    Science.gov (United States)

    ... causing this fat to accumulate in cells. This fat buildup causes cells to malfunction and eventually die. Over time, cell loss impairs function of tissues and organs including the brain, lungs, spleen, and liver in people with Niemann-Pick disease types A and B. Mutations in either the NPC1 ...

  10. Diagnosis of Pick Disease%Pick病的诊断

    Institute of Scientific and Technical Information of China (English)

    贾建军; 卢文甫; 王鲁宁; 汤洪川; 尹岭

    2001-01-01

    目的探讨Pick病(Pick disease)诊断的正确性。方法分析2例临床上曾诊断为阿尔茨海默病(Alzheimer disease,AD),经核磁共振成像(MRI)检查证实的Pick病,其中1例经正电子发射型计算机断层扫描(PET)得到进一步证实。结果 Pick病与AD比较有如下特点:①特殊的语言方式及语言改变;②临床上以缓慢进展的性格改变及社会活动能力衰退为主,而记忆力、理解判断力、计算力障碍等出现相对较晚;③病程中有不同程度的Klüver-Bucy综合征表现;④脑MRI检查提示:额和(或)颞叶萎缩,颞极为著;⑤PET检查提示:双侧额、颞叶代谢减低,颞极明显。 结论根据Pick病临床表现及神经影像学特征,在排除AD及其它脑变性病的基础上,生前诊断Pick病是可能的。%Objective To explore the definite diagnosis of pick disease. Methods Two cases of the pick disease diag nosised by clinical and MRI findings,one of them certified by PET. The patients had been diagnosised as Alzheimer dis ease(AD) before. Results There are the following features on pick disease as compared with AD:①The special type of speech and speech disorder;②The slowly progressive change of character and involution of social action emerged earlier in clinical and the disturbance of memory,comprehension and calculation emerged later;③Klüver-Bucy syndrome can be found in the course of the illness;④MRI showed:the atrophy of frontal-temporal lobe is obviously, especially on tempo ral pole;⑤Frontal-temporal lobe deficits on PET,especially on temporal pole. Conclusion The antemortem diagnosis of pick disease might be possible on the detailed basis of clinical manifestations, MRI and PET features, but other neu rodegeneration disorders such as AD should be ruled out.

  11. A case of Niemann – Pick disease type C

    Directory of Open Access Journals (Sweden)

    Sergei Anatolyevich Klyushnikov

    2013-01-01

    Full Text Available The paper describes a clinical case of a 27-year-old female patient with Niemann – Pick disease type C (NPC, a rare inherited orphan disease, belonging to a group of lipid storage diseases. It gives an update on the etiology and pathogenesis of this type of glycosphingolipidosis and on established gene mutations. The clinical polymorphism of NPC and the trends in the development of somatic, mental, and neurological disorders are highlighted in relation to the onset age of the disease. The problem of differential diagnosis is discussed. The diagnostic NPC probability index in scores and the latest methods for laboratory diagnostic verification, including molecular genetic testing, are presented.Information is given on specific substrate reduction therapy with miglustat for NPC.

  12. The cost of brain diseases

    DEFF Research Database (Denmark)

    DiLuca, Monica; Olesen, Jes

    2014-01-01

    Brain diseases represent a considerable social and economic burden in Europe. With yearly costs of about 800 billion euros and an estimated 179 million people afflicted in 2010, brain diseases are an unquestionable emergency and a grand challenge for neuroscientists.......Brain diseases represent a considerable social and economic burden in Europe. With yearly costs of about 800 billion euros and an estimated 179 million people afflicted in 2010, brain diseases are an unquestionable emergency and a grand challenge for neuroscientists....

  13. Inflammatory diseases of the brain

    Energy Technology Data Exchange (ETDEWEB)

    Haehnel, Stefan (ed.) [University of Heidelberg Medical Center (Germany). Div. of Neuroradiology

    2009-07-01

    This book provides a comprehensive overview of inflammatory brain diseases from a neuroradiological point of view. Such diseases may be either infectious (e.g., viral encephalitis and pyogenic brain abscess) or non-infectious (e.g., multiple sclerosis), and many of these entities are becoming increasingly important for differential diagnosis, particularly in immunocompromised persons. Neuroimaging contributes greatly to the differentiation of infectious and noninfectious brain diseases and to the distinction between brain inflammation and other, for instance neoplastic, diseases. In order to ensure a standardized approach throughout the book, each chapter is subdivided into three principal sections: epidemiology, clinical presentation and therapy; imaging; and differential diagnosis. A separate chapter addresses technical and methodological issues and imaging protocols. All of the authors are recognized experts in their fields, and numerous high-quality and informative illustrations are included. This book will be of great value not only to neuroradiologists but also to neurologists, neuropediatricians, and general radiologists. (orig.)

  14. 'Limits and current knowledge of Pick's disease: its differential diagnosis'. A translation of the 1957 Delay, Brion, Escourolle article.

    Science.gov (United States)

    Thibodeau, Marie-Pierre; Miller, Bruce L

    2013-01-01

    This article is a translation of a French article by Delay, Brion, and Escourolle. In a seminal article published in French in 1957 these authors summarized the work of previous researchers and reviewed a wide sample of frontotemporal dementia (FTD) cases formerly referred to as Pick's disease. The authors were among the first to define the critical clinical and anatomical differences between Alzheimer's disease (AD) and FTD and they even delineated distinctive FTD subtypes making possible the advances that now constitute the base of our studies. Reviewing their work allows us to appreciate the progress research has made.

  15. Collaborative development of 2-hydroxypropyl-β-cyclodextrin for the treatment of Niemann-Pick type C1 disease.

    Science.gov (United States)

    Ottinger, Elizabeth A; Kao, Mark L; Carrillo-Carrasco, Nuria; Yanjanin, Nicole; Shankar, Roopa Kanakatti; Janssen, Marjo; Brewster, Marcus; Scott, Ilona; Xu, Xin; Cradock, Jim; Terse, Pramod; Dehdashti, Seameen J; Marugan, Juan; Zheng, Wei; Portilla, Lili; Hubbs, Alan; Pavan, William J; Heiss, John; Vite, Charles H; Walkley, Steven U; Ory, Daniel S; Silber, Steven A; Porter, Forbes D; Austin, Christopher P; McKew, John C

    2014-01-01

    In 2010, the National Institutes of Health (NIH) established the Therapeutics for Rare and Neglected Diseases (TRND) program within the National Center for Advancing Translational Sciences (NCATS), which was created to stimulate drug discovery and development for rare and neglected tropical diseases through a collaborative model between the NIH, academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies. This paper describes one of the first TRND programs, the development of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) for the treatment of Niemann-Pick disease type C1 (NPC1). NPC is a neurodegenerative, autosomal recessive rare disease caused by a mutation in either the NPC1 (about 95% of cases) or the NPC2 gene (about 5% of cases). These mutations affect the intracellular trafficking of cholesterol and other lipids, which leads to a progressive accumulation of unesterified cholesterol and glycosphingolipids in the CNS and visceral organs. Affected individuals typically exhibit ataxia, swallowing problems, seizures, and progressive impairment of motor and intellectual function in early childhood, and usually die in adolescence. There is no disease modifying therapy currently approved for NPC1 in the US. A collaborative drug development program has been established between TRND, public and private partners that has completed the pre-clinical development of HP-β-CD through IND filing for the current Phase I clinical trial that is underway. Here we discuss how this collaborative effort helped to overcome scientific, clinical and financial challenges facing the development of new drug treatments for rare and neglected diseases, and how it will incentivize the commercialization of HP-β-CD for the benefit of the NPC patient community.

  16. The hidden Niemann-Pick type C patient : Clinical niches for a rare inherited metabolic disease

    NARCIS (Netherlands)

    Hendriksz, Christian J.; Anheim, Mathieu; Bauer, Peter; Bonnot, Olivier; Chakrapani, Anupam; Corvol, Jean-Christophe; de Koning, Tom J.; Degtyareva, Anna; Dionisi-Vici, Carlo; Doss, Sarah; Duning, Thomas; Giunti, Paola; Iodice, Rosa; Johnston, Tracy; Kelly, Dierdre; Kluenemann, Hans-Hermann; Lorenzl, Stefan; Padovani, Alessandro; Pocovi, Miguel; Synofzik, Matthis; Terblanche, Alta; Bergh, Florian Then; Topcu, Meral; Tranchant, Christine; Walterfang, Mark; Velten, Christian; Kolb, Stefan A.

    2017-01-01

    Background: Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to unde

  17. Sphingomyelin-induced inhibition of the plasma membrane calcium ATPase causes neurodegeneration in type A Niemann-Pick disease.

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    Pérez-Cañamás, A; Benvegnù, S; Rueda, C B; Rábano, A; Satrústegui, J; Ledesma, M D

    2017-05-01

    Niemann-Pick disease type A (NPA) is a rare lysosomal storage disorder characterized by severe neurological alterations that leads to death in childhood. Loss-of-function mutations in the acid sphingomyelinase (ASM) gene cause NPA, and result in the accumulation of sphingomyelin (SM) in lysosomes and plasma membrane of neurons. Using ASM knockout (ASMko) mice as a NPA disease model, we investigated how high SM levels contribute to neural pathology in NPA. We found high levels of oxidative stress both in neurons from these mice and a NPA patient. Impaired activity of the plasma membrane calcium ATPase (PMCA) increases intracellular calcium. SM induces PMCA decreased activity, which causes oxidative stress. Incubating ASMko-cultured neurons in the histone deacetylase inhibitor, SAHA, restores PMCA activity and calcium homeostasis and, consequently, reduces the increased levels of oxidative stress. No recovery occurs when PMCA activity is pharmacologically impaired or genetically inhibited in vitro. Oral administration of SAHA prevents oxidative stress and neurodegeneration, and improves behavioral performance in ASMko mice. These results demonstrate a critical role for plasma membrane SM in neuronal calcium regulation. Thus, we identify changes in PMCA-triggered calcium homeostasis as an upstream mediator for NPA pathology. These findings can stimulate new approaches for pharmacological remediation in a disease with no current clinical treatments.

  18. Tau-mediated nuclear depletion and cytoplasmic accumulation of SFPQ in Alzheimer's and Pick's disease.

    Directory of Open Access Journals (Sweden)

    Yazi D Ke

    Full Text Available Tau dysfunction characterizes neurodegenerative diseases such as Alzheimer's disease (AD and frontotemporal lobar degeneration (FTLD. Here, we performed an unbiased SAGE (serial analysis of gene expression of differentially expressed mRNAs in the amygdala of transgenic pR5 mice that express human tau carrying the P301L mutation previously identified in familial cases of FTLD. SAGE identified 29 deregulated transcripts including Sfpq that encodes a nuclear factor implicated in the splicing and regulation of gene expression. To assess the relevance for human disease we analyzed brains from AD, Pick's disease (PiD, a form of FTLD, and control cases. Strikingly, in AD and PiD, both dementias with a tau pathology, affected brain areas showed a virtually complete nuclear depletion of SFPQ in both neurons and astrocytes, along with cytoplasmic accumulation. Accordingly, neurons harboring either AD tangles or Pick bodies were also depleted of SFPQ. Immunoblot analysis of human entorhinal cortex samples revealed reduced SFPQ levels with advanced Braak stages suggesting that the SFPQ pathology may progress together with the tau pathology in AD. To determine a causal role for tau, we stably expressed both wild-type and P301L human tau in human SH-SY5Y neuroblastoma cells, an established cell culture model of tau pathology. The cells were differentiated by two independent methods, mitomycin C-mediated cell cycle arrest or neuronal differentiation with retinoic acid. Confocal microscopy revealed that SFPQ was confined to nuclei in non-transfected wild-type cells, whereas in wild-type and P301L tau over-expressing cells, irrespective of the differentiation method, it formed aggregates in the cytoplasm, suggesting that pathogenic tau drives SFPQ pathology in post-mitotic cells. Our findings add SFPQ to a growing list of transcription factors with an altered nucleo-cytoplasmic distribution under neurodegenerative conditions.

  19. New murine Niemann-Pick type C models bearing a pseudoexon-generating mutation recapitulate the main neurobehavioural and molecular features of the disease

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    Gómez-Grau, Marta; Albaigès, Júlia; Casas, Josefina; Auladell, Carme; Dierssen, Mara; Vilageliu, Lluïsa; Grinberg, Daniel

    2017-01-01

    Niemann-Pick disease type C (NPC) is a rare neurovisceral disease caused mainly by mutations in the NPC1 gene. This autosomal recessive lysosomal disorder is characterised by the defective lysosomal secretion of cholesterol and sphingolipids. No effective therapy exists for the disease. We previously described a deep intronic point mutation (c.1554-1009 G > A) in NPC1 that generated a pseudoexon, which could be corrected at the cellular level using antisense oligonucleotides. Here, we describe the generation of two mouse models bearing this mutation, one in homozygosity and the other in compound heterozygosity with the c.1920delG mutation. Both the homozygotes for the c.1554-1009 G > A mutation and the compound heterozygotes recapitulated the hallmarks of NPC. Lipid analysis revealed accumulation of cholesterol in the liver and sphingolipids in the brain, with both types of transgenic mice displaying tremor and ataxia at 7–8 weeks of age. Behavioural tests showed motor impairment, hyperactivity, reduced anxiety-like behaviour and impaired learning and memory performances, features consistent with those reported previously in NPC animal models and human patients. These mutant mice, the first NPC models bearing a pseudoexon-generating mutation, could be suitable for assessing the efficacy of specific splicing-targeted therapeutic strategies against NPC. PMID:28167839

  20. The aurora sign in a patient with type B Niemann-Pick disease

    Energy Technology Data Exchange (ETDEWEB)

    Costa e. Silva, Eduardo J. da [Instituto Materno Infantil Professor Fernando Figueira, Departamento de Radiologia, Recife, Pernambuco (Brazil); IMIP, Departamento de Radiologia-Rua dos Coelhos, Recife, PE (Brazil); Cavalcanti de Albuquerque, Silvio; Queiroz Praxedes, Eduardo L. de; Amaral, Fernando J. do [Instituto Materno Infantil Professor Fernando Figueira, Departamento de Radiologia, Recife, Pernambuco (Brazil)

    2007-01-15

    The aurora sign, a sonographic sign found on the sagittal and transverse view, refers to multiple bands of ring-down artifacts posterior to the right hemidiaphragm. Parenchymal lung disease should be suspected when this is present. We report a case of type B Niemann-Pick disease with pulmonary involvement and the aurora sign on abdominal sonography. High-resolution CT of the chest showed corresponding thickened interlobular septa. (orig.)

  1. Clinical evaluation of chitotriosidase enzyme activity in Gaucher and Niemann Pick A/B diseases: A retrospective study from India.

    Science.gov (United States)

    Kadali, Srilatha; Kolusu, Anusha; Sunkara, Satish; Gummadi, Maheshwar Reddy; Undamatla, Jayanthi

    2016-06-01

    Plasma chitotriosidase originates from activated macrophages and is reported to be elevated in many Lysosomal Storage Disorders. Measurement of this enzyme activity has been an available tool for monitoring therapy of Gaucher disease. The degree of elevation of chitotriosidase is useful for differential diagnosis of Gaucher disease and Niemann Pick A/B. However the potential utility of this chitotriosidase assay depends on the frequency of deficient chitotriosidase activity in a particular population. We therefore aim to study the clinical utility of this assay Gaucher and Niemann Pick A/B diseases in the backdrop of chitotriosidase deficiency in our population. The study comprises 173 patients with clinical suspicion of either Gaucher disease (n=108) or Niemann Pick A/B (n=65) and 92 healthy controls. The plasma samples of controls, Gaucher disease, and Niemann Pick A/B showed chitotriosidase deficiency of 12%, 25% and 27% respectively. The degree of elevation of chitotriosidase in Gaucher disease and Niemann Pick A/B patients is 40-326 (11,325.7±6395.4nmol/h/ml) and 7-22 folds (1192.5±463.0nmol/h/ml) respectively. In view of these findings of distinguishable fold elevation of chitotriosidase in Gaucher disease or Niemann Pick A/B, it can be a potential surrogate differential diagnostic marker for these groups of diseases, except in the patients in whom this enzyme is deficient.

  2. Niemann-Pick disease type C

    OpenAIRE

    Vanier Marie T

    2010-01-01

    Abstract Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in...

  3. Stem Cells in Niemann-Pick Disease

    Directory of Open Access Journals (Sweden)

    Sun-Jung Kim

    2008-01-01

    Full Text Available Neural stem cells are multi-potent and able to self renew to maintain its character throughout the life. Loss of self renewal ability of stem cells prevents recovery or replacement of cells damaged by disease with new cells. The Niemann-Pick type C1 (NPC1 disease is one of the neurodegenerative diseases, caused by a mutation of NPC1 gene which affects the function of NPC1 protein. We reported that NPC 1 gene deficiency could lead to lack of the self renewal ability of neural stem cells in Niemann pick type C disease. We also investigated many genes which are involved in stem cells proliferation and differentiation by gene profile in NPC mice.

  4. Characterization of a spontaneous novel mutation in the NPC2 gene in a cat affected by Niemann Pick type C disease.

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    Stefania Zampieri

    Full Text Available Niemann-Pick C disease (NPC is an autosomal recessive lysosomal storage disorder characterized by accumulation of unesterified cholesterol and other lipids within the lysosomes due to mutation in NPC1 or NPC2 genes. A feline model of NPC carrying a mutation in NPC1 gene has been previously described. We have identified two kittens affected by NPC disease due to a mutation in NPC2 gene. They manifested with tremors at the age of 3 months, which progressed to dystonia and severe ataxia. At 6 months of age cat 2 was unable to stand without assistance and had bilaterally reduced menace response. It died at the age of 10 months. Post-mortem histological analysis of the brain showed the presence of neurons with cytoplasmic swelling and vacuoles, gliosis of the substantia nigra and degeneration of the white matter. Spheroids with accumulation of ubiquitinated aggregates were prominent in the cerebellar cortex. Purkinje cells were markedly reduced in number and they showed prominent intracytoplasmic storage. Scattered perivascular aggregates of lymphocytes and microglial cells proliferation were present in the thalamus and midbrain. Proliferation of Bergmann glia was also observed. In the liver, hepatocytes were swollen because of accumulation of small vacuoles and foamy Kupffer cells were also detected. Foamy macrophages were observed within the pulmonary interstitium and alveoli as well. At 9 months cat 1 was unable to walk, developed seizures and it was euthanized at 21 months. Filipin staining of cultured fibroblasts showed massive storage of unesterified cholesterol. Molecular analysis of NPC1 and NPC2 genes showed the presence of a homozygous intronic mutation (c.82+5G>A in the NPC2 gene. The subsequent analysis of the mRNA showed that the mutation causes the retention of 105 bp in the mature mRNA, which leads to the in frame insertion of 35 amino acids between residues 28 and 29 of NPC2 protein (p.G28_S29ins35.

  5. Efficacy of 2-Hydroxypropyl-β-cyclodextrin in Niemann-Pick Disease Type C Model Mice and Its Pharmacokinetic Analysis in a Patient with the Disease.

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    Tanaka, Yuta; Yamada, Yusei; Ishitsuka, Yoichi; Matsuo, Muneaki; Shiraishi, Koki; Wada, Koki; Uchio, Yushiro; Kondo, Yuki; Takeo, Toru; Nakagata, Naomi; Higashi, Taishi; Motoyama, Keiichi; Arima, Hidetoshi; Mochinaga, Sakiko; Higaki, Katsumi; Ohno, Kousaku; Irie, Tetsumi

    2015-01-01

    Niemann-Pick type C disease (NPC), an autosomal recessive lysosomal storage disorder, is an inherited disease characterized by the accumulation of intracellular unesterified cholesterol. A solubilizing agent of lipophilic compounds, 2-hydroxypropyl-β-cyclodextrin (HPBCD), is an attractive drug candidate against NPC disease. However, establishment of the optimum dosage of HPBCD remains to be determined. In this study, we evaluated the effective dosage of HPBCD in NPC model (Npc1(-/-)) mice, and determined serum HPBCD concentrations. Subcutaneous injection of 1000-4000 mg/kg HPBCD improved the lifespan of Npc1(-/-) mice. In addition, liver injury and cholesterol sequestration were significantly prevented by 4000 mg/kg HPBCD in Npc1(-/-) mice. Serum HPBCD concentrations, when treated at the effective dosages (1000-4000 mg/kg), were approximately 1200-2500 µg/mL at 0.5 h after subcutaneous injection, and blood HPBCD concentrations were immediately eliminated in Npc1(-/-) mice. Furthermore, we examined serum HPBCD concentrations when treated at 40000 mg (approximately 2500 mg/kg) in a patient with NPC. We observed that the effective concentration in the in vivo study using Npc1(-/-) mice was similar to that in the patient. In the patient, systemic clearance and the volume of distribution of HPBCD were in accordance with the glomerular filtration rate and extracellular fluid volume, respectively. These results could provide useful information for developing the optimal dosage regimen for HPBCD therapy when administered intravenously to NPC patients.

  6. National Niemann-Pick Disease Foundation

    Science.gov (United States)

    ... NIH Posted by jbeirl | RECEIVED FROM THE NIH Gene therapy shows promise for treating Niemann-Pick disease type C1 NIH mouse study... NNPDF Research Request for ASMD Posted by jbeirl | The NNPDF ...

  7. The relationship of psychological trauma with trichotillomania and skin picking

    Directory of Open Access Journals (Sweden)

    Özten E

    2015-05-01

    Full Text Available Eylem Özten,1 Gökben Hızlı Sayar,1 Gül Eryilmaz,1 Gaye Kağan,2 Sibel Işik,3 Oğuz Karamustafalioğlu4 1Neuropsychiatry Health, Practice, and Research Center, Üsküdar University, 2Istanbul Neuropsychiatry Hospital, Üsküdar University, 3Turkish Red Crescent Altintepe Medical Center, 4Department of Psychology, Faculty of Human and Social Sciences, Üsküdar University, Istanbul, Turkey Objective: Interactions between psychological, biological and environmental factors are important in development of trichotillomania and skin picking. The aim of this study is to determine the relationship of traumatic life events, symptoms of post-traumatic stress disorder and dissociation in patients with diagnoses of trichotillomania and skin picking disorder.Methods: The study included patients who was diagnosed with trichotillomania (n=23 or skin picking disorder (n=44, and healthy controls (n=37. Beck Depression Inventory, Traumatic Stress Symptoms Scale and Dissociative Experiences Scale were administered. All groups checked a list of traumatic life events to determine the exposed traumatic events.Results: There was no statistical significance between three groups in terms of Dissociative Experiences Scale scores (P=0.07. But Beck Depression Inventory and Traumatic Stress Symptoms Scale scores of trichotillomania and skin picking groups were significantly higher than the control group. Subjects with a diagnosis of trichotillomania and skin picking reported statistically significantly higher numbers of traumatic and negative events in childhood compared to healthy subjects.Conclusion: We can conclude that trauma may play a role in development of both trichotillomania and skin picking. Increased duration of trichotillomania or skin picking was correlated with decreased presence of post-traumatic stress symptoms. The reason for the negatively correlation of severity of post-traumatic stress symptoms and self-harming behavior may be speculated as

  8. Frontotemporal Dementia (Pick's Disease)

    Science.gov (United States)

    ... been shown to slow the progression of FTD. Behavior modification may help control unacceptable or dangerous behaviors. Aggressive, ... been shown to slow the progression of FTD. Behavior modification may help control unacceptable or dangerous behaviors. Aggressive, ...

  9. Recent Advances in the Diagnosis and Treatment of Niemann-Pick Disease Type C in Children: A Guide to Early Diagnosis for the General Pediatrician

    Directory of Open Access Journals (Sweden)

    Hanna Alobaidy

    2015-01-01

    Full Text Available Niemann-Pick disease (NP-C is a lysosomal storage disease in which impaired intracellular lipid transport leads to accumulation of cholesterol and glycosphingolipids in various neurovisceral tissues. It is an autosomal recessive disorder, caused by mutations in the NPC1 or NPC2 genes. The clinical spectrum is grouped by the age of onset and onset of neurological manifestation: pre/perinatal; early infantile; late infantile; and juvenile periods. The NP-C Suspicion Index (SI screening tool was developed to identify suspected patients with this disease. It is especially good at recognizing the disease in patients older than four years of age. Biochemical tests involving genetic markers and Filipin staining of skin fibroblast are being employed to assist diagnosis. Therapy is mostly supportive and since 2009, the first specific therapy approved for use was Miglustat (Zavesca aimed at stabilizing the rate of progression of neurological manifestation. The prognosis correlates with age at onset of neurological signs; patients with early onset form progress faster. The NP-C disease has heterogeneous neurovisceral manifestations. A SI is a screening tool that helps in diagnostic process. Filipin staining test is a specific biomarker diagnostic test. Miglustat is the first disease-specific therapy.

  10. Enhancement of the automatic onset time picking via wavelet thresholding

    Science.gov (United States)

    Gaci, Said

    2013-04-01

    Since arrival time-picking is a critical step in the analysis of geophysical data, many time picking algorithms have been developed. Nowadays, the ''short-time-average through long-time-average trigger'' (STA/LTA) in different forms are the most commonly used. This study aims at improving this algorithm in the presence of high amplitude noise. The suggested method consists of denoising the seismic trace using the discrete wavelet transform. Therefore, the STA/LTA curve obtained from the denoised trace displays a faster build up at the position of the wave arrival, and the picking error is reduced. The application of this technique is first demonstrated on synthetic seismic traces with varying noise levels, then extended to uphole seismic traces recorded in the Algerian Sahara. The results show that the picked first arrivals are more accurate than those yielded by the standard STA/LTA algorithm and this method can tolerate high noise levels. Keywords: picking, first arrival, seismic wave, wavelet thresholding.

  11. Pathological skin picking: case presentation and review of the literature

    Directory of Open Access Journals (Sweden)

    Maria Isabela Sarbu

    2015-04-01

    Full Text Available Pathological skin picking is a condition in which patients induce skin lesions through repetitive, compulsive excoriations of normal skin or skin with minor surface irregularities and they admit their role in the production of the lesions, but are unable to stop their behavior. Psychiatric comorbidities most often associated with skin picking include obsessive-compulsive disorder (OCD, anxiety disorders, mood disorders, body dysmorphic disorders, trichotillomania and compulsive-buying disorder. We report the case of a 17 year old female patient who addressed the dermatology department of our hospital with an eruption consisting of erythematous papules and plaques. The local examination revealed several clues of paramount importance in drawing the final conclusion and the psychiatric examination helped establish the diagnosis of pathological skin picking in a patient with obsessive-compulsive disorder.

  12. Defining natural history: assessment of the ability of college students to aid in characterizing clinical progression of Niemann-Pick disease, type C.

    Directory of Open Access Journals (Sweden)

    Jenny Shin

    Full Text Available Niemann-Pick Disease, type C (NPC is a fatal, neurodegenerative, lysosomal storage disorder. It is a rare disease with broad phenotypic spectrum and variable age of onset. These issues make it difficult to develop a universally accepted clinical outcome measure to assess urgently needed therapies. To this end, clinical investigators have defined emerging, disease severity scales. The average time from initial symptom to diagnosis is approximately 4 years. Further, some patients may not travel to specialized clinical centers even after diagnosis. We were therefore interested in investigating whether appropriately trained, community-based assessment of patient records could assist in defining disease progression using clinical severity scores. In this study we evolved a secure, step wise process to show that pre-existing medical records may be correctly assessed by non-clinical practitioners trained to quantify disease progression. Sixty-four undergraduate students at the University of Notre Dame were expertly trained in clinical disease assessment and recognition of major and minor symptoms of NPC. Seven clinical records, randomly selected from a total of thirty seven used to establish a leading clinical severity scale, were correctly assessed to show expected characteristics of linear disease progression. Student assessment of two new records donated by NPC families to our study also revealed linear progression of disease, but both showed accelerated disease progression, relative to the current severity scale, especially at the later stages. Together, these data suggest that college students may be trained in assessment of patient records, and thus provide insight into the natural history of a disease.

  13. A murine Niemann-Pick C1 I1061T knock-in model recapitulates the pathological features of the most prevalent human disease allele.

    Science.gov (United States)

    Praggastis, Maria; Tortelli, Brett; Zhang, Jessie; Fujiwara, Hideji; Sidhu, Rohini; Chacko, Anita; Chen, Zhouji; Chung, Chan; Lieberman, Andrew P; Sikora, Jakub; Davidson, Cristin; Walkley, Steven U; Pipalia, Nina H; Maxfield, Frederick R; Schaffer, Jean E; Ory, Daniel S

    2015-05-27

    Niemann-Pick Type C1 (NPC1) disease is a rare neurovisceral, cholesterol-sphingolipid lysosomal storage disorder characterized by ataxia, motor impairment, progressive intellectual decline, and dementia. The most prevalent mutation, NPC1(I1061T), encodes a misfolded protein with a reduced half-life caused by ER-associated degradation. Therapies directed at stabilization of the mutant NPC1 protein reduce cholesterol storage in fibroblasts but have not been tested in vivo because of lack of a suitable animal model. Whereas the prominent features of human NPC1 disease are replicated in the null Npc1(-/-) mouse, this model is not amenable to examining proteostatic therapies. The objective of the present study was to develop an NPC1 I1061T knock-in mouse in which to test proteostatic therapies. Compared with the Npc1(-/-) mouse, this Npc1(tm(I1061T)Dso) model displays a less severe, delayed form of NPC1 disease with respect to weight loss, decreased motor coordination, Purkinje cell death, lipid storage, and premature death. The murine NPC1(I1061T) protein has a reduced half-life in vivo, consistent with protein misfolding and rapid ER-associated degradation, and can be stabilized by histone deacetylase inhibition. This novel mouse model faithfully recapitulates human NPC1 disease and provides a powerful tool for preclinical evaluation of therapies targeting NPC1 protein variants with compromised stability.

  14. C1q, the classical complement pathway protein binds Hirano bodies in Pick's disease.

    Science.gov (United States)

    Singhrao, Sim K

    2013-06-01

    Haematoxylin/Eosin staining was performed to screen for Hirano bodies from the temporal lobe including the hippocampus in 10 Pick's disease cases containing Pick bodies. Although the inclusions were confirmed in 9 out of 10 cases, only 4 out of 10 were particularly enriched with the eosinophilic bodies. These were subjected to immunostaining with anticomplement antibodies and astrocyte marker antiglial fibrillary acidic protein antibody and the HLA class II CR3/43 antibody to visualize microglia. An intraneuronal Hirano body was observed in one case that otherwise contained mainly the extracellular inclusions. In all cases, the extracellular Hirano bodies were seen lying adjacent to soma of neurons within CA1 region of the hippocampus. The extracellular Hirano bodies stained intensely with C1q, the first component of the classical pathway of activation but remained unreactive against antibodies to C4 and the C3 activation products (C3b and iC3b) and the alternative complement pathway component factor B. Hirano bodies also remained negative with the antiglial fibrillary acidic protein for astrocytes and HLA class II antibody CR3/43 for microglia. The results demonstrate that Hirano bodies have strong immunoreactivity to C1q; however, whether other complement components are associated with these inclusions remains to be further investigated.

  15. Niemann-Pick disease treatment: a systematic review of clinical trials

    Science.gov (United States)

    Villamandos García, Diana; Sanchis-Gomar, Fabian; Fiuza-Luces, Carmen; Pareja-Galeano, Helios; Garatachea, Nuria; Nogales Gadea, Gisela; Lucia, Alejandro

    2015-01-01

    The aim of this systematic review was to analyse all the published clinical trials assessing treatments for Niemann-Pick (NP) disease. At present there are only trials investigating the treatment of NP disease type C. Furthermore, there is no uniformity among studies in treatment outcomes or in data analysis and presentation of results. Miglustat is able to delay neurodegeneration, with greater benefits in patients with a late onset of the disease and β-cyclodextrin-hydroxypropyl (HBP-CD) can attenuate clinical symptoms. As for cholesterol-lowering drugs, the combination of lovastatin, cholestyramine and nicotinic acid is the most effective one for lowering cholesterolemia. Further research is much needed, and ongoing trials using enzyme replacement therapy might hopefully show promising results in the foreseeable future. PMID:26807415

  16. Systematic Approaches to Experimentation: The Case of Pick's Theorem

    Science.gov (United States)

    Papadopoulos, Ioannis; Iatridou, Maria

    2010-01-01

    In this paper two 10th graders having an accumulated experience on problem-solving ancillary to the concept of area confronted the task to find Pick's formula for a lattice polygon's area. The formula was omitted from the theorem in order for the students to read the theorem as a problem to be solved. Their working is examined and emphasis is…

  17. Altered localization and functionality of TAR DNA Binding Protein 43 (TDP-43) in niemann- pick disease type C.

    Science.gov (United States)

    Dardis, A; Zampieri, S; Canterini, S; Newell, K L; Stuani, C; Murrell, J R; Ghetti, B; Fiorenza, M T; Bembi, B; Buratti, E

    2016-05-18

    Niemann-Pick type C (NPC) disease is a lysosomal storage disorder characterized by the occurrence of visceral and neurological symptoms. At present, the molecular mechanisms causing neurodegeneration in this disease are unknown. Here we report the altered expression and/or mislocalization of the TAR-DNA binding protein 43 (TDP-43) in both NPC mouse and in a human neuronal model of the disease. We also report the neuropathologic study of a NPC patient's brain, showing that while TDP-43 is below immunohistochemical detection in nuclei of cerebellar Purkinje cells, it has a predominant localization in the cytoplasm of these cells. From a functional point of view, the TDP-43 mislocalization, that occurs in a human experimental neuronal model system, is associated with specific alterations in TDP-43 controlled genes. Most interestingly, treatment with N-Acetyl-cysteine (NAC) or beta-cyclodextrin (CD) can partially restore TDP-43 nuclear localization. Taken together, the results of these studies extend the role of TDP-43 beyond the Amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD)/Alzheimer disease (AD) spectrum. These findings may open novel research/therapeutic avenues for a better understanding of both NPC disease and the TDP-43 proteinopathy disease mechanism.

  18. Editor’s Pick: Non-Alcoholic Fatty Liver Disease – Changing the Prevalence of Liver Cancer?

    Directory of Open Access Journals (Sweden)

    Benedetta Campana

    2015-01-01

    Full Text Available Due to its increasing prevalence, exceeding 25% of the Western population, non-alcoholic fatty liver disease (NAFLD merits recognition as one of the most frequent chronic liver diseases (CLD and requires consideration of the associated disease-related complications and their consequences for the surveillance and treatment of patients and the socio-economy worldwide. Along with the increasing incidence of NAFLD-related cirrhosis and end-stage liver disease, the frequency of NAFLD-related hepatocellular carcinoma (HCC is rising and expected to surpass HCC related to chronic hepatitis C in the upcoming future. These epidemiologic changes will impact on the overall mortality of CLD and the requirement of organs for transplantation. Although the risk of HCC in NAFLD, similar to other CLD, is related to fibrosis (advanced fibrosis increases the risk of HCC 25-fold, there are reports suggesting a considerable rate of HCC also developing in simple hepatic steatosis. Moreover, HCC is nowadays the leading cause of obesity-related cancer mortality; cancers of other origin such as colorectal cancer are more prevalent in patients with NAFLD and obesity. The pathophysiology of HCC has mainly been studied in models of viral hepatitis. Given the expected raise in NAFLD-related HCC, a better understanding of the pathophysiology of carcinogenesis in NAFLD and obesity is desired in order to better define chemopreventive strategies. Here we review the epidemiology, aetiology, and pathogenesis of HCC on the background of NAFLD and deduce potential consequences for the management of patients in respect to the NAFLD epidemic.

  19. Alleged Detrimental Mutations in the SMPD1 Gene in Patients with Niemann-Pick Disease

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    Cosima Rhein

    2015-06-01

    Full Text Available Loss-of-function mutations in the sphingomyelin phosphodiesterase 1 (SMPD1 gene are associated with decreased catalytic activity of acid sphingomyelinase (ASM and are the cause of the autosomal recessive lysosomal storage disorder Niemann-Pick disease (NPD types A and B. Currently, >100 missense mutations in SMPD1 are listed in the Human Gene Mutation Database. However, not every sequence variation in SMPD1 is detrimental and gives rise to NPD. We have analysed several alleged SMPD1 missense mutations mentioned in a recent publication and found them to be common variants of SMPD1 that give rise to normal in vivo and in vitro ASM activity. (Comment on Manshadi et al. Int. J. Mol. Sci. 2015, 16, 6668–6676.

  20. Niemann-Pick disease type C

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    Vanier Marie T

    2010-06-01

    Full Text Available Abstract Niemann-Pick C disease (NP-C is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood. The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period, gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period, and ataxia not unfrequently following initial psychiatric disturbances (adult form. The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype. Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential

  1. Niemann-Pick disease type C.

    Science.gov (United States)

    Vanier, Marie T

    2010-06-03

    Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120,000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include

  2. A Preliminary Analysis of the Phenomenology of Skin-Picking in Prader-Willi Syndrome

    Science.gov (United States)

    Morgan, Jessica R.; Storch, Eric A.; Woods, Douglas W.; Bodzin, Danielle; Lewin, Adam B.; Murphy, Tanya K.

    2010-01-01

    To examine the nature and psychosocial correlates of skin-picking behavior in youth with Prader-Willi Syndrome (PWS). Parents of 67 youth (aged 5-19 years) with PWS were recruited to complete an internet-based survey that included measures of: skin-picking behaviors, the automatic and/or focused nature of skin-picking, severity of skin-picking…

  3. Close up of the pick and place tool carrying a dummy silicon sensor.

    CERN Multimedia

    Bernd Surrow

    1999-01-01

    The gantry positioning head contains a vacuum pick-up system thatallows several different pick-up tools to be used. This one isdesigned to pick up the silicon sensors. The pick-up tool containsa pressure sensitive contact which can stop the motion of the machine when the tool touches a fixed object. The shiny cylinderis the end of the microscope optics of the CCD camera.

  4. Classic Pick's disease type with ubiquitin-positive and tau-negative inclusions: case report

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    Brito-Marques Paulo Roberto de

    2001-01-01

    Full Text Available We report on a patient presenting Pick's disease similar to the one reported by Pick in 1892, with ubiquitin-positive and tau-negative inclusions. His diagnosis was made on the basis of clinical (language disturbance and behavioural disorders, neuropsychological (progressive aphasia of the expression type and late mutism, neuroimaging with magnetic resonance (bilateral frontal and temporal lobes atrophy and brain single photon emission computed tomography (frontal and temporal lobes hypoperfusion studies. Macroscopic examination showed atrophy on the frontal and temporal lobes. The left hippocampus displayed a major circumscribed atrophy. The diagnostic confirmation was made by the neuropathological findings of the autopsy that showed neuronal loss with gliosis of the adjacent white matter and apearence of status spongiosus in the middle frontal and especially in the upper temporal lobes. There were also neuronal swelling (ballooned cell and argyrophilic inclusions (Pick's bodies in the left and right hippocampi. Anti-ubiquitin reaction tested positive and anti-tau tested negative.

  5. Diagnostic workup and management of patients with suspected Niemann-Pick type C disease.

    Science.gov (United States)

    Papandreou, Apostolos; Gissen, Paul

    2016-05-01

    Niemann-Pick type C (NP-C) disease is a neurovisceral disorder caused by mutations in the NPC1 and NPC2 genes. It is characterized by lysosomal storage of a broad range of lipids as a result of abnormal intracellular lipid trafficking. Typically patients develop neurodegeneration; however, the speed of disease progression is variable. The exact functions of NPC1 and NPC2 proteins have not been determined and therefore the molecular pathophysiology of NP-C is still not clearly understood. Due to the disease's rarity and clinical heterogeneity, delays from symptom onset to diagnosis and treatment initiation are common. Current therapeutic approaches focus on multidisciplinary symptom control and deceleration (rather than reversal) of disease progression. Thus identification of cases at early stages of disease is particularly important. Recent advances in genetic and biochemical testing have resulted in the generation of relatively non-invasive, quick and cost-effective laboratory assays that are highly sensitive and specific and have the capacity to enhance the clinicians' ability to reach a diagnosis earlier. Miglustat is a compound recently licensed in many countries for the treatment of NP-C that has been shown to decelerate neurological regression, whereas many other promising drugs are currently being trialled in preclinical models or human studies. This review summarizes key clinical, genetic and biochemical features of NP-C, suggests a simple diagnostic investigation strategy and gives an overview of available therapeutic options as well as potential novel treatments currently under development.

  6. Induced Pluripotent Stem Cells for Disease Modeling and Evaluation of Therapeutics for Niemann-Pick Disease Type A.

    Science.gov (United States)

    Long, Yan; Xu, Miao; Li, Rong; Dai, Sheng; Beers, Jeanette; Chen, Guokai; Soheilian, Ferri; Baxa, Ulrich; Wang, Mengqiao; Marugan, Juan J; Muro, Silvia; Li, Zhiyuan; Brady, Roscoe; Zheng, Wei

    2016-12-01

    : Niemann-Pick disease type A (NPA) is a lysosomal storage disease caused by mutations in the SMPD1 gene that encodes acid sphingomyelinase (ASM). Deficiency in ASM function results in lysosomal accumulation of sphingomyelin and neurodegeneration. Currently, there is no effective treatment for NPA. To accelerate drug discovery for treatment of NPA, we generated induced pluripotent stem cells from two patient dermal fibroblast lines and differentiated them into neural stem cells. The NPA neural stem cells exhibit a disease phenotype of lysosomal sphingomyelin accumulation and enlarged lysosomes. By using this disease model, we also evaluated three compounds that reportedly reduced lysosomal lipid accumulation in Niemann-Pick disease type C as well as enzyme replacement therapy with ASM. We found that α-tocopherol, δ-tocopherol, hydroxypropyl-β-cyclodextrin, and ASM reduced sphingomyelin accumulation and enlarged lysosomes in NPA neural stem cells. Therefore, the NPA neural stem cells possess the characteristic NPA disease phenotype that can be ameliorated by tocopherols, cyclodextrin, and ASM. Our results demonstrate the efficacies of cyclodextrin and tocopherols in the NPA cell-based model. Our data also indicate that the NPA neural stem cells can be used as a new cell-based disease model for further study of disease pathophysiology and for high-throughput screening to identify new lead compounds for drug development. Currently, there is no effective treatment for Niemann-Pick disease type A (NPA). To accelerate drug discovery for treatment of NPA, NPA-induced pluripotent stem cells were generated from patient dermal fibroblasts and differentiated into neural stem cells. By using the differentiated NPA neuronal cells as a cell-based disease model system, α-tocopherol, δ-tocopherol, and hydroxypropyl-β-cyclodextrin significantly reduced sphingomyelin accumulation in these NPA neuronal cells. Therefore, this cell-based NPA model can be used for further study of

  7. The Milwaukee Inventory for the Dimensions of Adult Skin Picking (MIDAS): initial development and psychometric properties.

    Science.gov (United States)

    Walther, Michael R; Flessner, Christopher A; Conelea, Christine A; Woods, Douglas W

    2009-03-01

    This article describes the development and initial psychometric properties of the Milwaukee Inventory for the Dimensions of Adult Skin picking (MIDAS), a measure designed to assess "automatic" and "focused" skin picking. Data were collected from 92 participants who completed an anonymous internet-based survey. Results of an exploratory factor analysis revealed a two-factor solution. Factors 1 ("focused" picking scale) and 2 ("automatic" picking scale) each consisted of 6 items, and preliminary data demonstrated adequate internal consistency, good construct validity, and good discriminant validity. The MIDAS provides researchers with a reliable and valid assessment of "automatic" and "focused" skin picking.

  8. Evaluation of an anti-tumor necrosis factor therapeutic in a mouse model of Niemann-Pick C liver disease.

    Directory of Open Access Journals (Sweden)

    Melanie Vincent

    Full Text Available BACKGROUND: Niemann-Pick type C (NPC disease is a lysosomal storage disease characterized by the accumulation of cholesterol and glycosphingolipids. The majority of NPC patients die in their teen years due to progressive neurodegeneration; however, half of NPC patients also suffer from cholestasis, prolonged jaundice, and hepatosplenomegaly. We previously showed that a key mediator of NPC liver disease is tumor necrosis factor (TNF α, which is involved in both proinflammatory and apoptotic signaling cascades. In this study, we tested the hypothesis that blocking TNF action with an anti-TNF monoclonal antibody (CNTO5048 will slow the progression of NPC liver disease. METHODOLOGY/PRINCIPAL FINDINGS: Treatment of wild-type C57BL/6 mice with NPC1-specific antisense oligonucleotides led to knockdown of NPC1 protein expression in the liver. This caused classical symptoms of NPC liver disease, including hepatic cholesterol accumulation, hepatomegaly, elevated serum liver enzymes, and lipid laden macrophage accumulation. In addition, there was a significant increase in the number of apoptotic cells and a proliferation of stellate cells. Concurrent treatment of NPC1 knockdown mice with anti-TNF had no effect on the primary lipid storage or accumulation of lipid-laden macrophages. However, anti-TNF treatment slightly blunted the increase in hepatic apoptosis and stellate cell activation that was seen with NPC1 knockdown. CONCLUSIONS/SIGNIFICANCE: Current therapeutic options for NPC disease are limited. Our results provide proof of principle that pharmacologically blocking the TNF-α inflammatory cascade can slightly reduce certain markers of NPC disease. Small molecule inhibitors of TNF that penetrate tissues and cross the blood-brain barrier may prove even more beneficial.

  9. Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease.

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    André R A Marques

    Full Text Available Impaired function of NPC1 or NPC2 lysosomal proteins leads to the intracellular accumulation of unesterified cholesterol, the primary defect underlying Niemann-Pick type C (NPC disease. In addition, glycosphingolipids (GSLs accumulate in lysosomes as well. Intralysosomal lipid accumulation triggers the activation of a set of genes, including potential biomarkers. Transcript levels of Gpnmb have been shown to be elevated in various tissues of an NPC mouse model. We speculated that Gpnmb could serve as a marker for visceral lipid accumulation in NPC disease. We report that Gpnmb expression is increased at protein level in macrophages in the viscera of Npc1nih/nih mice. Interestingly, soluble Gpnmb was also found to be increased in murine and NPC patient plasma. Exposure of RAW264.7 macrophages to the NPC-phenotype-inducing drug U18666A also upregulated Gpnmb expression. Inhibition of GSL synthesis with the glucosylceramide synthase (GCS inhibitor N-butyl-1-deoxynojirimycin prevented U18666A-induced Gpnmb induction and secretion. In summary, we show that Gpnmb is upregulated in NPC mice and patients, most likely due to GSL accumulation.

  10. Niemann-Pick disease, type B with TRAP-positive storage cells and secondary sea blue histiocytosis

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    R. Saxena

    2009-09-01

    Full Text Available We present 2 cases of Niemann Pick disease, type B with secondary sea-blue histiocytosis. Strikingly, in both cases the Pick cells were positive for tartrate resistant acid phosphatase, a finding hitherto described only in Gaucher cells. This report highlights the importance of this finding as a potential cytochemical diagnostic pitfall in the diagnosis of Niemann Pick disease.

  11. Identification of a distinct mutation spectrum in the SMPD1 gene of Chinese patients with acid sphingomyelinase-deficient Niemann-Pick disease

    Directory of Open Access Journals (Sweden)

    Zhang Huiwen

    2013-01-01

    Full Text Available Abstract Background Clinical observations and molecular analysis of the SMPD1 gene in Chinese patients with acid sphingomyelinase deficiency Niemann-Pick disease (NPD are scarce. Methods A cohort of 27 Chinese patients diagnosed with acid sphingomyelinase deficiency, within the past five years, were collected and investigated for genotype, phenotype, and their correlations. Results The majority of our patients (25/27 were under 18 years of age. From the cohort group, eight (30% fulfilled characters of type A. Four other patients experienced neurologic involvement after two years of age, these were classified as intermediate type. The remaining fifteen presented without clear neurologic involvement and were regarded as type B. One patient, from the type B group, presented with the unusual symptom of a secondary amenorrhea. Three patients, one from the type B group and two from the intermediate group, presented with pronounced proteinuria, in the late stages of the disease, indicating possible kidney involvement in NPD. Twenty-four SMPD1 gene mutations had been identified; eighteen of these are novel ones. These included four exonic small deletions/duplications (c.4delC, c.147_150del4, c.842-849dup8, c.1307-1312dup6, one termination mutation (p.Glu248X, and thirteen exonic point mutations (p.Gly336Ser, p.Trp342Cys, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser, p.Trp437Arg, p.Thr451Pro, p.His461Pro, p.Ala484Val, p.Ser486Arg, p.Tyr500His, p.Pro533Leu, p.Val559Leu. Notably, eight mutations had more than one occurrence with c.4delC and p.Glu248X accounting for ~30% of all alleles. Correlation analysis of genotype and phenotype indicated eight mutations, c.842-849dup8, p.Glu248X, p.Arg230Cys, p.Trp437Arg, p.His461Pro, p.Ala484Val p.Ser486Arg, and p.Pro533Leu,to be severe mutations. Five mutations, c.4delC, p.Leu382Phe, p.Pro429Leu, p.Pro430Ser and p.Val559Leu were projected to be mild mutations. Interestingly, three intermediate individuals carried

  12. A case of variant biochemical phenotype of Niemann-Pick disease type C accompanying savant syndrome.

    Science.gov (United States)

    Hamatani, Mio; Jingami, Naoto; Uemura, Kengo; Nakasone, Naoe; Kinoshita, Hisanori; Yamakado, Hodaka; Ninomiya, Haruaki; Takahashi, Ryosuke

    2016-06-22

    A 40-year-old man was referred to our hospital because of vertical supranuclear gaze palsy, frequent sudden loss of muscle tonus and ataxia for several years. He had a history of prolonged neonatal jaundice. He was given a diagnosis of autism in his childhood, followed by a diagnosis of schizophrenia in his teenage. He also developed a savant skill of calendar calculating. (123)I-IMP-SPECT showed decreased cerebral blood flow in the left frontotemporal lobe as often seen in savant syndrome. Although genetic analysis of NPC1 and NPC2 revealed no pathogenic mutation, filipin staining of cultured fibroblasts from his biopsied skin revealed a certain amount of intracellular cholesterol storage pattern, indicating a variant biochemical phenotype of Niemann-Pick disease type C (NPC). The diagnosis of adulthood onset NPC is difficult and challenging, especially for neurologists, because the symptoms and signs are not as clear as those in the classical childhood onset NPC and this subtype is not yet widely known. However, the diagnosis can be made by a combination of filipin staining of fibroblast and/or gene analysis. As a disease-specific therapy for NPC has been approved in Japan, the diagnosis of NPC is of significance.

  13. A comparison of brain volume and cortical thickness in excoriation (skin picking) disorder and trichotillomania (hair pulling disorder) in women.

    Science.gov (United States)

    Roos, Annerine; Grant, Jon E; Fouche, Jean-Paul; Stein, Dan J; Lochner, Christine

    2015-02-15

    Skin picking disorder (SPD) and trichotillomania (hair pulling disorder, or HPD) significantly overlap in terms of clinical features. However, few studies have directly compared structural brain data in these disorders. The aim of this study was to compare volumes of brain structures and cortical thickness in patients with SPD and HPD, and determine involvement of fronto-striatal pathways. Seventeen female SPD, 17 HPD and 15 healthy age-matched controls underwent clinical assessment and structural MRI imaging. Group differences were determined in brain volume and cortical thickness, controlling for illness severity. Participants with SPD had greater volume of the ventral striatum bilaterally; and reduced cortical thickness in right hemisphere frontal areas, and greater thickness of the cuneus bilaterally compared to HPD and control participants. HPD participants demonstrated reduced thickness of the right parahippocampal gyrus compared to SPD and control participants. The findings here are partially consistent with previous structural work in SPD, and suggest some differences in the neurobiology of SPD and HPD. The more extensive involvement of the ventral striatum in SPD may suggest greater involvement of the reward system, while the more extensive involvement of the parahippocampal gyrus in HPD may be consistent with the dissociative symptoms often seen in these patients.

  14. Implementation of a new picking procedure in the Antelope software

    Science.gov (United States)

    Tiberi, Lara; Costa, Giovanni; Spallarossa, Daniele

    2014-05-01

    Automatic estimates of earthquake parameters continues to be of considerable interest to the seismological community. In this study we present a new automatic procedure for a quasi real-time location of events. This procedure is a combination of the solid and tested Antelope sotfware with a new picking procedure, the AutoPicker (DipTeRiS, University of Genova). Antelope picking procedure consists on: a) Prefiltering into different frequency pass bands; b) Run STA/LTA detectors in one or more channels of the waveform data; c) Associate event locations by searching over one or more spatial grids for a candidate hypocenter that produces theoretical time moveout (P and S) to each station that most closely matches the observations. The main characteristics of the AutoPicker picking algorithm are: a) Pre-filtering and envelope calculation to prearrange the onset; b) Preliminary detection of P onset using the AIC based picker; c) P validation, Signal Variance/Noise Variance analysis sample by sample; d) Preliminary earthquake location; e) Detection of S onset adopting the AIC based picker; f) S/N analysis, S validation; g) Earthquake location. We have applied these two automatic procedures to the Emilia sequence occurred in May-June 2012. In this comparison the distribution of the differences between the manual and the two automatic P-onset are comparable. The average values of P differences are similar, but we have to point out that the AutoPicker procedure gives a st.deviation value lower than the Antelope ones and most important it picks the 16% of phases more than the other algoritm. For S-phases the AutoPicker algorithm picks 178 phases with a mean value of 0.09 sec, instead of the 16s of Antelope with a mean value of 3.75 sec. For more than 90% events the epicentral differences of AutoPicker is less than 5 kms, instead of the Antelope differences which are less than 10 kms. For the depth differences the mean values and the distributions of the two procedures are

  15. Skin picking behaviors: An examination of the prevalence and severity in a community sample.

    Science.gov (United States)

    Hayes, Stephania L; Storch, Eric A; Berlanga, Lissette

    2009-04-01

    Body-focused repetitive behaviors such as skin picking have gained recent attention in the psychiatric literature. Prevalence of skin picking has not been well researched and is difficult to estimate; however, consequences of such behaviors can include severe medical complications and impaired social and occupational functioning. Given this, this study examined: (1) the prevalence and severity of skin picking in a nonclinical community sample, and (2) associations between skin picking and other measures of psychological functioning. Three hundred and fifty-four participants completed measures of psychological functioning and skin picking frequency and severity. A total of 62.7% endorsed some form of skin picking and 5.4% reported clinical levels of skin picking and associated distress/impact. Direct associations were found between skin picking and depressive, anxiety, and obsessive-compulsive symptoms, which may support the emotional regulation model of pathological skin picking. To establish proper diagnostic classification of pathological skin picking and optimize treatment planning and outcome, further investigation of functional relationships between skin picking and affective distress is needed.

  16. Prion diseases of the brain; Prionenerkrankung des Gehirns

    Energy Technology Data Exchange (ETDEWEB)

    Lutz, Kira; Urbach, Horst [Universitaetsklinik Freiburg (Germany). Klinik fuer Neuroradiologie

    2015-09-15

    The prion diseases of the brain, especially Creutzfeldt-Jakob disease, are rare fatal neurodegenerative disorders. A definitive CJD diagnosis is currently only possible by a brain biopsy or post mortem autopsy. The diagnosis of Creutzfeldt-Jakob disease is based on clinical signs, pathognomonic EEG, on typical MRI findings and the examination of the cerebrospinal fluid. Using the MRI the diagnosis Creutzfeldt-Jakob disease can be confirmed or excluded with high certainty. The MRI examination should contain diffusion-weighted and FLAIR imaging sequences. This review article provides an overview of the prion diseases of the brain with the corresponding imaging findings.

  17. Effects of intracerebroventricular administration of 2-hydroxypropyl-β-cyclodextrin in a patient with Niemann–Pick Type C disease

    Directory of Open Access Journals (Sweden)

    Muneaki Matsuo

    2014-01-01

    Full Text Available Niemann–Pick Type C disease (NPC is an autosomal recessive lysosomal storage disorder characterized by progressive neurological deterioration. Previously, we reported that intravenous administration of 2-hydroxypropyl-β-cyclodextrin (HPB-CD in two patients with NPC had only partial and transient beneficial effects on neurological function. The most likely reason for HPB-CD not significantly improving the neurological deficits of NPC is its inability to cross the blood–brain barrier. Herein, we describe the effects of intrathecal HPB-CD in an eight-year-old patient with a perinatal onset of NPC, administered initially at a dose of 10 mg/kg every other week and increased up to 10 mg/kg twice a week. Clinically, the patient maintained residual neurological functions for two years, at which time nuclear magnetic resonance spectroscopy showed a decreased choline to creatine ratio and increased N-acetylaspartate to creatine ratio, and positron emission tomography revealed increased standardized uptake values. Total-tau in the cerebrospinal fluid (CSF was also decreased after two years. No adverse effects were observed over the course of treatment. The CSF concentrations of HPB-CD during the distribution phase after the injections were comparable with those at which HPB-CD could normalize cellular cholesterol abnormality in vitro. Further studies are necessary to elucidate the mechanisms of action of HPB-CD in NPC, and to determine the optimal dose and intervals of HPB-CD injection.

  18. Effects of intracerebroventricular administration of 2-hydroxypropyl-β-cyclodextrin in a patient with Niemann-Pick Type C disease.

    Science.gov (United States)

    Matsuo, Muneaki; Shraishi, Koki; Wada, Koki; Ishitsuka, Yoichi; Doi, Hirohito; Maeda, Miyuki; Mizoguchi, Tatsuhiro; Eto, Junya; Mochinaga, Sakiko; Arima, Hidetoshi; Irie, Tetsumi

    2014-01-01

    Niemann-Pick Type C disease (NPC) is an autosomal recessive lysosomal storage disorder characterized by progressive neurological deterioration. Previously, we reported that intravenous administration of 2-hydroxypropyl-β-cyclodextrin (HPB-CD) in two patients with NPC had only partial and transient beneficial effects on neurological function. The most likely reason for HPB-CD not significantly improving the neurological deficits of NPC is its inability to cross the blood-brain barrier. Herein, we describe the effects of intrathecal HPB-CD in an eight-year-old patient with a perinatal onset of NPC, administered initially at a dose of 10 mg/kg every other week and increased up to 10 mg/kg twice a week. Clinically, the patient maintained residual neurological functions for two years, at which time nuclear magnetic resonance spectroscopy showed a decreased choline to creatine ratio and increased N-acetylaspartate to creatine ratio, and positron emission tomography revealed increased standardized uptake values. Total-tau in the cerebrospinal fluid (CSF) was also decreased after two years. No adverse effects were observed over the course of treatment. The CSF concentrations of HPB-CD during the distribution phase after the injections were comparable with those at which HPB-CD could normalize cellular cholesterol abnormality in vitro. Further studies are necessary to elucidate the mechanisms of action of HPB-CD in NPC, and to determine the optimal dose and intervals of HPB-CD injection.

  19. Protein replacement therapy partially corrects the cholesterol-storage phenotype in a mouse model of Niemann-Pick type C2 disease.

    Directory of Open Access Journals (Sweden)

    Gitte Krogh Nielsen

    Full Text Available Niemann-Pick type C2 (NPC2 disease is a fatal autosomal recessive neurovisceral degenerative disorder characterized by late endosomal-lysosomal sequestration of low-density lipoprotein derived cholesterol. The breach in intracellular cholesterol homeostasis is caused by deficiency of functional NPC2, a soluble sterol binding protein targeted to the lysosomes by binding the mannose-6-phosphate receptor. As currently there is no effective treatment for the disorder, we have investigated the efficacy of NPC2 replacement therapy in a murine gene-trap model of NPC2-disease generated on the 129P2/OlaHsd genetic background. NPC2 was purified from bovine milk and its functional competence assured in NPC2-deficient fibroblasts using the specific cholesterol fluorescent probe filipin. For evaluation of phenotype correction in vivo, three-week-old NPC2(-/- mice received two weekly intravenous injections of 5 mg/kg NPC2 until trial termination 66 days later. Whereas the saline treated NPC2(-/- mice exhibited massive visceral cholesterol storage as compared to their wild-type littermates, administration of NPC2 caused a marked reduction in cholesterol build up. The histological findings, indicating an amelioration of the disease pathology in liver, spleen, and lungs, corroborated the biochemical results. Little or no difference in the overall cholesterol levels was observed in the kidneys, blood, cerebral cortex and hippocampus when comparing NPC2(-/- and wild type mice. However, cerebellum cholesterol was increased about two fold in NPC2(-/- mice compared with wild-type littermates. Weight gain performance was slightly improved as a result of the NPC2 treatment but significant motor coordination deficits were still observed. Accordingly, ultrastructural cerebellar abnormalities were detected in both saline treated and NPC2 treated NPC2(-/- animals 87 days post partum. Our data indicate that protein replacement may be a beneficial therapeutic approach in the

  20. Niemann-Pick disease type C: a case series of Brazilian patients

    Directory of Open Access Journals (Sweden)

    Paulo José Lorenzoni

    2014-03-01

    Full Text Available The aim of the study was to analyze a series of Brazilian patients with Niemann-Pick disease type C (NP-C. Method Correlations between clinical findings, laboratory data, molecular findings and treatment response are presented. Result The sample consisted of 5 patients aged 8 to 26 years. Vertical supranuclear gaze palsy, cerebellar ataxia, dementia, dystonia and dysarthria were present in all cases. Filipin staining showed the “classical” pattern in two patients and a “variant” pattern in three patients. Molecular analysis found mutations in the NPC1 gene in all alleles. Miglustat treatment was administered to 4 patients. Conclusion Although filipin staining should be used to confirm the diagnosis, bone marrow sea-blue histiocytes often help to diagnosis of NP-C. The p.P1007A mutation seems to be correlated with the “variant” pattern in filipin staining. Miglustat treatment response seems to be correlated with the age at disease onset and disability scale score at diagnosis.

  1. Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model.

    Science.gov (United States)

    Alam, Md Suhail; Getz, Michelle; Haldar, Kasturi

    2016-02-17

    Histone deacetylase inhibitors (HDACi) are approved for treating rare cancers and are of interest as potential therapies for neurodegenerative disorders. We evaluated a triple combination formulation (TCF) comprising the pan-HDACi vorinostat, the caging agent 2-hydroxypropyl-β-cyclodextrin (HPBCD), and polyethylene glycol (PEG) for treating a mouse model (the Npc1(nmf164) mouse) of Niemann-Pick type C (NPC) disease, a difficult-to-treat cerebellar disorder. Vorinostat alone showed activity in cultured primary cells derived from Npc1(nmf164) mice but did not improve animal survival. However, low-dose, once-weekly intraperitoneal injections of the TCF containing vorinostat increased histone acetylation in the mouse brain, preserved neurites and Purkinje cells, delayed symptoms of neurodegeneration, and extended mouse life span from 4 to almost 9 months. We demonstrate that the TCF boosted the ability of HDACi to cross the blood-brain barrier and was not toxic even when used long term. Further, the TCF enabled dose reduction, which has been a major challenge in HDACi therapy. TCF simultaneously treats neurodegenerative and systemic symptoms of Niemann-Pick type C disease in a mouse model.

  2. The Research on Improving the Order Picking Efficiency in Medical Logistics Area of CPL Based on Serial Partition Relay Picking Model

    Directory of Open Access Journals (Sweden)

    Xu Wei

    2013-01-01

    Full Text Available The medical business of China Post Logistics is developing day by day. China Post Logistics have been using the Parallel partition picking mode for a long time, but too many shortages have appearing in these two years, especially in the order picking cost and efficiency. This paper analyzes the current order picking mode of China Post Logistics and compare with the Parallel partition picking mode. By analysis the advantages and disadvantages of these two modes and combine with the actual situation, we choose the serial partition relay picking model as the picking mode of CPL in medical logistics area. And then it optimizes the order picking route in view of the current deficiency combined with the use of Ant Colony Optimization (ACO. The example simulation result shows that this optimizing is effective and the order picking cost decrease 17.36% and the route decrease 9.80% than that as before. This research not only to Chain Post Logistics but also to other logistics company which runs the medical business has certain reference.

  3. The Skin Picking Impact Project: phenomenology, interference, and treatment utilization of pathological skin picking in a population-based sample.

    Science.gov (United States)

    Tucker, Benjamin T P; Woods, Douglas W; Flessner, Christopher A; Franklin, Shana A; Franklin, Martin E

    2011-01-01

    The current study examined the characteristics of pathological skin picking (PSP) in a population-based sample. Participants were recruited through several online resources for PSP and related conditions to complete a web-based survey assessing the functional and topographical phenomenology, physical and psychosocial impact, treatment utilization, and associated psychopathology of PSP. A total of 1663 participants consented, of whom 760 were over 18 and met study criteria for PSP. Results showed considerable heterogeneity in picking methods, body sites, and function (e.g., regulation of emotional, sensory, and cognitive states). Participants generally reported moderate psychosocial and physical impact from picking and tended to perceive available treatment as poor in quality. Severity of associated symptoms of psychopathology (depression, anxiety, and stress) was comparable to severity levels found in previous samples of persons with trichotillomania and obsessive-compulsive disorder. Severity of PSP was a statistically significant predictor of overall impairment after controlling for depression and anxiety symptoms. Results suggest that PSP is a significant public health concern in need of further rigorous investigation.

  4. The hidden Niemann-Pick type C patient: clinical niches for a rare inherited metabolic disease.

    Science.gov (United States)

    Hendriksz, Christian J; Anheim, Mathieu; Bauer, Peter; Bonnot, Olivier; Chakrapani, Anupam; Corvol, Jean-Christophe; de Koning, Tom J; Degtyareva, Anna; Dionisi-Vici, Carlo; Doss, Sarah; Duning, Thomas; Giunti, Paola; Iodice, Rosa; Johnston, Tracy; Kelly, Dierdre; Klünemann, Hans-Hermann; Lorenzl, Stefan; Padovani, Alessandro; Pocovi, Miguel; Synofzik, Matthis; Terblanche, Alta; Then Bergh, Florian; Topçu, Meral; Tranchant, Christine; Walterfang, Mark; Velten, Christian; Kolb, Stefan A

    2017-05-01

    Niemann-Pick disease type C (NP-C) is a rare, inherited neurodegenerative disease of impaired intracellular lipid trafficking. Clinical symptoms are highly heterogeneous, including neurological, visceral, or psychiatric manifestations. The incidence of NP-C is under-estimated due to under-recognition or misdiagnosis across a wide range of medical fields. New screening and diagnostic methods provide an opportunity to improve detection of unrecognized cases in clinical sub-populations associated with a higher risk of NP-C. Patients in these at-risk groups ("clinical niches") have symptoms that are potentially related to NP-C, but go unrecognized due to other, more prevalent clinical features, and lack of awareness regarding underlying metabolic causes. Twelve potential clinical niches identified by clinical experts were evaluated based on a comprehensive, non-systematic review of literature published to date. Relevant publications were identified by targeted literature searches of EMBASE and PubMed using key search terms specific to each niche. Articles published in English or other European languages up to 2016 were included. Several niches were found to be relevant based on available data: movement disorders (early-onset ataxia and dystonia), organic psychosis, early-onset cholestasis/(hepato)splenomegaly, cases with relevant antenatal findings or fetal abnormalities, and patients affected by family history, consanguinity, and endogamy. Potentially relevant niches requiring further supportive data included: early-onset cognitive decline, frontotemporal dementia, parkinsonism, and chronic inflammatory CNS disease. There was relatively weak evidence to suggest amyotrophic lateral sclerosis or progressive supranuclear gaze palsy as potential niches. Several clinical niches have been identified that harbor patients at increased risk of NP-C.

  5. Comparative study of the radial and tangential shearer cutting picks from an energetic point of view

    Energy Technology Data Exchange (ETDEWEB)

    Marian, I.; Elczner, G.; Kovacs, I.; Koronka, F.

    1984-11-01

    After having calculated and established the deformation energies of radial and tangential shearer cutting picks by laboratory test, it is concluded that in the conditions specific for the lignite operations in Romania the tangential type of picks, among many other advantages, ensure important energy savings. The tests were aimed at improving the parameters and construction of the shearer cutting picks and at increasing their cutting efficiency. 4 references.

  6. Human acid sphingomyelinase structures provide insight to molecular basis of Niemann–Pick disease

    Science.gov (United States)

    Zhou, Yan-Feng; Metcalf, Matthew C.; Garman, Scott C.; Edmunds, Tim; Qiu, Huawei; Wei, Ronnie R.

    2016-01-01

    Acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and phosphocholine, essential components of myelin in neurons. Genetic alterations in ASM lead to ASM deficiency (ASMD) and have been linked to Niemann–Pick disease types A and B. Olipudase alfa, a recombinant form of human ASM, is being developed as enzyme replacement therapy to treat the non-neurological manifestations of ASMD. Here we present the human ASM holoenzyme and product bound structures encompassing all of the functional domains. The catalytic domain has a metallophosphatase fold, and two zinc ions and one reaction product phosphocholine are identified in a histidine-rich active site. The structures reveal the underlying catalytic mechanism, in which two zinc ions activate a water molecule for nucleophilic attack of the phosphodiester bond. Docking of sphingomyelin provides a model that allows insight into the selectivity of the enzyme and how the ASM domains collaborate to complete hydrolysis. Mapping of known mutations provides a basic understanding on correlations between enzyme dysfunction and phenotypes observed in ASMD patients. PMID:27725636

  7. Human acid sphingomyelinase structures provide insight to molecular basis of Niemann–Pick disease

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Yan-Feng; Metcalf, Matthew C.; Garman, Scott C.; Edmunds, Tim; Qiu, Huawei; Wei, Ronnie R. (Sanofi Aventis); (UMASS, Amherst)

    2016-10-26

    Acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and phosphocholine, essential components of myelin in neurons. Genetic alterations in ASM lead to ASM deficiency (ASMD) and have been linked to Niemann–Pick disease types A and B. Olipudase alfa, a recombinant form of human ASM, is being developed as enzyme replacement therapy to treat the non-neurological manifestations of ASMD. Here we present the human ASM holoenzyme and product bound structures encompassing all of the functional domains. The catalytic domain has a metallophosphatase fold, and two zinc ions and one reaction product phosphocholine are identified in a histidine-rich active site. The structures reveal the underlying catalytic mechanism, in which two zinc ions activate a water molecule for nucleophilic attack of the phosphodiester bond. Docking of sphingomyelin provides a model that allows insight into the selectivity of the enzyme and how the ASM domains collaborate to complete hydrolysis. Mapping of known mutations provides a basic understanding on correlations between enzyme dysfunction and phenotypes observed in ASMD patients.

  8. Blood-brain barrier transport of drugs for the treatment of brain diseases.

    Science.gov (United States)

    Gabathuler, Reinhard

    2009-06-01

    The central nervous system is a sanctuary protected by barriers that regulate brain homeostasis and control the transport of endogenous compounds into the brain. The blood-brain barrier, formed by endothelial cells of the brain capillaries, restricts access to brain cells allowing entry only to amino acids, glucose and hormones needed for normal brain cell function and metabolism. This very tight regulation of brain cell access is essential for the survival of neurons which do not have a significant capacity to regenerate, but also prevents therapeutic compounds, small and large, from reaching the brain. As a result, various strategies are being developed to enhance access of drugs to the brain parenchyma at therapeutically meaningful concentrations to effectively manage disease.

  9. Restarting stalled autophagy a potential therapeutic approach for the lipid storage disorder, Niemann-Pick type C1 disease.

    Science.gov (United States)

    Sarkar, Sovan; Maetzel, Dorothea; Korolchuk, Viktor I; Jaenisch, Rudolf

    2014-06-01

    Autophagy is essential for cellular homeostasis and its dysfunction in human diseases has been implicated in the accumulation of misfolded protein and in cellular toxicity. We have recently shown impairment in autophagic flux in the lipid storage disorder, Niemann-Pick type C1 (NPC1) disease associated with abnormal cholesterol sequestration, where maturation of autophagosomes is impaired due to defective amphisome formation caused by failure in SNARE machinery. Abrogation of autophagy also causes cholesterol accumulation, suggesting that defective autophagic flux in NPC1 disease may act as a primary causative factor not only by imparting its deleterious effects, but also by increasing cholesterol load. However, cholesterol depletion treatment with HP-β-cyclodextrin impedes autophagy, whereas pharmacologically stimulating autophagy restores its function independent of amphisome formation. Of potential therapeutic relevance is that a low dose of HP-β-cyclodextrin that does not perturb autophagy, coupled with an autophagy inducer, may rescue both the cholesterol and autophagy defects in NPC1 disease.

  10. Urinary Biomarkers of Brain Diseases

    Directory of Open Access Journals (Sweden)

    Manxia An

    2015-12-01

    Full Text Available Biomarkers are the measurable changes associated with a physiological or pathophysiological process. Unlike blood, urine is not subject to homeostatic mechanisms. Therefore, greater fluctuations could occur in urine than in blood, better reflecting the changes in human body. The roadmap of urine biomarker era was proposed. Although urine analysis has been attempted for clinical diagnosis, and urine has been monitored during the progression of many diseases, particularly urinary system diseases, whether urine can reflect brain disease status remains uncertain. As some biomarkers of brain diseases can be detected in the body fluids such as cerebrospinal fluid and blood, there is a possibility that urine also contain biomarkers of brain diseases. This review summarizes the clues of brain diseases reflected in the urine proteome and metabolome.

  11. Molecular determinants for the complex binding specificity of the PDZ domain in PICK1

    DEFF Research Database (Denmark)

    Madsen, Kenneth L; Beuming, Thijs; Niv, Masha Y

    2005-01-01

    PICK1 (protein interacting with C kinase 1) contains a single PDZ domain known to mediate interaction with the C termini of several receptors, transporters, ion channels, and kinases. In contrast to most PDZ domains, the PICK1 PDZ domain interacts with binding sequences classifiable as type I...... (terminating in (S/T)XPhi; X, any residue) as well as type II (PhiXPhi; Phi, any hydrophobic residue). To enable direct assessment of the affinity of the PICK1 PDZ domain for its binding partners we developed a purification scheme for PICK1 and a novel quantitative binding assay based on fluorescence...... polarization. Our results showed that the PICK1 PDZ domain binds the type II sequence presented by the human dopamine transporter (-WLKV) with an almost 15-fold and >100-fold higher affinity than the type I sequences presented by protein kinase Calpha (-QSAV) and the beta(2)-adrenergic receptor (-DSLL...

  12. Efficacy of thepick and roll” offense in top level European basketball teams

    Directory of Open Access Journals (Sweden)

    Marmarinos Christos

    2016-06-01

    Full Text Available Team offense in basketball games consists of a set of offensive actions carried out with the cooperation of two or more players. Of these actions, the most commonly used in the last decade is the on-ball screen called thepick and roll.” The aim of this study was to analyze all of the pick and rolls conducted in the Euroleague championship from all of the 24 participating teams and to investigate the possible relationships between success in the pick and roll and overall success of the teams. For this purpose, 12,376 pick and rolls from 502 matches were analyzed and classified in categories according to the end result of the offensive possession. The results showed that the most effective type of pick and roll offense was when a shot was attempted after 2 passes from the pick and roll occurrence, followed by the screener’s shot when he rolled to the basket. Additionally, linear regression analysis confirmed that pick and roll effectiveness could predict the final classification of the teams. Conclusively, coaches of the high level European clubs should focus on training the players to the most efficient phases of the pick and roll offense, so that the chances of winning the championship to be maximized.

  13. Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression.

    Directory of Open Access Journals (Sweden)

    Cristin D Davidson

    Full Text Available Niemann-Pick type C (NPC disease is a fatal neurodegenerative disorder caused most commonly by a defect in the NPC1 protein and characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids (GSLs. While current treatment therapies are limited, a few drugs tested in Npc1(-/- mice have shown partial benefit. During a combination treatment trial using two such compounds, N-butyldeoxynojirimycin (NB-DNJ and allopregnanolone, we noted increased lifespan for Npc1(-/- mice receiving only 2-hydroxypropyl-beta-cyclodextrin (CD, the vehicle for allopregnanolone. This finding suggested that administration of CD alone, but with greater frequency, might provide additional benefit.Administration of CD to Npc1(-/- mice beginning at either P7 or P21 and continuing every other day delayed clinical onset, reduced intraneuronal cholesterol and GSL storage as well as free sphingosine accumulation, reduced markers of neurodegeneration, and led to longer survival than any previous treatment regime. We reasoned that other lysosomal diseases characterized by cholesterol and GSL accumulation, including NPC disease due to NPC2 deficiency, GM1 gangliosidosis and mucopolysaccharidosis (MPS type IIIA, might likewise benefit from CD treatment. Treated Npc2(-/- mice showed benefits similar to NPC1 disease, however, mice with GM1 gangliosidosis or MPS IIIA failed to show reduction in storage.Treatment with CD delayed clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan of both Npc1(-/- and Npc2(-/- mice. In contrast, CD failed to ameliorate cholesterol or glycosphingolipid storage in GM1 gangliosidosis and MPS IIIA disease. Understanding the mechanism(s by which CD leads to reduced neuronal storage may provide important new opportunities for treatment of NPC and related neurodegenerative diseases characterized by cholesterol dyshomeostasis.

  14. Structure–activity relationships of a small-molecule inhibitor of the PDZ domain of PICK1

    DEFF Research Database (Denmark)

    Bach, Anders; Stuhr-Hansen, Nicolai; Thorsen, Thor S.

    2010-01-01

    Recently, we described the first small-molecule inhibitor, (E)-ethyl 2-cyano-3-(3,4-dichlorophenyl)acryloylcarbamate (1), of the PDZ domain of protein interacting with Ca-kinase 1 (PICK1), a potential drug target against brain ischemia, pain and cocaine addiction. Herein, we explore structure......, docking studies were used to correlate biological affinities with structural considerations for ligand–protein interactions. The most potent analogue obtained in this study showed an improvement in affinity compared to 1 and is currently a lead in further studies of PICK1 inhibition....

  15. Performance of helical cutting drum with additional picks on the face side

    Energy Technology Data Exchange (ETDEWEB)

    Krauze, K.; Paraszczak, J. (University of Mining Metallurgy, Krakow (Poland))

    1990-01-01

    Extensive study has shown that it is necessary to apply additional picks to a shearer in order to eliminate or diminish the forces pushing it out of the coal face. The presented design of the cutting drum with three or four additional picks has met these conditions, and tests and observations have confirmed the value of this design. 4 figs., 1 tab.

  16. Small vessel ischemic disease of the brain and brain metastases in lung cancer patients.

    Directory of Open Access Journals (Sweden)

    Peter J Mazzone

    Full Text Available BACKGROUND: Brain metastases occur commonly in patients with lung cancer. Small vessel ischemic disease is frequently found when imaging the brain to detect metastases. We aimed to determine if the presence of small vessel ischemic disease (SVID of the brain is protective against the development of brain metastases in lung cancer patients. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective cohort of 523 patients with biopsy confirmed lung cancer who had received magnetic resonance imaging of the brain as part of their standard initial staging evaluation was reviewed. Information collected included demographics, comorbidities, details of the lung cancer, and the presence of SVID of the brain. A portion of the cohort had the degree of SVID graded. The primary outcome measure was the portion of study subjects with and without SVID of the brain who had evidence of brain metastases at the time of initial staging of their lung cancer.109 patients (20.8% had evidence of brain metastases at presentation and 345 (66.0% had evidence of SVID. 13.9% of those with SVID and 34.3% of those without SVID presented with brain metastases (p<0.0001. In a model including age, diabetes mellitus, hypertension, hyperlipidemia, and tobacco use, SVID of the brain was found to be the only protective factor against the development of brain metastases, with an OR of 0.31 (0.20, 0.48; p<0.001. The grade of SVID was higher in those without brain metastases. CONCLUSIONS/SIGNIFICANCE: These findings suggest that vascular changes in the brain are protective against the development of brain metastases in lung cancer patients.

  17. The impact of COI-based storage on order-picking times

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    Grzegorz Tarczyński

    2017-09-01

    Full Text Available Background: The increasing competitiveness on the global markets enforces the need for a fast and reliable delivery. This task is possible to perform by improving the order-picking systems. The implementation of automated storage and retrieval systems (AS/RS is not always profitable. In the warehouses where the order-picking is performed in accordance with the principle of picker-to-part rule, the picking efficiency optimization includes among others: the warehouse layout, the storage policy, the routing heuristic, the way of zoning, the order-batching method, and the sequencing of pick-lists. In the paper the impact of the storage policy on the order-picking times is checked. Methods: The influence of storage based on Heskett’s cube-per-order index (COI on the average order-picking times is analyzed. The items based on increasing values of COI index are divided on classes. To determine the demand for items the analytical function proposed by Caron is used. Results: In the paper the benefits of storage based on COI index are compared with random storage and storage based only on picking frequency. It is assumed that the bin, to which the picker collects items has limited capacity – some orders has to be divided on smaller pick-lists. The analysis was performed using simulation tools. Additionally, the algorithm (taking into account different sizes of picker’s bin for order-batching is presented. Conclusions: The analysis shows that the COI-based storage is particularly effective when the size of items increases. The COI-based curve is less skewed than the curve based only on picking frequency. The choice of storage policy should be carried out together with routing heuristic. The use of batching algorithm significantly increases the effectiveness of the order-picking process, but the optimal size of picker’s bin (and batch should be optimized with consideration the sorting process.

  18. Drosophila melanogaster as a Model Organism of Brain Diseases

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    Werner Paulus

    2009-02-01

    Full Text Available Drosophila melanogaster has been utilized to model human brain diseases. In most of these invertebrate transgenic models, some aspects of human disease are reproduced. Although investigation of rodent models has been of significant impact, invertebrate models offer a wide variety of experimental tools that can potentially address some of the outstanding questions underlying neurological disease. This review considers what has been gleaned from invertebrate models of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, metabolic diseases such as Leigh disease, Niemann-Pick disease and ceroid lipofuscinoses, tumor syndromes such as neurofibromatosis and tuberous sclerosis, epilepsy as well as CNS injury. It is to be expected that genetic tools in Drosophila will reveal new pathways and interactions, which hopefully will result in molecular based therapy approaches.

  19. Rapid Diagnosis of 83 Patients with Niemann Pick Type C Disease and Related Cholesterol Transport Disorders by Cholestantriol Screening

    Directory of Open Access Journals (Sweden)

    Janine Reunert

    2016-02-01

    Full Text Available Niemann Pick type C (NP-C is a rare neurodegenerative disorder caused by an impairment of intracellular lipid transport. Due to the heterogeneous clinical phenotype and the lack of a reliable blood test, diagnosis and therapy are often delayed for years. In the cell, accumulating cholesterol leads to increased formation of oxysterols that can be used as a powerful screening parameter for NP-C. In a large scale study, we evaluated the oxysterol cholestane-3β,5α,6β-triol (c-triol as potential biomarker for a rapid diagnosis of NP-C. Using GC/MS, c-triol has been analyzed in 1902 plasma samples of patients with the suspicion for NP-C. Diagnosis in patients with elevated oxysterols was confirmed by genetic analysis. 71 new NP-C patients (69 NP-C1 and two NP-C2 and 12 Niemann Pick type A/B patients were identified. 24 new mutations in NPC1, one new mutation in NPC2 and three new mutations in the SMPD1 gene were found. Cholestane-3β,5α,6β-triol was elevated in Niemann Pick type C1, type C2, type A/B and in CESD disease. No other study has ever identified so many NP-C patients, proving that c-triol is a rapid and reliable biomarker to detect patients with NP-C disease and related cholesterol transport disorders. It should replace the filipin test as the first-line diagnostic assay.

  20. Altered expression of CRMPs in the brain of bovine spongiform encephalopathy-infected mice during disease progression.

    Science.gov (United States)

    Auvergnon, Nathalie; Reibel, Sophie; Touret, Monique; Honnorat, Jérôme; Baron, Thierry; Giraudon, Pascale; Bencsik, Anna

    2009-03-19

    While recent studies suggest that synaptic alterations are first events in the mechanisms of prion-mediated neurodegeneration, little is known on the identity of the neuronal plasticity-related genes potentially concerned. Here the expression of 4 Collapsin Response Mediator Proteins (CRMPs), a family of signal transduction proteins involved in brain development and altered in Alzheimer's disease, was studied in the brain of C57Bl/6 mice infected with the BSE strain of prion agent, using RT-PCR and Western-blot methods. At the terminal stage of the disease, gene expression of each CRMP had decreased, while at the mid-stage of the disease only CRMP4 (mRNA and protein) expression had increased, concomitant to the start of PrP(Sc) accumulation in the brainstem. Altogether our findings picked out originally CRMPs, and especially CRMP4, as potential contributors to prion pathogenesis.

  1. A rare cause of fatal pulmonary alveolar proteinosis: Niemann-Pick disease type C2 and a novel mutation.

    Science.gov (United States)

    Yaman, Ayhan; Eminoğlu, Fatma T; Kendirli, Tanıl; Ödek, Çağlar; Ceylaner, Serdar; Kansu, Aydan; İnce, Elif; Deda, Gülhis

    2015-09-01

    Niemann-Pick disease type C (NPC) is a fatal autosomal recessive lipid storage disease associated with impaired trafficking of unesterified cholesterol and glycolipids in lysosomes and late endosomes. This disease is commonly characterized by hepatosplenomegaly and severe progressive neurological dysfunction. There are two defective genes that cause this illness. One of these genes is NPC1 gene which is the cause of illness in 95% of the patients. The other gene is the rare type NPC2 which is the cause of illness in 5% of the patients. Patients with NPC2 usually present with respiratory distress in early infancy, which is rather unusual with NPC1. This article discusses about a patient who died at an early age from pulmonary involvement and who subsequently was found to have a novel homozygous mutation of NPC2 gene.

  2. Improved Operating Performance of Mining Machine Picks

    Science.gov (United States)

    Prokopenko, S.; Li, A.; Kurzina, I.; Sushko, A.

    2016-08-01

    The reasons of low performance of mining machine picks are stated herein. In order to improve the wear resistance and the cutting ability of picks a new design of a cutting carbide tip insert to be fixed on a removable and rotating pick head is developed. Owing to the new design, the tool ensures a twofold increase in the cutting force maintained longer, a twofold reduction in the specific power consumption of the breaking process, and extended service life of picks and the possibility of their multiple use.

  3. Neuroimaging of Cerebrovascular Disease in the Aging Brain

    OpenAIRE

    Gupta, Ajay; Nair, Sreejit; Andrew D Schweitzer; Kishore, Sirish; Johnson, Carl E.; Comunale, Joseph P.; Tsiouris, Apostolos J; Sanelli, Pina C.

    2012-01-01

    Cerebrovascular disease remains a significant public health burden with its greatest impact on the elderly population. Advances in neuroimaging techniques allow detailed and sophisticated evaluation of many manifestations of cerebrovascular disease in the brain parenchyma as well as in the intracranial and extracranial vasculature. These tools continue to contribute to our understanding of the multifactorial processes that occur in the age-dependent development of cerebrovascular disease. Str...

  4. Influence of the Hard-Faced Layer Welded on Tangential-Rotary Pick Operational Part on to Its Wear Rate

    Science.gov (United States)

    Krauze, Krzysztof; Skowronek, Tadeusz; Mucha, Kamil

    2016-12-01

    Problems related with abrasive wear of tangential-rotary picks during cutting process and its limitations, have been discussed in the present study. Essential for the parameters of cutting process geometrical, kinematic and material parameters of tangential-rotary picks and types of their wear, have been discussed. Testing procedure in aspect of the wear of tangential-rotary picks and their durability estimation, has been described. Manners of the abrasion of pick body and pick edge of the tangential-rotary picks, have been determined. Particular attention was paid to procedure of hard facing of the pick operational part and its influence onto mining process. Results of examination of tangential-rotary picks with hard facing layer on operational part near insert made of abrasion sintered carbide are also cited.

  5. Alois Alzheimer and vascular brain disease: Arteriosclerotic atrophy of the brain

    Directory of Open Access Journals (Sweden)

    Eliasz Engelhardt

    Full Text Available Alois Alzheimer is best known for his description of neurofibrillary changes in brain neurons of a demented patient, identifying a novel disease, soon named after him by Kraepelin. However, the range of his studies was broad, including vascular brain diseases, published between 1894 and 1902. Alzheimer described the clinical picture of Arteriosclerotic atrophy of the brain, differentiating it from other similar disorders. He stated that autopsy allowed pathological distinction between arteriosclerosis and syphilis, thereby achieving some of his objectives of segregating disorders and separating them from syphilis. His studies contributed greatly to establishing the key information on vascular brain diseases, predating the present state of knowledge on the issue, while providing early descriptions of what would be later regarded as the dimensional presentation of the now called "Vascular cognitive impairment", constituted by a spectrum that includes a stage of "Vascular cognitive impairment not dementia" and another of "Vascular dementia".

  6. Impaired functions of neural stem cells by abnormal nitric oxide-mediated signaling in an in vitro model of Niemann-Pick type C disease

    Institute of Scientific and Technical Information of China (English)

    Sun-Jung Kim; Myung-Sin Lim; Soo-Kyung Kang; Yong-Soon Lee; Kyung-Sun Kang

    2008-01-01

    Nitric oxide (NO) has been implicated in the promotion of neurodegeneration.However,little is known about the relationship between NO and the self-renewal or differentiation capacity of neural stem cells (NSCs) in neurodegenerative disease.In this study,we investigated the effect of NO on self-renewal of NSCs in an animal model for Niemann-Pick type C (NPC) disease.We found that NO production was significantly increased in NSCs from NPC1-deficient mice (NPC1-/-),which showed reduced NSC self-renewal.The number of nestin-positive cells and the size of neurospheres were both significantly decreased.The expression of NO synthase (NOS) was increased in neurospheres derived from the brain of NPC1-/- mice in comparison to wild-type neurospheres.NO-mediated activation of glycogen synthase kinase-3β(GSK3β) and caspase-3 was also observed in NSCs from NPC1-/- mice.The self-renewal ability of NSCs from NPC1-/- mice was restored by an NOS inhibitor,L-NAME,which resulted in the inhibition of GSK3β and caspase-3.In addition,the differentiation ability of NSCs was partially restored and the number of Fluoro-Jade C-positive degenerating neurons was reduced.These data suggest that overproduction of NO in NPC disease impaired the self-renewal of NSCs.Control of NO production may be key for the treatment of NPC disease.

  7. Cherry picking in ESRD: an ethical challenge in the era of pay for performance.

    Science.gov (United States)

    Parker, J Clint

    2011-01-01

    In poorly designed pay-for-performance schemes in which case mix adjustments are not adequate, self-interest could lead nephrologists toward cherry picking dialysis patients. Cherry picking, however, is morally problematic. First, it may manifest itself as a subtle form of covert rationing which threatens to undermine patient trust. Second, it involves shifting the burden of caring for sicker (and less financially attractive) patients to other nephrologists and dialysis units that do not practice cherry picking, creating injustices in the health care system. Finally, it treats patients as mere means through which nephrologists achieve reimbursement instead of as persons possessing dignity and deserving of respect.

  8. Spectrum of SMPD1 mutations in Asian-Indian patients with acid sphingomyelinase (ASM)-deficient Niemann-Pick disease.

    Science.gov (United States)

    Ranganath, Prajnya; Matta, Divya; Bhavani, Gandham SriLakshmi; Wangnekar, Savita; Jain, Jamal Mohammed Nurul; Verma, Ishwar C; Kabra, Madhulika; Puri, Ratna Dua; Danda, Sumita; Gupta, Neerja; Girisha, Katta M; Sankar, Vaikom H; Patil, Siddaramappa J; Ramadevi, Akella Radha; Bhat, Meenakshi; Gowrishankar, Kalpana; Mandal, Kausik; Aggarwal, Shagun; Tamhankar, Parag Mohan; Tilak, Preetha; Phadke, Shubha R; Dalal, Ashwin

    2016-10-01

    Acid sphingomyelinase (ASM)-deficient Niemann-Pick disease is an autosomal recessive lysosomal storage disorder caused by biallelic mutations in the SMPD1 gene. To date, around 185 mutations have been reported in patients with ASM-deficient NPD world-wide, but the mutation spectrum of this disease in India has not yet been reported. The aim of this study was to ascertain the mutation profile in Indian patients with ASM-deficient NPD. We sequenced SMPD1 in 60 unrelated families affected with ASM-deficient NPD. A total of 45 distinct pathogenic sequence variants were found, of which 14 were known and 31 were novel. The variants included 30 missense, 4 nonsense, and 9 frameshift (7 single base deletions and 2 single base insertions) mutations, 1 indel, and 1 intronic duplication. The pathogenicity of the novel mutations was inferred with the help of the mutation prediction software MutationTaster, SIFT, Polyphen-2, PROVEAN, and HANSA. The effects of the identified sequence variants on the protein structure were studied using the structure modeled with the help of the SWISS-MODEL workspace program. The p. (Arg542*) (c.1624C>T) mutation was the most commonly identified mutation, found in 22% (26 out of 120) of the alleles tested, but haplotype analysis for this mutation did not identify a founder effect for the Indian population. To the best of our knowledge, this is the largest study on mutation analysis of patients with ASM-deficient Niemann-Pick disease reported in literature and also the first study on the SMPD1 gene mutation spectrum in India. © 2016 Wiley Periodicals, Inc.

  9. A novel triple repeat mutant tau transgenic model that mimics aspects of pick's disease and fronto-temporal tauopathies.

    Directory of Open Access Journals (Sweden)

    Edward Rockenstein

    Full Text Available Tauopathies are a group of disorders leading to cognitive and behavioral impairment in the aging population. While four-repeat (4R Tau is more abundant in corticobasal degeneration, progressive supranuclear palsy, and Alzheimer's disease, three-repeat (3R Tau is the most abundant splice, in Pick's disease. A number of transgenic models expressing wild-type and mutant forms of the 4R Tau have been developed. However, few models of three-repeat Tau are available. A transgenic mouse model expressing three-repeat Tau was developed bearing the mutations associated with familial forms of Pick's disease (L266V and G272V mutations. Two lines expressing high (Line 13 and low (Line 2 levels of the three-repeat mutant Tau were analyzed. By Western blot, using antibodies specific to three-repeat Tau, Line 13 expressed 5-times more Tau than Line 2. The Tau expressed by these mice was most abundant in the frontal-temporal cortex and limbic system and was phosphorylated at residues detected by the PHF-1, AT8, CP9 and CP13 antibodies. The higher-expressing mice displayed hyperactivity, memory deficits in the water maze and alterations in the round beam. The behavioral deficits started at 6-8 months of age and were associated with a progressive increase in the accumulation of 3R Tau. By immunocytochemistry, mice from Line 13 displayed extensive accumulation of 3R Tau in neuronal cells bodies in the pyramidal neurons of the neocortex, CA1-3 regions, and dentate gyrus of the hippocampus. Aggregates in the granular cells had a globus appearance and mimic Pick's-like inclusions. There were abundant dystrophic neurites, astrogliosis and synapto-dendritic damage in the neocortex and hippocampus of the higher expresser line. The hippocampal lesions were moderately argyrophilic and Thioflavin-S negative. By electron microscopy, discrete straight filament aggregates were detected in some neurons in the hippocampus. This model holds promise for better understanding the

  10. Using the Min/Max Method for Replenishment of Picking Locations

    Directory of Open Access Journals (Sweden)

    Apsalons Raitis

    2017-03-01

    Full Text Available The irregularity of removing quantities from a definite picking location in a warehouse very often results in the stock out in the particular picking address. In practice, the Red Card principle is used to determine a critical level for each picking location when it is necessary to start the replenishment of stock in the picking address. The question is how to calculate an adequate critical level. The guidelines in this paper explain in detail the solution of the problem using the Min/Max stock control method and mathematical algorithms adjusted by authors. In order to check the validity of these mathematical algorithms of the Min/Max method, the simulation modelling has been also done and presented.

  11. Loss of functional GABAA receptors in the Alzheimer diseased brain

    Science.gov (United States)

    Limon, Agenor; Reyes-Ruiz, Jorge Mauricio; Miledi, Ricardo

    2012-01-01

    The cholinergic and glutamatergic neurotransmission systems are known to be severely disrupted in Alzheimer's disease (AD). GABAergic neurotransmission, in contrast, is generally thought to be well preserved. Evidence from animal models and human postmortem tissue suggest GABAergic remodeling in the AD brain. Nevertheless, there is no information on changes, if any, in the electrophysiological properties of human native GABA receptors as a consequence of AD. To gain such information, we have microtransplanted cell membranes, isolated from temporal cortices of control and AD brains, into Xenopus oocytes, and recorded the electrophysiological activity of the transplanted GABA receptors. We found an age-dependent reduction of GABA currents in the AD brain. This reduction was larger when the AD membranes were obtained from younger subjects. We also found that GABA currents from AD brains have a faster rate of desensitization than those from non-AD brains. Furthermore, GABA receptors from AD brains were slightly, but significantly, less sensitive to GABA than receptors from non-AD brains. The reduction of GABA currents in AD was associated with reductions of mRNA and protein of the principal GABA receptor subunits normally present in the temporal cortex. Pairwise analysis of the transcripts within control and AD groups and analyses of the proportion of GABA receptor subunits revealed down-regulation of α1 and γ2 subunits in AD. In contrast, the proportions of α2, β1, and γ1 transcripts were up-regulated in the AD brains. Our data support a functional remodeling of GABAergic neurotransmission in the human AD brain. PMID:22691495

  12. The use of technologies for the process of picking: implications and propositions

    Directory of Open Access Journals (Sweden)

    Jorge Arnaldo Troche Escobar

    2015-02-01

    Full Text Available In the present, businesses are facing numerous challenges with regard to their competitiveness in a global and complex marketplace, being required an ongoing review and evaluation of their management processes. The process of picking in Warehouses is one of the most critical, both for its complexity either by its high cost, so high levels of efficiency are necessary and desirable. The objective of this paper is to present the results of a research about the technologies on picking process in warehouses. They were developed a conceptual model and a methodology to support the choice of technological solutions for picker-to-part’s strategy. The proposed approach incorporates the various dimensions of decision process for assessment and selection of picking technologies based both, in the literature review, as from empirical contributions obtained from a provider of order picking technologies. In the decision process highlights the highly complexity, as it involves several levels of decision and several dimensions that pass through the layout of the warehouse, the methodology of picking, the level of traceability wanted, the coding model of products, among others determinant factors, beyond the cost of the technological solution itself.

  13. The advanced development of Niemann-Pick C1 Like 1%Niemann-Pick C1 Like 1研究新进展

    Institute of Scientific and Technical Information of China (English)

    朱雁飞; 李幼生; 黎介寿

    2009-01-01

    Identification and characterization of Niemann-Pick C1 Like 1 (NPC1L1) has established NPC1L1 as an essential protein in the intestinal cholesterol absorption process,and NPC1L1 is the molecular target of ezetimibe, which is a cholesterol absorption inhibitor. The expression of the gene and protein of NPC1L1 may be regulated by some nuclear receptors. Lack of NPC1L1 auses a nearly complete protection from the development of atherosclerosis in apoE-/- mice c, which provides new target for the treatment for atherosclerosis and cardiovascular disease.%Niemann-Pick C1 Like 1(NPC1L1)是肠道胆固醇吸收的关键蛋白,也是胆固醇吸收抑制剂依泽替米贝的分子作用靶点.NPC1L1的表达受一些核因子受体调控.敲除apoE-/-小鼠NPC1L1基因能显著抑制动脉粥样硬化的发生和发展,为动脉粥样硬化和冠状动脉性心脏病提供了新的治疗靶点.

  14. Heat Shock Protein Beta-1 Modifies Anterior to Posterior Purkinje Cell Vulnerability in a Mouse Model of Niemann-Pick Type C Disease.

    Directory of Open Access Journals (Sweden)

    Chan Chung

    2016-05-01

    Full Text Available Selective neuronal vulnerability is characteristic of most degenerative disorders of the CNS, yet mechanisms underlying this phenomenon remain poorly characterized. Many forms of cerebellar degeneration exhibit an anterior-to-posterior gradient of Purkinje cell loss including Niemann-Pick type C1 (NPC disease, a lysosomal storage disorder characterized by progressive neurological deficits that often begin in childhood. Here, we sought to identify candidate genes underlying vulnerability of Purkinje cells in anterior cerebellar lobules using data freely available in the Allen Brain Atlas. This approach led to the identification of 16 candidate neuroprotective or susceptibility genes. We demonstrate that one candidate gene, heat shock protein beta-1 (HSPB1, promoted neuronal survival in cellular models of NPC disease through a mechanism that involved inhibition of apoptosis. Additionally, we show that over-expression of wild type HSPB1 or a phosphomimetic mutant in NPC mice slowed the progression of motor impairment and diminished cerebellar Purkinje cell loss. We confirmed the modulatory effect of Hspb1 on Purkinje cell degeneration in vivo, as knockdown by Hspb1 shRNA significantly enhanced neuron loss. These results suggest that strategies to promote HSPB1 activity may slow the rate of cerebellar degeneration in NPC disease and highlight the use of bioinformatics tools to uncover pathways leading to neuronal protection in neurodegenerative disorders.

  15. In vivo calcium imaging of the aging and diseased brain

    Energy Technology Data Exchange (ETDEWEB)

    Eichhoff, Gerhard; Busche, Marc A.; Garaschuk, Olga [Technical University of Munich, Institute of Neuroscience, Munich (Germany)

    2008-03-15

    Over the last decade, in vivo calcium imaging became a powerful tool for studying brain function. With the use of two-photon microscopy and modern labelling techniques, it allows functional studies of individual living cells, their processes and their interactions within neuronal networks. In vivo calcium imaging is even more important for studying the aged brain, which is hard to investigate in situ due to the fragility of neuronal tissue. In this article, we give a brief overview of the techniques applicable to image aged rodent brain at cellular resolution. We use multicolor imaging to visualize specific cell types (neurons, astrocytes, microglia) as well as the autofluorescence of the ''aging pigment'' lipofuscin. Further, we illustrate an approach for simultaneous imaging of cortical cells and senile plaques in mouse models of Alzheimer's disease. (orig.)

  16. [Niemann-Pick type C disease: pathophysiology, diagnosis and treatment].

    Science.gov (United States)

    Ohno, Kousaku

    2016-03-01

    Niemann-Pick type C (NPC) disease is an autosomal recessive neurodegenerative disorder which is caused in 95% by a mutation in the NPC1 gene on chromosome 18 or by NPC2 mutation, encoding for 2 different lysosomal lipid transport proteins. The impaired protein function leads to systemic intralysosomal accumulation of free cholesterol and shingolipids particularly in the CNS. In Japan, currently 34 living NPC patients are known as of December 2015. Considering the prevalence of the disease in the Western countries, the real number of NPC patients is most likely to be five-folds higher. For NPC, treatment methods are established and an approved disease-specific medications are available. It is important that patients early in their disease are referred to expert centers, in order to ensure timely initiation of treatment and to delay the progression of neurological symptoms as a goal.

  17. Revisiting the theory of the evolution of pick-up ion distributions: magnetic or adiabatic cooling?

    Directory of Open Access Journals (Sweden)

    H. J. Fahr

    2008-01-01

    Full Text Available We study the phasespace behaviour of heliospheric pick-up ions after the time of their injection as newly created ions into the solar wind bulk flow from either charge exchange or photoionization of interplanetary neutral atoms. As interaction with the ambient MHD wave fields we allow for rapid pitch angle diffusion, but for the beginning of this paper we shall neglect the effect of quasilinear or nonlinear energy diffusion (Fermi-2 acceleration induced by counterflowing ambient waves. In the up-to-now literature connected with the convection of pick-up ions by the solar wind only adiabatic cooling of these ions is considered which in the solar wind frame takes care of filling the gap between the injection energy and energies of the thermal bulk of solar wind ions. Here we reinvestigate the basics of the theory behind this assumption of adiabatic pick-up ion reactions and correlated predictions derived from it. We then compare it with the new assumption of a pure magnetic cooling of pick-up ions simply resulting from their being convected in an interplanetary magnetic field which decreases in magnitude with increase of solar distance. We compare the results for pick-up ion distribution functions derived along both ways and can point out essential differences of observational and diagnostic relevance. Furthermore we then include stochastic acceleration processes by wave-particle interactions. As we can show, magnetic cooling in conjunction with diffusive acceleration by wave-particle interaction allows for an unbroken power law with the unique power index γ=−5 beginning from lowest velocities up to highest energy particles of about 100 KeV which just marginally can be in resonance with magnetoacoustic turbulences. Consequences for the resulting pick-up ion pressures are also analysed.

  18. [Assessment for intelligence on patients with Pick's disease].

    Science.gov (United States)

    Nagano, K; Tanabe, H; Kazui, H; Ikeda, M; Hashimoto, M; Yamada, N; Nakagawa, Y; Nishimura, T

    1995-11-01

    In contrast to Alzheimer's disease, it is unclear whether the MMS (Mini-Mental State) or the RCPM (Raven's Coloured Progressive Matrices) is clinically useful as a mental test battery in patients with Pick's disease, and it has not been fully evaluated whether intelligence of these patients really deteriorate along with the staging of dementia. The present study aimed to make these problems clear. We administered the MMS and the RCPM to 17 cases of Pick's disease, including 7 cases with predominantly frontal lobe atrophy and 10 cases with predominantly temporal lobe atrophy, which were all classified into 3 groups according to the staging of dementia by using the NM scale (New Clinical Scale for Rating of Mental States). We also investigated whether these patients had "Denkfaulheit" (laziness of thinking) and/or "gogi" aphasia (word meaning aphasia), which may affect performances on the mental test batteries. Two cases with predominantly frontal lobe atrophy and 5 cases with predominantly temporal lobe atrophy were assessed by the same examinations several years later. In cases with predominantly frontal lobe atrophy, all the patients presented with "Denkfaulheit". However, the mean RCPM score was normal in the mildly damaged patients, suggesting that their intelligence were relatively preserved. In the moderately and severely damaged groups, their intelligence could not be assessed owing to their severe "Denkfaulheit". In cases with predominantly temporal lobe atrophy, all the patients had "gogi" aphasia and 3 cases of the severely damaged groups presented with "Denkfaulheit".(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Intelligent Control Mechanism of Part Picking Operations of Automated Warehouse

    Institute of Scientific and Technical Information of China (English)

    Chwen-Tzeng; Su

    2002-01-01

    This paper studies the part picking operations of a ut omated warehouse. It assumed the demand of picking orders of automated warehouse are dynamic generated. Once the picking orders of certain period of time are kn own, it is necessary to decide an efficient order picking sequence and routing t o minimize the total travel distance to complete those orders. Assumed there are n i items to be picked in order O i. Each item in the picking ord er is located in different locations in the warehouse. Since i...

  20. Use of miglustat in a child with late-infantile-onset Niemann-Pick disease type C and frequent seizures: a case report

    Directory of Open Access Journals (Sweden)

    Skorpen Johannes

    2012-11-01

    Full Text Available Abstract Introduction Niemann-Pick disease type C is a rare genetic lysosomal storage disease associated with impaired intracellular lipid trafficking and a range of progressive neurological manifestations. The influence of seizure activity on disease course and response to miglustat therapy is not currently clear. Case presentation Niemann-Pick disease type C homozygous for NPC1 mutation p.S940L [c. 2819 C>T] was diagnosed in a four-and-a-half-year-old Norwegian Caucasian girl. The patient, who died at eight years and seven months of age, had a history of prolonged neonatal jaundice and subsequently displayed progressive neurological manifestations that started with delayed speech, ataxia, and gelastic cataplexy. A regimen of 100mg of miglustat three times a day was initiated when she was four years and 11 months old. She showed decreased neurological deterioration during about three and a half years of treatment. However, she displayed periods of distinct worsening that coincided with frequent epileptic seizures. Anti-epileptic therapy reduced seizure frequency and severity and allowed re-stabilization of her neurological function. Prior to her death, which was possibly due to acute cardiac arrest, seizure activity was well controlled. Conclusions Miglustat delayed the expected deterioration of neurological function in this patient with p.S940L-homozygous late-infantile-onset Niemann-Pick disease type C and provided important quality-of-life benefits. This case demonstrates the importance of effective seizure control therapy in achieving and maintaining neurological stabilization in Niemann-Pick disease type C.

  1. Rescue of an in vitro neuron phenotype identified in Niemann-Pick disease, type C1 induced pluripotent stem cell-derived neurons by modulating the WNT pathway and calcium signaling.

    Science.gov (United States)

    Efthymiou, Anastasia G; Steiner, Joe; Pavan, William J; Wincovitch, Stephen; Larson, Denise M; Porter, Forbes D; Rao, Mahendra S; Malik, Nasir

    2015-03-01

    Niemann-Pick disease, type C1 (NPC1) is a familial disorder that has devastating consequences on postnatal development with multisystem effects, including neurodegeneration. There is no Food and Drug Administration-approved treatment option for NPC1; however, several potentially therapeutic compounds have been identified in assays using yeast, rodent models, and NPC1 human fibroblasts. Although these discoveries were made in fibroblasts from NPC1 subjects and were in some instances validated in animal models of the disease, testing these drugs on a cell type more relevant for NPC1 neurological disease would greatly facilitate both study of the disease and identification of more relevant therapeutic compounds. Toward this goal, we have generated an induced pluripotent stem cell line from a subject homozygous for the most frequent NPC1 mutation (p.I1061T) and subsequently created a stable line of neural stem cells (NSCs). These NSCs were then used to create neurons as an appropriate disease model. NPC1 neurons display a premature cell death phenotype, and gene expression analysis of these cells suggests dysfunction of important signaling pathways, including calcium and WNT. The clear readout from these cells makes them ideal candidates for high-throughput screening and will be a valuable tool to better understand the development of NPC1 in neural cells, as well as to develop better therapeutic options for NPC1.

  2. Pharmacological reversion of sphingomyelin-induced dendritic spine anomalies in a Niemann Pick disease type A mouse model

    Science.gov (United States)

    Arroyo, Ana I; Camoletto, Paola G; Morando, Laura; Sassoe-Pognetto, Marco; Giustetto, Maurizio; Van Veldhoven, Paul P; Schuchman, Edward H; Ledesma, Maria D

    2014-01-01

    Understanding the role of lipids in synapses and the aberrant molecular mechanisms causing the cognitive deficits that characterize most lipidosis is necessary to develop therapies for these diseases. Here we describe sphingomyelin (SM) as a key modulator of the dendritic spine actin cytoskeleton. We show that increased SM levels in neurons of acid sphingomyelinase knock out mice (ASMko), which mimic Niemann Pick disease type A (NPA), result in reduced spine number and size and low levels of filamentous actin. Mechanistically, SM accumulation decreases the levels of metabotropic glutamate receptors type I (mGluR1/5) at the synaptic membrane impairing membrane attachment and activity of RhoA and its effectors ROCK and ProfilinIIa. Pharmacological enhancement of the neutral sphingomyelinase rescues the aberrant molecular and morphological phenotypes in vitro and in vivo and improves motor and memory deficits in ASMko mice. Altogether, these data demonstrate the influence of SM and its catabolic enzymes in dendritic spine physiology and contribute to our understanding of the cognitive deficits of NPA patients, opening new perspectives for therapeutic interventions. Subject Categories Genetics, Gene Therapy & Genetic Disease; Neuroscience PMID:24448491

  3. The Impact of Visual Guided Order Picking on Ocular Comfort, Ocular Surface and Tear Function.

    Directory of Open Access Journals (Sweden)

    Angelika Klein-Theyer

    Full Text Available We investigated the effects of a visual picking system on ocular comfort, the ocular surface and tear function compared to those of a voice guided picking solution.Prospective, observational, cohort study.Institutional.A total of 25 young asymptomatic volunteers performed commissioning over 10 hours on two consecutive days.The operators were guided in the picking process by two different picking solutions, either visually or by voice while their subjective symptoms and ocular surface and tear function parameters were recorded.The visual analogue scale (VAS values, according to subjective dry eye symptoms, in the visual condition were significantly higher at the end of the commissioning than the baseline measurements. In the voice condition, the VAS values remained stable during the commissioning. The tear break-up time (BUT values declined significantly in the visual condition (pre-task: 16.6 sec and post-task: 9.6 sec in the right eyes, that were exposed to the displays, the left eyes in the visual condition showed only a minor decline, whereas the BUT values in the voice condition remained constant (right eyes or even increased (left eyes over the time. No significant differences in the tear meniscus height values before and after the commissioning were observed in either condition.In our study, the use of visually guided picking solutions was correlated with post-task subjective symptoms and tear film instability.

  4. Identifying P phase arrival of weak events: The Akaike Information Criterion picking application based on the Empirical Mode Decomposition

    Science.gov (United States)

    Li, Xibing; Shang, Xueyi; Morales-Esteban, A.; Wang, Zewei

    2017-03-01

    Seismic P phase arrival picking of weak events is a difficult problem in seismology. The algorithm proposed in this research is based on Empirical Mode Decomposition (EMD) and on the Akaike Information Criterion (AIC) picker. It has been called the EMD-AIC picker. The EMD is a self-adaptive signal decomposition method that not only improves Signal to Noise Ratio (SNR) but also retains P phase arrival information. Then, P phase arrival picking has been determined by applying the AIC picker to the selected main Intrinsic Mode Functions (IMFs). The performance of the EMD-AIC picker has been evaluated on the basis of 1938 micro-seismic signals from the Yongshaba mine (China). The P phases identified by this algorithm have been compared with manual pickings. The evaluation results confirm that the EMD-AIC pickings are highly accurate for the majority of the micro-seismograms. Moreover, the pickings are independent of the kind of noise. Finally, the results obtained by this algorithm have been compared to the wavelet based Discrete Wavelet Transform (DWT)-AIC pickings. This comparison has demonstrated that the EMD-AIC picking method has a better picking accuracy than the DWT-AIC picking method, thus showing this method's reliability and potential.

  5. Heterogeneity and frequency of movement disorders in juvenile and adult-onset Niemann-Pick C disease.

    Science.gov (United States)

    Anheim, Mathieu; Lagha-Boukbiza, Ouhaïd; Fleury-Lesaunier, Marie-Céline; Valenti-Hirsch, Maria-Paola; Hirsch, Edouard; Gervais-Bernard, Hélène; Broussolle, Emmanuel; Thobois, Stéphane; Vanier, Marie T; Latour, Philippe; Tranchant, Christine

    2014-01-01

    Niemann-Pick type C disease (NPC) is a recessive neurolipidosis. We report five adolescent and adult NPC cases to underscore the frequency and heterogeneity of movement disorders in NPC. Clinical, morphologic, biochemical and genetic study was performed in the five patients. Disease onset was between 8 and 50 years. Movement disorders were present in all cases, were heterogeneous and often combined [cerebellar ataxia (5/5), myoclonus (3/5), dystonia (2/5), chorea (1/5) and tremor (1/5)] and were the first sign in 4/5. Two patients were reported to have no vertical supranuclear gaze palsy (VSGP) at the first examination. Two patients experienced acute neuropsychiatric signs leading to death in one case due to myoclonic storm. Filipin staining was always positive. Two NPC1 mutations were identified in three patients, only one in two siblings. NPC should be considered in case of unexplained movement disorders, even when VSGP or cataplexy are not reported. Filipin staining remains a strong support for the diagnosis. Treatment with miglustat should be considered which is currently the only approved disease-specific treatment of NPC in children and adults.

  6. Abnormal brain activation in excoriation (skin-picking) disorder

    DEFF Research Database (Denmark)

    Odlaug, Brian L.; Hampshire, Adam; Chamberlain, Samuel R

    2016-01-01

    Background: Excoriation (skin-picking) disorder (SPD) is a relatively common psychiatric condition whose neurobiological basis is unknown. Aims: To probe the function of fronto-striatal circuitry in SPD. Method: Eighteen participants with SPD and 15 matched healthy controls undertook an executive...... involved in habit formation, action monitoring and inhibition appear involved in the pathophysiology of SPD. Implications exist for understanding the basis of excessive grooming and the relationship of SPD with putative obsessive-compulsive spectrum disorders.......Background: Excoriation (skin-picking) disorder (SPD) is a relatively common psychiatric condition whose neurobiological basis is unknown. Aims: To probe the function of fronto-striatal circuitry in SPD. Method: Eighteen participants with SPD and 15 matched healthy controls undertook an executive...

  7. Clinical and Genetic Characteristics of Mexican Patients with Juvenile Presentation of Niemann-Pick Type C Disease

    Directory of Open Access Journals (Sweden)

    Raul E. Piña-Aguilar

    2014-01-01

    Full Text Available Niemann-Pick type C disease (NPC is a rare lysosomal disease with a protean presentation, ranging from a fatal neonatal course with visceromegaly to an adult presentation with only neurological or psychiatric symptomatology. In this report we describe the genetic and clinical characteristics of 3 Mexican patients from different families with juvenile presentation of NPC. Clinical examination, imaging of central nervous and gastrointestinal system, and EEG were performed. Genetic studies include sequencing and deletion/duplication analysis of NPC1 and NPC2 genes. All patients presented with cognitive impairment, ataxia, and supranuclear vertical gaze palsy; one case had gelastic cataplexy. Also they developed epilepsy and cortical atrophy and two patients had thinning of corpus callosum. The 3 patients were compound heterozygotes for NPC1 sequence variants, including 5 missense and 1 nonsense mutations: p.P1007A and p.F1087L in Case 1; p.Q921P and p.G992R in Case 2; and p.R348* and p.V1165M in case 3. Mexican patients with juvenile NPC presented with a variable clinical phenotype and compound heterozygosity. This suggests a relative high frequency of mutation carriers as it is reported for European population. Consequently, clinicians should consider NPC as a diagnosis possibility in any adolescent or young adult patient with juvenile dementia and/or ataxia, even in absence of gelastic cataplexy and supranuclear vertical gaze palsy.

  8. Pharmacological reversion of sphingomyelin-induced dendritic spine anomalies in a Niemann Pick disease type A mouse model.

    Science.gov (United States)

    Arroyo, Ana I; Camoletto, Paola G; Morando, Laura; Sassoe-Pognetto, Marco; Giustetto, Maurizio; Van Veldhoven, Paul P; Schuchman, Edward H; Ledesma, Maria D

    2014-03-01

    Understanding the role of lipids in synapses and the aberrant molecular mechanisms causing the cognitive deficits that characterize most lipidosis is necessary to develop therapies for these diseases. Here we describe sphingomyelin (SM) as a key modulator of the dendritic spine actin cytoskeleton. We show that increased SM levels in neurons of acid sphingomyelinase knock out mice (ASMko), which mimic Niemann Pick disease type A (NPA), result in reduced spine number and size and low levels of filamentous actin. Mechanistically, SM accumulation decreases the levels of metabotropic glutamate receptors type I (mGluR1/5) at the synaptic membrane impairing membrane attachment and activity of RhoA and its effectors ROCK and ProfilinIIa. Pharmacological enhancement of the neutral sphingomyelinase rescues the aberrant molecular and morphological phenotypes in vitro and in vivo and improves motor and memory deficits in ASMko mice. Altogether, these data demonstrate the influence of SM and its catabolic enzymes in dendritic spine physiology and contribute to our understanding of the cognitive deficits of NPA patients, opening new perspectives for therapeutic interventions.

  9. Membrane localization is critical for activation of the PICK1 BAR domain

    DEFF Research Database (Denmark)

    Madsen, Kenneth L; Eriksen, Jacob; Milan-Lobo, Laura

    2008-01-01

    The PSD-95/Discs-large/ZO-1 homology (PDZ) domain protein, protein interacting with C kinase 1 (PICK1) contains a C-terminal Bin/amphiphysin/Rvs (BAR) domain mediating recognition of curved membranes; however, the molecular mechanisms controlling the activity of this domain are poorly understood....... In agreement with negative regulation of the BAR domain by the N-terminal PDZ domain, PICK1 distributed evenly in the cytoplasm, whereas truncation of the PDZ domain caused BAR domain-dependent redistribution to clusters colocalizing with markers of recycling endosomal compartments. A similar clustering...... was observed both upon truncation of a short putative alpha-helical segment in the linker between the PDZ and the BAR domains and upon coexpression of PICK1 with a transmembrane PDZ ligand, including the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR2 subunit, the GluR2 C...

  10. Changes in Caries Risk and Activity of a 9-Year-Old Patient with Niemann-Pick Disease Type C

    Directory of Open Access Journals (Sweden)

    Késsia Suênia Fidelis Mesquita-Guimarães

    2015-01-01

    Full Text Available Objective. This case report describes the changes in caries risk and activity and dental treatment of a 9-year-old patient who presented with signs and symptoms of Niemann-Pick disease type C (NPC. Treatment. The preventive dental treatment included instructions to caregivers for oral hygiene and diet. A calcium hydroxide pulpotomy and restorative dental treatments were performed in a dental office with desensitization techniques and behavioral management. The patient was attended every 3 months for the control of dental plaque biofilm, for topical fluoride application, and for observing the pulpotomized tooth. Results. The bacterial plaque biofilm was being adequately controlled by the caregiver. After 2 years, the clinical and radiographic examination of the pulpotomized tooth showed the absence of internal root resorption and bone rarefaction, and clinical examination showed tooth sensitivity, dental pain, and gingival swelling. Conclusion. The pulpotomy prevented clinical and radiographic success. Dentists must be aware of and be able to identify systemic and local aspects associated with caries risk of children with NPC disease. Furthermore, dentists must employ stringent preventive measures and provide instructions to caregivers to reduce caries risk.

  11. Role of Diffusion Tensor Imaging in Prognostication and Treatment Monitoring in Niemann-Pick Disease Type C1

    Directory of Open Access Journals (Sweden)

    Meghann W. Lau

    2016-09-01

    Full Text Available Niemann-Pick Disease, type C1 (NPC1 is a rapidly progressive neurodegenerative disorder characterized by cholesterol sequestration within late endosomes and lysosomes, for which no reliable imaging marker exists for prognostication and management. Cerebellar volume deficits are found to correlate with disease severity and diffusion tensor imaging (DTI of the corpus callosum and brainstem, which has shown that microstructural disorganization is associated with NPC1 severity. This study investigates the utility of cerebellar DTI in clinical severity assessment. We hypothesize that cerebellar volume, fractional anisotropy (FA and mean diffusivity (MD negatively correlate with NIH NPC neurological severity score (NNSS and motor severity subscores. Magnetic resonance imaging (MRI was obtained for thirty-nine NPC1 subjects, ages 1–21.9 years (mean = 11.1, SD = 6.1. Using an atlas-based automated approach, the cerebellum of each patient was measured for FA, MD and volume. Additionally, each patient was given an NNSS. Decreased cerebellar FA and volume, and elevated MD correlate with higher NNSS. The cognition subscore and motor subscores for eye movement, ambulation, speech, swallowing, and fine motor skills were also statistically significant. Microstructural disorganization negatively correlated with motor severity in subjects. Additionally, Miglustat therapy correlated with lower severity scores across ranges of FA, MD and volume in all regions except the inferior peduncle, where a paradoxical effect was observed at high FA values. These findings suggest that DTI is a promising prognostication tool.

  12. Clinical analysis of 4 case of Niemann-Pick disease type C%C型尼曼-匹克病4例临床分析

    Institute of Scientific and Technical Information of China (English)

    邓小鹿; 尹飞; 毛华雄; 彭镜

    2011-01-01

    Objective To summarize and analyze the clinical features, diagnostic approaches and treatment of Niemann-Pick disease type C (NPC) in children. Methods Data of 4 cases of NPC children being followed up from 2006 to 2010 in Xiangya Hospital, Central South University were collected and analyzed. Results Among the 4 cases,age of onset of clinical signs ranged from 6 months to 10 years. The primary symptoms were instability of gait, alalia, and splenomegaly. Clinical features included visceral signs, cortical signs and extrapyramidal signs. Brain stem signs included vertical supranuclear ophthalmoplegia (3 cases), dysarthria (3 cases), and dysphagia (2 cases). Bone marrow biopsy showed Niemann-Pick cells (2 cases) and sea-blue histiocytes (2 cases).Brain MRI showed either normal (2 cases) or mild encephalatrophy (2 cases).The EEG presented abnormal in 4 cases which showed slow background activity.Epileptiform discharges were found in 3 cases of the patients. Activity of acid sphingomyelinase was performed in 2 cases,and the results were normal. Four patients were given low-fat diet and mixed vitamin.Two patients receiving antiepileptic drugs treatment did not show significant improvement. The follow-up ranged from 1 month to 4 years. One patient died,and three patients showed retrogressive mental and motor development with brain stem signs. Conclusion NPC is a fatal autosomal recessive disorder. Clinical featnres are hepatosplenomegaly, ataxia, neurodegenerative changes and brain stem dysfunction. Until recently, there has been no available disease-specific therapies for NPC.Miglustat is available to stabilize the disease course and prolongs lifespan.%目的 分析C型尼曼-匹克病(NPC)临床特征、诊断及治疗方法.方法 总结中南大学湘雅医院2006年1月至2010年4月收治的4例NPC患儿的临床表现、实验室资料及治疗情况.结果 4例起病年龄6个月至10岁.首发症状为步态不稳2例,吐字不清1例,脾大1例.就诊时主要

  13. Ion pick-up near the icy Galilean satellites

    Science.gov (United States)

    Volwerk, M.; Khurana, K. K.

    2010-12-01

    The ion pick-up near the icy Galilean satellites is studied using ion cyclotron waves. Using Galileo magnetometer data, we show evidence for the existence of ion cyclotron waves, which are generated by pick-up of freshly ionized particles. Near Europa, in the wake various kinds of ions are detected, which were already predicted to be present on the moon. Upstream of the moon there is evidence for water ion pick-up, which could facilitate the slow down of the plasma flow. Ganymede shows evidence for either water or oxygen pick up on the flanks of the magnetosphere. Callisto shows indication of hydrogen pick-up from its atmosphere.

  14. Functional modulation of the glutamate transporter variant GLT1b by the PDZ domain protein PICK1

    DEFF Research Database (Denmark)

    Søgaard, Rikke; Borre, Lars; Braunstein, Thomas H

    2013-01-01

    effect on trafficking of AMPA-type glutamate receptors. The 11 extreme C-terminal residues specific for the GLT1b variant are essential for its specific interaction with the PICK1 PDZ domain, but a functional consequence of this interaction has remained unresolved. To identify a functional effect of PICK...

  15. The number of pickers and stock-keeping unit arrangement on a uni-directional picking line

    Directory of Open Access Journals (Sweden)

    Hagspihl, Robert

    2014-10-01

    Full Text Available The order picking process is often the single largest expense in a distribution centre (DC. The DC considered in this paper uses a picking line configuration to perform order picking. The number of pickers in a picking line, and the initial arrangement of stock-keeping units (SKUs, are two important factors that affect the total completion time of the picking lines. In this paper, the picking line configuration is simulated with an agent-based approach to describe the behaviour of an individual picker. The simulation is then used to analyse the effect of the number of pickers and the SKU arrangement. Verification and validation of this model shows that the model represents the real-world picking line to a satisfactory degree. Marginal analysis (MA was chosen to determine a ‘good’ number of pickers by means of the simulation model. A look-up table is presented to provide decision support for the choice of a ‘good’ number of pickers to improve completion times of the picking line, for the properties of a specific picking line. The initial SKU arrangement on a picking line is shown to be a factor that can affect the level of picker congestion and the total completion time. The greedy ranking and partitioning (GRP and organ pipe arrangement (OPA techniques from the literature, as well as the historical SKU arrangements used by the retailer under consideration, were compared with the proposed classroom discipline heuristic (CDH for SKU arrangement. It was found that the CDH provides an more even spread of SKUs that are picked most frequently, thus decreasing congestion and total completion time.

  16. Picking up the Pieces

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Despite hardship and suffering,many quake survivors remain generous and optimistic Liu Jing’s hometown,Xiangxi Village in Anxian County,Sichuan Province,was a picturesque place, in an area known to many as the back garden of the industrial city Mianyang, until May 12. Since then it has become better known

  17. Performance Approximation and Design of Pick-and-Pass Order Picking Systems

    NARCIS (Netherlands)

    M. Yu (Mengfei); M.B.M. de Koster (René)

    2007-01-01

    textabstractIn this paper, we discuss an approximation method based on G/G/m queuing network modeling using Whitt’s (1983) queuing network analyzer to analyze pick-and-pass order picking systems. The objective of this approximation method is to provide an instrument for obtaining rapid performance

  18. Design and Control of Warehouse Order Picking: a literature review

    NARCIS (Netherlands)

    M.B.M. de Koster (René); T. Le-Duc (Tho); K.J. Roodbergen (Kees-Jan)

    2006-01-01

    textabstractOrder picking has long been identified as the most labour-intensive and costly activity for almost every warehouse; the cost of order picking is estimated to be as much as 55% of the total warehouse operating expense. Any underperformance in order picking can lead to unsatisfactory servi

  19. The class characteristic mark of the H&M Mul-T-Lock picking tool in toolmarks examination.

    Science.gov (United States)

    Volkov, Nikolai; Finkelstein, Nir; Novoselsky, Yehuda; Tsach, Tsadok

    2014-07-01

    Mul-T-Lock is a high security lock cylinder distinguished by the use of a telescoping "pin-in-pin"-tumbler design. Picking the Mul-T-Lock cylinder with a traditional picking tool is highly complicated because it can get stuck between the inner and outer pins. The H&M Mul-T-Lock picking tool was designed to overcome this problem and facilitate the picking of the "pin-in-pin" cylinder. The purpose of this research is to determine whether H&M Mul-T-Lock picking tool leaves class characteristic mark and whether it can be distinguished from traditional picking tools marks and from regular key marks. It also describes and determines the class characteristic mark left on telescopic pins, its origin, recurrence, and its benefit to the toolmarks examiner. When receiving a Mul-T-Lock from a crime scene, a toolmarks examiner can quickly determine whether or not it was picked by an H&M Mul-T-Lock picking tool by noticing the class characteristic mark which this typical tool leaves.

  20. The Effect of Slot-Code Optimization in Warehouse Order Picking

    Directory of Open Access Journals (Sweden)

    Andrea Fumi

    2013-07-01

    most appropriate material handling resource configuration. Building on previous work on the effect of slot-code optimization on travel times in single/dual command cycles, the authors broaden the scope to include the most general picking case, thus widening the range of applicability and realising former suggestions for future research.

  1. Design study of a resonant Schottky pick-up for the Rare-RI Ring project

    Energy Technology Data Exchange (ETDEWEB)

    Suzaki, F., E-mail: suzaki@ribf.riken.jp [Department of Physics, Saitama University, Saitama 338-8570 (Japan); Zenihiro, J. [RIKEN Nishina Center, RIKEN, Wako, Saitama 351-0198 (Japan); Yamaguchi, T., E-mail: yamaguti@phy.saitama-u.ac.jp [Department of Physics, Saitama University, Saitama 338-8570 (Japan); Ozawa, A. [Institute of Physics, University of Tsukuba, Ibaraki 305-8571 (Japan); Uesaka, T.; Wakasugi, M.; Yamada, K.; Yamaguchi, Y. [RIKEN Nishina Center, RIKEN, Wako, Saitama 351-0198 (Japan)

    2013-12-15

    Highlights: • The heavy-ion storage ring project, the Rare-RI Ring, is ongoing at the RIKEN RI Beam Factory. • The Rare-RI Ring will enable precision isochronous mass spectrometry of r-process nuclei. • A resonant Schottky pick-up will be used for the precise tuning of isochronous optics of the storage ring. • Simulation results of 3D electromagnetic field calculations show a high sensitivity of stored single-ion detection. -- Abstract: The new heavy-ion storage ring project Rare-RI Ring at the RIKEN RI Beam Factory launched in 2012 aims at precision isochronous mass spectrometry for single ions of exotic nuclides. To precisely tune the storage-ring ion optical conditions to the isochronous field setting, Schottky noise pick-up technique will be employed. Pillbox-type resonant cavity, similar to the Schottky pick-up system successfully operating at the experimental storage ring ESR at GSI, is adopted for the pick-up probe. To determine the design values of the cavity, we systematically performed a simulation study of three-dimensional electromagnetic field calculations in the high frequency region. High shunt impedance obtained in the simulation will enable us to detect stored single ions with charge down to q≃15.

  2. "They just come, pick and go." The Acceptability of Integrated Medication Adherence Clubs for HIV and Non Communicable Disease (NCD) Patients in Kibera, Kenya

    Science.gov (United States)

    Venables, Emilie; Edwards, Jeffrey K.; Baert, Saar; Etienne, William; Khabala, Kelly; Bygrave, Helen

    2016-01-01

    Introduction The number of people on antiretroviral therapy (ART) for the long-term management of HIV in low- and middle-income countries (LMICs) is continuing to increase, along with the prevalence of Non-Communicable Diseases (NCDs). The need to provide large volumes of HIV patients with ART has led to significant adaptations in how medication is delivered, but access to NCD care remains limited in many contexts. Medication Adherence Clubs (MACs) were established in Kibera, Kenya to address the large numbers of patients requiring chronic HIV and/or NCD care. Stable NCD and HIV patients can now collect their chronic medication every three months through a club, rather than through individual clinic appointments. Methodology We conducted a qualitative research study to assess patient and health-care worker perceptions and experiences of MACs in the urban informal settlement of Kibera, Kenya. A total of 106 patients (with HIV and/or other NCDs) and health-care workers were purposively sampled and included in the study. Ten focus groups and 19 in-depth interviews were conducted and 15 sessions of participant observation were carried out at the clinic where the MACs took place. Thematic data analysis was conducted using NVivo software, and coding focussed on people’s experiences of MACs, the challenges they faced and their perceptions about models of care for chronic conditions. Results MACs were considered acceptable to patients and health-care workers because they saved time, prevented unnecessary queues in the clinic and provided people with health education and group support whilst they collected their medication. Some patients and health-care workers felt that MACs reduced stigma for HIV positive patients by treating HIV as any other chronic condition. Staff and patients reported challenges recruiting patients into MACs, including patients not fully understanding the eligibility criteria for the clubs. There were also some practical challenges during the

  3. Importance of the brain Angiotensin system in Parkinson's disease.

    Science.gov (United States)

    Wright, John W; Harding, Joseph W

    2012-01-01

    Parkinson's disease (PD) has become a major health problem affecting 1.5% of the world's population over 65 years of age. As life expectancy has increased so has the occurrence of PD. The primary direct consequence of this disease is the loss of dopaminergic (DA) neurons in the substantia nigra and striatum. As the intensity of motor dysfunction increases, the symptomatic triad of bradykinesia, tremors-at-rest, and rigidity occur. Progressive neurodegeneration may also impact non-DA neurotransmitter systems including cholinergic, noradrenergic, and serotonergic, often leading to the development of depression, sleep disturbances, dementia, and autonomic nervous system failure. L-DOPA is the most efficacious oral delivery treatment for controlling motor symptoms; however, this approach is ineffective regarding nonmotor symptoms. New treatment strategies are needed designed to provide neuroprotection and encourage neurogenesis and synaptogenesis to slow or reverse this disease process. The hepatocyte growth factor (HGF)/c-Met receptor system is a member of the growth factor family and has been shown to protect against degeneration of DA neurons in animal models. Recently, small angiotensin-based blood-brain barrier penetrant mimetics have been developed that activate this HGF/c-Met system. These compounds may offer a new and novel approach to the treatment of Parkinson's disease.

  4. A Normative Study of the Person Picking an Apple from a Tree (PPAT) Assessment

    Science.gov (United States)

    Bucciarelli, Amy

    2011-01-01

    The Person Picking an Apple from a Tree (PPAT) is an art therapy assessment task that is scored using the Formal Elements Art Therapy Scale (FEATS) to identify a client's mental health symptoms and progress in art therapy. Normative data are needed to empirically validate assumptions about the PPAT. This report summarizes a normative study of the…

  5. Cholinergic Abnormalities, Endosomal Alterations and Up-Regulation of Nerve Growth Factor Signaling in Niemann-Pick Type C Disease

    Directory of Open Access Journals (Sweden)

    Cabeza Carolina

    2012-03-01

    Full Text Available Abstract Background Neurotrophins and their receptors regulate several aspects of the developing and mature nervous system, including neuronal morphology and survival. Neurotrophin receptors are active in signaling endosomes, which are organelles that propagate neurotrophin signaling along neuronal processes. Defects in the Npc1 gene are associated with the accumulation of cholesterol and lipids in late endosomes and lysosomes, leading to neurodegeneration and Niemann-Pick type C (NPC disease. The aim of this work was to assess whether the endosomal and lysosomal alterations observed in NPC disease disrupt neurotrophin signaling. As models, we used i NPC1-deficient mice to evaluate the central cholinergic septo-hippocampal pathway and its response to nerve growth factor (NGF after axotomy and ii PC12 cells treated with U18666A, a pharmacological cellular model of NPC, stimulated with NGF. Results NPC1-deficient cholinergic cells respond to NGF after axotomy and exhibit increased levels of choline acetyl transferase (ChAT, whose gene is under the control of NGF signaling, compared to wild type cholinergic neurons. This finding was correlated with increased ChAT and phosphorylated Akt in basal forebrain homogenates. In addition, we found that cholinergic neurons from NPC1-deficient mice had disrupted neuronal morphology, suggesting early signs of neurodegeneration. Consistently, PC12 cells treated with U18666A presented a clear NPC cellular phenotype with a prominent endocytic dysfunction that includes an increased size of TrkA-containing endosomes and reduced recycling of the receptor. This result correlates with increased sensitivity to NGF, and, in particular, with up-regulation of the Akt and PLC-γ signaling pathways, increased neurite extension, increased phosphorylation of tau protein and cell death when PC12 cells are differentiated and treated with U18666A. Conclusions Our results suggest that the NPC cellular phenotype causes neuronal

  6. The Value of Inaccurate Advance Time Window Information in a Pick-up and Delivery Problem

    NARCIS (Netherlands)

    F.J. Srour (Jordan); N.A.H. Agatz (Niels); J. Oppen (Johan)

    2014-01-01

    textabstractWe examine different routing strategies to cope with inaccurate time window in- formation in the context of a dynamic pick-up and delivery problem with time windows. Our experiments show that advance information, even if inaccurate, can provide benefits from a planning perspective. We

  7. The effects of environmental enrichment devices on feather picking in commercially housed Pekin ducks.

    Science.gov (United States)

    Colton, S; Fraley, G S

    2014-09-01

    Like other poultry species, Pekin ducks occasionally show an auto-mutilation behavior referred to as feather picking. Self-picking can lead to further pecking by conspecifics and ultimately to reduced feather quality and poor overall health of the bird. Although the reasons underlying feather picking are not clear, it appears to occur when the ducks are transitioning between downy feathers and adult plumage, between 17 and 22 d of age. We hypothesized that giving Pekin ducks a substitute outlet for this behavior in the form of environmental enrichment devices (EED) would decrease feather picking and improve feather quality and duck health and welfare. The EED were plastic Wiffle-style balls, each threaded with 4 zip-ties. In the first experiment, we set out to determine that placement of EED would not induce fear or harmful behaviors. Five barns were each divided into 2 pens, holding an average combined total of approximately 4,500 ducks with one pen per barn used as control. Upon placement of the EED in one pen per barn, both pens were videotaped for a total of 2 h per day. The physical characteristics of 100 ducks per pen were scored at age 7, 21, 28, and 35. Results showed a decrease (P = 0.034) in both self-picking and conspecific-pecking in pens with EED compared with pens without EED. Although no differences in body condition scores were observed at 7 d of age, by d 21 ducks with EED showed better (P = 0.021) feather quality and cleanliness scores compared with ducks without EED. In a second experiment, we set out to determine if ducks had a color preference for blue/green, red, or white EED. Again, ducks with EED showed reduced (P = 0.038) feather picking compared with ducks without EED. Ducks interacted considerably more (P = 0.00089) frequently with blue/green EED then either red or white EED. These results suggest that providing environmental enrichment may minimize feather picking and improve feather quality and duck welfare.

  8. Perturbations of the solar wind flow by radial and latitudinal pick-up ion pressure gradients

    Directory of Open Access Journals (Sweden)

    H. J. Fahr

    2004-06-01

    Full Text Available It has been found that pick-up ions at their dynamical incorporation into the solar wind modify the original conditions of the asymptotic solar wind plasma flow. In this respect, it has meanwhile been revealed in many papers that these type of solar wind modifications, i.e. deceleration and decrease of effective Mach number, are not only due to the pick-up ion loading effects, but also to the action of pick-up ion pressure gradients. Up to now only the effects of radial pick-up ion pressure gradients were considered, however, analogously but latitudinal pressure gradients also appear to be important. Here we study the effects of radial and latitudinal pick-up ion pressure gradients, occurring especially during solar minimum conditions at mid-latitude regions where slow solar wind streams change to fast solar wind streams. First, we give estimates of the latitudinal wind components connected with these gradients, and then after revealing its importance, present a more quantitative calculation of solar wind velocity and density perturbations resulting from these pressure forces. It is shown that the relative density perturbations near and in the ecliptic increase with radial distance and thus may well explain the measured non-spherically symmetric density decrease with distance. We also show that the solar wind decelerations actually seen with Voyager-1/2 are in conciliation with interstellar hydrogen densities of nH∞≥0.1cm-3, in contrast to earlier claims for nH∞=0.05cm-3.

  9. The effects of brief cognitive-behaviour therapy for pathological skin picking: A randomized comparison to wait-list control.

    Science.gov (United States)

    Schuck, Kathrin; Keijsers, Ger P J; Rinck, Mike

    2011-01-01

    Thirty-four college students suffering from pathological skin picking were randomly assigned to a four-session cognitive-behavioural treatment (n=17) or a waiting-list condition (n=17). Severity of skin picking, psycho-social impact of skin picking, strength of skin-picking-related dysfunctional cognitions, and severity of skin injury were measured at pre-, post-, and two-months follow-up assessment. Participants in the treatment condition showed a significantly larger reduction on all measured variables in comparison to the waiting-list condition. The obtained effect sizes for the outcome measures were large, ranging from .90 to 1.89. Treatment effects were maintained at follow-up. In conclusion, cognitive-behavioural therapy, even in brief form, constitutes an adequate treatment option for pathological skin-picking behaviour.

  10. Argyrophilic grain disease mimicking temporal Pick's disease: a clinical, radiological, and pathological study of an autopsy case with a clinical course of 15 years.

    Science.gov (United States)

    Tsuchiya, K; Mitani, K; Arai, T; Yamada, S; Komiya, T; Esaki, Y; Haga, C; Yamanouchi, H; Ikeda, K

    2001-08-01

    This report concerns an autopsy case of argyrophilic grain disease (AGD) mimicking temporal Pick's disease. The patient was a Japanese woman without hereditary burden who was 89 years old at the time of death. She developed memory impairment and began wandering at the age of 74, followed by prominent character changes about 6 years after disease onset. A neurological examination 5 months before her death revealed poor rapport, unconcern, severe dementia, and double incontinence, without aphasia or muscle rigidity. Serial neuroradiological examination revealed progressive enlargement of the bilateral inferior horns of the lateral ventricle, reflecting progressive atrophy of the medial temporal lobes. Macroscopically, neuropathological examination showed circumscribed atrophy of the bilateral amygdalae, hippocampi, parahippocampal gyri, and lateral occipitotemporal gyri. Histologically, there was neuronal loss in the areas mentioned above, the caudate nucleus, putamen, thalamus, substantia nigra, and locus ceruleus, with ballooned neurons in the cerebral cortex and amygdala. Numerous argyrophilic grains with coiled bodies were present not only in the limbic system, but also in the affected cerebrum. Rare neurofibrillary changes were present in the limbic areas, consistent with Braak stage II, with no senile plaques. Based on these findings and a review of the literature, we note that AGD is clinicopathologically similar not only to mesolimbocortical dementia, but also to atypical senile dementia of Alzheimer type. This report may contribute to the elucidation of the clinicopathological hallmarks of AGD.

  11. Niemann-Pick C1 Functions Independently of Niemann-Pick C2 in the Initial Stage of Retrograde Transport of Membrane-impermeable Lysosomal Cargo*

    Science.gov (United States)

    Goldman, Stephen D. B.; Krise, Jeffrey P.

    2010-01-01

    The rare neurodegenerative disease Niemann-Pick Type C (NPC) results from mutations in either NPC1 or NPC2, which are membrane-bound and soluble lysosomal proteins, respectively. Previous studies have shown that mutations in either protein result in biochemically indistinguishable phenotypes, most notably the hyper-accumulation of cholesterol and other cargo in lysosomes. We comparatively evaluated the kinetics of [3H]dextran release from lysosomes of wild type, NPC1, NPC2, and NPC1/NPC2 pseudo-double mutant cells and found significant differences between all cell types examined. Specifically, NPC1 or NPC2 mutant fibroblasts treated with NPC1 or NPC2 siRNA (to create NPC1/NPC2 pseudo-double mutants) secreted dextran less efficiently than did either NPC1 or NPC2 single mutant cell lines, suggesting that the two proteins may work independently of one another in the egress of membrane-impermeable lysosomal cargo. To investigate the basis for these differences, we examined the role of NPC1 and NPC2 in the retrograde fusion of lysosomes with late endosomes to create so-called hybrid organelles, which is believed to be the initial step in the egress of cargo from lysosomes. We show here that cells with mutated NPC1 have significantly reduced rates of late endosome/lysosome fusion relative to wild type cells, whereas cells with mutations in NPC2 have rates that are similar to those observed in wild type cells. Instead of being involved in hybrid organelle formation, we show that NPC2 is required for efficient membrane fission events from nascent hybrid organelles, which is thought to be required for the reformation of lysosomes and the release of lysosomal cargo-containing membrane vesicles. Collectively, these results suggest that NPC1 and NPC2 can function independently of one another in the egress of certain membrane-impermeable lysosomal cargo. PMID:20007703

  12. Niemann-Pick C1 functions independently of Niemann-Pick C2 in the initial stage of retrograde transport of membrane-impermeable lysosomal cargo.

    Science.gov (United States)

    Goldman, Stephen D B; Krise, Jeffrey P

    2010-02-12

    The rare neurodegenerative disease Niemann-Pick Type C (NPC) results from mutations in either NPC1 or NPC2, which are membrane-bound and soluble lysosomal proteins, respectively. Previous studies have shown that mutations in either protein result in biochemically indistinguishable phenotypes, most notably the hyper-accumulation of cholesterol and other cargo in lysosomes. We comparatively evaluated the kinetics of [(3)H]dextran release from lysosomes of wild type, NPC1, NPC2, and NPC1/NPC2 pseudo-double mutant cells and found significant differences between all cell types examined. Specifically, NPC1 or NPC2 mutant fibroblasts treated with NPC1 or NPC2 siRNA (to create NPC1/NPC2 pseudo-double mutants) secreted dextran less efficiently than did either NPC1 or NPC2 single mutant cell lines, suggesting that the two proteins may work independently of one another in the egress of membrane-impermeable lysosomal cargo. To investigate the basis for these differences, we examined the role of NPC1 and NPC2 in the retrograde fusion of lysosomes with late endosomes to create so-called hybrid organelles, which is believed to be the initial step in the egress of cargo from lysosomes. We show here that cells with mutated NPC1 have significantly reduced rates of late endosome/lysosome fusion relative to wild type cells, whereas cells with mutations in NPC2 have rates that are similar to those observed in wild type cells. Instead of being involved in hybrid organelle formation, we show that NPC2 is required for efficient membrane fission events from nascent hybrid organelles, which is thought to be required for the reformation of lysosomes and the release of lysosomal cargo-containing membrane vesicles. Collectively, these results suggest that NPC1 and NPC2 can function independently of one another in the egress of certain membrane-impermeable lysosomal cargo.

  13. Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology

    DEFF Research Database (Denmark)

    Kirkegaard, Thomas; Roth, Anke G; Petersen, Nikolaj H T

    2010-01-01

    inhibition of ASM, effectively revert the Hsp70-mediated stabilization of lysosomes. Notably, the reduced ASM activity in cells from patients with Niemann-Pick disease (NPD) A and B-severe lysosomal storage disorders caused by mutations in the sphingomyelin phosphodiesterase 1 gene (SMPD1) encoding for ASM...

  14. Dataset in support of the generation of Niemann-Pick disease Type C1 patient-specific iPS cell lines carrying the novel NPC1 mutation c.1180T>C or the prevalent c.3182T>C mutation – Analysis of pluripotency and neuronal differentiation

    Directory of Open Access Journals (Sweden)

    Franziska Peter

    2017-06-01

    Full Text Available Data presented in this article demonstrate the generation and characterization of two novel Niemann-Pick disease Type C1 (NPC1 patient-specific induced pluripotent stem cell (iPSC lines, related to the research article Trilck et al. (Diversity of Glycosphingolipid GM2 and Cholesterol Accumulation in NPC1 Patient-Specific iPSC-Derived Neurons; Brain Res.; 2017; 1657:52-61. doi: 10.1016/j.brainres.2016.11.031. For reprogramming fibroblasts, carrying the novel homozygous mutation c.1180T>C and the prevalent homozygous mutation c.3182T>C, were used. Reprogramming into patient-specific iPSCs was induced by retroviral transduction of the transcription factors Sox2, Klf4, Oct4 and c-Myc, and confirmed according to their pluripotency. The iPSCs were subsequently differentiated into neural progenitor cells, which were terminally differentiated into functional neurons and glial cells. The generation of these cell lines provides further valuable tools to investigate pathogenic mechanism of NPC1 in human neuronal cells carrying different NPC1 mutations.

  15. Dataset in support of the generation of Niemann-Pick disease Type C1 patient-specific iPS cell lines carrying the novel NPC1 mutation c.1180T>C or the prevalent c.3182T>C mutation - Analysis of pluripotency and neuronal differentiation.

    Science.gov (United States)

    Peter, Franziska; Trilck, Michaela; Rabenstein, Michael; Rolfs, Arndt; Frech, Moritz J

    2017-06-01

    Data presented in this article demonstrate the generation and characterization of two novel Niemann-Pick disease Type C1 (NPC1) patient-specific induced pluripotent stem cell (iPSC) lines, related to the research article Trilck et al. (Diversity of Glycosphingolipid GM2 and Cholesterol Accumulation in NPC1 Patient-Specific iPSC-Derived Neurons; Brain Res.; 2017; 1657:52-61. doi: 10.1016/j.brainres.2016.11.031). For reprogramming fibroblasts, carrying the novel homozygous mutation c.1180T>C and the prevalent homozygous mutation c.3182T>C, were used. Reprogramming into patient-specific iPSCs was induced by retroviral transduction of the transcription factors Sox2, Klf4, Oct4 and c-Myc, and confirmed according to their pluripotency. The iPSCs were subsequently differentiated into neural progenitor cells, which were terminally differentiated into functional neurons and glial cells. The generation of these cell lines provides further valuable tools to investigate pathogenic mechanism of NPC1 in human neuronal cells carrying different NPC1 mutations.

  16. Membrane Binding and Modulation of the PDZ Domain of PICK1

    DEFF Research Database (Denmark)

    Erlendsson, Simon; Madsen, Kenneth Lindegaard

    2015-01-01

    Scaffolding proteins serve to assemble protein complexes in dynamic processes by means of specific protein-protein and protein-lipid binding domains. Many of these domains bind either proteins or lipids exclusively; however, it has become increasingly evident that certain domains are capable of b...... lipids. Moreover, we review how these PDZ-membrane interactions are regulated in the case of the synaptic scaffolding protein PICK1 and how this might affect cellular localization and function....

  17. Identification of a small-molecule inhibitor of the PICK1 PDZ domain that inhibits hippocampal LTP and LTD

    DEFF Research Database (Denmark)

    Thorsen, Thor S; Madsen, Kenneth L; Rebola, Nelson

    2010-01-01

    interacting protein 1 (GRIP1). Pretreatment of cultured hippocampal neurons with FSC231 inhibited coimmunopreciptation of the AMPA receptor GluR2 subunit with PICK1. In agreement with inhibiting the role of PICK1 in GluR2 trafficking, FSC231 accelerated recycling of pHluorin-tagged GluR2 in hippocampal...... neurons after internalization in response to NMDA receptor activation. FSC231 blocked the expression of both long-term depression and long-term potentiation in hippocampal CA1 neurons from acute slices, consistent with inhibition of the bidirectional function of PICK1 in synaptic plasticity. Given...

  18. MRI/MRA evaluation of sickle cell disease of the brain

    Energy Technology Data Exchange (ETDEWEB)

    Zimmerman, Robert A. [Childrens Hospital, Department of Radiology, Philadelphia, PA (United States)

    2005-03-01

    Sickle cell disease is a major cause of pediatric stroke. Understanding the disease that affects the brain as infarctions, both clinically apparent and silent, requires an understanding of how the blood vessels are affected, the way in which both the brain and the blood vessels are imaged by MRI and MRA and the mechanism of injury. (orig.)

  19. Complement is dispensable for neurodegeneration in Niemann-Pick disease type C

    Directory of Open Access Journals (Sweden)

    Lopez Manuel E

    2012-09-01

    Full Text Available Abstract Background The immune system has been implicated in neurodegeneration during development and disease. In various studies, the absence of complement (that is, C1q deficiency impeded the elimination of apoptotic neurons, allowing survival. In the genetic lysosomal storage disease Niemann-Pick C (NPC, caused by loss of NPC1 function, the expression of complement system components, C1q especially, is elevated in degenerating brain regions of Npc1-/- mice. Here we test whether complement is mediating neurodegeneration in NPC disease. Findings In normal mature mice, C1q mRNA was found in neurons, particularly cerebellar Purkinje neurons (PNs. In Npc1-/- mice, C1q mRNA was additionally found in activated microglia, which accumulate during disease progression and PN loss. Interestingly, C1q was not enriched on or near degenerating neurons. Instead, C1q was concentrated in other brain regions, where it partially co-localized with a potential C1q inhibitor, chondroitin sulfate proteoglycan (CSPG. Genetic deletion of C1q, or of the downstream complement pathway component C3, did not significantly alter patterned neuron loss or disease progression. Deletion of other immune response factors, a Toll-like receptor, a matrix metalloprotease, or the apoptosis facilitator BIM, also failed to alter neuron loss. Conclusion We conclude that complement is not involved in the death and clearance of neurons in NPC disease. This study supports a view of neuroinflammation as a secondary response with non-causal relationship to neuron injury in the disease. This disease model may prove useful for understanding the conditions in which complement and immunity do contribute to neurodegeneration in other disorders.

  20. Stirring, charging, and picking: hunting tactics of potamotrygonid rays in the upper Paraná River

    Directory of Open Access Journals (Sweden)

    Domingos Garrone-Neto

    Full Text Available Hunting tactics of potamotrygonid freshwater rays remain unreported under natural conditions. Three main foraging tactics of Potamotrygon falkneri and P. motoro are described here based on underwater observations in the upper Paraná River. Both species displayed similar behaviors. The most common tactic was to undulate the disc margins close to, or on, the bottom and thus stirring the substrate and uncovering hidden preys. Another tactic was to charge upon prey concentrated in the shallows. The least common tactic was to pick out prey adhered to the substrate. The first tactic is widespread in several species of marine rays in the Dasyatidae, whereas the remainder (especially picking up prey on substrata above water surface may be restricted to the Potamotrygonidae.

  1. The Skin Picking Impact Scale: Factor structure, validity and development of a short version.

    Science.gov (United States)

    Snorrason, Ivar; Olafsson, Ragnar P; Flessner, Christopher A; Keuthen, Nancy J; Franklin, Martin E; Woods, Douglas W

    2013-08-01

    In the present study, we examined the psychometric properties of the Skin Picking Impact Scale (SPIS; Keuthen, Deckersbach, Wilhelm et al., 2001), a 10 item self-report questionnaire designed to assess the psychosocial impact of skin picking disorder (SPD). Participants were 650 individuals who met criteria for SPD in an online survey. Exploratory and confirmatory factor analyses demonstrated a unitary factor structure with high internal consistency (α = 0.94). Consequently, we constructed an abbreviated 4-item version that retained good internal consistency (α = 0.87) and a robust factor structure. Both the short and the full versions demonstrated discriminant and convergent/concurrent validity. In conclusion, the findings indicate that both versions are psychometrically sound measures of SPD related psychosocial impact; however, some potential limitations of the full scale are discussed.

  2. The planning of order picking in a warehouse by heuristic algorithms

    OpenAIRE

    Uršič, Jakob

    2014-01-01

    Planning of order picking is essential process in every warehouse. In this thesis, we developed a simple warehouse simulator, which allows us to do various searches on path finding for a certain amount of items for one or more robots, using the A* algorithm. Heuristic guidance of search is mainly based on heuristic evaluation. We have implemented five different heuristic estimates, which we tested experimentally on examples with different warehouse configurations and with different numbers of...

  3. Picking up the pieces of Super-Kamiokande

    CERN Multimedia

    Lee, T

    2002-01-01

    On Nov 12th as the tank of the SuperK detector was being refilled after routine maintenance, a shock wave calculated at 100 times greater than atmospheric pressure was triggered by the implosion of one weakened photomultiplier tube. In only five seconds the resulting chain reaction destroyed 6,665 PMTs, wrecking the detector and seriously delaying neutrino research.

  4. Colour picking: the pecking order of form and function

    NARCIS (Netherlands)

    Nack, F.-M.; Manniesing, A.S.K.; Hardman, L.

    2003-01-01

    Multimedia presentation generation has to be able to balance the functional aspects of a presentation that address the information needs of the user, and its aesthetic form. We demonstrate our approach using automatic colour design for which we integrate relevant aspects of colour theory. Colour sel

  5. Colour Picking - the Pecking Order of Form and Function

    NARCIS (Netherlands)

    Nack, F.-M.; Manniesing, A.S.K.; Hardman, L.

    2003-01-01

    Multimedia presentation generation has to be able to balance the functional aspects of a presentation that address the information needs of the user and its aesthetic form. We demonstrate our approach using automatic colour design for which we integrate relevant aspects of colour theory. We do not p

  6. Anesthesia Management in a Patient with Niemann Pick Disease

    Directory of Open Access Journals (Sweden)

    Zeynep Akoğul

    2013-04-01

    Full Text Available Niemann-Pick disease (NPD is an autosomal recessive, lipid storage disorder caused by the deficiency of the lysosomal enzyme sphingomyelinase or defective cholesterol transport from lysosome to cytosol. The clinical symptoms and signs include dysphagia, loss of motor function, hepatosplenomegaly, recurred respiratory infections, seizure, mental retardation, spasticity, myoclonic jerks and ataxia, but vary depending on the type of this disease. According to the observed pathology, patients require specialized therapy. Due to the high prevalence of the pathology in this group of patients, surgical interventions requiring general anaesthesia are common. Anesthetists have some difficulties with this group of patients. One of them is difficult ventilation because of hepatosplenomegaly and the other is difficult intubation. The metabolism of some of the anesthetic agents may be affected due to chronic use of anticonvulsant agents. Liver enzymes are elevated and platelet counts are reduced. Here we report an anesthesia management, difficulties and post-op follow up in a female child having NPD. Anesthetists have some difficulties in ventilation and intubation with NPD patients. In this situation ventilation should be with low tidal volume and high frequency. Because anesthetic agents might cause liver damage, they should be used cautiously. As a result, with keeping mind all these pathologies, anesthesia management to these patients should be used cautiously. (Journal of Current Pediatrics 2013; 11: 42-4

  7. The effects of brief cognitive-behaviour therapy for pathological skin picking: A randomized comparison to wait-list control

    NARCIS (Netherlands)

    Schuck, K.; Keijsers, G.P.J.; Rinck, M.

    2011-01-01

    Thirty-four college students suffering from pathological skin picking were randomly assigned to a four-session cognitive-behavioural treatment (n = 17) or a waiting-list condition (n = 17). Severity of skin picking, psycho-social impact of skin picking, strength of skin-picking-related dysfunctional

  8. Interaction between the glutamate transporter GLT1b and the synaptic PDZ domain protein PICK1

    DEFF Research Database (Denmark)

    Bassan, Merav; Liu, Hongguang; Madsen, Kenneth L

    2008-01-01

    with the PDZ domain protein PICK1, which plays a critical role in regulating the expression of glutamate receptors at excitatory synapses. A yeast two-hybrid screen of a neuronal library using the carboxyl tail of GLT1b yielded clones expressing PICK1. The GLT1b C-terminal peptide bound to PICK1 with high...... affinity (K(i) = 6.5 +/- 0.4 microM) in an in vitro fluorescence polarization assay. We also tested peptides based on other variants of GLT1 and other glutamate transporters. GLT1b co-immunoprecipitated with PICK1 from rat brain lysates and COS7 cell lysates derived from cells transfected with plasmids...... expressing PICK1 and GLT1b. In addition, expression of GLT1b in COS7 cells changed the distribution of PICK1, bringing it to the surface. GLT1b and PICK1 co-localized with each other and with synaptic markers in hippocampal neurons in culture. Phorbol ester, an activator of protein kinase C (PKC), a known...

  9. Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease

    Directory of Open Access Journals (Sweden)

    Sandra Torres

    2017-04-01

    Full Text Available Niemann Pick type C (NPC disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature of NPC disease is the intracellular accumulation of cholesterol and gangliosides, predominantly in endolysosomes, mitochondrial cholesterol accumulation has also been reported. As accumulation of cholesterol in mitochondria is known to impair the transport of GSH into mitochondria, resulting in mitochondrial GSH (mGSH depletion, we investigated the impact of mGSH recovery in NPC disease. We show that GSH ethyl ester (GSH-EE, but not N-acetylcysteine (NAC, restored the mGSH pool in liver and brain of Npc1-/- mice and in fibroblasts from NPC patients, while both GSH-EE and NAC increased total GSH levels. GSH-EE but not NAC increased the median survival and maximal life span of Npc1-/- mice. Moreover, intraperitoneal therapy with GSH-EE protected against oxidative stress and oxidant-induced cell death, restored calbindin levels in cerebellar Purkinje cells and reversed locomotor impairment in Npc1-/- mice. High-resolution respirometry analyses revealed that GSH-EE improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1-/- mice. Lipidomic analyses showed that GSH-EE treatment had not effect in the profile of most sphingolipids in liver and brain, except for some particular species in brain of Npc1-/- mice. These findings indicate that the specific replenishment of mGSH may be a potential promising therapy for NPC disease, worth exploring alone or in combination with other options.

  10. Mitochondrial GSH replenishment as a potential therapeutic approach for Niemann Pick type C disease.

    Science.gov (United States)

    Torres, Sandra; Matías, Nuria; Baulies, Anna; Nuñez, Susana; Alarcon-Vila, Cristina; Martinez, Laura; Nuño, Natalia; Fernandez, Anna; Caballeria, Joan; Levade, Thierry; Gonzalez-Franquesa, Alba; Garcia-Rovés, Pablo; Balboa, Elisa; Zanlungo, Silvana; Fabrías, Gemma; Casas, Josefina; Enrich, Carlos; Garcia-Ruiz, Carmen; Fernández-Checa, José C

    2017-04-01

    Niemann Pick type C (NPC) disease is a progressive lysosomal storage disorder caused by mutations in genes encoding NPC1/NPC2 proteins, characterized by neurological defects, hepatosplenomegaly and premature death. While the primary biochemical feature of NPC disease is the intracellular accumulation of cholesterol and gangliosides, predominantly in endolysosomes, mitochondrial cholesterol accumulation has also been reported. As accumulation of cholesterol in mitochondria is known to impair the transport of GSH into mitochondria, resulting in mitochondrial GSH (mGSH) depletion, we investigated the impact of mGSH recovery in NPC disease. We show that GSH ethyl ester (GSH-EE), but not N-acetylcysteine (NAC), restored the mGSH pool in liver and brain of Npc1(-/-) mice and in fibroblasts from NPC patients, while both GSH-EE and NAC increased total GSH levels. GSH-EE but not NAC increased the median survival and maximal life span of Npc1(-/-) mice. Moreover, intraperitoneal therapy with GSH-EE protected against oxidative stress and oxidant-induced cell death, restored calbindin levels in cerebellar Purkinje cells and reversed locomotor impairment in Npc1(-/-) mice. High-resolution respirometry analyses revealed that GSH-EE improved oxidative phosphorylation, coupled respiration and maximal electron transfer in cerebellum of Npc1(-/-) mice. Lipidomic analyses showed that GSH-EE treatment had not effect in the profile of most sphingolipids in liver and brain, except for some particular species in brain of Npc1(-/-) mice. These findings indicate that the specific replenishment of mGSH may be a potential promising therapy for NPC disease, worth exploring alone or in combination with other options.

  11. [Theoretic basis on the same therapeutic program for different degenerative brain diseases in terms of the Governor Vessel: Alzheimer's disease and Parkinson's disease].

    Science.gov (United States)

    Wu, Junyan; Wang, Jie; Zhang, Junlong

    2015-05-01

    Through the consultation of TCM ancient classical theory, the relationship of kidney essence, marrow and brain is analyzed. It is discovered that the degenerative brain diseases, represented by Alzheimer's disease (AD) and Parkinson's disease (PD) share the same etiological basis as "kidney essence deficiency and brain marrow emptiness" and have the mutual pathological outcomes as yang qi declining. The Governor Vessel gathers yang qi of the whole body and maintains the normal functional activity of zangfu organs in the human body through the storage, regulation and invigoration of yang qi. It is viewed that the theory of the Governor Vessel is applied to treat the different degenerative brain diseases, which provides the theoretic support and practice guide for the thought of TCM as the same therapeutic program for the different diseases. As a result, the degenerative brain diseases can be retarded and the approach is provided to the effective prevention and treatment of degenerative diseases in central nerve system:

  12. Hankel vector moment sequences and the non-tangential regularity at infinity of two variable Pick functions

    CERN Document Server

    Agler, Jim

    2011-01-01

    A Pick function of $d$ variables is a holomorphic map from $\\Pi^d$ to $\\Pi$, where $\\Pi$ is the upper halfplane. Some Pick functions of one variable have an asymptotic expansion at infinity, a power series $\\sum_{n=1}^\\infty \\rho_n z^{-n}$ with real numbers $\\rho_n$ that gives an asymptotic expansion on non-tangential approach regions to infinity. H. Hamburger in 1921 characterized which sequences $\\{\\rho_n\\} $ can occur. We give an extension of Hamburger's results to Pick functions of two variables.

  13. Inhibition of Intermediate-Conductance Calcium-Activated K Channel (KCa3.1) and Fibroblast Mitogenesis by α-Linolenic Acid and Alterations of Channel Expression in the Lysosomal Storage Disorders, Fabry Disease, and Niemann Pick C

    Science.gov (United States)

    Oliván-Viguera, Aida; Lozano-Gerona, Javier; López de Frutos, Laura; Cebolla, Jorge J.; Irún, Pilar; Abarca-Lachen, Edgar; García-Malinis, Ana J.; García-Otín, Ángel Luis; Gilaberte, Yolanda; Giraldo, Pilar; Köhler, Ralf

    2017-01-01

    The calcium/calmodulin-gated KCa3.1 channel regulates normal and abnormal mitogenesis by controlling K+-efflux, cell volume, and membrane hyperpolarization-driven calcium-entry. Recent studies suggest modulation of KCa3.1 by omega-3 fatty acids as negative modulators and impaired KCa3.1 functions in the inherited lysosomal storage disorder (LSD), Fabry disease (FD). In the first part of present study, we characterize KCa3.1 in murine and human fibroblasts and test the impact of omega-3 fatty acids on fibroblast proliferation. In the second, we study whether KCa3.1 is altered in the LSDs, FD, and Niemann-Pick disease type C (NPC). Our patch-clamp and mRNA-expression studies on murine and human fibroblasts show functional expression of KCa3.1. KCa currents display the typical pharmacological fingerprint of KCa3.1: Ca2+-activation, potentiation by the positive-gating modulators, SKA-31 and SKA-121, and inhibition by TRAM-34, Senicapoc (ICA-17043), and the negative-gating modulator, 13b. Considering modulation by omega-3 fatty acids we found that α-linolenic acid (α-LA) and docosahexanenoic acid (DHA) inhibit KCa3.1 currents and strongly reduce fibroblast growth. The α-LA-rich linseed oil and γ-LA-rich borage oil at 0.5% produce channel inhibition while α-LA/γ-LA-low oils has no anti-proliferative effect. Concerning KCa3.1 in LSD, mRNA expression studies, and patch-clamp on primary fibroblasts from FD and NPC patients reveal lower KCa3.1-gene expression and membrane expression than in control fibroblasts. In conclusion, the omega-3 fatty acid, α-LA, and α-LA/γ-LA-rich plant oils, inhibit fibroblast KCa3.1 channels and mitogenesis. Reduced fibroblast KCa3.1 functions are a feature and possible biomarker of cell dysfunction in FD and NPC and supports the concept that biased lipid metabolism is capable of negatively modulating KCa3.1 expression. PMID:28197106

  14. The exceptional brain of Maurice Ravel.

    Science.gov (United States)

    Otte, Andreas; De Bondt, Pieter; Van De Wiele, Christophe; Audenaert, Kurt; Dierckx, Rudi

    2003-06-01

    This historical review describes the brain disease which afflicted the great impressionist-classicist composer Maurice Ravel (1875-1937). The usual interpretation of the symptoms Ravel exhibited during his disease is primary progressive aphasia / Pick's disease. Some authors see this as the cause for his lost musical creativity during the last years of his life. By contrast, in our review it is presented why a car accident in 1932, with the probable consequence of a mild to moderate traumatic brain injury, could be the key event in his life, triggering the loss of his ability to compose. In addition, the influence of Ravel's disease on his musical style is evaluated. Although some authors see a link, we try to explain why there is no clear evidence for this.

  15. Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C: a prospective observational study.

    Science.gov (United States)

    De Castro-Orós, Isabel; Irún, Pilar; Cebolla, Jorge Javier; Rodriguez-Sureda, Victor; Mallén, Miguel; Pueyo, María Jesús; Mozas, Pilar; Dominguez, Carmen; Pocoví, Miguel

    2017-02-21

    Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. The diagnosis of NP-C remains challenging due to the non-specific, heterogeneous nature of signs/symptoms. This study assessed the utility of plasma chitotriosidase (ChT) and Chemokine (C-C motif) ligand 18 (CCL18)/pulmonary and activation-regulated chemokine (PARC) in conjunction with the NP-C suspicion index (NP-C SI) for guiding confirmatory laboratory testing in patients with suspected NP-C. In a prospective observational cohort study, incorporating a retrospective determination of NP-C SI scores, two different diagnostic approaches were applied in two separate groups of unrelated patients from 51 Spanish medical centers (n = 118 in both groups). From Jan 2010 to Apr 2012 (Period 1), patients with ≥2 clinical signs/symptoms of NP-C were considered 'suspected NP-C' cases, and NPC1/NPC2 sequencing, plasma chitotriosidase (ChT), CCL18/PARC and sphingomyelinase levels were assessed. Based on findings in Period 1, plasma ChT and CCL18/PARC, and NP-C SI prediction scores were determined in a second group of patients between May 2012 and Apr 2014 (Period 2), and NPC1 and NPC2 were sequenced only in those with elevated ChT and/or elevated CCL18/PARC and/or NP-C SI ≥70. Filipin staining and 7-ketocholesterol (7-KC) measurements were performed in all patients with NP-C gene mutations, where possible. In total across Periods 1 and 2, 10/236 (4%) patients had a confirmed diagnosis o NP-C based on gene sequencing (5/118 [4.2%] in each Period): all of these patients had two causal NPC1 mutations. Single mutant NPC1 alleles were detected in 8/236 (3%) patients, overall. Positive filipin staining results comprised three classical and five variant biochemical phenotypes. No NPC2 mutations were detected. All patients with NPC1 mutations had high ChT activity, high CCL18/PARC concentrations and/or NP-C SI scores ≥70. Plasma 7

  16. Infectious diseases of the brain: imaging and differential diagnosis; Infektioese Hirnerkrankungen: Bildgebung und differenzialdiagnostische Aspekte

    Energy Technology Data Exchange (ETDEWEB)

    Haehnel, S.; Seitz, A. [Abt. Neuroradiologie, Neurologische Klinik, Universitaetsklinikum Heidelberg (Germany); Storch-Hagenlocher, B. [Abt. Neurologie, Neurologische Klinik, Universitaetsklinikum Heidelberg (Germany)

    2006-09-15

    Infectious diseases of the central nervous system have to be considered in differential diagnosis particularly in immunocompromised persons. Neuro-imaging, specifically advanced techniques such as diffusion weighted MRI and perfusion MRI contribute much to the differentiation of brain infections and for differentiating brain infections from other, for instance, neoplastic diseases. In this review we present the imaging criteria of the most important brains infections in adults and in pediatric patients and discuss differential diagnostic aspects in detail. (orig.)

  17. Level of PICALM, a key component of clathrin-mediated endocytosis, is correlated with levels of phosphotau and autophagy-related proteins and is associated with tau inclusions in AD, PSP and Pick disease.

    Science.gov (United States)

    Ando, Kunie; Tomimura, Karen; Sazdovitch, Véronique; Suain, Valérie; Yilmaz, Zehra; Authelet, Michèle; Ndjim, Marième; Vergara, Cristina; Belkouch, Mounir; Potier, Marie-Claude; Duyckaerts, Charles; Brion, Jean-Pierre

    2016-10-01

    Single nucleotide polymorphisms in PICALM, a key component of clathrin-mediated endocytosis machinery, have been identified as genetic susceptibility loci for late onset Alzheimer's disease (LOAD). We previously reported that PICALM protein levels were decreased in AD brains and that PICALM was co-localised with neurofibrillary tangles in LOAD, familial AD with PSEN1 mutations and Down syndrome. In the present study, we analysed PICALM expression, cell localisation and association with pathological cellular inclusions in other tauopathies and in non-tau related neurodegenerative diseases. We observed that PICALM was associated with neuronal tau pathology in Pick disease and in progressive supranuclear palsy (PSP) and co-localised with both 3R and 4R tau positive inclusions unlike in corticobasal degeneration (CBD) or in frontotemporal lobar degeneration (FTLD)-MAPT P301L. PICALM immunoreactivities were not detected in tau-positive tufted astrocytes in PSP, astrocytic plaques in CBD, Lewy bodies in Lewy body disease, diffuse type (LBD) and in TDP-43-positive inclusions in FTLD. In the frontal cortex in tauopathies, the ratio of insoluble to soluble PICALM was increased while the level of soluble PICALM was decreased and was inversely correlated with the level of phosphotau. PICALM decrease was also significantly correlated with increased LC3-II and decreased Beclin-1 levels in tauopathies and in non-tau related neurodegenerative diseases. These results suggest that there is a close relationship between abnormal PICALM processing, tau pathology and impairment of autophagy in human neurodegenerative diseases.

  18. Design of planar pick-ups for beam position monitor in the bunch compressor at FLASH and XFEL

    Energy Technology Data Exchange (ETDEWEB)

    Angelovski, Aleksandar; Penirschke, Andreas; Jakoby, Rolf [Institut fuer Mikrowellentechnik und Photonik, TU Darmstadt (Germany); Sydlo, Cezary; Mavric, Uros; Gerth, Christopher [DESY, Hamburg (Germany)

    2013-07-01

    For obtaining ultra short electron bunches at the Free Electron Laser at DESY (FLASH) the beam is compressed in magnetic chicanes. During the compression process the precise knowledge of the energy of the bunches is essential for the longitudinal dynamics control. The measurement of the beam position in the chicane allows for non-destructive measurements of the energy. For that purpose, two stripline pick-ups perpendicular to the beam direction are installed in the chicane at FLASH as a part of the Beam Position Monitor. The recent upgrade in the electronics as well as the increased aperture and length of the beam pipe (for the European XFEL) requires the design of new pick-ups which will fulfill the new demands. Namely, the pick-ups should have maximum signal at 3 GHz with minimum reflections. In this talk, we will present the design of planar transmission line pick-ups for FLASH and XFEL. The planar design of the pick-ups can provide for a proper impedance matching to the subsequent electronics as well as sufficient mechanical stability along the aperture when using alumina substrate. A prototype of the pick-ups was build and installed in a non-hermetic body. The measured S parameters are compared to the simulation.

  19. Travel motives of participants in the Cape Argus Pick n Pay Cycle Tour

    African Journals Online (AJOL)

    South African Journal for Research in Sport, Physical Education and Recreation. Journal Home ... The Cape Argus Pick n Pay Cycle Tour is the largest cycling events in South Africa. The event ... South Africa; Marketing; Factor analysis.

  20. Stellar wind interaction and pick-up ion escape of the Kepler-11 "super-Earths"

    Science.gov (United States)

    Kislyakova, Kristina; Johnstone, Colin; Odert, Petra; Erkaev, Nikolai; Lammer, Helmut; Lüftinger, Theresa; Holmstöm, Mats; Khodachenko, Maxim; Güdel, Manuel

    2014-05-01

    We present the results of modeling of the interactions between stellar wind and the extended hydrogen-dominated upper atmospheres of planets and estimate the resulting escape of planetary pick-up ions from the 5 «super-Earths» in the compact Kepler-11 system. We compare the escape rates with the efficiency of the thermal escape of neutral hydrogen atoms. Assuming the stellar wind of Kepler-11 is similar to the solar wind, we used a polytropic 1D hydrodynamic wind model to estimate the wind properties at the planetary orbits. We applied a Direct Simulation Monte Carlo Model to model the hydrogen coronae and the stellar wind plasma interaction around Kepler-11b-f planets within a realistic expected heating efficiency range of 15-40%. The same model was used to estimate the ion pick-up escape from the XUV heated and hydrodynamically extended upper atmospheres of Kepler-11b-f. Modeling clarifies the influence of possible magnetic moments on escape processes and allows to estimate the charge exchange and photoionization production rates of planetary ions as well as the loss rates of pick-up H+ ions for all five planets. This study presents also the comparison of the results between the five 'super-Earths' and in a more general sense also with the thermal escape rates of the neutral planetary hydrogen atoms. Our results show that for all Kepler-11b-f exoplanets, a huge neutral hydrogen corona is formed around the planet. The non-symmetric form of the corona changes from planet to planet and is defined mostly by radiation pressure, charge-exchange and gravitational effects. According to our estimates, nonthermal escape rates of pick-up ionized hydrogen atoms for Kepler-11 «super-Earths» vary between ~ 6.4 × 1030 s-1 and ~ 4.1 × 1031 s-1 depending on the planet's orbital location and assumed heating efficiency. These values correspond to non-thermal mass loss rates of ~ 1.07 × 107 g·s-1 and ~ 6.8 × 107 g·s-1 respectively, which is a few percent of the thermal

  1. A derangement of the brain wound healing process may cause some cases of Alzheimer's disease.

    Science.gov (United States)

    Lehrer, Steven; Rheinstein, Peter H

    2016-08-01

    A derangement of brain wound healing may cause some cases of Alzheimer's disease. Wound healing, a highly complex process, has four stages: hemostasis, inflammation, repair, and remodeling. Hemostasis and the initial phases of inflammation in brain tissue are typical of all vascularized tissue, such as skin. However, distinct differences arise in brain tissue during the later stages of inflammation, repair, and remodeling, and closely parallel the changes of Alzheimer's disease. Our hypothesis -- Alzheimer's disease is brain wound healing gone awry at least in some cases -- could be tested by measuring progression with biomarkers for the four stages of wound healing in humans or appropriate animal models. Autopsy studies might be done. Chronic traumatic encephalopathy might also result from the brain wound healing process.

  2. Factor Structure, Validity and Reliability of the Revised Version of Skin Picking Scale

    Directory of Open Access Journals (Sweden)

    Mehdi Rabiei

    2014-09-01

    Full Text Available Background: The purpose of this study was to examine the factor structure, validity and reliability of the Skin Picking Scale-Revised Version. Materials and Methods: In this descriptive and validation study, participants were 550 (250 male and 300 female of the University of Isfahan were selected randomly from 15000 students. In order to examine the factor structure of the SPS-R we conducted both exploratory and confirmatory factor analyses and Cronbach's alpha. Results: Convergent validity of SPS-R with YBOCS-BDD, OCI-R and DASS 21-item were r=0.45, r=0.51 and r=0.70 (p<0.001. Exploratory and confirmatory factor analyses revealed two factors, one assessing impairment and the other symptom severity (4 items each. These factors could determine 58.1% of the variance. The Cronbach's alpha for the two factors were above 0.88. Also, results were shown to possess good psychometric properties, as well as discriminant validity and classification accuracy, in both clinical and community populations. Conclusion: It can be concluded that this instrument is a useful measure for assess skin-picking disorder symptoms in clinical assessment.

  3. Brain Diseases

    Science.gov (United States)

    The brain is the control center of the body. It controls thoughts, memory, speech, and movement. It regulates the function of many organs. When the brain is healthy, it works quickly and automatically. However, ...

  4. Exercise Regulation of Cognitive Function and Neuroplasticity in the Healthy and Diseased Brain.

    Science.gov (United States)

    Hamilton, Gilian F; Rhodes, Justin S

    2015-01-01

    Regular exercise broadly enhances physical and mental health throughout the lifespan. Animal models have provided us with the tools to gain a better understanding of the underlying biochemical, physiological, and morphological mechanisms through which exercise exerts its beneficial cognitive effects. One brain region in particular, the hippocampus, is especially responsive to exercise. It is critically involved in learning and memory and is one of two regions in the mammalian brain that continues to generate new neurons throughout life. Exercise prevents the decline of the hippocampus from aging and ameliorates many neurodegenerative diseases, in part by increasing adult hippocampal neurogenesis but also by activating a multitude of molecular mechanisms that promote brain health. In this chapter, we first describe some rodent models used to study effects of exercise on the brain. Then we review the rodent work focusing on the mechanisms behind which exercise improves cognition and brain health in both the normal and the diseased brain, with emphasis on the hippocampus.

  5. Stellar wind interaction and pick-up ion escape of the Kepler-11 "super-Earths"

    CERN Document Server

    Kislyakova, K G; Odert, P; Erkaev, N V; Lammer, H; üftinger, T L; Holmström, M; Khodachenko, M L; üdel, M G

    2013-01-01

    We study the interactions between stellar wind and the extended hydrogen-dominated upper atmospheres of planets and the resulting escape of planetary pick-up ions from the 5 "super-Earths" in the compact Kepler-11 system and compare the escape rates with the efficiency of the thermal escape of neutral hydrogen atoms. Assuming the stellar wind of Kepler-11 is similar to the solar wind, we use a polytropic 1D hydrodynamic wind model to estimate the wind properties at the planetary orbits. We apply a Direct Simulation Monte Carlo Model to model the hydrogen coronae and the stellar wind plasma interaction around Kepler-11b-f within a realistic expected heating efficiency range of 15-40%. The same model is used to estimate the ion pick-up escape from the XUV heated and hydrodynamically extended upper atmospheres of Kepler-11b-f. From the interaction model we study the influence of possible magnetic moments, calculate the charge exchange and photoionization production rates of planetary ions and estimate the loss r...

  6. Human and mouse neuroinflammation markers in Niemann-Pick disease, type C1.

    Science.gov (United States)

    Cologna, Stephanie M; Cluzeau, Celine V M; Yanjanin, Nicole M; Blank, Paul S; Dail, Michelle K; Siebel, Stephan; Toth, Cynthia L; Wassif, Christopher A; Lieberman, Andrew P; Porter, Forbes D

    2014-01-01

    Niemann-Pick disease, type C1 (NPC1) is an autosomal recessive lipid storage disorder in which a pathological cascade, including neuroinflammation occurs. While data demonstrating neuroinflammation is prevalent in mouse models, data from NPC1 patients is lacking. The current study focuses on identifying potential markers of neuroinflammation in NPC1 from both the Npc1 mouse model and NPC1 patients. We identified in the mouse model significant changes in expression of genes associated with inflammation and compared these results to the pattern of expression in human cortex and cerebellar tissue. From gene expression array analysis, complement 3 (C3) was increased in mouse and human post-mortem NPC1 brain tissues. We also characterized protein levels of inflammatory markers in cerebrospinal fluid (CSF) from NPC1 patients and controls. We found increased levels of interleukin 3, chemokine (C-X-C motif) ligand 5, interleukin 16 and chemokine ligand 3 (CCL3), and decreased levels of interleukin 4, 10, 13 and 12p40 in CSF from NPC1 patients. CSF markers were evaluated with respect to phenotypic severity. Miglustat treatment in NPC1 patients slightly decreased IL-3, IL-10 and IL-13 CSF levels; however, further studies are needed to establish a strong effect of miglustat on inflammation markers. The identification of inflammatory markers with altered levels in the cerebrospinal fluid of NPC1 patients may provide a means to follow secondary events in NPC1 disease during therapeutic trials.

  7. A theoretical model for predicting the Peak Cutting Force of conical picks

    Directory of Open Access Journals (Sweden)

    Gao Kuidong

    2014-01-01

    Full Text Available In order to predict the PCF (Peak Cutting Force of conical pick in rock cutting process, a theoretical model is established based on elastic fracture mechanics theory. The vertical fracture model of rock cutting fragment is also established based on the maximum tensile criterion. The relation between vertical fracture angle and associated parameters (cutting parameter  and ratio B of rock compressive strength to tensile strength is obtained by numerical analysis method and polynomial regression method, and the correctness of rock vertical fracture model is verified through experiments. Linear regression coefficient between the PCF of prediction and experiments is 0.81, and significance level less than 0.05 shows that the model for predicting the PCF is correct and reliable. A comparative analysis between the PCF obtained from this model and Evans model reveals that the result of this prediction model is more reliable and accurate. The results of this work could provide some guidance for studying the rock cutting theory of conical pick and designing the cutting mechanism.

  8. The role of gap junctions in the brain in health and disease.

    Science.gov (United States)

    Dere, Ekrem; Zlomuzica, Armin

    2012-01-01

    Gap junctions connect the cytosolic compartments of adjacent cells for direct electrotonic and metabolic cell-to-cell communication. Gap junctions between glial cells or neurons are ubiquitously expressed in the brain and play a role in brain development including cell differentiation, cell migration and survival, tissue homeostasis, as well as in human diseases including hearing loss, skin disease, neuropathies, epilepsy, brain trauma, and cardiovascular disease. Furthermore, gap junctions are involved in the synchronization and rhythmic oscillation of hippocampal and neocotical neuronal ensembles which might be important for memory formation and consolidation. In this review the accumulated evidence from mouse mutant and pharmacological studies using gap junction blockers is summarized and the progress made in dissecting the physiological, pathophysiological and behavioral roles of gap junction mediated intercellular communication in the brain is discussed. Copyright © 2011 Elsevier Ltd. All rights reserved.

  9. Spotting Fruit versus Picking Fruit as the Selective Advantage of Human Colour Vision

    Directory of Open Access Journals (Sweden)

    Aline Bompas

    2013-04-01

    Full Text Available The spatiochromatic properties of the red–green dimension of human colour vision appear to be optimized for picking fruit in leaves at about arms' reach. However, other evidence suggests that the task of spotting fruit from a distance might be more important. This discrepancy may arise because the task a system (e.g. human trichromacy is best at is not necessarily the same task where the largest advantage occurs over the evolutionary alternatives (dichromacy or anomalous trichromacy. We tested human dichromats, anomalous trichromats and “normal” trichromats in a naturalistic visual search task in which they had to find fruit pieces in a bush at 1, 4, 8 or 12 m viewing distance. We found that the largest advantage (in terms of either performance ratio or performance difference of normal trichromacy over both types of colour deficiency was for the largest viewing distance. We infer that in the evolution of human colour vision, spotting fruit from a distance was a more important selective advantage than picking fruit at arms' reach.

  10. Influence of assistance of high-pressure water jet in the process of rock cutting upon the temperature, wear cutting force and dustiness of the shearer pick edge

    Energy Technology Data Exchange (ETDEWEB)

    Klich, A.; Kotwica, K.; Res, J. [University of Mining and Metallurgy, Cracow (Poland)

    1995-08-01

    The cutting of artificial samples of rock with and without cutting process assistance of a high-pressure water jet was investigated in the laboratory. During the research the temperature, pick edge wear, pressure and adjacent force and dustiness were measured under several selected mining parameters. The research used Rapid 85 shearer radial picks and the adjacent Alpine picks. The cutting with radial picks was assisted with a high-pressure water jet from the front and back whereas the adjacent picks cutting was assisted only from the front. For cutting with assistance of a high-pressure water jet the Saphintec type nozzles of d=0.3, 0.55 and 0.8 mm diameter and water pressure of p=1, 20, 40 and 60 MPa were used. 6 refs., 15 figs., 3 tabs.

  11. The modulatory effect of adaptive deep brain stimulation on beta bursts in Parkinson's disease.

    Science.gov (United States)

    Tinkhauser, Gerd; Pogosyan, Alek; Little, Simon; Beudel, Martijn; Herz, Damian M; Tan, Huiling; Brown, Peter

    2017-02-13

    Adaptive deep brain stimulation uses feedback about the state of neural circuits to control stimulation rather than delivering fixed stimulation all the time, as currently performed. In patients with Parkinson's disease, elevations in beta activity (13-35 Hz) in the subthalamic nucleus have been demonstrated to correlate with clinical impairment and have provided the basis for feedback control in trials of adaptive deep brain stimulation. These pilot studies have suggested that adaptive deep brain stimulation may potentially be more effective, efficient and selective than conventional deep brain stimulation, implying mechanistic differences between the two approaches. Here we test the hypothesis that such differences arise through differential effects on the temporal dynamics of beta activity. The latter is not constantly increased in Parkinson's disease, but comes in bursts of different durations and amplitudes. We demonstrate that the amplitude of beta activity in the subthalamic nucleus increases in proportion to burst duration, consistent with progressively increasing synchronization. Effective adaptive deep brain stimulation truncated long beta bursts shifting the distribution of burst duration away from long duration with large amplitude towards short duration, lower amplitude bursts. Critically, bursts with shorter duration are negatively and bursts with longer duration positively correlated with the motor impairment off stimulation. Conventional deep brain stimulation did not change the distribution of burst durations. Although both adaptive and conventional deep brain stimulation suppressed mean beta activity amplitude compared to the unstimulated state, this was achieved by a selective effect on burst duration during adaptive deep brain stimulation, whereas conventional deep brain stimulation globally suppressed beta activity. We posit that the relatively selective effect of adaptive deep brain stimulation provides a rationale for why this approach could

  12. The balance between cognitive reserve and brain imaging biomarkers of cerebrovascular and Alzheimer's diseases.

    Science.gov (United States)

    Murray, Alison D; Staff, Roger T; McNeil, Christopher J; Salarirad, Sima; Ahearn, Trevor S; Mustafa, Nazahah; Whalley, Lawrence J

    2011-12-01

    The cognitive reserve hypothesis explains the disparity between clinical and pathological phenotypes and why, in two individuals with the same extent of neuropathology, one may be demented while the other remains cognitively intact. We examined the balance between brain magnetic resonance imaging measures of the two most common pathologies associated with brain ageing, cerebrovascular disease and Alzheimer's disease, and parameters of cerebral reserve in well-characterized participants born in 1936, for whom childhood intelligence is known. Brain magnetic resonance imaging was carried out at 1.5T using fluid attenuation inversion recovery and T(1)-weighted volumetric sequences in 249 participants. Cerebrovascular disease was quantified by measuring brain white matter hyperintensities on fluid attenuation inversion recovery images using Scheltens' scale and Alzheimer's disease was measured from volumetric data using FreeSurfer to extract whole brain volume and hippocampal volumes in turn. The effect of these measures of brain burden on life-long cognitive ageing from the age of 11 to 68 years was compared with the effect of educational attainment and occupational grade using structural equation modelling. Complete brain burden and reserve data were available in 224 participants. We found that educational attainment, but not occupation, has a measurable and positive effect, with a standardized regression weight of +0.23, on late life cognitive ability in people without cognitive impairment aged 68 years, allowing for the influence of childhood intelligence and the two most common subclinical brain pathological burdens in the ageing brain. In addition, we demonstrate that the magnitude of the contribution of education is greater than the negative impact of either neuropathological burden alone, with standardized regression weights of -0.14 for white matter hyperintensities and -0.20 for hippocampal atrophy. This study illustrates how education counteracts the

  13. Diffusion tensor imaging analysis of the brain in the canine model of Krabbe disease.

    Science.gov (United States)

    Bradbury, Allison; Peterson, David; Vite, Charles; Chen, Steven; Ellinwood, N Matthew; Provenzale, James

    2016-12-01

    The goal of this study was to compare the diffusion tensor imaging (DTI) metrics from an end-stage canine Krabbe brain evaluated by MR imaging ex vivo to those of a normal dog brain. We hypothesized that the white matter of the canine Krabbe brain would show decreased fractional anisotropy (FA) values and increased apparent diffusion coefficient (ADC) and radial diffusivity (RD) values. An 11-week-old Krabbe dog was euthanized after disease progression. The brain was removed and was placed in a solution of 10% formalin. MR imaging was performed and compared to the brain images of a normal dog that was similarly fixed post-mortem. Both brains were scanned using similar protocols on a 7 T small-animal MRI system. For each brain, maps of ADC, FA, and RD were calculated for 11 white-matter regions and five control gray-matter regions. Large decreases in FA values, increases in ADC values, and increases in RD (consistent with demyelination) values, were seen in white matter of the Krabbe brain but not gray matter. ADC values in gray matter of the Krabbe brain were decreased by approximately 29% but increased by approximately 3.6% in white matter of the Krabbe brain. FA values in gray matter were decreased by approximately 3.3% but decreased by approximately 29% in white matter. RD values were decreased by approximately 27.2% in gray matter but increased by approximately 20% in white matter. We found substantial abnormalities of FA, ADC, and RD values in an ex vivo canine Krabbe brain. © The Author(s) 2016.

  14. Serine 77 in the PDZ domain of PICK1 is a protein kinase Cα phosphorylation site regulated by lipid membrane binding

    DEFF Research Database (Denmark)

    Ammendrup-Johnsen, Ina; Thorsen, Thor Seneca; Gether, Ulrik

    2012-01-01

    PICK1 (protein interacting with C kinase 1) contains an N-terminal protein binding PDZ domain and a C-terminal lipid binding BAR domain. PICK1 plays a key role in several physiological processes, including synaptic plasticity. However, little is known about the cellular mechanisms governing...... the activity of PICK1 itself. Here we show that PICK1 is a substrate in vitro both for PKCα (protein kinase Cα), as previously shown, and for CaMKIIα (Ca(2+)-calmodulin-dependent protein kinase IIα). By mutation of predicted phosphorylation sites, we identify Ser77 in the PDZ domain as a major phosphorylation...... for optimal phosphorylation. Binding of PKCα to the PICK1 PDZ domain was not required for phosphorylation, but a PDZ domain peptide ligand reduced the overall level of phosphorylation ~30%. The phosphomimic S77D reduced the extent of cytosolic clustering of eYFP-PICK1 in COS7 cells and thereby conceivably its...

  15. Heliospheric pick-up ions influencing thermodynamics and dynamics of the distant solar wind

    Directory of Open Access Journals (Sweden)

    H. J. Fahr

    2002-01-01

    Full Text Available Neutral interstellar H-atoms penetrate into the inner heliosphere and upon the event of ionization are converted into pick-up ions (PUIs. The magnetized solar wind flow incorporates these ions into the plasma bulk and enforces their co-motion. By nonlinear interactions with wind-entrained Alfvén waves, these ions are then processed in the comoving velocity space. The complete pick-up process is connected with forces acting back to the original solar wind ion flow, thereby decelerating and heating the solar wind plasma. As we show here, the resulting deceleration cannot be treated as a pure loading effect, but requires adequate consideration of the action of the pressure of PUI-scattered waves operating by the PUI pressure gradient. Hereby, it is important to take into proper account the stochastic acceleration which PUIs suffer from at their convection out of the inner heliosphere by quasi-linear interactions with MHD turbulences. Only then can the presently reported VOYAGER observations of solar wind decelerations and heatings in the outer heliosphere be understood in view of the most likely values of interstellar gas parameters, such as an H-atom density of 0.12 cm-3 . Solar wind protons (SWPs appear to be globally heated in their motion to larger solar distances. Ascribing the needed heat transfer to the action of suprathermal PUIs, which drive MHD waves that are partly absorbed by SWPs, in order to establish the observed SWP polytropy, we can obtain a quantitative expression for the solar wind proton pressure as a function of solar distance. This expression clearly shows the change from an adiabatic to a quasi-polytropic SWP behaviour with a decreasing polytropic index at increasing distances. This also allows one to calculate the average percentage of initial pick-up energy fed into the thermal proton energy. In a first order evaluation of this expression, we can estimate that about 10% of the initial PUI injection energy is eventually

  16. Up-Regulated Production and Activation of the Complement System in Alzheimer’s Disease Brain

    OpenAIRE

    Yasojima, Koji; Schwab, Claudia; McGeer, Edith G.; McGeer, Patrick L.

    1999-01-01

    We used reverse transcriptase-polymerase chain reaction and Western blotting techniques to measure the levels of complement mRNAs and their protein products in Alzheimer’s disease (AD) brain compared with non-AD brain. mRNAs for C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, and C9 were detected in the 11 regions of brain that were investigated. The mRNA levels were markedly up-regulated in affected areas of AD brain. In the entorhinal cortex, hippocampus, and midtemporal gyrus, which had dense a...

  17. Psychiatric and neurological symptoms in patients with Niemann-Pick disease type C (NP-C): findings from the International NPC Registry.

    Science.gov (United States)

    Bonnot, Olivier; Gama, Clarissa S; Mengel, Eugen; Pineda, Mercè; Vanier, Marie T; Watson, Louise; Watissée, Marie; Schwierin, Barbara; Patterson, Marc C

    2017-09-15

    Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease that should be recognized by psychiatrists as a possible underlying cause of psychiatric abnormalities. This study describes NP-C patients who had psychiatric manifestations at enrolment in the international NPC Registry, a unique multicentre, prospective, observational disease registry. Treating physicians' data entries describing psychiatric manifestations in NPC patients were coded and grouped by expert psychiatrists. Out of 386 NP-C patients included in the Registry as of October 2015, psychiatric abnormalities were reported to be present in 34% (94/280) of those with available data. Forty-four patients were confirmed to have identifiable psychiatric manifestations, with text describing these psychiatric manifestations. In these 44 patients, the median (range) age at onset of psychiatric manifestations was 17.9 years (2.5-67.9; n = 15), while the median (range) age at NP-C diagnosis was 23.7 years (0.2-69.8; n = 34). Almost all patients (43/44 [98%]) had an occurrence of ≥1 neurological manifestation at enrolment. These data show that substantial delays in diagnosis of NP-C are long among patients with psychiatric symptoms and, moreover, patients presenting with psychiatric features and at least one of cognitive impairment, neurological manifestations, and/or visceral symptoms should be screened for NP-C.

  18. Characterizing the role of brain derived neurotrophic factor genetic variation in Alzheimer's disease neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Robyn A Honea

    Full Text Available There is accumulating evidence that neurotrophins, like brain-derived neurotrophic factor (BDNF, may impact aging and Alzheimer's Disease. However, traditional genetic association studies have not found a clear relationship between BDNF and AD. Our goal was to test whether BDNF single nucleotide polymorphisms (SNPs impact Alzheimer's Disease-related brain imaging and cognitive markers of disease. We completed an imaging genetics study on 645 Alzheimer's Disease Neuroimaging Initiative participants (ND=175, MCI=316, AD=154 who had cognitive, brain imaging, and genetics data at baseline and a subset of those with brain imaging data at two years. Samples were genotyped using the Illumina Human610-Quad BeadChip. 13 SNPs in BDNF were identified in the dataset following quality control measures (rs6265(Val66Met, rs12273363, rs11030094, rs925946, rs1050187, rs2203877, rs11030104, rs11030108, rs10835211, rs7934165, rs908867, rs1491850, rs1157459. We analyzed a subgroup of 8 SNPs that were in low linkage disequilibrium with each other. Automated brain morphometric measures were available through ADNI investigators, and we analyzed baseline cognitive scores, hippocampal and whole brain volumes, and rates of hippocampal and whole brain atrophy and rates of change in the ADAS-Cog over one and two years. Three out of eight BDNF SNPs analyzed were significantly associated with measures of cognitive decline (rs1157659, rs11030094, rs11030108. No SNPs were significantly associated with baseline brain volume measures, however six SNPs were significantly associated with hippocampal and/or whole brain atrophy over two years (rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850. We also found an interaction between the BDNF Val66Met SNP and age with whole brain volume. Our imaging-genetics analysis in a large dataset suggests that while BDNF genetic variation is not specifically associated with a diagnosis of AD, it appears to play a role in AD

  19. Niemann-Pick disease Type C - Sea-blue histiocytosis: Phenotypic and imaging observations and mini review

    Directory of Open Access Journals (Sweden)

    Praveen K

    2007-01-01

    Full Text Available We present a report on an 18-year-old boy with Niemann-Pick disease Type C (NP-C who presented with progressive decline in scholastic performance since 9 years of age. At 12 years, he developed abnormal behavior and after 2 years had insidious onset, progressive gait ataxia and dysarthria followed by dystonia of the right upper extremity, excessive drooling, dysphagia and nasal regurgitation. He had coarse facies, depressed nasal bridge, high arched palate, crowded teeth, splenomegaly and peculiar facial grin. In addition, impaired vertical saccadic and pursuit eye movements, brisk muscle stretch reflexes and limb and gait ataxia were observed. He had a low IQ of 47 on Binet-Kamat test. The ultrasound examination of the abdomen confirmed the presence of moderate splenomegaly. Magnetic resonance imaging brain showed symmetrical leucoencephalopathy and mild cerebellar atrophy. Bone marrow aspiration showed numerous foamy macrophages and sea-blue histiocytes suggesting the diagnosis of NP-C.

  20. Relation of cerebral small-vessel disease and brain atrophy to mild Parkinsonism in the elderly.

    Science.gov (United States)

    Reitz, Christiane; Trenkwalder, Claudia; Kretzschmar, Konrad; Roesler, Andreas; V Eckardstein, Arnold; Berger, Klaus

    2006-11-01

    The association between cerebral small-vessel disease, brain atrophy, and the risk and severity of mild parkinsonian signs (MPS) remains unclear. The objective of this study is to examine the effect of lacunar brain infarcts, cerebral white matter lesions (WMLs), and cortical atrophy on the risk and severity of MPS. This study is a cross-sectional community-based cohort study comprising 268 subjects, 65 to 83 years of age, residing in the Augsburg region of southern Germany, and without contraindications for magnetic resonance imaging (MRI) of the brain. Main outcome measures. Subcortical and periventricular WMLs, lacunar brain infarcts, and cortical atrophy determined using a standardized MRI protocol developed for the Rotterdam Scan Study and an established rating scale. MPS, assessed in a standardized neurological examination and based on the Unified Parkinson's Disease Rating Scale motor scale. Lacunar brain infarcts and large subcortical white matter lesions were associated with an elevated risk of resting tremor. More severe cortical atrophy was related to an increased risk of rigidity and bradykinesia. In a linear regression analysis relating each individual MRI measurement with the severity of MPS, the number of lacunar brain infarcts and the degree of brain atrophy were correlated with the severity of resting tremor, whereas the size of subcortical and periventricular WMLs was correlated with the severity of rigidity. A higher degree of brain atrophy was associated with increased severity of either cardinal sign. In our study, presence and volume of lacunar brain infarcts, cerebral WMLs, and cortical atrophy were associated with the risk as well as severity of MPS. Determining the presence of these brain changes using brain imaging might contribute to identify persons at risk for MPS.

  1. Automating the Process of Work-Piece Recognition and Location for a Pick-and-Place Robot in a SFMS

    OpenAIRE

    R. V. Sharan; G. C. Onwubolu

    2014-01-01

    This paper reports the development of a vision system to automatically classify work-pieces with respect to their shape and color together with determining their location for manipulation by an in-house developed pick-and-place robot from its work-plane. The vision-based pick-and-place robot has been developed as part of a smart flexible manufacturing system for unloading work-pieces for drilling operations at a drilling workstation from an automatic guided vehicle designed to transport the w...

  2. Lymphatic Clearance of the Brain: Perivascular, Paravascular and Significance for Neurodegenerative Diseases.

    Science.gov (United States)

    Bakker, Erik N T P; Bacskai, Brian J; Arbel-Ornath, Michal; Aldea, Roxana; Bedussi, Beatrice; Morris, Alan W J; Weller, Roy O; Carare, Roxana O

    2016-03-01

    The lymphatic clearance pathways of the brain are different compared to the other organs of the body and have been the subject of heated debates. Drainage of brain extracellular fluids, particularly interstitial fluid (ISF) and cerebrospinal fluid (CSF), is not only important for volume regulation, but also for removal of waste products such as amyloid beta (Aβ). CSF plays a special role in clinical medicine, as it is available for analysis of biomarkers for Alzheimer's disease. Despite the lack of a complete anatomical and physiological picture of the communications between the subarachnoid space (SAS) and the brain parenchyma, it is often assumed that Aβ is cleared from the cerebral ISF into the CSF. Recent work suggests that clearance of the brain mainly occurs during sleep, with a specific role for peri- and para-vascular spaces as drainage pathways from the brain parenchyma. However, the direction of flow, the anatomical structures involved and the driving forces remain elusive, with partially conflicting data in literature. The presence of Aβ in the glia limitans in Alzheimer's disease suggests a direct communication of ISF with CSF. Nonetheless, there is also the well-described pathology of cerebral amyloid angiopathy associated with the failure of perivascular drainage of Aβ. Herein, we review the role of the vasculature and the impact of vascular pathology on the peri- and para-vascular clearance pathways of the brain. The different views on the possible routes for ISF drainage of the brain are discussed in the context of pathological significance.

  3. On the Stability of Pick-up Ion Ring Distributions in the Outer Heliosheath

    Science.gov (United States)

    Summerlin, Errol J.; Viñas, Adolfo F.; Moore, Thomas E.; Christian, Eric R.; Cooper, John F.

    2014-10-01

    The "secondary energetic neutral atom (ENA)" hypothesis for the ribbon feature observed by the Interstellar Boundary Explorer (IBEX) posits that the neutral component of the solar wind continues beyond the heliopause and charge exchanges with interstellar ions in the Outer Heliosheath (OHS). This creates pick-up ions that gyrate about the draped interstellar magnetic field (ISMF) lines at pitch angles near 90° on the locus where the ISMF lies tangential to the heliopause and perpendicular to the heliocentric radial direction. This location closely coincides with the location of the ribbon feature according to the prevailing inferences of the ISMF orientation and draping. The locally gyrating ions undergo additional charge exchange and escape as free-flying neutral atoms, many of which travel back toward the inner solar system and are imaged by IBEX as a ribbon tracing out the locus described above. For this mechanism to succeed, the pick-up ions must diffuse in pitch angle slowly enough to permit secondary charge exchange before their pitch angle distribution substantially broadens away from 90°. Previous work using linear Vlasov dispersion analysis of parallel propagating waves has suggested that the ring distribution in the OHS is highly unstable, which, if true, would make the secondary ENA hypothesis incapable of rendering the observed ribbon. In this paper, we extend this earlier work to more realistic ring distribution functions. We find that, at the low densities necessary to produce the observed IBEX ribbon via the secondary ENA hypothesis, growth rates are highly sensitive to the temperature of the beam and that even very modest temperatures of the ring beam corresponding to beam widths of <1° are sufficient to damp the self-generated waves associated with the ring beam. Thus, at least from the perspective of linear Vlasov dispersion analysis of parallel propagating waves, there is no reason to expect that the ring distributions necessary to produce the

  4. On the stability of pick-up ion ring distributions in the outer heliosheath

    Energy Technology Data Exchange (ETDEWEB)

    Summerlin, Errol J.; Viñas, Adolfo F.; Moore, Thomas E.; Christian, Eric R.; Cooper, John F., E-mail: errol.summerlin@nasa.gov, E-mail: adolfo.figueroa-vinas-1@nasa.gov, E-mail: thomas.e.moore@nasa.gov, E-mail: eric.r.christian@nasa.gov, E-mail: john.f.cooper@nasa.gov [Heliophysics Science Division, NASAs Goddard Space Flight Center, 8800 Greenbelt Road, Greenbelt, MD (United States)

    2014-10-01

    The 'secondary energetic neutral atom (ENA)' hypothesis for the ribbon feature observed by the Interstellar Boundary Explorer (IBEX) posits that the neutral component of the solar wind continues beyond the heliopause and charge exchanges with interstellar ions in the Outer Heliosheath (OHS). This creates pick-up ions that gyrate about the draped interstellar magnetic field (ISMF) lines at pitch angles near 90° on the locus where the ISMF lies tangential to the heliopause and perpendicular to the heliocentric radial direction. This location closely coincides with the location of the ribbon feature according to the prevailing inferences of the ISMF orientation and draping. The locally gyrating ions undergo additional charge exchange and escape as free-flying neutral atoms, many of which travel back toward the inner solar system and are imaged by IBEX as a ribbon tracing out the locus described above. For this mechanism to succeed, the pick-up ions must diffuse in pitch angle slowly enough to permit secondary charge exchange before their pitch angle distribution substantially broadens away from 90°. Previous work using linear Vlasov dispersion analysis of parallel propagating waves has suggested that the ring distribution in the OHS is highly unstable, which, if true, would make the secondary ENA hypothesis incapable of rendering the observed ribbon. In this paper, we extend this earlier work to more realistic ring distribution functions. We find that, at the low densities necessary to produce the observed IBEX ribbon via the secondary ENA hypothesis, growth rates are highly sensitive to the temperature of the beam and that even very modest temperatures of the ring beam corresponding to beam widths of <1° are sufficient to damp the self-generated waves associated with the ring beam. Thus, at least from the perspective of linear Vlasov dispersion analysis of parallel propagating waves, there is no reason to expect that the ring distributions necessary to

  5. Synchrotron FTIR microspectroscopy of Alzheimer's diseased brain tissue at the SRC beamline

    Science.gov (United States)

    Bromberg, Pam S.; Gough, Kathleen M.; Ogg, Mandy; Del Bigio, M. R.; Julian, Robert

    1999-10-01

    Alzheimer's Disease is a neurodegenerative disorder marked by progressive cognitive decline. AD presents with many of the same clinical symptoms as senile dementia, but the diagnosis of AD must be confirmed by post-mortem examination of the morphological and histopathological features of the brain. The two classical lesions found in the cortical and hippocampal regions of the brain are the (beta) -amyloid- bearing neuritic plaques and the intraneuronal neurofibrillary tangles.

  6. Automatic detection of the hippocampal region associated with Alzheimer's disease from microscopic images of mice brain

    Science.gov (United States)

    Albaidhani, Tahseen; Hawkes, Cheryl; Jassim, Sabah; Al-Assam, Hisham

    2016-05-01

    The hippocampus is the region of the brain that is primarily associated with memory and spatial navigation. It is one of the first brain regions to be damaged when a person suffers from Alzheimer's disease. Recent research in this field has focussed on the assessment of damage to different blood vessels within the hippocampal region from a high throughput brain microscopic images. The ultimate aim of our research is the creation of an automatic system to count and classify different blood vessels such as capillaries, veins, and arteries in the hippocampus region. This work should provide biologists with efficient and accurate tools in their investigation of the causes of Alzheimer's disease. Locating the boundary of the Region of Interest in the hippocampus from microscopic images of mice brain is the first essential stage towards developing such a system. This task benefits from the variation in colour channels and texture between the two sides of the hippocampus and the boundary region. Accordingly, the developed initial step of our research to locating the hippocampus edge uses a colour-based segmentation of the brain image followed by Hough transforms on the colour channel that isolate the hippocampus region. The output is then used to split the brain image into two sides of the detected section of the boundary: the inside region and the outside region. Experimental results on a sufficiently number of microscopic images demonstrate the effectiveness of the developed solution.

  7. Automatic first-break picking using the instantaneous traveltime attribute

    KAUST Repository

    Saragiotis, Christos

    2012-01-01

    Picking the first breaks is an important step in seismic processing. The large volume of the seismic data calls for automatic and objective picking. We introduce a new automatic first-break picker, which uses specifically designed time windows and an iterative procedure based on the instantaneous traveltime attribute. The method is fast as it only uses a few FFT\\'s per trace. We demonstrate the effectiveness of this automatic method by applying it on real test data.

  8. An improved contour symmetry axes extraction algorithm and its application in the location of picking points of apples

    Directory of Open Access Journals (Sweden)

    Dandan Wang

    2015-03-01

    Full Text Available The key problem for picking robots is to locate the picking points of fruit. A method based on the moment of inertia and symmetry of apples is proposed in this paper to locate the picking points of apples. Image pre-processing procedures, which are crucial to improving the accuracy of the location, were carried out to remove noise and smooth the edges of apples. The moment of inertia method has the disadvantage of high computational complexity, which should be solved, so convex hull was used to improve this problem. To verify the validity of this algorithm, a test was conducted using four types of apple images containing 107 apple targets. These images were single and unblocked apple images, single and blocked apple images, images containing adjacent apples, and apples in panoramas. The root mean square error values of these four types of apple images were 6.3, 15.0, 21.6 and 18.4, respectively, and the average location errors were 4.9°, 10.2°, 16.3° and 13.8°, respectively. Furthermore, the improved algorithm was effective in terms of average runtime, with 3.7 ms and 9.2 ms for single and unblocked and single and blocked apple images, respectively. For the other two types of apple images, the runtime was determined by the number of apples and blocked apples contained in the images. The results showed that the improved algorithm could extract symmetry axes and locate the picking points of apples more efficiently. In conclusion, the improved algorithm is feasible for extracting symmetry axes and locating the picking points of apples.

  9. An improved contour symmetry axes extraction algorithm and its application in the location of picking points of apples

    Energy Technology Data Exchange (ETDEWEB)

    Wang, D.; Song, H.; Yu, X.; Zhang, W.; Qu, W.; Xu, Y.

    2015-07-01

    The key problem for picking robots is to locate the picking points of fruit. A method based on the moment of inertia and symmetry of apples is proposed in this paper to locate the picking points of apples. Image pre-processing procedures, which are crucial to improving the accuracy of the location, were carried out to remove noise and smooth the edges of apples. The moment of inertia method has the disadvantage of high computational complexity, which should be solved, so convex hull was used to improve this problem. To verify the validity of this algorithm, a test was conducted using four types of apple images containing 107 apple targets. These images were single and unblocked apple images, single and blocked apple images, images containing adjacent apples, and apples in panoramas. The root mean square error values of these four types of apple images were 6.3, 15.0, 21.6 and 18.4, respectively, and the average location errors were 4.9°, 10.2°, 16.3° and 13.8°, respectively. Furthermore, the improved algorithm was effective in terms of average runtime, with 3.7 ms and 9.2 ms for single and unblocked and single and blocked apple images, respectively. For the other two types of apple images, the runtime was determined by the number of apples and blocked apples contained in the images. The results showed that the improved algorithm could extract symmetry axes and locate the picking points of apples more efficiently. In conclusion, the improved algorithm is feasible for extracting symmetry axes and locating the picking points of apples. (Author)

  10. Disruption of the blood-brain barrier in Parkinson's disease: curse or route to a cure?

    Science.gov (United States)

    Lee, Heyne; Pienaar, Ilse S

    2014-01-01

    The vertebrate blood-brain barrier (BBB) is critical for ensuring the maintenance of brain homeostasis, whilst protecting the brain against toxic insults. Various pathological events disrupt BBB integrity, holding several important clinical implications. In instances where the normal mechanisms controlling passage of substances into the brain are compromised, these could sensitize or even worsen endogenous pathological conditions. Recognition has grown recently that patients diagnosed with Parkinson's disease (PD) present with concurrent medical problems, including cerebrovascular lesions. However, cerebrovascular disturbances may also result from PD-related disease processes; the pathological mechanisms which could entail interaction between environment-derived and genetic factors. The current review addresses the accumulation of studies aimed at better understanding the series of processes affecting the neurovascular unit in human Parkinsonism, due in part to the BBB presenting as a formidable opponent in the effective delivery of therapeutics that have shown promise as therapeutic strategies for treating aspects of PD when tested in vitro.

  11. A fluorescence polarization based screening assay for identification of small molecule inhibitors of the PICK1 PDZ domain

    DEFF Research Database (Denmark)

    Thorsen, Thor S; Madsen, Kenneth L; Dyhring, Tino

    2011-01-01

    domain in PICK1 (protein interacting with C kinase 1). We screened 43,380 compounds for their ability to inhibit binding of an Oregon Green labeled C-terminal dopamine transporter peptide (OrG-DAT C13) to purified PICK1 in solution. The assay was highly reliable with excellent screening assay parameters...... (Z'˜0.7 and Z˜0.6). Out of ~200 compounds that reduced FP to less than 80% of the control wells, six compounds were further characterized. The apparent affinities of the compounds were determined in FP competition binding experiments and ranged from ~5.0 µM to ~193 µM. Binding to the PICK1 PDZ domain...... was confirmed for five of the compounds (CSC-03, CSC-04, CSC-43, FSC-231 and FSC-240) in a non-fluorescence based assay by their ability to inhibit pull-down of PICK1 by a C-terminal DAT GST fusion protein. CSC-03 displayed the highest apparent affinity (5.0 µM) in the FP assay, and was according...

  12. Nanoparticle technology for treatment of Parkinson's disease: the role of surface phenomena in reaching the brain.

    Science.gov (United States)

    Leyva-Gómez, Gerardo; Cortés, Hernán; Magaña, Jonathan J; Leyva-García, Norberto; Quintanar-Guerrero, David; Florán, Benjamín

    2015-07-01

    The absence of a definitive treatment for Parkinson's disease has driven the emerging investigation in the search for novel therapeutic alternatives. At present, the formulation of different drugs on nanoparticles has represented several advantages over conventional treatments. This type of multifunctional carrier, owing to its size and composition, has different interactions in biological systems that can lead to a decrease in ability to cross the blood-brain barrier. Therefore, this review focuses on the latest advances in obtaining nanoparticles for Parkinson's disease and provides an overview of technical aspects in the design of brain drug delivery of nanoparticles and an analysis of surface phenomena, a key aspect in the development of functional nanoparticles for Parkinson's disease.

  13. Picking Up the Mantle of "Expert": Assigned Roles, Assertion of Identity, and Peer Recognition within a Programming Class

    Science.gov (United States)

    Fields, Deborah; Enyedy, Noel

    2013-01-01

    Changing an established role in a classroom is difficult. It involves constructing a new set of relations within a community. In this article we investigate how students with newly developed interest and experience in programming developed outside the classroom pick up and establish their roles as experts in programming within the classroom…

  14. Factors affecting the outcome of in vitro bovine embryo production using ovum pick-up-derived cumulus oocyte complexes

    NARCIS (Netherlands)

    Merton, J.S.

    2013-01-01

    Optimization of bovine ovum pick up (OPU) followed by in vitro embryo production (IVP) has been driven by the desire of both beef and dairy cattle breeders to enhance genetic improvement. The work presented in this thesis focuses on optimizing the efficiency and efficacy of the OPU-IVP program. Atte

  15. High-Frequency Deep Brain Stimulation of the Putamen Improves Bradykinesia in Parkinson’s Disease

    Science.gov (United States)

    Montgomery, Erwin B.; Huang, He; Walker, Harrison C.; Guthrie, Barton L.; Watts, Ray L.

    2014-01-01

    Deep brain stimulation is effective for a wide range of neurological disorders; however, its mechanisms of action remain unclear. With respect to Parkinson’s disease, the existence of multiple effective targets suggests that putamen stimulation also may be effective and raises questions as to the mechanisms of action. Are there as many mechanisms of action as there are effective targets or some single or small set of mechanisms common to all effective targets? During the course of routine surgery of the globus pallidus interna in patients with Parkinson’s disease, the deep brain stimulation lead was placed in the putamen en route to the globus pallidus interna. Recordings of hand opening and closing during high-frequency and no stimulation were made. Speed of the movements, based on the amplitude and frequency of the repetitive hand movements as well as the decay in amplitude, were studied. Hand speed in 6 subjects was statistically significantly faster during active deep brain stimulation than the no-stimulation condition. There were no statistically significant differences in decay in the amplitude of hand movements. High-frequency deep brain stimulation of the putamen improves bradykinesia in a hand-opening and -closing task in patients with Parkinson’s disease. Consequently, high-frequency deep brain stimulation of virtually every structure in the basal ganglia-thalamic-cortical system improves bradykinesia. These observations, together with microelectrode recordings reported in the literature, argue that deep brain stimulation effects may be system specific and not structure specific. PMID:21714010

  16. Stock Picking and Market Timing of the Egyptian Fund Managers: Evidence from the Financial Crisis

    Directory of Open Access Journals (Sweden)

    Mohammad Elmesseary

    2014-10-01

    Full Text Available The findings of over-or-under performance of fund managers across the crisis periods are mixed. By analyzing the data of 35 Egyptian funds, this paper investigates the two skills of market timing and selectivity during-and-post the 2007-2008 financial turmoil; it also examines the comparative performance between the conventionaland Islamic mutual funds. The results show no evidence of these skills even for the overall period or for the crisis one, where Chow – test documents that there are no structural changes either for the regression line or for its coefficients across the two sub-periods. These findings are supported by using a well-known benchmark. Thus, it seems that investors cannot gain superior returns by investing in the mutual funds industry as a whole. Furthermore, the outcomes of the cross-sectional analysis report that investors cannot also attain higher returns by investing in a particular fund group against the other, implying that the ethical screening, which is adopted by the Islamic ones, and which limits their potentials of diversification does not impact their performance.JEL classification: G1; G2Keywords: Capital markets, Islamic mutual funds, performance evaluation, market timing ability,stock picking ability

  17. Microprobe PIXE analysis and EDX analysis on the brain of patients with Alzheimer`s disease

    Energy Technology Data Exchange (ETDEWEB)

    Yumoto, S. [Tokyo Univ. (Japan). Faculty of Medicine; Horino, Y.; Mokuno, Y.; Fujii, K.; Kakimi, S.; Mizutani, T.; Matsushima, H.; Ishikawa, A.

    1996-12-31

    To investigate the cause of Alzheimer`s disease (senile dementia of Alzheimer`s disease type), we examined aluminium (Al) in the brain (hippocampus) of patients with Alzheimer`s disease using heavy ion (5 MeV Si{sup 3+}) microprobe particle-induced X-ray emission (PIXE) analysis. Heavy ion microprobes (3 MeV Si{sup 2+}) have several times higher sensitivity for Al detection than 2 MeV proton microprobes. We also examined Al in the brain of these patients by energy dispersive X-ray spectroscopy (EDX). (1) Al was detected in the cell nuclei isolated from the brain of patients with Alzheimer`s disease using 5 MeV Si{sup 3+} microprobe PIXE analysis, and EDX analysis. (2) EDX analysis demonstrated high levels of Al in the nucleolus of nerve cells in frozen sections prepared from the brain of these patients. Our results support the theory that Alzheimer`s disease is caused by accumulation of Al in the nuclei of brain cells. (author)

  18. Positron Emission Tomography and Magnetic Resonance Imaging of the Brain in Fabry Disease

    DEFF Research Database (Denmark)

    Korsholm, Kirsten; Feldt-Rasmussen, Ulla; Granqvist, Henrik;

    2015-01-01

    risk of cerebrovascular disease at a young age in addition to heart and kidney failure. OBJECTIVE: The objective of this study was to assess brain function and structure in the Danish cohort of patients with Fabry disease in a prospective way using 18-fluoro-deoxyglucose (F-18 FDG) positron emission....... CONCLUSION: Our data indicated that, in patients with Fabry disease, MRI is the preferable clinical modality--if applicable--when monitoring cerebral status, as no additional major brain-pathology was detected with FDG-PET.......BACKGROUND: Fabry disease is a rare metabolic glycosphingolipid storage disease caused by deficiency of the lysosomal enzyme α-galactosidase A--leading to cellular accumulation of globotriasylceramide in different organs, vessels, tissues, and nerves. The disease is associated with an increased...

  19. Stock Picking and Market Timing of the Gulf Fund Managers: Evidence from the Financial Crisis

    Directory of Open Access Journals (Sweden)

    Mohamed Elmesseary

    2014-10-01

    Full Text Available From five Gulf countries over the 2007-2012 period, this paper offers a comprehensive investigation for these managerial skills during and after the Financial Crisis (FC of 2007- 2008; it also inspects the relative differences in performance between equity conventional mutual funds (CMFS and Islamic ones. The results show no evidence of over-or-under performance for the fund managers due to these two skills, where there are no structuralchanges for the regression line across the two sub-periods, but it reveals the superiority of equity CMFS performance in Kuwait in particular along the overall period. Thus, it seemsthat if the investors cannot gain superior returns by investing in the Gulf mutual funds on general, they may attain a comparative advantage by investing in the conventional fundsagainst the Islamic ones especially in Kuwait. It also implies that the ethical screening, which is adopted by the Islamic funds of Kuwait, already limits their diversification  opportunities and then adversely affects their performance.JEL classification: G1; G2Keywords: Capital markets, Islamic mutual funds, performance evaluation, market timing ability, stock picking ability

  20. Analysis of Pick-Up Development in Punching

    DEFF Research Database (Denmark)

    Olsson, David Dam; Bay, Niels; Andreasen, Jan Lasson

    2002-01-01

    The development of pick-up of work piece material on the punch surface with increasing number of strokes during punching of stainless steel sheet is investigated applying Scanning Electron Microscopy (SEM), 3D roughness mapping and measurements of the backstroke force. It is found that pick......-up on the punch stem develops gradually backwards from the tip of the punch with increasing number of strokes saturating at a certain level while the radial build-up in the case of dry friction conditions continues until the clearance between the punch and die has been filled up. The rate of pick......-up is significantly smaller in case of lubrication and may be very low if an efficient boundary lubricant is applied. Good correlation between the pick-up development and the backstroke force is found....

  1. Automatic picking of the first arrival event using the unwrapped-phase of the Fourier transformed wavefield

    KAUST Repository

    Choi, Yun Seok

    2011-01-01

    First-arrival picking has long suffered from cycle skipping, especially when the first arrival is contaminated with noise or have experienced complex near surface phenomena. We propose a new algorithm for automatic picking of first arrivals using an approach based on unwrapping the phase. We unwrap the phase by taking the derivative of the Fourier-transformed wavefield with respect to the angular frequency and isolate its amplitude component. To do so, we first apply a damping function to the seismic trace, calculate the derivative of the wavefield with respect to the angular frequency, divide the derivative of wavefield by the wavefield itself, and finally take its imaginary part. We compare our derivative approach to the logarithmic one and show that the derivative approach does not suffer from the phase wrapping or cycle-skipping effects. Numerical examples show that our automatic picking algorithm gives convergent and reliable results for the noise-free synthetic data and noisy field data. © 2011 Society of Exploration Geophysicists.

  2. Acceptance-Enhanced Behavior Therapy (AEBT) for Trichotillomania and Chronic Skin Picking: Exploring the Effects of Component Sequencing

    Science.gov (United States)

    Flessner, Christopher A.; Busch, Andrew M.; Heideman, Paul W.; Woods, Douglas W.

    2008-01-01

    This pilot study examined the utility of acceptance-enhanced behavior therapy (AEBT) for trichotillomania (TTM) and chronic skin picking (CSP) and the impact of altering treatment sequence on overall treatment efficacy. Participants referred to a TTM and CSP specialty clinic were assessed by an independent evaluator within separate, nonconcurrent,…

  3. MRI of the brain and craniocervical junction in Morquio`s disease

    Energy Technology Data Exchange (ETDEWEB)

    Hughes, D.G. [Department of Radiology, Hope Hospital, Stott Lane, Salford, Manchester M6 8HD (United Kingdom); Chadderton, R.D. [Department of Neurosurgery, Hope Hospital, Salford, Manchester M6 8HD (United Kingdom); Cowie, R.A. [Department of Neurosurgery, Hope Hospital, Salford, Manchester M6 8HD (United Kingdom); Wraith, J.E. [Willink Biochemical Genetics Unit, Royal Manchester Children`s Hospital, Manchester M27 4HA (United Kingdom); Jenkins, J.P.R. [Department of Clinical Radiology, Manchester Royal Infirmary, Oxford Road, Manchester (United Kingdom)

    1997-05-01

    We reviewed MRI of the brain and cervical spine in 11 patients with Morquio`s disease. No abnormality was seen in the brain. The odontoid peg was abnormal in all patients, with varying degrees of cord compression due to an anterior soft tissue mass and indentation by the posterior arch of the atlas. The degree of cord compression was more marked than suggested by the symptoms and signs. We recommend MRI of the cervical spine in children with Morquio`s disease before the development of neurological symptoms, to optimise the timing and type of surgical intervention. (orig.). With 5 figs., 2 tabs.

  4. The Potential of the Human Connectome as a Biomarker of Brain Disease

    Directory of Open Access Journals (Sweden)

    Marcus eKaiser

    2013-08-01

    Full Text Available The human connectome at the level of fiber tracts between brain regions has been shown to differ in patients with brain disorders compared to healthy control groups. Nonetheless, there is a potentially large number of different network organizations for individual patients that could lead to cognitive deficits prohibiting correct diagnosis. Therefore changes that can distinguish groups might not be sufficient to diagnose the disease that an individual patient suffers from and to indicate the best treatment option for that patient. We describe the challenges introduced by the large variability of connectomes within healthy subjects and patients and outline three common strategies to use connectomes as biomarkers of brain diseases. Finally, we propose a fourth option in using models of simulated brain activity (the dynamic connectome based on structural connectivity rather than the structure (connectome itself as a biomarker of disease. Dynamic connectomes, in addition to currently used structural, functional, or effective connectivity, could be an important future biomarker for clinical applications.

  5. The ACRV Picking Benchmark (APB): A Robotic Shelf Picking Benchmark to Foster Reproducible Research

    OpenAIRE

    Leitner, Jürgen; Tow, Adam W.; Dean, Jake E.; Suenderhauf, Niko; Durham, Joseph W.; Cooper, Matthew; Eich, Markus; Lehnert, Christopher; Mangels, Ruben; McCool, Christopher; Kujala, Peter; Nicholson, Lachlan; Van Pham, Trung; Sergeant, James; Wu, Liao

    2016-01-01

    Robotic challenges like the Amazon Picking Challenge (APC) or the DARPA Challenges are an established and important way to drive scientific progress. They make research comparable on a well-defined benchmark with equal test conditions for all participants. However, such challenge events occur only occasionally, are limited to a small number of contestants, and the test conditions are very difficult to replicate after the main event. We present a new physical benchmark challenge for robotic pi...

  6. Role of ACAT1-positive late endosomes in macrophages: cholesterol metabolism and therapeutic applications for Niemann-Pick disease type C.

    Science.gov (United States)

    Sakashita, Naomi; Lei, XiaoFeng; Kamikawa, Masashi; Nishitsuji, Kazuchika

    2014-01-01

    Macrophages in hyperlipidemic conditions accumulate cholesterol esters and develop into foamy transformed macrophages. During this transformation, macrophages demonstrate endoplasmic reticulum fragmentation and consequently produce acyl coenzyme A: cholesterol acyltransferase 1 (ACAT1)-positive late endosomes (ACAT1-LE). ACAT1-LE-positive macrophages effectively esterify modified or native low-density lipoprotein-derived free cholesterol, which results in efficient cholesterol esterification as well as atherosclerotic plaque formation. These macrophages show significant cholesterol ester formation even when free cholesterol egress from late endosomes is impaired, which indicates that free cholesterol is esterified at ACAT1-LE. Genetic blockade of cholesterol egress from late endosomes causes Niemann-Pick disease type C (NPC), an inherited lysosomal storage disease with progressive neurodegeneration. Induction of ACAT1-LE in macrophages with the NPC phenotype led to significant recovery of cholesterol esterification. In addition, in vivo ACAT1-LE induction significantly extended the lifespan of mice with the NPC phenotype. Thus, ACAT1-LE not only regulates intracellular cholesterol metabolism but also ameliorates NPC pathophysiology.

  7. Diagnostic Usefulness of 3 Tesla MRI of the Brain for Cushing Disease in a Child

    OpenAIRE

    Ono, Erina; Ozawa, Ayako; Matoba, Kaori; Motoki, Takanori; Tajima, Asako; Miyata, Ichiro; Ito, Junko; Inoshita, Naoko; Yamada, Syozo; Ida, Hiroyuki

    2011-01-01

    It is sometimes difficult to confirm the location of a microadenoma in Cushing disease. Recently, we experienced an 11-yr-old female case of Cushing disease with hyperprolactinemia. She was referred to our hospital because of decrease of height velocity with body weight gain. On admission, she had typical symptoms of Cushing syndrome. Although no pituitary microadenomas were detected on 1.5 Tesla MRI of the brain, endocrinological examinations including IPS and CS sampling were consistent wit...

  8. Network science and the human brain: Using graph theory to understand the brain and one of its hubs, the amygdala, in health and disease.

    Science.gov (United States)

    Mears, David; Pollard, Harvey B

    2016-06-01

    Over the past 15 years, the emerging field of network science has revealed the key features of brain networks, which include small-world topology, the presence of highly connected hubs, and hierarchical modularity. The value of network studies of the brain is underscored by the range of network alterations that have been identified in neurological and psychiatric disorders, including epilepsy, depression, Alzheimer's disease, schizophrenia, and many others. Here we briefly summarize the concepts of graph theory that are used to quantify network properties and describe common experimental approaches for analysis of brain networks of structural and functional connectivity. These range from tract tracing to functional magnetic resonance imaging, diffusion tensor imaging, electroencephalography, and magnetoencephalography. We then summarize the major findings from the application of graph theory to nervous systems ranging from Caenorhabditis elegans to more complex primate brains, including man. Focusing, then, on studies involving the amygdala, a brain region that has attracted intense interest as a center for emotional processing, fear, and motivation, we discuss the features of the amygdala in brain networks for fear conditioning and emotional perception. Finally, to highlight the utility of graph theory for studying dysfunction of the amygdala in mental illness, we review data with regard to changes in the hub properties of the amygdala in brain networks of patients with depression. We suggest that network studies of the human brain may serve to focus attention on regions and connections that act as principal drivers and controllers of brain function in health and disease.

  9. Effect of Transcranial Brain Stimulation for the Treatment of Alzheimer Disease: A Review

    OpenAIRE

    Raffaele Nardone; Jürgen Bergmann; Monica Christova; Francesca Caleri; Frediano Tezzon; Gunther Ladurner; Eugen Trinka; Stefan Golaszewski

    2011-01-01

    Available pharmacological treatments for Alzheimer disease (AD) have limited effectiveness, are expensive, and sometimes induce side effects. Therefore, alternative or complementary adjuvant therapeutic strategies have gained increasing attention. The development of novel noninvasive methods of brain stimulation has increased the interest in neuromodulatory techniques as potential therapeutic tool for cognitive rehabilitation in AD. In particular, repetitive transcranial magnetic stimulat...

  10. 3.3 Å structure of Niemann–Pick C1 protein reveals insights into the function of the C-terminal luminal domain in cholesterol transport

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xiaochun; Lu, Feiran; Trinh, Michael N.; Schmiege, Philip; Seemann, Joachim; Wang, Jiawei; Blobel, Günter

    2017-08-07

    Niemann–Pick C1 (NPC1) and NPC2 proteins are indispensable for the export of LDL-derived cholesterol from late endosomes. Mutations in these proteins result in Niemann–Pick type C disease, a lysosomal storage disease. Despite recent reports of the NPC1 structure depicting its overall architecture, the function of its C-terminal luminal domain (CTD) remains poorly understood even though 45% of NPC disease-causing mutations are in this domain. Here, we report a crystal structure at 3.3 Å resolution of NPC1* (residues 314–1,278), which—in contrast to previous lower resolution structures—features the entire CTD well resolved. Notably, all eight cysteines of the CTD form four disulfide bonds, one of which (C909–C914) enforces a specific loop that in turn mediates an interaction with a loop of the N-terminal domain (NTD). Importantly, this loop and its interaction with the NTD were not observed in any previous structures due to the lower resolution. Our mutagenesis experiments highlight the physiological relevance of the CTD–NTD interaction, which might function to keep the NTD in the proper orientation for receiving cholesterol from NPC2. Additionally, this structure allows us to more precisely map all of the disease-causing mutations, allowing future molecular insights into the pathogenesis of NPC disease.

  11. Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway [version 2; referees: 2 approved, 2 approved with reservations

    Directory of Open Access Journals (Sweden)

    Paul Fineran

    2017-06-01

    Full Text Available Background. Tuberculosis remains a major global health concern. The ability to prevent phagosome-lysosome fusion is a key mechanism by which intracellular mycobacteria, including Mycobacterium tuberculosis, achieve long-term persistence within host cells. The mechanisms underpinning this key intracellular pro-survival strategy remain incompletely understood. Host macrophages infected with intracellular mycobacteria share phenotypic similarities with cells taken from patients suffering from Niemann-Pick Disease Type C (NPC, a rare lysosomal storage disease in which endocytic trafficking defects and lipid accumulation within the lysosome lead to cell dysfunction and cell death. We investigated whether these shared phenotypes reflected an underlying mechanistic connection between mycobacterial intracellular persistence and the host cell pathway dysfunctional in NPC.  Methods. The induction of NPC phenotypes in macrophages from wild-type mice or obtained from healthy human donors was assessed via infection with mycobacteria and subsequent measurement of lipid levels and intracellular calcium homeostasis. The effect of NPC therapeutics on intracellular mycobacterial load was also assessed.  Results. Macrophages infected with intracellular mycobacteria phenocopied NPC cells, exhibiting accumulation of multiple lipid types, reduced lysosomal Ca 2+ levels, and defects in intracellular trafficking. These NPC phenotypes could also be induced using only lipids/glycomycolates from the mycobacterial cell wall. These data suggest that intracellular mycobacteria inhibit the NPC pathway, likely via inhibition of the NPC1 protein, and subsequently induce altered acidic store Ca 2+ homeostasis. Reduced lysosomal calcium levels may provide a mechanistic explanation for the reduced levels of phagosome-lysosome fusion in mycobacterial infection. Treatments capable of correcting defects in NPC mutant cells via modulation of host cell calcium were of benefit in

  12. Microprobe PIXE analysis of aluminium in the brains of patients with Alzheimer's disease

    Science.gov (United States)

    Yumoto, S.; Horino, Y.; Mokuno, Y.; Kakimi, S.; Fujii, K.

    1996-04-01

    To investigate the cause of Alzheimer's disease (senile dementia), we examined aluminium (Al) in the rat liver, and in the brains (hippocampus) of Alzheimer's disease patients using heavy ion (5 MeV Si 3+) microprobe and proton (2 MeV) microprobe PIXE analysis. Heavy ion microprobes (3 MeV Si 2+) have several time's higher sensitivity for Al detection than 2 MeV proton microprobes. (1) In the rat liver, Al was detected in the cell nuclei, where phosphorus (P) was most densely distributed. (2) We also demonstrated Al in the cell nuclei isolated from Alzheimer's disease brains using heavy ion (5 MeV Si 3+) microprobes. Al spectra were detected using 2 MeV proton microprobes in the isolated brain cell nuclei. Al could not be observed in areas where P was present in relatively small amounts, or was absent. Our results indicate that Alzheimer's disease is caused by irreversible accumulation of Al in the nuclei of brain cells.

  13. Niemann-Pick C1 affects the gene delivery efficacy of degradable polymeric nanoparticles.

    Science.gov (United States)

    Eltoukhy, Ahmed A; Sahay, Gaurav; Cunningham, James M; Anderson, Daniel G

    2014-08-26

    Despite intensive research effort, the rational design of improved nanoparticulate drug carriers remains challenging, in part due to a limited understanding of the determinants of nanoparticle entry and transport in target cells. Recent studies have shown that Niemann-Pick C1 (NPC1), the lysosome membrane protein that mediates trafficking of cholesterol in cells, is involved in the endosomal escape and subsequent infection caused by filoviruses, and that its absence promotes the retention and efficacy of lipid nanoparticles encapsulating siRNA. Here, we report that NPC1 deficiency results in dramatic reduction in internalization and transfection efficiency mediated by degradable cationic gene delivery polymers, poly(β-amino ester)s (PBAEs). PBAEs utilized cholesterol and dynamin-dependent endocytosis pathways, and these were found to be heavily compromised in NPC1-deficient cells. In contrast, the absence of NPC1 had minor effects on DNA uptake mediated by polyethylenimine or Lipofectamine 2000. Strikingly, stable overexpression of human NPC1 in chinese hamster ovary cells was associated with enhanced gene uptake (3-fold) and transfection (10-fold) by PBAEs. These findings reveal a role of NPC1 in the regulation of endocytic mechanisms affecting nanoparticle trafficking. We hypothesize that in-depth understanding sites of entry and endosomal escape may lead to highly efficient nanotechnologies for drug delivery.

  14. Magnetic characterization of ferrite materials used in the ELENA magnetic pick-ups

    CERN Document Server

    Favia, Giorgia; CERN. Geneva. ATS Department

    2015-01-01

    The CERN Extra Low ENergy Antiproton (ELENA) Ring is a new synchrotron designed for cooling and further decelerating the 5.3 MeV antiprotons delivered by the CERN Antiproton Decelerator (AD). The ring is equipped with two magnetic pick-ups used for longitudinal beam diagnostics. These ultra low noise AC beam transformers consist of a doubly shielded, ferrite-loaded cavity with a ceramic gap in the beam pipe, a secondary winding to which an ultralow noise JFET head amplifier with feedback is connected. The JFET head amplifier is mounted close to the cavity and the AC beam transformers are covering respectively the 0.003-3MHz frequency range (low frequency type) and 0.8-30 MHz frequency range (high frequency type) [1]. The ferrite material used to couple primary and secondary in the beam transformer, has a key impact in the noise characteristics of the amplifier. For this reason a magnetic characterization of the selected ferrite rings has been carried out and is reported in the following.

  15. A Derangement of the Brain Wound Healing Process May Cause Some Cases of Alzheimer’s Disease

    OpenAIRE

    Lehrer, Steven; Rheinstein, Peter H.

    2016-01-01

    A derangement of brain wound healing may cause some cases of Alzheimer’s disease. Wound healing, a highly complex process, has four stages: hemostasis, inflammation, repair, and remodeling. Hemostasis and the initial phases of inflammation in brain tissue are typical of all vascularized tissue, such as skin. However, distinct differences arise in brain tissue during the later stages of inflammation, repair, and remodeling, and closely parallel the changes of Alzheimer’s disease. Our hypothesi...

  16. The levels of soluble versus insoluble brain Abeta distinguish Alzheimer's disease from normal and pathologic aging.

    Science.gov (United States)

    Wang, J; Dickson, D W; Trojanowski, J Q; Lee, V M

    1999-08-01

    The abundance and solubility of Abeta peptides are critical determinants of amyloidosis in Alzheimer's disease (AD). Hence, we compared levels of total soluble, insoluble, and total Abeta1-40 and Abeta1-42 in AD brains with those in age-matched normal and pathologic aging brains using a sandwich enzyme-linked immunosorbent assay (ELISA). Since the measurement of Abeta1-40 and Abeta1-42 depends critically on the specificity of the monoclonal antibodies used in the sandwich ELISA, we first demonstrated that each assay is specific for Abeta1-40 or Abeta1-42 and the levels of these peptides are not affected by the amyloid precursor protein in the brain extracts. Thus, this sandwich ELISA enabled us to show that the average levels of total cortical soluble and insoluble Abeta1-40 and Abeta1-42 were highest in AD, lowest in normal aging, and intermediate in pathologic aging. Remarkably, the average levels of insoluble Abeta1-40 were increased 20-fold while the average levels of insoluble Abeta1-42 were increased only 2-fold in the AD brains compared to pathologic aging brains. Further, the soluble pools of Abeta1-40 and Abeta1-42 were the largest fractions of total Abeta in the normal brain (i.e., 50 and 23%, respectively), but they were the smallest in the AD brain (i.e., 2.7 and 0.7%, respectively) and intermediate (i.e., 8 and 0.8%, respectively) in pathologic aging brains. Thus, our data suggest that pathologic aging is a transition state between normal aging and AD. More importantly, our findings imply that a progressive shift of brain Abeta1-40 and Abeta1-42 from soluble to insoluble pools and a profound increase in the levels of insoluble Abeta1-40 plays mechanistic roles in the onset and/or progression of AD.

  17. Somatic expansion of the Huntington's disease CAG repeat in the brain is associated with an earlier age of disease onset.

    Science.gov (United States)

    Swami, Meera; Hendricks, Audrey E; Gillis, Tammy; Massood, Tiffany; Mysore, Jayalakshmi; Myers, Richard H; Wheeler, Vanessa C

    2009-08-15

    The age of onset of Huntington's disease (HD) is determined primarily by the length of the HD CAG repeat mutation, but is also influenced by other modifying factors. Delineating these modifiers is a critical step towards developing validated therapeutic targets in HD patients. The HD CAG repeat is somatically unstable, undergoing progressive length increases over time, particularly in brain regions that are the targets of neurodegeneration. Here, we have explored the hypothesis that somatic instability of the HD CAG repeat is itself a modifier of disease. Using small-pool PCR, we quantified somatic instability in the cortex region of the brain from a cohort of HD individuals exhibiting phenotypic extremes of young and old disease onset as predicted by the length of their constitutive HD CAG repeat lengths. After accounting for constitutive repeat length, somatic instability was found to be a significant predictor of onset age, with larger repeat length gains associated with earlier disease onset. These data are consistent with the hypothesis that somatic HD CAG repeat length expansions in target tissues contribute to the HD pathogenic process, and support pursuing factors that modify somatic instability as viable therapeutic targets.

  18. Effect of Acupuncture on the Auditory Evoked Brain Stem Potential in Parkinson's Disease

    Institute of Scientific and Technical Information of China (English)

    王玲玲; 何崇; 刘跃光; 朱莉莉

    2002-01-01

    @@ Under the auditory evoked brain stem potential (ABP) examination, the latent period of V wave and the intermittent periods of III-V peak and I-V peak were significantly shortened in Parkinson's disease patients of the treatment group (N=29) after acupuncture treatment. The difference of cumulative scores in Webster's scale was also decreased in correlation analysis. The increase of dopamine in the brain and the excitability of the dopamine neurons may contribute to the therapeutic effects, in TCM terms, of subduing the pathogenic wind and tranquilizing the mind.

  19. Effect of acupuncture on the auditory evoked brain stem potential in Parkinson's disease.

    Science.gov (United States)

    Wang, Lingling; He, Chong; Liu, Yueguang; Zhu, Lili

    2002-03-01

    Under the auditory evoked brain stem potential (ABP) examination, the latent period of V wave and the intermittent periods of III-V peak and I-V peak were significantly shortened in Parkinson's disease patients of the treatment group (N = 29) after acupuncture treatment. The difference of cumulative scores in Webster's scale was also decreased in correlation analysis. The increase of dopamine in the brain and the excitability of the dopamine neurons may contribute to the therapeutic effects, in TCM terms, of subduing the pathogenic wind and tranquilizing the mind.

  20. The role of ceramides in selected brain pathologies: ischemia/hypoxia, Alzheimer disease

    Directory of Open Access Journals (Sweden)

    Halina Car

    2012-05-01

    Full Text Available  Ceramides, members of the sphingolipids, are produced in the central nervous system by de novo synthesis, sphingomyelin hydrolysis or the so-called salvage pathway. They are engaged in formation of lipid rafts that are essential in regulation and transduction of signals coming to the cell from the environment. Ceramides represent the major transmitters of the sphingomyelin pathway of signal transduction. They regulate proliferation, differentiation, programmed cell death and senescence. Ceramide overexpression, mainly as a result of sphingomyelin hydrolysis, is a component of brain damage caused by ischemia and early reperfusion. Their high concentrations induce mitochondria-dependent neuronal apoptosis, exacerbate the synthesis of reactive oxygen species, decrease ATP level, inhibit electron transport and release cytochrome c, and activate caspase-3. Reduced ceramide accumulation in the brain, dependent mainly on ceramide synthesized de novo, may exert an anti-apoptotic effect after pre-conditioning. The increase of ceramide content in the brain was observed in Alzheimer disease and its animal models. Enhanced ceramide concentration in this pathology is an effect of their synthesis de novo or sphingomyelin metabolism augmentation. The ceramide pathway can directly stimulate biochemical changes in the brain noted at the onset of disease: tau overphosphorylation and β-amyloid peptide accumulation. The higher concentration of ceramides in blood in the pre-clinical phase of the illness may mark early brain changes.

  1. [The role of ceramides in selected brain pathologies: ischemia/hypoxia, Alzheimer disease].

    Science.gov (United States)

    Car, Halina; Zendzian-Piotrowska, Małgorzata; Fiedorowicz, Anna; Prokopiuk, Sławomir; Sadowska, Anna; Kurek, Krzysztof

    2012-05-30

     Ceramides, members of the sphingolipids, are produced in the central nervous system by de novo synthesis, sphingomyelin hydrolysis or the so-called salvage pathway. They are engaged in formation of lipid rafts that are essential in regulation and transduction of signals coming to the cell from the environment. Ceramides represent the major transmitters of the sphingomyelin pathway of signal transduction. They regulate proliferation, differentiation, programmed cell death and senescence. Ceramide overexpression, mainly as a result of sphingomyelin hydrolysis, is a component of brain damage caused by ischemia and early reperfusion. Their high concentrations induce mitochondria-dependent neuronal apoptosis, exacerbate the synthesis of reactive oxygen species, decrease ATP level, inhibit electron transport and release cytochrome c, and activate caspase-3. Reduced ceramide accumulation in the brain, dependent mainly on ceramide synthesized de novo, may exert an anti-apoptotic effect after pre-conditioning. The increase of ceramide content in the brain was observed in Alzheimer disease and its animal models. Enhanced ceramide concentration in this pathology is an effect of their synthesis de novo or sphingomyelin metabolism augmentation. The ceramide pathway can directly stimulate biochemical changes in the brain noted at the onset of disease: tau overphosphorylation and β-amyloid peptide accumulation. The higher concentration of ceramides in blood in the pre-clinical phase of the illness may mark early brain changes.

  2. Determining Number of Zones in a Pick-and-pack Orderpicking System

    NARCIS (Netherlands)

    T. Le-Duc (Tho); M.B.M. de Koster (René)

    2005-01-01

    textabstractIn this study we consider a pick-to-pack orderpicking system, in which batches of orders are picked simultaneously from different(work) zones by a group of order pickers. After picking, the orders are transported by a conveyor to the next station for packing. Our aim is to determine the

  3. Picking the right transition strategy.

    Science.gov (United States)

    Watkins, Michael D

    2009-01-01

    Leaders in transition reflexively rely on the skills and strategies that worked for them in the past. That's a mistake, says Watkins, whose research shows that executives moving into new roles must gain a deep understanding of the situation at hand and adapt to it. To help them accurately assess their organizations and tailor their strategies and styles accordingly, he developed the STARS framework. "STARS" is an acronym for the five common situations leaders move into: start-up, turnaround, accelerated growth, realignment, and sustaining success. Thus, the model outlines the challenges of launching a venture or project; saving a business or initiative that's in serious trouble; dealing with rapid expansion; reenergizing a once-leading company that's now facing problems; and following in the footsteps of a highly regarded leader with a strong legacy of success. Executives can accelerate their immersion in new roles by following certain fundamental principles: Organize to learn about the business, establish A-item priorities, define strategic intent, quickly build the leadership team, secure early wins, and create supportive alliances across the company. But the way those principles should be applied depends very much on the business situation, which the STARS framework can help leaders analyze. Turnarounds and realignments present especially distinct leadership challenges that call for particular transition strategies. Regardless of the business situation, leaders must figure out which things need to happen--perhaps a jump in market share or an expansion into different markets--for their business to achieve its goals. And they must determine which leadership style best fits the new culture they're joining. Armed with such clarity, executives can design effective plans to manage their organizations and themselves.

  4. Pick and Alzheimer diseases: a rare comorbidity presenting as corticobasal syndrome.

    Science.gov (United States)

    Rusina, Robert; Pazdera, Ladislav; Kulišťák, Petr; Vyšata, Oldřich; Matěj, Radoslav

    2013-12-01

    We describe a patient with corticobasal syndrome in whom neuropathological examination on autopsy revealed Pick and Alzheimer diseases in comorbidity. Corticobasal degeneration is a tauopathy usually associated with asymmetric parkinsonism, parietal lobe involvement, and cognitive impairment. Corticobasal syndrome is the clinical presentation of corticobasal degeneration without neuropathological confirmation. A 66-year-old right-handed man slowly developed speech difficulties, right-hand clumsiness, and forgetfulness. His speech apraxia progressed to mutism with preserved comprehension, and his clumsiness progressed to severe apraxia involving both hands. He developed behavioral changes and severe amnesia. All of these features were consistent with corticobasal syndrome. His loss of episodic, verbal, and visuospatial memory suggested Alzheimer disease; however, beyond his frontotemporal neuropsychological profile, he had few symptoms characteristic of frontal lobe dementia. Magnetic resonance imaging scans showed worsening temporal, frontal, and parietal atrophy, predominant in the left hemisphere. Neuropathological examination at autopsy revealed abundant neuritic plaques and neurofibrillary tangles consistent with fully developed Alzheimer disease, as well as numerous intraneuronal Pick bodies in the frontotemporal lobes. Our findings confirm the importance of clinical and neuropathological correlations in patients with atypical neurodegenerative dementias.

  5. The Italian Seismic Bulletin: strategies, revised pickings and locations of the central Italy seismic sequence

    Directory of Open Access Journals (Sweden)

    Alessandro Marchetti

    2016-12-01

    Full Text Available The central Italy seismic sequence, started with the Mw = 6.0 Amatrice earthquake on August 24th 2016, is the first significant one after the Italian Seismic Bulletin (BSI changed its analysis strategies in 2015. These new strategies consist on the release of the BSI every four months, the review of the events with ML ≥ 1.5 and the priority on the review of events with ML ≥ 3.5. Furthermore, in the last year we improved the bulletin tools and made possible the analysis of all the stations whose data are stored in the European Integrated Data Archive (EIDA. The new procedures and software utilities allowed, during the first month of 2016 emergency, to integrate, in the Bulletin, the temporary stations installed by the emergency group SISMIKO, both in real–time transmission and in stand-alone recording. In the early days of the sequence many of the BSI analysts were engaged in the monitoring room shifts, nevertheless at the end of August all events occurred in those days with ML ≥ 4 were analyzed; the largest event recovered and localized is a ML = 4.5 event immediately following the main shock. In September 2016, 83 events with ML ≥ 3.5 were analyzed and re-checked, the number of pickings greatly improved. The focal mechanism of the main shock was evaluated using first motion polarities, and compared with the available Time Domain Moment Tensors and Regional Centroid Moment Tensor. The first eight hours of the day on August 24th, the most critical for the INGV surveillance room, were carefully analyzed: the number of located events increased from 133 to 408. The magnitude of completeness, after the analysis of the BSI, has dropped significantly from about 3.5 to 2.7. The mainshock focal mechanism and the relative locations of the first 8 hours’ aftershocks give clues on the initial fault activation. The seismic sequence in November 2016 is still ongoing; it included a mainshock of Mw = 6.5 on October 30th and 3 events of magnitude

  6. Picking up the mantle of “expert”: Assigned roles, assertion of identity, and peer recognition within a programming class

    OpenAIRE

    Fields, Deborah A.; Enyedy, N

    2013-01-01

    Changing an established role in a classroom is difficult. It involves constructing a new set of relations within a community. In this article we investigate how students with newly developed interest and experience in programming developed outside the classroom pick up and establish their roles as experts in programming within the classroom community. More specifically, we focus on how two 11-year-old software designers shifted their established roles in their classroom to gain status as expe...

  7. Cholesterol lowering effects of mono-lactose-appended β-cyclodextrin in Niemann–Pick type C disease-like HepG2 cells

    Science.gov (United States)

    Motoyama, Keiichi; Hirai, Yumi; Nishiyama, Rena; Maeda, Yuki; Higashi, Taishi; Ishitsuka, Yoichi; Kondo, Yuki; Irie, Tetsumi; Era, Takumi

    2015-01-01

    Summary The Niemann–Pick type C disease (NPC) is one of inherited lysosomal storage disorders, emerges the accumulation of unesterified cholesterol in endolysosomes. Currently, 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) has been applied for the treatment of NPC. HP-β-CyD improved hepatosplenomegaly in NPC patients, however, a high dose of HP-β-CyD was necessary. Therefore, the decrease in dose by actively targeted-β-CyD to hepatocytes is expected. In the present study, to deliver β-CyD selectively to hepatocytes, we newly fabricated mono-lactose-appended β-CyD (Lac-β-CyD) and evaluated its cholesterol lowering effects in NPC-like HepG2 cells, cholesterol accumulated HepG2 cells induced by treatment with U18666A. Lac-β-CyD (degree of substitution of lactose (DSL) 1) significantly decreased the intracellular cholesterol content in a concentration-dependent manner. TRITC-Lac-β-CyD was associated with NPC-like HepG2 cells higher than TRITC-β-CyD. In addition, TRITC-Lac-β-CyD was partially localized with endolysosomes after endocytosis. Thus, Lac-β-CyD entered NPC-like HepG2 cells via asialoglycoprotein receptor (ASGPR)-mediated endocytosis and decreased the accumulation of intracellular cholesterol in NPC-like HepG2 cells. These results suggest that Lac-β-CyD may have the potential as a drug for the treatment of hepatosplenomegaly in NPC disease. PMID:26664628

  8. Cholesterol lowering effects of mono-lactose-appended β-cyclodextrin in Niemann–Pick type C disease-like HepG2 cells

    Directory of Open Access Journals (Sweden)

    Keiichi Motoyama

    2015-11-01

    Full Text Available The Niemann–Pick type C disease (NPC is one of inherited lysosomal storage disorders, emerges the accumulation of unesterified cholesterol in endolysosomes. Currently, 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD has been applied for the treatment of NPC. HP-β-CyD improved hepatosplenomegaly in NPC patients, however, a high dose of HP-β-CyD was necessary. Therefore, the decrease in dose by actively targeted-β-CyD to hepatocytes is expected. In the present study, to deliver β-CyD selectively to hepatocytes, we newly fabricated mono-lactose-appended β-CyD (Lac-β-CyD and evaluated its cholesterol lowering effects in NPC-like HepG2 cells, cholesterol accumulated HepG2 cells induced by treatment with U18666A. Lac-β-CyD (degree of substitution of lactose (DSL 1 significantly decreased the intracellular cholesterol content in a concentration-dependent manner. TRITC-Lac-β-CyD was associated with NPC-like HepG2 cells higher than TRITC-β-CyD. In addition, TRITC-Lac-β-CyD was partially localized with endolysosomes after endocytosis. Thus, Lac-β-CyD entered NPC-like HepG2 cells via asialoglycoprotein receptor (ASGPR-mediated endocytosis and decreased the accumulation of intracellular cholesterol in NPC-like HepG2 cells. These results suggest that Lac-β-CyD may have the potential as a drug for the treatment of hepatosplenomegaly in NPC disease.

  9. Quantitative comparison of the efficacy of various compounds in lowering intracellular cholesterol levels in Niemann-Pick type C fibroblasts.

    Directory of Open Access Journals (Sweden)

    Zachary T Wehrmann

    Full Text Available Niemann-Pick Type C disease (NPC is a lethal, autosomal recessive disorder caused by mutations in the NPC1 and NPC2 cholesterol transport proteins. NPC's hallmark symptoms include an accumulation of unesterified cholesterol and other lipids in the late endosomal and lysosomal cellular compartments, causing progressive neurodegeneration and death. Although the age of onset may vary in those affected, NPC most often manifests in juveniles, and is usually fatal before adolescence. In this study, we investigated the effects of various drugs, many of which modify the epigenetic control of NPC1/NPC2 gene expression, in lowering the otherwise harmful elevated intracellular cholesterol levels in NPC cells. Our studies utilized a previously described image analysis technique, which allowed us to make quantitative comparisons of the efficacy of these drugs in lowering cholesterol levels in a common NPC1 mutant model. Of the drugs analyzed, several that have been previously studied (vorinostat, panobinostat, and β-cyclodextrin significantly lowered the relative amount of unesterified cellular cholesterol, consistent with earlier observations. In addition, a novel potential treatment, rapamycin, likewise alleviated the NPC phenotype. We also studied combinations of effective compounds with β-cyclodextrin; the addition of β-cyclodextrin significantly enhanced the cholesterol-lowering activity of vorinostat and panobinostat, but had mixed effects with rapamycin. Collectively, these results may provide a basis for the eventual development of improved NPC therapies.

  10. Quantification, morphology, and viability of equine preantral follicles obtained via the Biopsy Pick-Up method.

    Science.gov (United States)

    Haag, K T; Magalhães-Padilha, D M; Fonseca, G R; Wischral, A; Gastal, M O; King, S S; Jones, K L; Figueiredo, J R; Gastal, E L

    2013-03-01

    A Biopsy Pick-Up (BPU) method was tested to determine the feasibility of retrieving preantral follicles from mare ovaries in vivo. A total of 33 ovarian biopsy procedures were performed on 18 mares during the breeding season. Mares were 5 to 21 years old and biopsies were performed during the estrous and/or diestrous phase, as confirmed by transrectal ultrasonography. Follicles were mechanically isolated using a tissue chopper, counted, and classified as normal or abnormal and primordial or primary. Viability of isolated follicles was determined by Trypan Blue dye. A total of 256 biopsy attempts were made resulting in 185 successful tissue sample collections (72% success rate). The mean weight of ovarian tissue collected per procedure was 25.0 ± 1.6 mg. Overall, 620 preantral follicles were collected and isolated (95% primordial and 5% primary). The mean (±SEM) number of follicles isolated per biopsy procedure was 18.8 ± 1.9. Primordial and primary follicles had an average diameter of 31.3 ± 6.2 and 41.1 ± 6.6 μm, respectively. Viability rate was higher (P 0.05) according to phase of the estrous cycle. Younger mares (5 to 7 years old) had more (P 0.05) by any biopsy procedure, and there were no adverse effects on cyclicity or general reproductive health. In conclusion, the BPU method provided large numbers of normal and viable preantral follicles for the study of early follicular development in mares. The BPU method might be used in the future to obtain preantral follicles for in vitro culture to enable the use of numerous oocytes present within the equine ovary. This could allow for the preservation of genetic material or large-scale embryo production.

  11. Cerebral hemodynamics of the aging brain: risk of Alzheimer disease and benefit of aerobic exercise

    Directory of Open Access Journals (Sweden)

    Takashi eTarumi

    2014-01-01

    Full Text Available Alzheimer disease (AD and cerebrovascular disease often coexist with advanced age. Mounting evidence indicates that the presence of vascular disease and its risk factors increase the risk of AD, suggesting a potential overlap of the underlying pathophysiological mechanisms. In particular, atherosclerosis, endothelial dysfunction, and stiffening of central elastic arteries have been shown to associate with AD. Currently, there are no effective treatments for the cure and prevention of AD. Vascular risk factors are modifiable via either pharmacological or lifestyle intervention. In this regard, habitual aerobic exercise is increasingly recognized for its benefits on brain structure and cognitive function. Considering the well-established benefits of regular aerobic exercise on vascular health, exercise-related improvements in brain structure and cognitive function may be mediated by vascular adaptations. In this review, we will present the current evidence for the physiological mechanisms by which vascular health alters the structural and functional integrity of the aging brain and how improvements in vascular health, via regular aerobic exercise, potentially benefits cognitive function.

  12. Cerebral hemodynamics of the aging brain: risk of Alzheimer disease and benefit of aerobic exercise.

    Science.gov (United States)

    Tarumi, Takashi; Zhang, Rong

    2014-01-01

    Alzheimer disease (AD) and cerebrovascular disease often coexist with advanced age. Mounting evidence indicates that the presence of vascular disease and its risk factors increase the risk of AD, suggesting a potential overlap of the underlying pathophysiological mechanisms. In particular, atherosclerosis, endothelial dysfunction, and stiffening of central elastic arteries have been shown to associate with AD. Currently, there are no effective treatments for the cure and prevention of AD. Vascular risk factors are modifiable via either pharmacological or lifestyle intervention. In this regard, habitual aerobic exercise is increasingly recognized for its benefits on brain structure and cognitive function. Considering the well-established benefits of regular aerobic exercise on vascular health, exercise-related improvements in brain structure and cognitive function may be mediated by vascular adaptations. In this review, we will present the current evidence for the physiological mechanisms by which vascular health alters the structural and functional integrity of the aging brain and how improvements in vascular health, via regular aerobic exercise, potentially benefits cognitive function.

  13. Variation within the Huntington's disease gene influences normal brain structure.

    Directory of Open Access Journals (Sweden)

    Mark Mühlau

    Full Text Available Genetics of the variability of normal and diseased brain structure largely remains to be elucidated. Expansions of certain trinucleotide repeats cause neurodegenerative disorders of which Huntington's disease constitutes the most common example. Here, we test the hypothesis that variation within the IT15 gene on chromosome 4, whose expansion causes Huntington's disease, influences normal human brain structure. In 278 normal subjects, we determined CAG repeat length within the IT15 gene on chromosome 4 and analyzed high-resolution T1-weighted magnetic resonance images by the use of voxel-based morphometry. We found an increase of GM with increasing long CAG repeat and its interaction with age within the pallidum, which is involved in Huntington's disease. Our study demonstrates that a certain trinucleotide repeat influences normal brain structure in humans. This result may have important implications for the understanding of both the healthy and diseased brain.

  14. MRI of brain disease in veterinary patients part 1: Basic principles and congenital brain disorders.

    Science.gov (United States)

    Hecht, Silke; Adams, William H

    2010-01-01

    Magnetic resonance imaging (MRI) is increasingly being used in the diagnosis of central nervous system disorders in veterinary patients and is quickly becoming the imaging modality of choice in evaluation of brain and intracranial disease. This article provides an overview of the basic principles of MRI, a description of sequences and their applications in brain imaging, and an approach to interpretation of brain MRI. A detailed discussion of imaging findings in general intracranial disorders including hydrocephalus, vasogenic edema, brain herniation, and seizure-associated changes, and the MR diagnosis of congenital brain disorders is provided. MRI evaluation of acquired brain disorders is described in a second companion article.

  15. The Effect of Disease-Modifying Drugs on Brain Atrophy in Relapsing-Remitting Multiple Sclerosis: A Meta-Analysis

    OpenAIRE

    Pierre Branger; Jean-Jacques Parienti; Maria Pia Sormani; Gilles Defer

    2016-01-01

    Background The quantification of brain atrophy in relapsing-remitting multiple sclerosis (RRMS) may serve as a marker of disease progression and treatment response. We compared the association between first-line (FL) or second-line (SL) disease-modifying drugs (DMDs) and brain volume changes over time in RRMS. Materials and Methods We reviewed clinical trials in RRMS between January 1, 1995 and June 1, 2014 that assessed the effect of DMDs and reported data on brain atrophy in Medline, Embase...

  16. To Pass or Not to Pass: Modeling the Movement and Affordance Dynamics of a Pick and Place Task

    Directory of Open Access Journals (Sweden)

    Maurice Lamb

    2017-06-01

    Full Text Available Humans commonly engage in tasks that require or are made more efficient by coordinating with other humans. In this paper we introduce a task dynamics approach for modeling multi-agent interaction and decision making in a pick and place task where an agent must move an object from one location to another and decide whether to act alone or with a partner. Our aims were to identify and model (1 the affordance related dynamics that define an actor's choice to move an object alone or to pass it to their co-actor and (2 the trajectory dynamics of an actor's hand movements when moving to grasp, relocate, or pass the object. Using a virtual reality pick and place task, we demonstrate that both the decision to pass or not pass an object and the movement trajectories of the participants can be characterized in terms of a behavioral dynamics model. Simulations suggest that the proposed behavioral dynamics model exhibits features observed in human participants including hysteresis in decision making, non-straight line trajectories, and non-constant velocity profiles. The proposed model highlights how the same low-dimensional behavioral dynamics can operate to constrain multiple (and often nested levels of human activity and suggests that knowledge of what, when, where and how to move or act during pick and place behavior may be defined by these low dimensional task dynamics and, thus, can emerge spontaneously and in real-time with little a priori planning.

  17. The neurological effects of ghrelin in brain diseases: Beyond metabolic functions.

    Science.gov (United States)

    Jiao, Qian; Du, Xixun; Li, Yong; Gong, Bing; Shi, Limin; Tang, Tingting; Jiang, Hong

    2017-02-01

    Ghrelin, a peptide released by the stomach that plays a major role in regulating energy metabolism, has recently been shown to have effects on neurobiological behaviors. Ghrelin enhances neuronal survival by reducing apoptosis, alleviating inflammation and oxidative stress, and accordingly improving mitochondrial function. Ghrelin also stimulates the proliferation, differentiation and migration of neural stem/progenitor cells (NS/PCs). Additionally, the ghrelin is benefit for the recovery of memory, mood and cognitive dysfunction after stroke or traumatic brain injury. Because of its neuroprotective and neurogenic roles, ghrelin may be used as a therapeutic agent in the brain to combat neurodegenerative disease. In this review, we highlight the pre-clinical evidence and the proposed mechanisms underlying the role of ghrelin in physiological and pathological brain function.

  18. Diagnostic usefulness of 3 tesla MRI of the brain for cushing disease in a child.

    Science.gov (United States)

    Ono, Erina; Ozawa, Ayako; Matoba, Kaori; Motoki, Takanori; Tajima, Asako; Miyata, Ichiro; Ito, Junko; Inoshita, Naoko; Yamada, Syozo; Ida, Hiroyuki

    2011-10-01

    It is sometimes difficult to confirm the location of a microadenoma in Cushing disease. Recently, we experienced an 11-yr-old female case of Cushing disease with hyperprolactinemia. She was referred to our hospital because of decrease of height velocity with body weight gain. On admission, she had typical symptoms of Cushing syndrome. Although no pituitary microadenomas were detected on 1.5 Tesla MRI of the brain, endocrinological examinations including IPS and CS sampling were consistent with Cushing disease with hyperprolactinemia. Oral administration of methyrapone instead of neurosurgery was started after discharge, but subsequent 3 Tesla MRI of the brain clearly demonstrated a 3-mm less-enhanced lesion in the left side of the pituitary gland. Finally, transsphenoidal surgery was performed, and a 3.5-mm left-sided microadenoma was resected. Compared with 1.5 Tesla MRI, 3 Tesla MRI offers the advantage of a higher signal to noise ratio (SNR), which provides higher resolution and proper image quality. Therefore, 3 Tesla MRI is a very useful tool to localize microadenomas in Cushing disease in children as well as in adults. It will be the first choice of radiological examinations in suspected cases of Cushing disease.

  19. Dictionary of cotton: Picking & ginning

    Science.gov (United States)

    Cotton is an essential commodity for textiles and has long been an important item of trade in the world’s economy. Cotton is currently grown in over 100 countries by an estimated 100 producers. The basic unit of the cotton trade is the cotton bale which consists of approximately 500 pounds of raw c...

  20. Microbiome-Derived Lipopolysaccharide Enriched in the Perinuclear Region of Alzheimer’s Disease Brain

    Directory of Open Access Journals (Sweden)

    Yuhai Zhao

    2017-09-01

    Full Text Available Abundant clinical, epidemiological, imaging, genetic, molecular, and pathophysiological data together indicate that there occur an unusual inflammatory reaction and a disruption of the innate-immune signaling system in Alzheimer’s disease (AD brain. Despite many years of intense study, the origin and molecular mechanics of these AD-relevant pathogenic signals are still not well understood. Here, we provide evidence that an intensely pro-inflammatory bacterial lipopolysaccharide (LPS, part of a complex mixture of pro-inflammatory neurotoxins arising from abundant Gram-negative bacilli of the human gastrointestinal (GI tract, are abundant in AD-affected brain neocortex and hippocampus. For the first time, we provide evidence that LPS immunohistochemical signals appear to aggregate in clumps in the parenchyma in control brains, and in AD, about 75% of anti-LPS signals were clustered around the periphery of DAPI-stained nuclei. As LPS is an abundant secretory product of Gram-negative bacilli resident in the human GI-tract, these observations suggest (i that a major source of pro-inflammatory signals in AD brain may originate from internally derived noxious exudates of the GI-tract microbiome; (ii that due to aging, vascular deficits or degenerative disease these neurotoxic molecules may “leak” into the systemic circulation, cerebral vasculature, and on into the brain; and (iii that this internal source of microbiome-derived neurotoxins may play a particularly strong role in shaping the human immune system and contributing to neural degeneration, particularly in the aging CNS. This “Perspectives” paper will further highlight some very recent developments that implicate GI-tract microbiome-derived LPS as an important contributor to inflammatory-neurodegeneration in the AD brain.

  1. Loss of neprilysin alters protein expression in the brain of Alzheimer's disease model mice.

    Science.gov (United States)

    Nilsson, Per; Loganathan, Krishnapriya; Sekiguchi, Misaki; Winblad, Bengt; Iwata, Nobuhisa; Saido, Takaomi C; Tjernberg, Lars O

    2015-10-01

    Alzheimer's disease (AD) is a neurodegenerative disease displaying extracellular plaques formed by the neurotoxic amyloid β-peptide (Aβ), and intracellular neurofibrillary tangles consisting of protein tau. However, how these pathologies relate to the massive neuronal death that occurs in AD brains remain elusive. Neprilysin is the major Aβ-degrading enzyme and a lack thereof increases Aβ levels in the brain twofold. To identify altered protein expression levels induced by increased Aβ levels, we performed a proteomic analysis of the brain of the AD mouse model APPsw and compared it to that of APPsw mice lacking neprilysin. To this end we established an LC-MS/MS method to analyze brain homogenate, using an (18) O-labeled internal standard to accurately quantify the protein levels. To distinguish between alterations in protein levels caused by increased Aβ levels and those induced by neprilysin deficiency independently of Aβ, the brain proteome of neprilysin deficient APPsw mice was also compared to that of neprilysin deficient mice. By this approach we identified approximately 600 proteins and the levels of 300 of these were quantified. Pathway analysis showed that many of the proteins with altered expression were involved in neurological disorders, and that tau, presenilin and APP were key regulators in the identified networks. The data have been deposited to the ProteomeXchange Consortium with identifiers PXD000968 and PXD001786 (http://proteomecentral.proteomexchange.org/dataset/PXD000968 and (http://proteomecentral.proteomexchange.org/dataset/PXD001786). Interestingly, the levels of several proteins, including some not previously reported to be linked to AD, were associated with increased Aβ levels. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. RELATION OF EFFECTIVENESS IN PICK N’ ROLL APPLICATION BETWEEN THE NATIONAL GREEK TEAM OF AND ITS OPPONENTS DURING THE MEN’S WORLD BASKETBALL CHAMPIONSHIP OF 2006

    Directory of Open Access Journals (Sweden)

    POLYKRATIS MATTHEOS

    2010-12-01

    Full Text Available The purpose of this study was to register and analyse the alterations of Pick n’ Roll effectiveness between the national team of Greece and its opponents during the Mundobasket 2006 in Japan. The sampleconsisted of the 9 games that took place between them during the Mundobasket 2006. In the 1528 cases which were registered, we analyzed all the Pick n’ Rolls according to 26 pre-estimated factors (form, court area, players combination, way of attack, attack player, shot area, way of defending Pick n’ Roll, to reveal all the comparingdifferences in the Pick n’ Roll application and the relation of Pick n’ Roll effectiveness and productivity. The statistical analysis package SPSS was used for the statistical analysis of the data, correlation analysis, classification (cluster and Crosstabs command with χ2 (Chi-square test. The results of the Crosstab analysis,revealed that there are statistically significant differences between the Greek and the other National Teams according to the use of Pick n’ Roll move in the offensive set plays and also according the offence efficacy and offence productivity. The Correlation analysis revealed extremely high interrelation between offence efficacyand shot area (p= -0,209(** , α=0,01, and as far as offence productivity is concerned extremely high interrelation revealed first of all with the final shot player and secondly with the shot area ( p= -0,2877(**α=0,01. According to the Cluster analysis the results revealed that as far as both offence efficacy and offence roductivity are concerned the maximum similarity is modulating in relation with the Pick n’ Roll form.

  3. Up-regulated production and activation of the complement system in Alzheimer's disease brain.

    Science.gov (United States)

    Yasojima, K; Schwab, C; McGeer, E G; McGeer, P L

    1999-03-01

    We used reverse transcriptase-polymerase chain reaction and Western blotting techniques to measure the levels of complement mRNAs and their protein products in Alzheimer's disease (AD) brain compared with non-AD brain. mRNAs for C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, and C9 were detected in the 11 regions of brain that were investigated. The mRNA levels were markedly up-regulated in affected areas of AD brain. In the entorhinal cortex, hippocampus, and midtemporal gyrus, which had dense accumulations of plaques and tangles, C1q mRNA was increased 11- to 80-fold over control levels, and C9 mRNA 10- to 27-fold. These levels were substantially higher than in the livers of the same cases. Western blot analysis of AD hippocampus established the presence of all of the native complement proteins as well as their activation products C4d, C3d, and the membrane attack complex. These data indicate that high levels of complement are being produced in affected areas of AD brain, that full activation of the classical complement pathway is continuously taking place, and that this activation may be contributing significantly to AD pathology.

  4. DNA methylation of Alzheimer disease and tauopathy-related genes in postmortem brain.

    Science.gov (United States)

    Barrachina, Marta; Ferrer, Isidre

    2009-08-01

    DNA methylation occurs predominantly at cytosines that precede guanines in dinucleotide CpG sites; it is one of the most important mechanisms for epigenetic DNA regulation during normal development and for aberrant DNA in cancer. To determine the feasibility of DNA methylation studies in the postmortem human brain, we evaluated brain samples with variable postmortem artificially increased delays up to 48 hours. DNA methylation was analyzed in selected regions of MAPT, APP, and PSEN1 in the frontal cortex and hippocampus of controls (n=26) and those with Alzheimer disease at Stages I to II (n=17); Alzheimer disease at Stages III to IV (n=15); Alzheimer disease at Stages V to VI (n=12); argyrophilic grain disease (n=10); frontotemporal lobar degeneration linked to tau mutations (n=6); frontotemporal lobar degeneration with ubiquitin-immunoreactive inclusions (n=4); frontotemporal lobar degeneration with motor neuron disease (n=3); Pick disease (n=3); Parkinson disease (n=8); dementia with Lewy bodies, pure form (n=5); and dementia with Lewy bodies, common form (n=15). UCHL1 (ubiquitin carboxyl-terminal hydrolase 1 gene) was analyzed in the frontal cortex of controls and those with Parkinson disease and related synucleinopathies. DNA methylation sites were very reproducible in every case. No differences in the percentage of CpG methylation were found between control and disease samples or among the different pathological entities in any region analyzed. Because small changes in methylation of DNA promoters in vulnerable cells might have not been detected in total homogenates, however, these results should be interpreted with caution, particularly as they relate to chronic degenerative diseases in which small modifications may be sufficient to modulate disease progression.

  5. The role of vitamin D in the brain and related neurological diseases

    Directory of Open Access Journals (Sweden)

    Mustafa Yılmaz

    2013-09-01

    Full Text Available Vitamin D is a steroid hormone that is produced photochemicallyin epidermis. It is known that vitamin D involvedin the regulation of bone mineralization and calcium-phosphorus balance. However, in recent studies havesuggested that vitamin D may have a significant impactin the development of the cell proliferation, differentiation,neurotransmission, neuroplasticity, neurotropic andneuroprotective effects in central nervous system (CNS.For the reason of the effects, it can be considered as aneurosteroid was reported. It was discussed that the levelof vitamin D may be associated to neurodegenerativediseases such as Parkinson’s disease, Alzheimer’s disease,multiple sclerosis (MS, amyotrophic lateral sclerosis(ALS. The role of vitamin D and the mechanisms ofthese diseases will be discussed in the review. J Clin ExpInvest 2013; 4 (3: 411-415Key words: Vitamin D, neurosteroid, brain, neurologicdiseases

  6. The treatment of Parkinson’s disease with deep brain stimulation:current issues

    Institute of Scientific and Technical Information of China (English)

    Alexia-Sabine Moldovan; Stefan Jun Groiss; Saskia Elben; Martin Südmeyer; Alfons Schnitzler; Lars Wojtecki

    2015-01-01

    Deep brain stimulation has become a well-established symptomatic treatment for Parkinson’s disease during the last 25 years. Besides improving motor symptoms and long-term motor com-plications, positive effects on patients’ mobility, activities of daily living, emotional well-being and health-related quality of life have been recognized. Apart from that, numerous clinical trials analyzed effects on non-motor symptoms and side effects of deep brain stimulation. Several technical issues and stimulation paradigms have been and are still being developed to optimize the therapeutic effects, minimize the side effects and facilitate handling. This review summarizes current therapeutic issues,i.e., patient and target selection, surgical procedure and programming paradigms. In addition it focuses on neuropsychological effects and side effects of deep brain stimulation.

  7. Automated detection of brain atrophy patterns based on MRI for the prediction of Alzheimer's disease

    Science.gov (United States)

    Plant, Claudia; Teipel, Stefan J.; Oswald, Annahita; Böhm, Christian; Meindl, Thomas; Mourao-Miranda, Janaina; Bokde, Arun W.; Hampel, Harald; Ewers, Michael

    2010-01-01

    Subjects with mild cognitive impairment (MCI) have an increased risk to develop Alzheimer's disease (AD). Voxel-based MRI studies have demonstrated that widely distributed cortical and subcortical brain areas show atrophic changes in MCI, preceding the onset of AD-type dementia. Here we developed a novel data mining framework in combination with three different classifiers including support vector machine (SVM), Bayes statistics, and voting feature intervals (VFI) to derive a quantitative index of pattern matching for the prediction of the conversion from MCI to AD. MRI was collected in 32 AD patients, 24 MCI subjects and 18 healthy controls (HC). Nine out of 24 MCI subjects converted to AD after an average follow-up interval of 2.5 years. Using feature selection algorithms, brain regions showing the highest accuracy for the discrimination between AD and HC were identified, reaching a classification accuracy of up to 92%. The extracted AD clusters were used as a search region to extract those brain areas that are predictive of conversion to AD within MCI subjects. The most predictive brain areas included the anterior cingulate gyrus and orbitofrontal cortex. The best prediction accuracy, which was cross-validated via train-and-test, was 75% for the prediction of the conversion from MCI to AD. The present results suggest that novel multivariate methods of pattern matching reach a clinically relevant accuracy for the a priori prediction of the progression from MCI to AD. PMID:19961938

  8. Impact of small vessel disease in the brain on gait and balance

    Science.gov (United States)

    Pinter, Daniela; Ritchie, Stuart J.; Doubal, Fergus; Gattringer, Thomas; Morris, Zoe; Bastin, Mark E.; del C. Valdés Hernández, Maria; Royle, Natalie A.; Corley, Janie; Muñoz Maniega, Susana; Pattie, Alison; Dickie, David A.; Staals, Julie; Gow, Alan J.; Starr, John M.; Deary, Ian J.; Enzinger, Christian; Fazekas, Franz; Wardlaw, Joanna

    2017-01-01

    Gait and balance impairment is highly prevalent in older people. We aimed to assess whether and how single markers of small vessel disease (SVD) or a combination thereof explain gait and balance function in the elderly. We analysed 678 community-dwelling healthy subjects from the Lothian Birth Cohort 1936 at the age of 71–74 years who had undergone comprehensive risk factor assessment, gait and balance assessment as well as brain MRI. We investigated the impact of individual SVD markers (white matter hyperintensity – WMH, microbleeds, lacunes, enlarged perivascular spaces, brain atrophy) as seen on structural brain MRI and of a global SVD score on the patients’ performance. A regression model revealed that age, sex, and hypertension significantly explained gait speed. Among SVD markers white matter hyperintensity (WMH) score or volume were additional significant and independent predictors of gait speed in the regression model. A similar association was seen with the global SVD score. Our study confirms a negative impact of SVD-related morphologic brain changes on gait speed in addition to age, sex and hypertension independent from brain atrophy. The presence of WMH seems to be the major driving force for SVD on gait impairment in healthy elderly subjects. PMID:28134332

  9. Impact of small vessel disease in the brain on gait and balance.

    Science.gov (United States)

    Pinter, Daniela; Ritchie, Stuart J; Doubal, Fergus; Gattringer, Thomas; Morris, Zoe; Bastin, Mark E; Del C Valdés Hernández, Maria; Royle, Natalie A; Corley, Janie; Muñoz Maniega, Susana; Pattie, Alison; Dickie, David A; Staals, Julie; Gow, Alan J; Starr, John M; Deary, Ian J; Enzinger, Christian; Fazekas, Franz; Wardlaw, Joanna

    2017-01-30

    Gait and balance impairment is highly prevalent in older people. We aimed to assess whether and how single markers of small vessel disease (SVD) or a combination thereof explain gait and balance function in the elderly. We analysed 678 community-dwelling healthy subjects from the Lothian Birth Cohort 1936 at the age of 71-74 years who had undergone comprehensive risk factor assessment, gait and balance assessment as well as brain MRI. We investigated the impact of individual SVD markers (white matter hyperintensity - WMH, microbleeds, lacunes, enlarged perivascular spaces, brain atrophy) as seen on structural brain MRI and of a global SVD score on the patients' performance. A regression model revealed that age, sex, and hypertension significantly explained gait speed. Among SVD markers white matter hyperintensity (WMH) score or volume were additional significant and independent predictors of gait speed in the regression model. A similar association was seen with the global SVD score. Our study confirms a negative impact of SVD-related morphologic brain changes on gait speed in addition to age, sex and hypertension independent from brain atrophy. The presence of WMH seems to be the major driving force for SVD on gait impairment in healthy elderly subjects.

  10. An analysis of the topography, severity, potential sources of reinforcement, and treatments utilized for skin picking in Prader-Willi syndrome.

    Science.gov (United States)

    Hustyi, Kristin M; Hammond, Jennifer L; Rezvani, Ava B; Hall, Scott S

    2013-09-01

    We examined the topography, severity, potential sources of reinforcement, and treatments utilized for skin-picking behavior shown by individuals with Prader-Willi syndrome (PWS). The parents of 55 individuals with PWS, aged 6-25 years, were interviewed about their child's skin-picking behavior using the Self-Injury Trauma Scale (SIT; Iwata, Pace, Kissel, Nau, & Farber, 1990) and the Functional Analysis Screening Tool (FAST; Iwata, DeLeon, & Roscoe, 2013). Results showed that skin picking in PWS occurred on the extremities (i.e., arms, legs, hands, and feet) for 75% of cases and resulted in bodily injury for 83.7% cases. Skin picking posed a high risk to the individual concerned in 41.8% of cases. Automatic sensory stimulation was identified as a potential source of reinforcement in the majority of cases (52.7%) followed by access to social attention or preferred items (36.4%). Treatments utilized by parents were primarily behavioral strategies (56.3%) followed by basic first aid (54.5%). There were no differences in the topography, severity or potential source of reinforcement between those with the deletion (DEL) subtype and those with the uniparental disomy (UPD) subtype. Taken together, these data indicate that skin picking shown by individuals with PWS is a particularly severe and intractable behavioral issue that may be maintained by (as yet unknown) sensory consequences. Further studies to identify the determinants of skin picking in PWS are therefore needed. The implications for interventions are discussed.

  11. High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

    Science.gov (United States)

    Gabandé-Rodríguez, E; Boya, P; Labrador, V; Dotti, C G; Ledesma, M D

    2014-01-01

    Niemann Pick disease type A (NPA), which is caused by loss of function mutations in the acid sphingomyelinase (ASM) gene, is a lysosomal storage disorder leading to neurodegeneration. Yet, lysosomal dysfunction and its consequences in the disease are poorly characterized. Here we show that undegraded molecules build up in neurons of acid sphingomyelinase knockout mice and in fibroblasts from NPA patients in which autophagolysosomes accumulate. The latter is not due to alterations in autophagy initiation or autophagosome–lysosome fusion but because of inefficient autophago–lysosomal clearance. This, in turn, can be explained by lysosomal membrane permeabilization leading to cytosolic release of Cathepsin B. High sphingomyelin (SM) levels account for these effects as they can be induced in control cells on addition of the lipid and reverted on SM-lowering strategies in ASM-deficient cells. These results unveil a relevant role for SM in autophagy modulation and characterize autophagy anomalies in NPA, opening new perspectives for therapeutic interventions. PMID:24488099

  12. Pick-up and impact of flexible bodies

    CERN Document Server

    Singh, H

    2016-01-01

    Picking up, laying down, colliding, rolling, and peeling are partial-contact interactions involving moving discontinuities. We examine the balances of momentum and energy across a moving discontinuity in a string, with allowance for injection or dissipation by singular supplies. We split the energy dissipation according to its invariance properties, discuss analogies with systems of particles and connections with the literature on shocks and phase transition fronts in various bodies, and derive a compatibility relation between supplies of momentum and translation-invariant energy. For a moving contact discontinuity between a string and a smooth rigid plane in the presence of gravity, we find a surprising asymmetry between the processes of picking up and laying down, such that steady-state kinks in geometry and associated jumps in tension are not admissible during pick-up. This prediction is consistent with experimental observations. We briefly discuss related problems including the falling folded chain, peeli...

  13. MR imaging of the brain: findings in asymptomatic patients with thalassemia intermedia and sickle cell-thalassemia disease.

    Science.gov (United States)

    Manfrè, L; Giarratano, E; Maggio, A; Banco, A; Vaccaro, G; Lagalla, R

    1999-12-01

    The purpose of this study was to evaluate the spectrum of MR findings of the brain in asymptomatic patients affected with thalassemia intermedia or sickle cell-thalassemia disease to prevent brain damage by identifying patients at risk for stroke so that transfusional or pharmacologic treatment could be implemented. Forty-one asymptomatic patients who were younger than 50 years and were affected by minor hemoglobinopathies underwent MR imaging of the brain. Ischemic lesions were classified as small, medium, or large and as single or multifocal. Atrophic changes were graded subjectively as mild, moderate, or severe. A grade of brain damage was assigned to every patient. The frequency and severity of brain damage were correlated with the number of sickle-cell crises per year, hemoglobin level, sickling hemoglobin level, platelet count, sex, and age. Of the patients with thalassemia intermedia, 37.5% showed asymptomatic brain damage, and 52% of those with sickle cell-thalassemia disease showed asymptomatic brain damage. In the thalassemia intermedia group, atrophy was always mild and ischemic lesions were generally small (25%) and single (25%). Among the patients with sickle cell-thalassemia disease, 24% had small, 16% had medium, and 12% had large ischemic lesions. Multifocal lesions were twice as common in the patients with sickle cell-thalassemia disease (20%) as in those with thalassemia intermedia (12.5%). Only in the patients with thalassemia intermedia did the frequency of brain damage increase with age. Moreover, brain damage inversely correlated with hemoglobin level in patients with thalassemia intermedia but not in those with sickle cell-thalassemia disease. Brain damage was more severe in patients with sickle cell-thalassemia disease who had more crises per year. This study suggests that patients with thalassemia intermedia and those with sickle cell-thalassemia disease may have asymptomatic brain damage. Our results suggest that MR imaging is useful in

  14. Conceptual Design of a Microwave Confocal Resonator Pick-up

    CERN Document Server

    Caspers, Friedhelm; Lofnes, T; Syratchev, I V; Ziemann, Volker

    2004-01-01

    A confocal resonator may be used as a pick-up for frequencies in the multi-GHz region. In this report we present the design, by analytical and numerical methods, of such a device. Furthermore, we discuss engineering issues, such as the damping of unwanted modes, shielding of image fields and manufacturing tolerances. Such a device can be used both as a pick-up and a kicker where the actual structure is several wavelengths away from the beam in the transverse direction. It is intended for highly relativistic beams and does not require changing the particle trajectory, as opposed to a diagnostic wiggler.

  15. Construction and Analysis of Weighted Brain Networks from SICE for the Study of Alzheimer's Disease

    Science.gov (United States)

    Munilla, Jorge; Ortiz, Andrés; Górriz, Juan M.; Ramírez, Javier; Weiner, Michael W.

    2017-01-01

    Alzheimer's Disease (AD) is the most common neurodegenerative disease in elderly people, and current drugs, unfortunately, do not represent yet a cure but only slow down its progression. This is explained, at least in part, because the understanding of the neurodegenerative process is still incomplete, being sometimes mistaken, particularly at the first steps of the illness, with the natural aging process. A better identification of how the functional activity deteriorates is thus crucial to develop new and more effective treatments. Sparse inverse covariance estimates (SICE) have been recently employed for deriving functional connectivity patterns from Positron Emission Tomography (PET) of brains affected by Alzheimer's Disease. SICE, unlike the traditional covariance methods, allows to analyze the interdependencies between brain regions factoring out the influence of others. To analyze the effects of the illness, connectivity patterns of brains affected by AD are compared with those obtained for control groups. These comparisons are, however, carried out for binary (undirected and unweighted) adjacency matrices with the same number of arcs. Additionally, the effect of the number of subjects employed or the validity of the regularization parameter used to compute the SICE have been not hitherto analyzed. In this paper, we delve into the construction of connectivity patterns from PET using SICE. In particular, we describe the effect that the number of subjects employed has on the results and identify, based on the reconstruction error of linear regression systems, a range of valid values for the regularization parameter. The amount of arcs is also proved as a discriminant value, and we show that it is possible to pass from unweighted (binary) to weighted adjacency matrices, where the weight of a connection corresponding to the existence of a relationship between two brain areas can be correlated to the persistence of this relationship when computed for different

  16. Development of Nonviral Vectors Targeting the Brain as a Therapeutic Approach For Parkinson's Disease and Other Brain Disorders.

    Science.gov (United States)

    Javed, Hayate; Menon, Sindhu A; Al-Mansoori, Karima M; Al-Wandi, Abdelmojib; Majbour, Nour K; Ardah, Mustafa T; Varghese, Shiji; Vaikath, Nishant N; Haque, M Emdadul; Azzouz, Mimoun; El-Agnaf, Omar Ma

    2016-04-01

    Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by tremor, rigidity, bradykinesia, and postural instability, for which there is no effective treatment available till date. Here, we report the development of nonviral vectors specific for neuronal cells that can deliver short interfering RNA (siRNA) against the α-synuclein gene (SNCA), and prevent PD-like symptoms both in vitro and in vivo. These vectors not only help siRNA duplexes cross the blood-brain barrier in mice, but also stabilize these siRNAs leading to a sustainable 60-90% knockdown of α-synuclein protein. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine rapidly develop PD-like symptoms which were significantly alleviated when SNCA was knocked down using our vectors. Together, our data not only confirm the central role of α-synuclein in the onset of PD, but also provide a proof of principle that these nonviral vectors can be used as novel tools to design effective strategies to combat central nervous system diseases.

  17. Evaluation of peak-picking algorithms for protein mass spectrometry.

    Science.gov (United States)

    Bauer, Chris; Cramer, Rainer; Schuchhardt, Johannes

    2011-01-01

    Peak picking is an early key step in MS data analysis. We compare three commonly used approaches to peak picking and discuss their merits by means of statistical analysis. Methods investigated encompass signal-to-noise ratio, continuous wavelet transform, and a correlation-based approach using a Gaussian template. Functionality of the three methods is illustrated and discussed in a practical context using a mass spectral data set created with MALDI-TOF technology. Sensitivity and specificity are investigated using a manually defined reference set of peaks. As an additional criterion, the robustness of the three methods is assessed by a perturbation analysis and illustrated using ROC curves.

  18. Mitochondrial ferritin in the regulation of brain iron homeostasis and neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Guofen eGao

    2014-02-01

    Full Text Available Mitochondrial ferritin (FtMt is a novel iron-storage protein in mitochondria. Evidences have shown that FtMt is structurally and functionally similar to the cytosolic H-chain ferritin. It protects mitochondria from iron-induced oxidative damage presumably through sequestration of potentially harmful excess free iron. It also participates in the regulation of iron distribution between cytosol and mitochondrial contents. Unlike the ubiquitously expressed H-ferritin, FtMt is mainly expressed in testis and brain, which suggests its tissue-related roles. FtMt is involved in pathogenesis of neurodegenerative diseases, as its increased expression has been observed in Alzheimer’s disease, restless legs syndrome and Friedreich’s ataxia. Studies from our laboratory showed that in Alzheimer’s disease, FtMt overexpression attenuated the β-amyloid induced neurotoxicity, which on the other hand increased significantly when FtMt expression was knocked down. It is also found that, by maintaining mitochondrial iron homeostasis, FtMt could prevent 6-hydroxydopamine induced dopaminergic cell damage in Parkinson’s disease. These recent findings on FtMt regarding its functions in regulation of brain iron homeostasis and its protective role in pathogenesis of neurodegenerative diseases are summarized and reviewed.

  19. Haloperidol augmentation of fluvoxamine in skin picking disorder: a case report

    Directory of Open Access Journals (Sweden)

    Luca Maria

    2012-07-01

    Full Text Available Abstract Introduction Compulsive skin picking, being part of the broader category of impulse control disorders, is considered a residual diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. It is characterized by excessive scratching or picking of normal skin, or skin with minor surface irregularities, and occurs in 2% of patients attending dermatology clinics. Despite the clinical relevance of this disorder, no clear guidelines are available yet; clinical management is, therefore, compromised and the day-to-day clinical practice is burdened by difficulties. Studies on selective serotonin reuptake inhibitors and anti-epileptic drugs have provided limited results. The association between anti-depressants and anti-epileptics has been found to be beneficial in some impulse control disorders, but in skin picking no previous studies have been conducted on this pharmacological approach. There are very few reports on the efficacy of anti-psychotics in skin picking. Case presentation The therapeutic path described in this case report produced good results for a 59-year-old Caucasian woman. The first therapeutic approach, with fluvoxamine and oxcarbazepine was partially effective; then, the suspension of oxcarbazepine and haloperidol augmentation of fluvoxamine were adopted. After 10 weeks, a significant improvement of the disease was observed: the clinical picture and the associated symptoms were nearly solved. Conclusions To the best of our knowledge, this is the first article reporting the association of fluvoxamine and haloperidol in skin picking disorder. It might be useful to perform further research regarding the treatment of skin picking disorder: in clinical practice, several variables might limit the choice of certain drugs. Therefore, it would be useful for the clinician to be aware of other therapeutic options.

  20. [Skin-picking disorder].

    Science.gov (United States)

    Niemeier, V; Peters, E; Gieler, U

    2015-10-01

    The disorder is characterized by compulsive repetitive skin-picking (SP), resulting in skin lesions. The patients must have undertaken several attempts to reduce or stop SP. The disorder must have led to clinically significant limitations in social, professional, or other important areas of life. The symptoms cannot be better explained by another emotional disorder or any other dermatological disease. In the new DSM-V, skin-picking disorder has been included in the diagnostic system as an independent disorder and describes the self-injury of the skin by picking or scratching with an underlying emotional disorder. SP is classified among the impulse-control disorders and is, thus, differentiated from compulsive disorders as such. There are often emotional comorbidities. In cases of pronounced psychosocial limitation, interdisciplinary cooperation with a psychotherapist and/or psychiatrist is indicated.

  1. Lipidomics of human brain aging and Alzheimer's disease pathology.

    Science.gov (United States)

    Naudí, Alba; Cabré, Rosanna; Jové, Mariona; Ayala, Victoria; Gonzalo, Hugo; Portero-Otín, Manuel; Ferrer, Isidre; Pamplona, Reinald

    2015-01-01

    Lipids stimulated and favored the evolution of the brain. Adult human brain contains a large amount of lipids, and the largest diversity of lipid classes and lipid molecular species. Lipidomics is defined as "the full characterization of lipid molecular species and of their biological roles with respect to expression of proteins involved in lipid metabolism and function, including gene regulation." Therefore, the study of brain lipidomics can help to unravel the diversity and to disclose the specificity of these lipid traits and its alterations in neural (neurons and glial) cells, groups of neural cells, brain, and fluids such as cerebrospinal fluid and plasma, thus helping to uncover potential biomarkers of human brain aging and Alzheimer disease. This review will discuss the lipid composition of the adult human brain. We first consider a brief approach to lipid definition, classification, and tools for analysis from the new point of view that has emerged with lipidomics, and then turn to the lipid profiles in human brain and how lipids affect brain function. Finally, we focus on the current status of lipidomics findings in human brain aging and Alzheimer's disease pathology. Neurolipidomics will increase knowledge about physiological and pathological functions of brain cells and will place the concept of selective neuronal vulnerability in a lipid context. © 2015 Elsevier Inc. All rights reserved.

  2. Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson's disease, PSP and MSA

    NARCIS (Netherlands)

    Bartels, A. L.; Willemsen, A. T. M.; Kortekaas, R.; de Jong, B. M.; de Vries, R.; de Klerk, O.; van Oostrom, J. C. H.; Portman, A.; Leenders, K. L.

    2008-01-01

    Decreased blood-brain barrier (BBB) efflux function of the P-glycoprotein (P-gp) transport system could facilitate the accumulation of toxic compounds in the brain, increasing the risk of neurodegenerative pathology such as Parkinson's disease (PD). This study investigated in vivo BBB P-gp function

  3. Anatomy of the Brain

    Science.gov (United States)

    ... Menu Brain Tumor Information Brain Anatomy Brain Structure Neuron Anatomy Brain Tumor Symptoms Diagnosis Types of Tumors Risk Factors ... form Brain Tumor Information Brain Anatomy Brain Structure Neuron Anatomy Brain Tumor Symptoms Diagnosis Types of Tumors Risk Factors ...

  4. Experimental functional analysis of severe skin-picking behavior in Prader-Willi syndrome.

    Science.gov (United States)

    Hall, Scott S; Hustyi, Kristin M; Chui, Clara; Hammond, Jennifer L

    2014-10-01

    Skin picking is an extremely distressing and treatment resistant behavior commonly shown by individuals with Prader-Willi syndrome (PWS). However, with the exception of a limited number of published single-case and survey studies, little is known about the environmental determinants of skin picking in this population. In this study, functional analyses were conducted with thirteen individuals with PWS, aged 6-23 years, who engaged in severe skin-picking behavior. In addition to the conditions typically employed in a functional analysis (i.e., alone, attention, play, demand), we included an ignore condition to examine potential effects of stimulus control by the presence of an adult. Twelve participants engaged in skin picking during the functional analysis, with the highest levels occurring in the alone and ignore conditions for eight participants, suggesting that skin picking in these participants was maintained by automatic reinforcement. For the remaining four participants, an undifferentiated pattern of low-rate skin picking was observed across conditions. These data confirm previous studies indicating that skin picking in PWS may be maintained most often by automatically produced sensory consequences. There were no associations between demographic characteristics of the participants (e.g., sex, age, IQ or BMI) and levels of skin picking observed in the functional analysis. Additional investigations are needed to identify the nature of the sensory consequences produced during episodes of skin picking in PWS. Behavioral interventions designed to extinguish or compete with the potential sensory consequences arising from skin picking in PWS are also warranted.

  5. The Effect of Lumbar Disc Herniation on Spine Loading Characteristics during Trunk Flexion and Two Types of Picking Up Activities

    Directory of Open Access Journals (Sweden)

    Shengzheng Kuai

    2017-01-01

    Full Text Available The main purpose of this study was to investigate the compensatory response of the muscle activities of seventeen major muscle groups in the spinal region, intradiscal forces of the five lumbar motion segment units (MSUs, and facet forces acting on the ten lumbar facet joints in patients with lumbar disc herniation (LDH. Twenty-six healthy adults and seven LDH patients performed trunk flexion, ipsilateral picking up, and contralateral picking up in sequence. Eight optical markers were placed on the landmarks of the pelvis and spinal process. The coordinates of these markers were captured to drive a musculoskeletal model to calculate the muscle activities, intradiscal forces, and facet forces. The muscle activities of the majority of the seventeen major muscle groups were found increases in LDH patients. In addition, the LDH patients displayed larger compressive forces and anteroposterior forces on all the five lumbar MSUs and more lumbar facet inventions on most facet joints. These findings suggest that the LDH patients demonstrate compensatory increases in the most trunk muscle activities and all spinal loads. These negative compensatory responses increase the risk of the aggravation of disc herniation. Therefore, treatment should intervene as earlier as possible for the severe LDH patients.

  6. Solar cycle variation of interstellar neutral He, Ne, O density and pick-up ions along the Earth's orbit

    OpenAIRE

    Sokół, Justyna M.; Bzowski, Maciej; Kubiak, Marzena A.; Möbius, Eberhard

    2016-01-01

    We simulated the modulation of the interstellar neutral (ISN) He, Ne, and O density and pick-up ion (PUI) production rate and count rate along the Earth's orbit over the solar cycle from 2002 to 2013 to verify if solar cycle-related effects may modify the inferred ecliptic longitude of the ISN inflow direction. We adopted the classical PUI model with isotropic distribution function and adiabatic cooling, modified by time- and heliolatitude-dependent ionization rates and non-zero injection spe...

  7. Psychosis in an adolescent girl: a common manifestation in Niemann-Pick Type C disease

    Science.gov (United States)

    2014-01-01

    Niemann-Pick disease type C (NP-C) is a rare autosomal-recessively inherited lysosomal storage disorder. It is caused by mutations in the NPC1 (95%) or NPC2 gene. It is a progressive and highly heterogeneous disease, characterized by the presentation of visceral, neurological, and psychiatric symptoms. Apart from the patients that die early from organic failure, most of the patients with juvenile and adolescent/adult onset of the disease, develop neurological and psychiatric symptoms. In some cases psychiatric signs, mostly psychosis, can be the first sign of the disease. A delay in diagnosis is often seen. By describing the case of a 16-year old girl, we would like to highlight current opinion about NP-C disease and resume recent findings on the clinical presentation, diagnosis and treatment. We focus on the psychiatric signs, and most important the specific combinations that are typical for the disease. There is no curative treatment for NP-C. Miglustat is used to modify neurological signs in NP-C. PMID:25071864

  8. Deep brain stimulation of the subthalamic nucleus improves pain in Parkinson's disease.

    Science.gov (United States)

    Pellaprat, Jean; Ory-Magne, Fabienne; Canivet, Cindy; Simonetta-Moreau, Marion; Lotterie, Jean-Albert; Radji, Fatai; Arbus, Christophe; Gerdelat, Angélique; Chaynes, Patrick; Brefel-Courbon, Christine

    2014-06-01

    In Parkinson's disease (PD), chronic pain is a common symptom which markedly affects the quality of life. Some physiological arguments proposed that Deep Brain Stimulation of the Subthalamic Nucleus (STN-DBS) could improve pain in PD. We investigated in 58 PD patients the effect of STN-DBS on pain using the short McGill Pain Questionnaire and other pain parameters such as the Bodily discomfort subscore of the Parkinson's disease Questionnaire 39 and the Unified Parkinson's Disease Rating Scale section II (UPDRS II) item 17. All pain scores were significantly improved 12 months after STN-DBS. This improvement was not correlated with motor improvement, depression scores or L-Dopa reduction. STN-DBS induced a substantial beneficial effect on pain in PD, independently of its motor effects and mood status of patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. The reconstructive management of hardware-related scalp erosion in deep brain stimulation for Parkinson disease.

    Science.gov (United States)

    Gómez, Raúl; Hontanilla, Bernardo

    2014-09-01

    The presence of foreign material in deep brain stimulation is a risk factor for infection, and hardware-related pressure under the scalp may cause skin erosion. The aim of this article is to present our experience in the coverage of scalp in relation to underlying hardware. We analyzed 21 patients with Parkinson disease who had undergone deep brain stimulation surgery and developed scalp erosion with hardware exposition during follow-up. Nine patients were programmed for a scalp rotation flap, whereas free tisue transfer was performed in the rest of the patients. Minimum follow-up was 2 years. A hardware-related ulcer appeared in 5 of 9 rotation flap patients. No ulceration or major complications were observed in free flap patients. Free flaps are probably the best option for stable coverage in hardware-related scalp erosion with a high rate of success.

  10. Vision guided robot bin picking of cylindrical objects

    DEFF Research Database (Denmark)

    Christensen, Georg Kronborg; Dyhr-Nielsen, Carsten

    1997-01-01

    In order to achieve increased flexibility on robotic production lines an investigation of the rovbot bin-picking problem is presented. In the paper, the limitations related to previous attempts to solve the problem are pointed uot and a set of innovative methods are presented. The main elements h...

  11. The immunology of traumatic brain injury: a prime target for Alzheimer’s disease prevention

    Directory of Open Access Journals (Sweden)

    Giunta Brian

    2012-08-01

    Full Text Available Abstract A global health problem, traumatic brain injury (TBI is especially prevalent in the current era of ongoing world military conflicts. Its pathological hallmark is one or more primary injury foci, followed by a spread to initially normal brain areas via cascades of inflammatory cytokines and chemokines resulting in an amplification of the original tissue injury by microglia and other central nervous system immune cells. In some cases this may predispose individuals to later development of Alzheimer’s disease (AD. The inflammatory-based progression of TBI has been shown to be active in humans for up to 17 years post TBI. Unfortunately, all neuroprotective drug trials have failed, and specific treatments remain less than efficacious. These poor results might be explained by too much of a scientific focus on neurons without addressing the functions of microglia in the brain, which are at the center of proinflammatory cytokine generation. To address this issue, we provide a survey of the TBI-related brain immunological mechanisms that may promote progression to AD. We discuss these immune and microglia-based inflammatory mechanisms involved in the progression of post-trauma brain damage to AD. Flavonoid-based strategies to oppose the antigen-presenting cell-like inflammatory phenotype of microglia will also be reviewed. The goal is to provide a rationale for investigations of inflammatory response following TBI which may represent a pathological link to AD. In the end, a better understanding of neuroinflammation could open therapeutic avenues for abrogation of secondary cell death and behavioral symptoms that may mediate the progression of TBI to later AD.

  12. [Effects of debagging time and picking off leaf on fruit quality of "Red Fuji" apple].

    Science.gov (United States)

    Zhang, Ji-Xiang; Yue, Yu-Ling; Wei, Qin-Ping; Wang, Xiao-Wei; Zhang, Qiang

    2010-08-01

    This paper studied the effects of debagging time and picking off leaves around fruits on the fruit quality and 1-year old shoots stored nutrition of "Red Fuji" apple. Properly advancing debagging time significantly increased the mean mass, anthocyanin content, and coloration area of the fruits (P picked off, the light environment around the fruits improved significantly (P picked off treatment. Picking off the leaves within 30-45 cm away from the fruits benefited the fruit coloration and anthocyanin accumulation. No significant effects were observed on the 1-year old shoots stored nutrition and their budding in next year among the treatments of picking off leaves. Advancing debagging time and picking off the leaves within 30-45 cm away from the fruits could improve fruit appearance and quality.

  13. Validation of Parkinsonian Disease-Related Metabolic Brain Patterns

    NARCIS (Netherlands)

    Teune, Laura K.; Renken, Remco J.; Mudali, Deborah; De Jong, Bauke M.; Dierckx, Rudi A.; Roerdink, Jos B.T.M.; Leenders, Klaus L.

    2013-01-01

    Background: The objective of this study was to validate disease-related metabolic brain patterns for Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Methods: The study included 20 patients with Parkinson’s disease, 21 with multiple system atrophy, and 17 with progre

  14. A preliminary investigation of acceptance and commitment therapy as a treatment for chronic skin picking.

    Science.gov (United States)

    Twohig, Michael P; Hayes, Steven C; Masuda, Akihiko

    2006-10-01

    The effectiveness of a deliberately limited version of Acceptance and Commitment Therapy (ACT) for chronic skin picking was evaluated in a pair of multiple baseline across participants designs. Self-monitoring of skin picking showed that four of the five participants reached near zero levels of picking by post-treatment, but these gains were not fully maintained for three of the four participants at follow-up. The findings of the self-reported skin picking were generally corroborated by ratings of photographs of the damaged areas and by ratings on a validated measure of skin picking severity. All participants rated the intervention as socially acceptable, and reductions were found on measures of anxiety, depression, and experiential avoidance for most participants as a result of the intervention. Results support the construction of more comprehensive ACT protocols for skin picking.

  15. Brain metabolic stress and neuroinflammation at the basis of cognitive impairment in Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Fernanda G. De Felice

    2015-05-01

    Full Text Available Brain metabolic dysfunction is known to influence brain activity in several neurological disorders, including Alzheimer’s disease (AD. In fact, deregulation of neuronal metabolism has been postulated to play a key role leading to the clinical outcomes observed in AD. Besides deficits in glucose utilization in AD patients, recent evidence has implicated neuroinflammation and endoplasmic reticulum stress as components of a novel form of brain metabolic stress that develop in AD and other neurological disorders. Here we review findings supporting this novel paradigm and further discuss how these mechanisms seem to participate in synapse and cognitive impairments that are germane to AD. These deleterious processes resemble pathways that act in peripheral tissues leading to insulin resistance and glucose intolerance, in an intriguing molecular connection linking AD to diabetes. The discovery of detailed mechanisms leading to neuronal metabolic stress may be a key step that will allow the understanding how cognitive impairment develops in AD, thereby offering new avenues for effective disease prevention and therapeutic targeting.

  16. Pick-and-place process for sensitivity improvement of the capacitive type CMOS MEMS 2-axis tilt sensor

    Science.gov (United States)

    Chang, Chun-I.; Tsai, Ming-Han; Liu, Yu-Chia; Sun, Chih-Ming; Fang, Weileun

    2013-09-01

    This study exploits the foundry available complimentary metal-oxide-semiconductor (CMOS) process and the packaging house available pick-and-place technology to implement a capacitive type micromachined 2-axis tilt sensor. The suspended micro mechanical structures such as the spring, stage and sensing electrodes are fabricated using the CMOS microelectromechanical systems (MEMS) processes. A bulk block is assembled onto the suspended stage by pick-and-place technology to increase the proof-mass of the tilt sensor. The low temperature UV-glue dispensing and curing processes are employed to bond the block onto the stage. Thus, the sensitivity of the CMOS MEMS capacitive type 2-axis tilt sensor is significantly improved. In application, this study successfully demonstrates the bonding of a bulk solder ball of 100 µm in diameter with a 2-axis tilt sensor fabricated using the standard TSMC 0.35 µm 2P4M CMOS process. Measurements show the sensitivities of the 2-axis tilt sensor are increased for 2.06-fold (x-axis) and 1.78-fold (y-axis) after adding the solder ball. Note that the sensitivity can be further improved by reducing the parasitic capacitance and the mismatch of sensing electrodes caused by the solder ball.

  17. Commentary on “Alzheimer’s disease drug development and the problem of the blood-brain barrier”

    OpenAIRE

    Simpkins, James W.

    2009-01-01

    The perspective by Dr. William Pardridge entitled “Alzheimer’s Disease Drug Discovery and the Problem of the Blood-Brain Barrier” makes a strong case for the imbalance in resource distribution to the drug-discovery and brain drug delivery processes, where the latter received less than 1% of the investment of the former. My own calculations are consistent with this striking imbalance. Dr. Pardridge predicts that current trials of passive immunity against β-amyloid peptide wil...

  18. Study on pick arrangement of shearer drum based on load fluctuation

    Institute of Scientific and Technical Information of China (English)

    DU Chang-long; LIU Song-yong; CUI Xin-xia; LI Ti-jian

    2008-01-01

    According to the coal or rock cutting theory, a mechanical model and computing formula for a pick and the drum load fluctuation model were established in order to obtain relationships between pick arrangements and drum fluctuation loads, drum rotary speeds and haulage speeds. Based on a minimum load fluctuation, an optimal mathematical model was established for drum pick arrangements. The effects of pick arrangements (including punnett square, sequence, aberrance Ⅰ and Ⅱ) on the drum load fluctuation coefficient are discussed. The relationships between the pick arrangements of the drum with different start vanes and the cutting load fluctuation coefficient, the drum rotary speed and haulage speed were also studied. The results indicate that the punnett square arrangement has a smaller cutting load fluctuation coefficient than other forms of arrangement and the drum with the 4-start vanes has the smallest coefficient. The drum rotary speed and haulage speed are affected not only by pick arrangements, but also by the number of vanes.

  19. Automating the Process of Work-Piece Recognition and Location for a Pick-and-Place Robot in a SFMS

    Directory of Open Access Journals (Sweden)

    R. V. Sharan

    2014-03-01

    Full Text Available This paper reports the development of a vision system to automatically classify work-pieces with respect to their shape and color together with determining their location for manipulation by an in-house developed pick-and-place robot from its work-plane. The vision-based pick-and-place robot has been developed as part of a smart flexible manufacturing system for unloading work-pieces for drilling operations at a drilling workstation from an automatic guided vehicle designed to transport the work-pieces in the manufacturing work-cell. Work-pieces with three different shapes and five different colors are scattered on the work-plane of the robot and manipulated based on the shape and color specification by the user through a graphical user interface. The number of corners and the hue, saturation, and value of the colors are used for shape and color recognition respectively in this work. Due to the distinct nature of the feature vectors for the fifteen work-piece classes, all work-pieces were successfully classified using minimum distance classification during repeated experimentations with work-pieces scattered randomly on the work-plane.

  20. An order-picking operations system for managing the batching activities in a warehouse

    Science.gov (United States)

    Lam, Cathy H. Y.; Choy, K. L.; Ho, G. T. S.; Lee, C. K. M.

    2014-06-01

    Nowadays, customer orders with high product variety in small quantities are often received and requested for timely delivery. However, the order-picking process is a labour-intensive and costly activity to handle those small orders separately. In such cases, small orders are often grouped into batches so that two or more orders can be served at once to increase the picking efficiency and thus reduce the travel distance. In this paper, an order-picking operations system (OPOS) is proposed to assist the formulation of an order-picking plan and batch-handling sequence. The study integrates a mathematical model and fuzzy logic technique to divide the receiving orders into batches and prioritise the batch-handling sequence for picking, respectively. Through the proposed system, the order-picking process can be managed as batches with common picking locations to minimise the travel distance, and the batch-picking sequence can be determined as well. To demonstrate the use of the system, a case study in a third-party logistics warehouse is presented, and the result shows that both the order-picking activity and labour utilisation can be better organised.

  1. Effect of horizontal pick and place locations on shoulder kinematics

    NARCIS (Netherlands)

    Könemann, R.; Bosch, T.; Kingma, I.; Dieën, J.H. van; Looze, M.P. de

    2015-01-01

    In this study the effects of horizontal bin locations in an order picking workstation on upper arm elevation, trunk inclination and hand use were investigated. Eight subjects moved (self-paced) light or heavy products (0.2 and 3.0 kg) from a central product bin to an inner or outer order bin (at 60

  2. The Effect of Head Orientation on Perceived Gaze Direction: Revisiting Gibson and Pick (1963) and Cline (1967)

    Science.gov (United States)

    Moors, Pieter; Verfaillie, Karl; Daems, Thalia; Pomianowska, Iwona; Germeys, Filip

    2016-01-01

    Two biases in perceived gaze direction have been observed when eye and head orientation are not aligned. An overshoot effect indicates that perceived gaze direction is shifted away from head orientation (i.e., a repulsive effect), whereas a towing effect indicates that perceived gaze direction falls in between head and eye orientation (i.e., an attraction effect). In the 60s, three influential papers have been published with respect to the effect of head orientation on perceived gaze direction (Gibson and Pick, 1963; Cline, 1967; Anstis et al., 1969). Throughout the years, the results of two of these (Gibson and Pick, 1963; Cline, 1967) have been interpreted differently by a number of authors. In this paper, we critically discuss potential sources of confusion that have led to differential interpretations of both studies. At first sight, the results of Cline (1967), despite having been a major topic of discussion, unambiguously seem to indicate a towing effect whereas Gibson and Pick’s (1963) results seem to be the most ambiguous, although they have never been questioned in the literature. To shed further light on this apparent inconsistency, we repeated the critical experiments reported in both studies. Our results indicate an overshoot effect in both studies. PMID:27559325

  3. Non-invasive brain stimulation for the treatment of brain diseases in childhood and adolescence: state of the art, current limits and future challenges

    Directory of Open Access Journals (Sweden)

    Carmelo Mario Vicario

    2013-11-01

    Full Text Available In the last decades interest in application of non-invasive brain stimulation for enhancing neural functions is growing continuously. However, the use of such techniques in pediatric populations remains rather limited and mainly confined to the treatment of severe neurological and psychiatric diseases. In this article we provide a complete review of non-invasive brain stimulation studies conducted in pediatric populations. We also provide a brief discussion about the current limitations and future directions in a field of research still very young and full of issues to be explored.

  4. Calculating the Number of People with Alzheimer's Disease in any Country Using Saturated Mutation Models of Brain Cell Loss that also Predict Widespread Natural Immunity to the Disease

    Directory of Open Access Journals (Sweden)

    Ivan Kramer

    2010-01-01

    Full Text Available The series of mutations that cause brain cells to spontaneously and randomly die leading to Alzheimer's disease (AD is modelled. The prevalence of AD as a function of age in males and females is calculated from two very different mutation models of brain cell death. Once the prevalence functions are determined, the number of people with AD in any country or city can be estimated.

  5. Expression of Alzheimer's disease risk genes in ischemic brain degeneration.

    Science.gov (United States)

    Ułamek-Kozioł, Marzena; Pluta, Ryszard; Januszewski, Sławomir; Kocki, Janusz; Bogucka-Kocka, Anna; Czuczwar, Stanisław J

    2016-12-01

    We review the Alzheimer-related expression of genes following brain ischemia as risk factors for late-onset of sporadic Alzheimer's disease and their role in Alzheimer's disease ischemia-reperfusion pathogenesis. More recent advances in understanding ischemic etiology of Alzheimer's disease have revealed dysregulation of Alzheimer-associated genes including amyloid protein precursor, β-secretase, presenilin 1 and 2, autophagy, mitophagy and apoptosis. We review the relationship between these genes dysregulated by brain ischemia and the cellular and neuropathological characteristics of Alzheimer's disease. Here we summarize the latest studies supporting the theory that Alzheimer-related genes play an important role in ischemic brain injury and that ischemia is a needful and leading supplier to the onset and progression of sporadic Alzheimer's disease. Although the exact molecular mechanisms of ischemic dependent neurodegenerative disease and neuronal susceptibility finally are unknown, a downregulated expression of neuronal defense genes like alfa-secretase in the ischemic brain makes the neurons less able to resist injury. The recent challenge is to find ways to raise the adaptive reserve of the brain to overcome such ischemic-associated deficits and support and/or promote neuronal survival. Understanding the mechanisms underlying the association of these genes with risk for Alzheimer's disease will provide the most meaningful targets for therapeutic development to date. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  6. An analysis of the first-arrival times picked on the DSS and wide-angle seismic section recorded in Italy since 1968

    Directory of Open Access Journals (Sweden)

    R. Tondi

    2004-06-01

    Full Text Available We performed an analysis of refraction data recorded in Italy since 1968 in the frame of the numerous deep seismic sounding and wide-angle reflection/refraction projects. The aims of this study are to construct a parametric database including the recording geometric information relative to each profile, the phase pickings and the results of some kinematic analyses performed on the data, and to define a reference 1D velocity model for the Italian territory from all the available refraction data. As concerns the first goal, for each seismic section we picked the P-wave first-arrival-times, evaluated the uncertainties of the arrival-times pickings and determined from each travel time-offset curve the 1D velocity model. The study was performed on 419 seismic sections. Picking was carried out manually by an algorithm which includes the computation of three picking functions and the picking- error estimation. For each of the travel time-offset curves a 1D velocity model has been calculated. Actually, the 1D velocity-depth functions were estimated in three different ways which assume: a constant velocitygradient model, a varying velocity-gradient model and a layered model. As regards the second objective of this work, a mean 1D velocity model for the Italian crust was defined and compared with those used for earthquake hypocentre locations and seismic tomographic studies by different institutions operating in the Italian area, to assess the significance of the model obtained. This model can be used in future works as input for a next joint tomographic inversion of active and passive seismic data.

  7. Brain transplants. A new approach to the therapy of neurodegenerative disease.

    Science.gov (United States)

    Tulipan, N

    1988-05-01

    There is now a wealth of experimental evidence to suggest that transplantation to the brain may ameliorate a variety of neurologic and endocrine disorders. Many unanswered questions remain. Chief among these questions are the duration of any salutary effects and the potential long-term risks to the host CNS. Answers to these questions will only come with carefully controlled long-term clinical studies. Given the high incidence and devastating nature of many of these diseases, such studies will have enormous scientific and social impact. Regardless of the outcome, there is the potential for a greater understanding of the pathologic mechanisms underlying neurodegenerative diseases and, thus, the possibility that definitive therapies will be found as a result.

  8. Relating Education, Brain Structure, and Cognition: The Role of Cardiovascular Disease Risk Factors

    Directory of Open Access Journals (Sweden)

    Moyra E. Mortby

    2014-01-01

    Full Text Available The protective effect of education on cognitive and brain health is well established. While the direct effects of individual cardiovascular disease (CVD risk factors (i.e., hypertension, smoking, diabetes, and obesity on cerebral structure have been investigated, little is understood about the possible interaction between the protective effect of education and the deleterious effects of CVD risk factors in predicting brain ageing and cognition. Using data from the PATH Through Life study (N=266, we investigated the protective effect of education on cerebral structure and function and tested a possible mediating role of CVD risk factors. Higher education was associated with larger regional grey/white matter volumes in the prefrontal cortex in men only. The association between education and cognition was mediated by brain volumes but only for grey matter and only in relation to information processing speed. CVD risk factors did not mediate the association between regional volumes and cognition. This study provides additional evidence in support for a protective effect of education on cerebral structures and cognition. However, it does not provide support for a mediating role of CVD risk factors in these associations.

  9. Pick 'n' mix: neuropatholgical detection of peri-tumour taupathy.

    LENUS (Irish Health Repository)

    Lonergan, Roisin

    2013-11-01

    Radiotherapy is used to treat recurrent oligodendrogliomas, WHO grade 2 tumours. Potential morbitities include steroid-responsive radiation necrosis and radiation leucoencephalopathy, characterised pathologically by reactive astrogliosis, focal necrosis, demyelination, axonal loss, and clinically by progressive subcortical deficits (ataxia, amnesia, incontinence, cognitive decline), with relative sparing of cortical function. Although subcortical features may overlap with neurodegenerative conditions (eg frontotemporal dementia), focal cortical atrophy of FTD causes loss of language function in addition to memory, and specific histopathological features characterise FTD subtypes (eg Pick disease). Association between mitotic disease and tauopathy has not been reported widely, but co-existence is possible. Diagnostic accuracy may guide management.

  10. Sleep facilitates clearance of metabolites from the brain: glymphatic function in aging and neurodegenerative diseases.

    Science.gov (United States)

    Mendelsohn, Andrew R; Larrick, James W

    2013-12-01

    Decline of cognition and increasing risk of neurodegenerative diseases are major problems associated with aging in humans. Of particular importance is how the brain removes potentially toxic biomolecules that accumulate with normal neuronal function. Recently, a biomolecule clearance system using convective flow between the cerebrospinal fluid (CSF) and interstitial fluid (ISF) to remove toxic metabolites in the brain was described. Xie and colleagues now report that in mice the clearance activity of this so-called "glymphatic system" is strongly stimulated by sleep and is associated with an increase in interstitial volume, possibly by shrinkage of astroglial cells. Moreover, anesthesia and attenuation of adrenergic signaling can activate the glymphatic system to clear potentially toxic proteins known to contribute to the pathology of Alzheimer disease (AD) such as beta-amyloid (Abeta). Clearance during sleep is as much as two-fold faster than during waking hours. These results support a new hypothesis to answer the age-old question of why sleep is necessary. Glymphatic dysfunction may pay a hitherto unsuspected role in the pathogenesis of neurodegenerative diseases as well as maintenance of cognition. Furthermore, clinical studies suggest that quality and duration of sleep may be predictive of the onset of AD, and that quality sleep may significantly reduce the risk of AD for apolipoprotein E (ApoE) ɛ4 carriers, who have significantly greater chances of developing AD. Further characterization of the glymphatic system in humans may lead to new therapies and methods of prevention of neurodegenerative diseases. A public health initiative to ensure adequate sleep among middle-aged and older people may prove useful in preventing AD, especially in apolipoprotein E (ApoE) ɛ4 carriers.

  11. Picking and Choosing the ‘Sovereign’Border

    DEFF Research Database (Denmark)

    Parker, Noel; Adler-Nissen, Rebecca

    2012-01-01

    We argue that the continued persistence of borders is an effect of their constitutive role for the many dimensions of a social particular. States cannot choose to have a border; but they can and do make choices amongst the materials available on the various planes of inscription for bordering....... For contemporary states the planes have become increasingly disaggregated, in the sense that they do not fall into place at one and the same border. Thus, states have to pick and choose different articulations (often inconsistently) on different planes. We illustrate these ideas with instances, present......-day and historical, of bordering. A corollary of there being more need to pick and choose is that articulations of sovereignty change. So, sovereignty is increasingly the material of ‘sovereignty games’, where sovereignty is used as a political instrument. In sum, our theory directs attention to state bordering...

  12. Ultrasound Delivery of an Anti-Aβ Therapeutic Agent to the Brain in a Mouse Model of Alzheimer's Disease

    Science.gov (United States)

    Jordão, Jessica F.; Ayala-Grosso, Carlos A.; Chopra, Rajiv; McLaurin, JoAnne; Aubert, Isabelle; Hynynen, Kullervo

    2009-04-01

    Plaques composed of amyloid-beta (Aβ) peptides represent a pathological hallmark in the brain of patients with Alzheimer's disease. Aβ oligomers are considered cytotoxic and several therapeutic approaches focus on reducing Aβ load in the brain of Alzheimer's patients. The efficacy of most anti-Aβ agents is significantly limited because they do not cross the blood-brain-barrier. Innovative technologies capable of enhancing the permeability of the blood-brain barrier, thereby allowing entry of therapeutic agents into the brain, show great promise in circumventing this problem. The application of low-intensity focused ultrasound in the presence of an ultrasound contrast agent causes localized and transient permeability of the blood-brain barrier. We demonstrate the value of this technology for the delivery of anti-Aβ antibodies to the brain of TgCRND8 mice, a mouse model of Alzheimer's disease exhibiting Aβ plaques. BAM-10, an anti-Aβ antibody, was injected into the tail vein simultaneously with exposure to MRI-guided, low-intensity focused ultrasound (FUS) to one hemisphere of TgCNRD8 mice. Four hours after treatment, antibodies were detected at significant amounts only in the brain of mice receiving FUS in addition to BAM-10. This data provides a proof-of-concept that FUS allows anti-Aβ therapeutics to efficiently enter the brain and target Aβ plaques. Four days following a single treatment with BAM-10 and MRI-guided FUS, a significant decrease in the number of Aβ plaques on the side of the treated hemisphere was observed in TgCRND8 mice. In conclusion low-intensity, focused ultrasound is effective in delivering Aβ antibodies to the brain. This technology has the potential to enhance current anti-Aβ treatments by allowing increased exposure of amyloid plaques to treatment agents.

  13. Effects of alternating current stimulation on the healthy and diseased brain

    Directory of Open Access Journals (Sweden)

    Aini Ismafairus eAbd Hamid

    2015-10-01

    Full Text Available Cognitive and neurological dysfunctions can severely impact a patient’s daily activities. In addition to medical treatment, non-invasive transcranial alternating current stimulation (tACS has been proposed as a therapeutic technique to improve the functional state of the brain. Although during the last years tACS was applied in numerous studies to improve motor, somatosensory, visual and higher order cognitive functions, our knowledge is still limited regarding the mechanisms as to which type of ACS can affect cortical functions and altered neuronal oscillations seem to be the key mechanism. Because alternating current send pulses to the brain at predetermined frequencies, the online- and after-effects of ACS strongly depend on the stimulation parameters so that ‘optimal’ ACS paradigms could be achieved. This is of interest not only for neuroscience research but also for clinical practice. In this study, we summarize recent findings on ACS-effects under both normal conditions and in brain diseases.

  14. Clinical NMR imaging of the brain in children: normal and neurologic disease

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, M.A, (Hammersmith Hospital, London, England); Pennock, J.M.; Bydder, G.M.; Steiner, R.E.; Thomas, D.J.; Hayward, R.; Bryant, D.R.T.; Payne, J.A.; Levene, M.I.; Whitelaw, A.; Dubowitz, L.M.S.; Dubowitz, V.

    1983-11-01

    The results of initial clinical nuclear magnetic resonance imaging of the brain in eight normal and 52 children with a wide variety of neurologic diseases were reviewed. The high level of gray-white matter contrast available with inversion-recovery sequences provided a basis for visualizing normal myelination as well as delays or deficits in this process. The appearances seen in cases of parenchymal hemorrhage, cerebral infarction, and proencephalic cysts are described. Ventricular enlargement was readily identified and marginal edema was demonstrated with spin-echo sequences. Abnormalities were seen in cerebral palsy, congenital malformations, Hallervorden-Spatz disease, aminoaciduria, and meningitis. Space-occupying lesions were identified by virtue of their increased relaxation times and mass effects. Nuclear magnetic resonance imaging has considerable potential in pediatric neuroradiologic practice, in some conditions supplying information not available by computed tomography or sonography.

  15. Can Electrical Vestibular Noise Be Used for the Treatment of Brain Diseases?

    Science.gov (United States)

    Yamamoto, Yoshiharu; Soma, Rika; Struzik, Zbigniew R.; Kwak, Shin

    2005-11-01

    The therapy currently available for the treatment of degenerative neurological diseases is far from satisfactory, and a novel therapeutic strategy, especially for pharmacologically unresponsive patients, would be welcomed. The vestibular nerves are known to influence neuronal circuits in the medullary cardiovascular areas and, through the cerebellar vermis, the basal ganglia and the limbic system. By means of noisy galvanic vestibular stimulation (GVS), it may now be possible to ameliorate blunted responsiveness of degenerated neuronal circuits in the brains of multiple system atrophy (MSA) and/or Parkinson's disease (PD) patients, through a mechanism known as stochastic resonance. We evaluate the effect of 24-hour noisy GVS on long-term heart rate dynamics in seven MSA patients, and on daytime locomotor activity dynamics in twelve patients with either PD or levodopa unresponsive parkinsonism. Short-range heart rate variability and long-range anti-correlation of trunk activity are significantly increased by the noisy GVS compared with sham stimulation, suggestive of improved autonomic and motor responsiveness. The noisy GVS is effective in boosting the neuro-degenerative brains of MSA and/or PD patients, including those unresponsive to standard levodopa therapy.

  16. Parvalbumin-immunoreactive neurons in the hippocampal formation of Alzheimer's diseased brain.

    Science.gov (United States)

    Brady, D R; Mufson, E J

    1997-10-01

    The number and topographic distribution of immunocytochemically stained parvalbumin interneurons was determined in the hippocampal formation of control and Alzheimer's diseased brain. In control hippocampus, parvalbumin interneurons were aspiny and pleomorphic, with extensive dendritic arbors. In dentate gyrus, parvalbumin cells, as well as a dense plexus of fibers and puncta, were associated with the granule cell layer. A few cells also occupied the molecular layer. In strata oriens and pyramidale of CA1-CA3 subfields, parvalbumin neurons gave rise to dendrites that extended into adjacent strata. Densely stained puncta and beaded fibers occupied stratum pyramidale, with less dense staining in adjacent strata oriens and radiatum. Virtually no parvalbumin profiles were observed in stratum lacunosum-moleculare or the alveus. Numerous polymorphic parvalbumin neurons and a dense plexus of fibers and puncta characterized the deep layer of the subiculum and the lamina principalis externa of the presubiculum. In Alzheimer's diseased hippocampus, there was an approximate 60% decrease in the number of parvalbumin interneurons in the dentate gyrus/CA4 subfield (Pparvalbumin neurons did not statistically decline in subfields CA3, subiculum or presubiculum in Alzheimer's diseased brains relative to controls. Concurrent staining with Thioflavin-S histochemistry did not reveal degenerative changes within parvalbumin-stained profiles. These findings reveal that parvalbumin interneurons within specific hippocampal subfields are selectively vulnerable in Alzheimer's disease. This vulnerability may be related to their differential connectivity, e.g., those regions connectionally related to the cerebral cortex (dentate gyrus and CA1) are more vulnerable than those regions connectionally related to subcortical loci (subiculum and presubiculum).

  17. Morphological and pathological evolution of the brain microcirculation in aging and Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Jesse M Hunter

    Full Text Available Key pathological hallmarks of Alzheimer's disease (AD, including amyloid plaques, cerebral amyloid angiopathy (CAA and neurofibrillary tangles do not completely account for cognitive impairment, therefore other factors such as cardiovascular and cerebrovascular pathologies, may contribute to AD. In order to elucidate the microvascular changes that contribute to aging and disease, direct neuropathological staining and immunohistochemistry, were used to quantify the structural integrity of the microvasculature and its innervation in three oldest-old cohorts: 1 nonagenarians with AD and a high amyloid plaque load; 2 nonagenarians with no dementia and a high amyloid plaque load; 3 nonagenarians without dementia or amyloid plaques. In addition, a non-demented (ND group (average age 71 years with no amyloid plaques was included for comparison. While gray matter thickness and overall brain mass were reduced in AD compared to ND control groups, overall capillary density was not different. However, degenerated string capillaries were elevated in AD, potentially suggesting greater microvascular "dysfunction" compared to ND groups. Intriguingly, apolipoprotein ε4 carriers had significantly higher string vessel counts relative to non-ε4 carriers. Taken together, these data suggest a concomitant loss of functional capillaries and brain volume in AD subjects. We also demonstrated a trend of decreasing vesicular acetylcholine transporter staining, a marker of cortical cholinergic afferents that contribute to arteriolar vasoregulation, in AD compared to ND control groups, suggesting impaired control of vasodilation in AD subjects. In addition, tyrosine hydroxylase, a marker of noradrenergic vascular innervation, was reduced which may also contribute to a loss of control of vasoconstriction. The data highlight the importance of the brain microcirculation in the pathogenesis and evolution of AD.

  18. Importance of the Brain Angiotensin System in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    John W. Wright

    2012-01-01

    Full Text Available Parkinson’s disease (PD has become a major health problem affecting 1.5% of the world’s population over 65 years of age. As life expectancy has increased so has the occurrence of PD. The primary direct consequence of this disease is the loss of dopaminergic (DA neurons in the substantia nigra and striatum. As the intensity of motor dysfunction increases, the symptomatic triad of bradykinesia, tremors-at-rest, and rigidity occur. Progressive neurodegeneration may also impact non-DA neurotransmitter systems including cholinergic, noradrenergic, and serotonergic, often leading to the development of depression, sleep disturbances, dementia, and autonomic nervous system failure. L-DOPA is the most efficacious oral delivery treatment for controlling motor symptoms; however, this approach is ineffective regarding nonmotor symptoms. New treatment strategies are needed designed to provide neuroprotection and encourage neurogenesis and synaptogenesis to slow or reverse this disease process. The hepatocyte growth factor (HGF/c-Met receptor system is a member of the growth factor family and has been shown to protect against degeneration of DA neurons in animal models. Recently, small angiotensin-based blood-brain barrier penetrant mimetics have been developed that activate this HGF/c-Met system. These compounds may offer a new and novel approach to the treatment of Parkinson’s disease.

  19. Reversible lesions in the brain parenchyma in Wilson's disease confirmed by magnetic resonance imaging: earlier administration of chelating therapy can reduce the damage to the brain.

    Science.gov (United States)

    Kozić, Duško B; Petrović, Igor; Svetel, Marina; Pekmezović, Tatjana; Ragaji, Aleksandar; Kostić, Vladimir S

    2014-11-01

    The aim of this study was to evaluate the resolution of brain lesions in patients with Wilson's disease during the long-term chelating therapy using magnetic resonance imaging and a possible significance of the time latency between the initial symptoms of the disease and the introduction of this therapy. Initial magnetic resonance examination was performed in 37 patients with proven neurological form of Wilson's disease with cerebellar, parkinsonian and dystonic presentation. Magnetic resonance reexamination was done 5.7 ± 1.3 years later in 14 patients. Patients were divided into: group A, where chelating therapy was initiated < 24 months from the first symptoms and group B, where the therapy started ≥ 24 months after the initial symptoms. Symmetry of the lesions was seen in 100% of patients. There was a significant difference between groups A and B regarding complete resolution of brain stem and putaminal lesions (P = 0.005 and P = 0.024, respectively). If the correct diagnosis and adequate treatment are not established less than 24 months after onset of the symptoms, irreversible lesions in the brain parenchyma could be expected. Signal abnormalities on magnetic resonance imaging might therefore, at least in the early stages, represent reversible myelinolisis or cytotoxic edema associated with copper toxicity.

  20. [Status of the ventricular system and dynamics of the cerebrospinal fluid changes in chronic brain diseases].

    Science.gov (United States)

    Burtsev, E M; Starodubtsev, A V

    1988-01-01

    Using noninvasive (echoventriculometry (Echo-VM), REG and invasive (planimetric PEG, graphic recording of the CSF pressure) methods of examination, the authors determined the size of cerebral ventricles and the status of the cerebral hemo- and CSF dynamics in 606 patients with various chronic diseases of the brain (consequences of craniocerebral injury, epilepsy, discirculatory encephalopathy, etc.). According to PEG and Echo-VM findings, two groups of patients were distinguished. In moderate dilatation of cerebral ventricles the most significant finding was an increase in the pulse pressure of the CSF, whereas its mean pressure was normal or slightly elevated. In patients with pronounced hydrocephaly the pulse and mean pressure of the CSF tended to decrease. The progress of hydrocephaly was parallelled by increasing disorders of the cerebral hemodynamics expressed in hindered venous outflow from the cranial cavity and elevated peripheral vascular resistance. Four CSF-related syndromes have been identified (normotension, total CSF hypertension, intraventricular tension, total CSF hypotension) differing in their diagnostic and prognostic significance and in the pathogenesis of disorders of the hemo- and CSF dynamics.

  1. Translational concepts of mGluR5 in synaptic diseases of the brain

    Directory of Open Access Journals (Sweden)

    Thomas M Piers

    2012-11-01

    Full Text Available The G-protein coupled receptor family of glutamate receptors, termed metabotropic glutamate receptors (mGluRs, are implicated in numerous cellular mechanisms ranging from neural development to the processing of cognitive, sensory, and motor information. Over the last decade, multiple mGluR-related signal cascades have been identified at excitatory synapses, indicating their potential roles in various forms of synaptic function and dysfunction. This review highlights recent studies investigating mGluR5, a subtype of group I mGluRs, and its association with a number of developmental, psychiatric and senile synaptic disorders with respect to associated synaptic proteins, with an emphasis on translational pre-clinical studies targeting mGluR5 in a range of synaptic diseases of the brain.

  2. Propranolol in the treatment of assaultive patients with organic brain disease.

    Science.gov (United States)

    Greendyke, R M; Schuster, D B; Wooton, J A

    1984-10-01

    Propranolol in doses up to 520 mg/day was administered to eight patients with organic brain disease characterized by violent and assaultive behavior refractory to conventional treatment. Improvement was demonstrated in the seven patients able to tolerate adequate drug dosages. Hypotension, bradycardia, and interactions with other medications constituted complications.

  3. Synthesis and characterization of brain penetrant prodrug of neuroprotective D-264: Potential therapeutic application in the treatment of Parkinson's disease.

    Science.gov (United States)

    Dholkawala, Fahd; Voshavar, Chandrashekhar; Dutta, Aloke K

    2016-06-01

    Parkinson's disease (PD) is one of the major debilitating neurodegenerative disorders affecting millions of people worldwide. Progressive loss of dopamine neurons resulting in development of motor dysfunction and other related non-motor symptoms is the hallmark of PD. Previously, we have reported on the neuroprotective property of a potent D3 preferring agonist D-264. In our goal to increase the bioavailability of D-264 in the brain, we have synthesized a modified cysteine based prodrug of D-264 and evaluated its potential in crossing the blood-brain barrier. Herein, we report the synthesis of a novel modified cysteine conjugated prodrug of potent neuroprotective D3 preferring agonist D-264 and systematic evaluation of the hydrolysis pattern of the prodrug to yield D-264 at different time intervals in rat plasma and brain homogenates using HPLC analysis. Furthermore, we have also performed in vivo experiments with the prodrug to evaluate its enhanced brain penetration ability.

  4. Clinical value of dipyridamole brain perfusion imaging in the diagnosis of ischemic cerebrovascular disease

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Using dipyridamole stress test to evaluate cerebral blood flow reserve in cerebrovascular disease (CVD). Dipyridamole stress tests were performed first, the baseline SPECT images were obtained under similar conditions 2-5 days later. By visual and semiquantitative analysis, the responses of cerebral blood flow to dipyridamole were divided into the following four patterns: A: The dipyridamole SPECT showed an expanded area of hypoperfusion, Asymmetry Index(AI) and Uptake Rate(UR) were all decreased; B: Rest images was normal but new hypoperfused areas appeared on stress test with decreased Al and UR; C: Hypoperfused areas were decreased in size or disappeared after stress test with increased Al and UR; D: No changes showed in cerebral perfusion imaging patterns, and in Al and UR between stress and rest studies. Dipyridarnole brain perfusion imaging may be helpful to the diagnosis of CVD, to the decision the therapeutic plan, and to predicting the therapeutic effect.

  5. Examining the relationship between heart rate and problem behavior: a case study of severe skin picking in Prader-Willi syndrome.

    Science.gov (United States)

    Hall, Scott S; Hammond, Jennifer L; Hustyi, Kristin M

    2013-11-01

    Few studies have examined the relationship between heart rate and self-injurious behavior (SIB) shown by individuals with IDD (intellectual and developmental disabilities). In this single-case study, we simultaneously monitored heart rate and activity levels during a functional analysis of severe skin picking behavior exhibited by a young man with Prader-Willi syndrome (PWS). Results of the functional analysis indicated that the participant's skin picking was maintained by automatic reinforcement. A within-session analysis of the data indicated that skin picking bouts resulted in an increase in heart rate, suggesting a positive- automatic reinforcement function. These data indicate that inclusion of heart rate and activity-level monitoring during a functional analysis may provide important additional information concerning the determinants of SIB.

  6. Measurement of the space charge tune spread with a quadrupolar pick-up: New (general) formula VS. "Usual" one

    CERN Document Server

    Metral, Elias

    2015-01-01

    In 1966, W. Hardt derived the oscillation frequencies obtained in the presence of space charge forces and gradients errors for elliptical beams. Since then, a simple formula is usually used to relate the shift of the quadrupolar mode (obtained from the quadrupolar pick-up) and the space charge tune spread, depending only on the ratio between the two transverse equilibrium beam sizes. However, this formula is not always valid, in particular for machines running close to the coupling resonance Qx = Qy with almost round beams. A new general formula is presented, giving the space charge tune spread as a function of i) the measured shift of the quadrupolar mode, ii) the ratio between the two transverse equilibrium beam sizes and iii) the distance between the two transverse tunes.

  7. Regional brain stiffness changes across the Alzheimer's disease spectrum.

    Science.gov (United States)

    Murphy, Matthew C; Jones, David T; Jack, Clifford R; Glaser, Kevin J; Senjem, Matthew L; Manduca, Armando; Felmlee, Joel P; Carter, Rickey E; Ehman, Richard L; Huston, John

    2016-01-01

    Magnetic resonance elastography (MRE) is an MRI-based technique to noninvasively measure tissue stiffness. Currently well established for clinical use in the liver, MRE is increasingly being investigated to measure brain stiffness as a novel biomarker of a variety of neurological diseases. The purpose of this work was to apply a recently developed MRE pipeline to measure regional brain stiffness changes in human subjects across the Alzheimer's disease (AD) spectrum, and to gain insights into the biological processes underlying those stiffness changes by correlating stiffness with existing biomarkers of AD. The results indicate that stiffness changes occur mostly in the frontal, parietal and temporal lobes, in accordance with the known topography of AD pathology. Furthermore, stiffness in those areas correlates with existing imaging biomarkers of AD including hippocampal volumes and amyloid PET. Additional analysis revealed preliminary but significant evidence that the relationship between brain stiffness and AD severity is nonlinear and non-monotonic. Given that similar relationships have been observed in functional MRI experiments, we used task-free fMRI data to test the hypothesis that brain stiffness was sensitive to structural changes associated with altered functional connectivity. The analysis revealed that brain stiffness is significantly and positively correlated with default mode network connectivity. Therefore, brain stiffness as measured by MRE has potential to provide new and essential insights into the temporal dynamics of AD, as well as the relationship between functional and structural plasticity as it relates to AD pathophysiology.

  8. Assessment of the degree of asymmetry of pathological features in neurodegenerative diseases. What is the significance for brain banks?

    Science.gov (United States)

    King, Andrew; Bodi, Istvan; Nolan, Matthew; Troakes, Claire; Al-Sarraj, Safa

    2015-10-01

    Brain banks allow researchers access to tissue from well-characterised neurodegenerative disease cases. Fixed tissue employed for diagnosis is often not appropriate for research and frozen tissue is therefore made available. Many brain banks use a protocol where half the brain is fixed and half frozen. Recently a study has shown that there can be asymmetry in protein deposition between the hemispheres especially with tau and TDP-43. We aimed to test this hypothesis by prospectively taking bilateral cortical blocks from 30 brains on arrival, and immunostaining to assess the degree of asymmetry. In 6 out 14 cases of AD (Alzheimer's Disease) (Modified Braak Stage V-VI), there was some asymmetrical staining for tau. In 2 cases, there was moderate discrepancy for tau staining between left and right calcarine cortices. However, careful analysis in both these cases revealed discrepancies in tau staining in adjacent regions even on the same side. The α-synuclein staining showed asymmetry in one case only, the Aβ showed only mild asymmetry in 3 cases of AD. The TDP-43 pathology appeared symmetrical in the 2 cases of frontotemporal lobar degeneration with motor neurone disease, but there was asymmetry noted when seen in conjunction with AD. In conclusion, there is the potential for asymmetrical pathology in neurodegenerative diseases and caution should be maintained when freezing half and fixing half of the brain in neurodegenerative diseases. Nevertheless, marked variability in staining can also be identified in adjacent cortical areas so there is no guarantee that an alternative strategy would be superior.

  9. Olfactory deficits in Niemann-Pick type C1 (NPC1 disease.

    Directory of Open Access Journals (Sweden)

    Marina Hovakimyan

    Full Text Available BACKGROUND: Niemann-Pick type C disease (NPC is a rare autosomal recessive lipid storage disease characterized by progressive neurodegeneration. As only a few studies have been conducted on the impact of NPC on sensory systems, we used a mutant mouse model (NPC1(-/- to examine the effects of this disorder to morphologically distinct regions of the olfactory system, namely the olfactory epithelium (OE and olfactory bulb (OB. METHODOLOGY/PRINCIPAL FINDINGS: For structural and functional analysis immunohistochemistry, electron microscopy, western blotting, and electrophysiology have been applied. For histochemistry and western blotting, we used antibodies against a series of neuronal and glia marker proteins, as well as macrophage markers. NPC1(-/- animals present myelin-like lysosomal deposits in virtually all types of cells of the peripheral and central olfactory system. Especially supporting cells of the OE and central glia cells are affected, resulting in pronounced astrocytosis and microgliosis in the OB and other olfactory cortices. Up-regulation of Galectin-3, Cathepsin D and GFAP in the cortical layers of the OB underlines the critical role and location of the OB as a possible entrance gate for noxious substances. Unmyelinated olfactory afferents of the lamina propria seem less affected than ensheathing cells. Supporting the structural findings, electro-olfactometry of the olfactory mucosa suggests that NPC1(-/- animals exhibit olfactory and trigeminal deficits. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate a pronounced neurodegeneration and glia activation in the olfactory system of NPC1(-/-, which is accompanied by sensory deficits.

  10. The high order Schwarz-Pick lemma on complex Hilbert balls

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    In this paper we prove a high order Schwarz-Pick lemma for holomorphic mappings between unit balls in complex Hilbert spaces.In addition,a Schwarz-Pick estimate for high order Fréchet derivatives of a holomorphic function f of a Hilbert ball into the right half-plane is obtained.

  11. Two new species of Anastrepha Schiner (Diptera, Tephritidae) closely related to Anastrepha pickeli Lima.

    Science.gov (United States)

    Canal, N A; Uramoto, K; Zucchi, R A

    2013-02-01

    Anastrepha entodonta n. sp. and Anastrepha hadropickeli n. sp. are described and illustrated. The new species belong to the spatulata group. Both species occur sympatrically with Anastrepha pickeli Lima in the semiarid region of the state of Minas Gerais, Brazil. Anastrepha hadropickeli occurs also in the semiarid of the state of Rio Grande do Norte, Brazil, where it was misidentified as A. pickeli.

  12. Role of Lipids in Brain Injury and Diseases.

    Science.gov (United States)

    Adibhatla, Rao Muralikrishna; Hatcher, J F

    2007-08-01

    Lipid metabolism is of particular interest due to its high concentration in CNS. The importance of lipids in cell signaling and tissue physiology is demonstrated by many CNS disorders and injuries that involve deregulated metabolism. The long suffering lipid field is gaining reputation and respect as evidenced through the Center of Biomedical Research Excellence in Lipidomics and Pathobiology (COBRE), Lipid MAPS (Metabolites And Pathways Strategy) Consortium sponsored by NIH, European initiatives for decoding the lipids through genomic approaches, and Genomics of Lipid-associated Disorder (GOLD) project initiated by Austrian government. This review attempts to provide an overview of the lipid imbalances associated with neurological disorders (Alzheimer's, Parkinson's; Niemann-Pick; Multiple sclerosis, Huntington, amyotrophic lateral sclerosis, schizophrenia, bipolar disorders and epilepsy) and CNS injury (Stroke, traumatic brain injury; and spinal cord injury) and a few provocative thoughts. Lipidomic analyses along with RNA silencing will provide new insights into the role of lipid intermediates in cell signaling and hopefully open new avenues for prevention or treatment options.

  13. Susceptibility-Weighted Imaging Manifestations in the Brain of Wilson's Disease Patients.

    Directory of Open Access Journals (Sweden)

    Jinjing Yang

    Full Text Available It is well known that patients with Wilson's disease (WD suffer copper metabolism disorder. However, recent studies point to an additional iron metabolism disorder in WD patients. The purpose of our study was to examine susceptibility-weighted imaging (SWI manifestations of WD in the brains of WD patients.A total of 33 patients with WD and 18 normal controls underwent conventional MRI (Magnetic resonance imaging and SWI. The phase values were measured on SWI-filtered phase images of the bilateral head of the caudate nuclei, globus pallidus, putamen, thalamus, substantia nigra, and red nucleus. Student's t-tests were used to compare the phase values between WD groups and normal controls.The mean phase values for the bilateral head of the caudate nuclei, globus pallidus, putamen, thalamus, substantia nigra, and red nucleus were significantly lower than those in the control group (P < 0.001, and bilateral putamen was most strongly affected.There is paramagnetic mineralization deposition in brain gray nuclei of WD patients and SWI is an effective method to evaluate these structures.

  14. Region-specific tauopathy and synucleinopathy in brain of the alpha-synuclein overexpressing mouse model of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Masliah Eliezer

    2011-08-01

    Full Text Available Abstract Background α-synuclein [α-Syn]-mediated activation of GSK-3β leading to increases in hyperphosphorylated Tau has been shown by us to occur in striata of Parkinson's diseased [PD] patients and in animal models of PD. In Alzheimer's disease, tauopathy exists in several brain regions; however, the pattern of distribution of tauopathy in other brain regions of PD or in animal models of PD is not known. The current studies were undertaken to analyze the distribution of tauopathy in different brain regions in a widely used mouse model of PD, the α-Syn overexpressing mouse. Results High levels of α-Syn levels were seen in the brain stem, with a much smaller increase in the frontal cortex; neither cerebellum nor hippocampus showed any overexpression of α-Syn. Elevated levels of p-Tau, hyperphosphorylated at Ser202, Ser262 and Ser396/404, were seen in brain stem, with lower levels seen in hippocampus. In both frontal cortex and cerebellum, increases were seen only in p-Ser396/404 Tau, but not in p-Ser202 and p-Ser262. p-GSK-3β levels were not elevated in any of the brain regions, although total GSK-3β was elevated in brain stem. p-p38MAPK levels were unchanged in all brain regions examined, while p-ERK levels were elevated in brain stem, hippocampus and cerebellum, but not the frontal cortex. p-JNK levels were increased in brain stem and cerebellum but not in the frontal cortex or hippocampus. Elevated levels of free tubulin, indicating microtubule destabilization, were seen only in the brain stem. Conclusion Our combined data suggest that in this animal model of PD, tauopathy, along with microtubule destabilization, exists primarily in the brain stem and striatum, which are also the two major brain regions known to express high levels of α-Syn and undergo the highest levels of degeneration in human PD. Thus, tauopathy in PD may have a very restricted pattern of distribution.

  15. The BAR Domain Protein PICK1 Controls Vesicle Number and Size in Adrenal Chromaffin Cells

    DEFF Research Database (Denmark)

    da Silva Pinheiro, Paulo César; Jansen, Anna M; de Wit, Heidi

    2014-01-01

    Protein Interacting with C Kinase 1 (PICK1) is a Bin/Amphiphysin/Rvs (BAR) domain protein involved in AMPA receptor trafficking. Here, we identify a selective role for PICK1 in the biogenesis of large, dense core vesicles (LDCVs) in mouse chromaffin cells. PICK1 colocalized with syntaxin-6......, a marker for immature granules. In chromaffin cells isolated from a PICK1 knockout (KO) mouse the amount of exocytosis was reduced, while release kinetics and Ca(2+) sensitivity were unaffected. Vesicle-fusion events had a reduced frequency and released lower amounts of transmitter per vesicle (i.......e., reduced quantal size). This was paralleled by a reduction in the mean single-vesicle capacitance, estimated by averaging time-locked capacitance traces. EM confirmed that LDCVs were fewer and of markedly reduced size in the PICK1 KO, demonstrating that all phenotypes can be explained by reductions...

  16. Brain diseases and tumorigenesis: The good and bad cops of pentraxin3.

    Science.gov (United States)

    Fornai, Francesco; Carrizzo, Albino; Ferrucci, Michela; Damato, Antonio; Biagioni, Francesca; Gaglione, Anderson; Puca, Annibale Alessandro; Vecchione, Carmine

    2015-12-01

    The prototype of long pentraxins, Pentraxin 3 (PTX3), is an evolutionarily conserved multifunctional, pattern-recognition protein constituted by a cyclic multimeric structure. PTX3 interacts with a variety of ligands, such as growth factors, extracellular matrix components, molecules of the complement cascade, pathogens recognition proteins, angiogenetic and adhesion molecules. PTX3 could be considered as a molecular link between innate and adaptive immunity as well as between focal and circulating responses during inflammation. In fact, it modulates the functions of resident dendritic cells and circulating lymphocytes. Recent evidence demonstrates that manipulation of PTX3 may produce even opposite effects depending on which target organ is considered and the physiopathological context. In the present review we discuss the good and bad cops of PTX3 concerning multifacted effects on inflammation, innate immunity, brain diseases and tumorigenesis. Finally, a perspective on PTX3 and autophagy is provided as a convergent pathway.

  17. Coexistence of reactive plasticity and neurodegeneration in Alzheimer diseased brains

    OpenAIRE

    J. Guevara; Dilhuydy, H.; Espinosa, B.; Delacourte, A; Quirion, R; Mena, R.; Joanette, Y.; Zenteno, E; Robitaille, Y

    2004-01-01

    Alzheimer’s disease (AD) is a pathological process characterized by neuron degeneration and, as recently suggested, brain plasticity. In this work, we compared the reactive plasticity in AD brains associated to O-glycosydically linked glycans, recognized by lectins from Amaranthus leucocarpus (ALL) and Macrobrachium rosenbergii (MRL), and the tau neuritic degeneration. The neuritic degenerative process was evaluated by the quantification of aggregated neuritic ...

  18. Impact Factors of Choosing Willingness for Picking up Service

    Directory of Open Access Journals (Sweden)

    Jun-Jie Xu

    2013-08-01

    Full Text Available To obtain promotion schemes for picking up service in e-commerce logistics system, a regression analysis model of customer willingness was established with four types of independent variables including personal characteristics, parcel characteristics, environment characteristics and service evaluation on traditional home delivery. An empirical study with 479 samples collected from Taobao networks was conducted, if controlling gender and age, significant effects were confirmed such as perceived convenience on home delivery, age of online shopping, frequency of online shopping and parcel’s value. However the anticipated effects of traffic congestion, parcel dimensions, service evaluation on home delivery and other factors were not proved. The results investigated that attraction of picking up service was limited, related firms should propose a targeted marketing plan focusing on customer characteristics and parcel properties

  19. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease.

    Science.gov (United States)

    Cunnane, Stephen C; Courchesne-Loyer, Alexandre; St-Pierre, Valérie; Vandenberghe, Camille; Pierotti, Tyler; Fortier, Mélanie; Croteau, Etienne; Castellano, Christian-Alexandre

    2016-03-01

    Brain glucose uptake is impaired in Alzheimer's disease (AD). A key question is whether cognitive decline can be delayed if this brain energy defect is at least partly corrected or bypassed early in the disease. The principal ketones (also called ketone bodies), β-hydroxybutyrate and acetoacetate, are the brain's main physiological alternative fuel to glucose. Three studies in mild-to-moderate AD have shown that, unlike with glucose, brain ketone uptake is not different from that in healthy age-matched controls. Published clinical trials demonstrate that increasing ketone availability to the brain via moderate nutritional ketosis has a modest beneficial effect on cognitive outcomes in mild-to-moderate AD and in mild cognitive impairment. Nutritional ketosis can be safely achieved by a high-fat ketogenic diet, by supplements providing 20-70 g/day of medium-chain triglycerides containing the eight- and ten-carbon fatty acids octanoate and decanoate, or by ketone esters. Given the acute dependence of the brain on its energy supply, it seems reasonable that the development of therapeutic strategies aimed at AD mandates consideration of how the underlying problem of deteriorating brain fuel supply can be corrected or delayed. © 2016 New York Academy of Sciences.

  20. Mystery of the brain metastatic disease in breast cancer patients: improved patient stratification, disease prediction and targeted prevention on the horizon?

    Science.gov (United States)

    Polivka, Jiri; Kralickova, Milena; Polivka, Jiri; Kaiser, Christina; Kuhn, Walther; Golubnitschaja, Olga

    2017-06-01

    The breast cancer (BC) diagnosis currently experiences the epidemic evolution with more than half of million deaths each year. Despite screening programmes applied and treatments available, breast cancer patients frequently develop distant metastases. The brain is one of the predominant sites of the metastatic spread recorded for more than 20% of BC patients, in contrast to the general population, where brain tumours are rarely diagnosed. Although highly clinically relevant, the brain tumour mystery in the cohort of breast cancer patients has not been yet adequately explained. This review summarises currently available information on the risk factors predicting brain metastases in BC patients to motivate the relevant scientific areas to explore the data/facts available and elucidate disease-specific mechanisms that are of a great clinical utility.

  1. "My religion picked my birth control": the influence of religion on contraceptive use.

    Science.gov (United States)

    Hill, Nicholas J; Siwatu, Mxolisi; Robinson, Alexander K

    2014-06-01

    This research investigates the influence of religious preference and practice on the use of contraception. Much of earlier research examines the level of religiosity on sexual activity. This research extends this reasoning by suggesting that peer group effects create a willingness to mask the level of sexuality through the use of contraception. While it is understood that certain religions, that is, Catholicism does not condone the use of contraceptives, this research finds that Catholics are more likely to use certain methods of contraception than other religious groups. With data on contraceptive use from the Center for Disease Control's Family Growth Survey, a likelihood probability model is employed to investigate the impact religious affiliation on contraception use. Findings suggest a preference for methods that ensure non-pregnancy while preventing feelings of shame and condemnation in their religious communities.

  2. Resting state functional MRI in Parkinson's disease: the impact of deep brain stimulation on 'effective' connectivity.

    Science.gov (United States)

    Kahan, Joshua; Urner, Maren; Moran, Rosalyn; Flandin, Guillaume; Marreiros, Andre; Mancini, Laura; White, Mark; Thornton, John; Yousry, Tarek; Zrinzo, Ludvic; Hariz, Marwan; Limousin, Patricia; Friston, Karl; Foltynie, Tom

    2014-04-01

    Depleted of dopamine, the dynamics of the parkinsonian brain impact on both 'action' and 'resting' motor behaviour. Deep brain stimulation has become an established means of managing these symptoms, although its mechanisms of action remain unclear. Non-invasive characterizations of induced brain responses, and the effective connectivity underlying them, generally appeals to dynamic causal modelling of neuroimaging data. When the brain is at rest, however, this sort of characterization has been limited to correlations (functional connectivity). In this work, we model the 'effective' connectivity underlying low frequency blood oxygen level-dependent fluctuations in the resting Parkinsonian motor network-disclosing the distributed effects of deep brain stimulation on cortico-subcortical connections. Specifically, we show that subthalamic nucleus deep brain stimulation modulates all the major components of the motor cortico-striato-thalamo-cortical loop, including the cortico-striatal, thalamo-cortical, direct and indirect basal ganglia pathways, and the hyperdirect subthalamic nucleus projections. The strength of effective subthalamic nucleus afferents and efferents were reduced by stimulation, whereas cortico-striatal, thalamo-cortical and direct pathways were strengthened. Remarkably, regression analysis revealed that the hyperdirect, direct, and basal ganglia afferents to the subthalamic nucleus predicted clinical status and therapeutic response to deep brain stimulation; however, suppression of the sensitivity of the subthalamic nucleus to its hyperdirect afferents by deep brain stimulation may subvert the clinical efficacy of deep brain stimulation. Our findings highlight the distributed effects of stimulation on the resting motor network and provide a framework for analysing effective connectivity in resting state functional MRI with strong a priori hypotheses.

  3. Influence of drug transporters and stereoselectivity on the brain penetration of pioglitazone as a potential medicine against Alzheimer's disease.

    Science.gov (United States)

    Chang, Kai Lun; Pee, Hai Ning; Yang, Shili; Ho, Paul C

    2015-03-11

    Pioglitazone is currently undergoing clinical trials for treatment of Alzheimer's disease (AD). However, poor brain penetration remains an obstacle to development of the drug for such intended clinical uses. In this study, we demonstrate that the inhibition of P-glycoprotein (P-gp) significantly increases brain penetration of pioglitazone, whereas inhibition of breast cancer resistance protein (BCRP) has little effect. We also investigate the stereoselectivity of pioglitazone uptake in the brain. When mice were dosed with racemic pioglitazone, the concentration of (+)-pioglitazone was 46.6% higher than that of (-)-pioglitazone in brain tissue and 67.7% lower than that of (-)-pioglitazone in plasma. Dosing mice with pure (+)-pioglitazone led to a 76% increase in brain exposure levels compared to those from an equivalent dose of racemic pioglitazone. Pure (+)-pioglitazone was also shown to have comparable amyloid-lowering capabilities to the racemic pioglitazone in an in vitro AD model. These results suggest that P-gp may act as a stereoselective barrier to prevent pioglitazone entry into the brain. Dosing with (+)-pioglitazone instead of the racemic mixture may result in higher levels of brain exposure to pioglitazone, thus potentially improving the development of pioglitazone treatment of AD.

  4. Automated assessment of symptom severity changes during deep brain stimulation (DBS) therapy for Parkinson's disease.

    Science.gov (United States)

    Angeles, Paolo; Tai, Yen; Pavese, Nicola; Wilson, Samuel; Vaidyanathan, Ravi

    2017-07-01

    Deep brain stimulation (DBS) is currently being used as a treatment for symptoms of Parkinson's disease (PD). Tracking symptom severity progression and deciding the optimal stimulation parameters for people with PD is extremely difficult. This study presents a sensor system that can quantify the three cardinal motor symptoms of PD - rigidity, bradykinesia and tremor. The first phase of this study assesses whether data recorded from the system during physical examinations can be used to correlate to clinician's severity score using supervised machine learning (ML) models. The second phase concludes whether the sensor system can distinguish differences before and after DBS optimisation by a clinician when Unified Parkinson's Disease Rating Scale (UPDRS) scores did not change. An average accuracy of 90.9 % was achieved by the best ML models in the first phase, when correlating sensor data to clinician's scores. Adding on to this, in the second phase of the study, the sensor system was able to pick up discernible differences before and after DBS optimisation sessions in instances where UPDRS scores did not change.

  5. Pick-up and impact of flexible bodies

    Science.gov (United States)

    Singh, H.; Hanna, J. A.

    2017-09-01

    Picking up, laying down, colliding, rolling, and peeling are partial-contact interactions involving moving discontinuities. We examine the balances of momentum and energy across a moving discontinuity in a string, with allowance for injection or dissipation by singular supplies. We split the energy dissipation according to its invariance properties, discuss analogies with systems of particles and connections with the literature on shocks and phase transition fronts in various bodies, and derive a compatibility relation between supplies of momentum and translation-invariant energy. For a moving contact discontinuity between a string and a smooth rigid plane in the presence of gravity, we find a surprising asymmetry between the processes of picking up and laying down, such that steady-state kinks in geometry and associated jumps in tension are not admissible during pick-up. This prediction is consistent with experimental observations. We briefly discuss related problems including the falling folded chain, peeling of an adhesive tape, and the ;chain fountain;. Our approach is applicable to the study of impact and locomotion, and to systems such as moored floating structures and some musical instruments that feature vibrating string and cable elements interacting with a surface.

  6. A rare case of Niemann–Pick disease type C without neurological involvement in a 66-year-old patient

    Directory of Open Access Journals (Sweden)

    C.R. Greenberg

    2015-06-01

    Synopsis: An elderly female patient with confirmed NP-C and isolated splenomegaly has remained asymptomatic for neurological, cognitive, psychiatric or ophthalmologic abnormailities into her seventh decade of life.

  7. Detection of Avian bornavirus 5 RNA in Eclectus roratus with feather picking disorder.

    Science.gov (United States)

    Horie, Masayuki; Ueda, Kengo; Ueda, Akiko; Honda, Tomoyuki; Tomonaga, Keizo

    2012-05-01

    Avian bornavirus (ABV) was discovered recently in parrots with proventricular dilatation disease (PDD), a fatal neurological disease. Although ABV has been shown to be a causative agent of PDD, its virological characteristics are largely unknown. Here we report the detection of ABV genotype 5 RNA in an Eclectus roratus with feather picking disorder (FPD). Interestingly, although the bird was persistently infected with ABV5 for at least 8 months, it had no clinical signs of PDD. Although it remains unclear whether ABV5 is associated with FPD, these findings raise the importance of epidemiological studies of birds with diseases other than PDD. © 2012 The Societies and Blackwell Publishing Asia Pty Ltd.

  8. Prevalence and heritability of skin picking in an adult community sample: a twin study.

    Science.gov (United States)

    Monzani, Benedetta; Rijsdijk, Fruhling; Cherkas, Lynn; Harris, Juliette; Keuthen, Nancy; Mataix-Cols, David

    2012-07-01

    Skin-picking disorder (SPD) is a disabling psychiatric condition that can lead to skin damage and other medical complications. Epidemiological data is scarce and its causes are unknown. The present study examined the prevalence and heritability of skin-picking symptoms in a large sample of twins. A total of 2,518 twins completed a valid and reliable self-report measure of skin-picking behavior. The prevalence of clinically significant skin picking was established using empirically derived cut-offs. Twin modeling methods were employed to decompose the variance in the liability to skin picking into additive genetic and shared and non-shared environmental factors. A total of 1.2% of twins scored above the cut-off, indicative of clinically significant skin picking. All these participants were women. Univariate model-fitting analyses (female twins only, N = 2,191) showed that genetic factors accounted for approximately 40% (95% CI 19-58%) of the variance in skin picking, with non-shared environmental factors and measurement error accounting for the remaining variance (60% [95% CI 42-81%]). Shared environmental factors were negligible. It is concluded that pathological skin picking is relatively prevalent problem, particularly among women, and that it tends to run in families primarily due to genetic factors. Non-shared environmental factors are also likely to play an important role in its etiology.

  9. Clearance systems in the brain-implications for Alzheimer disease.

    Science.gov (United States)

    Tarasoff-Conway, Jenna M; Carare, Roxana O; Osorio, Ricardo S; Glodzik, Lidia; Butler, Tracy; Fieremans, Els; Axel, Leon; Rusinek, Henry; Nicholson, Charles; Zlokovic, Berislav V; Frangione, Blas; Blennow, Kaj; Ménard, Joël; Zetterberg, Henrik; Wisniewski, Thomas; de Leon, Mony J

    2015-08-01

    Accumulation of toxic protein aggregates-amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.

  10. Demonstration of aluminum in amyloid fibers in the cores of senile plaques in the brains of patients with Alzheimer's disease.

    Science.gov (United States)

    Yumoto, Sakae; Kakimi, Shigeo; Ohsaki, Akihiro; Ishikawa, Akira

    2009-11-01

    Aluminum (Al) exposure has been reported to be a risk factor for Alzheimer's disease (senile dementia of Alzheimer type), although the role of Al in the etiology of Alzheimer's disease remains controversial. We examined the presence of Al in the Alzheimer's brain using energy-dispersive X-ray spectroscopy combined with transmission electron microscopy (TEM-EDX). TEM-EDX analysis allows simultaneous imaging of subcellular structures with high spatial resolution and analysis of small quantities of elements contained in the same subcellular structures. We identified senile plaques by observation using TEM and detected Al in amyloid fibers in the cores of senile plaques located in the hippocampus and the temporal lobe by EDX. Phosphorus and calcium were also present in the amyloid fibers. No Al could be detected in the extracellular space in senile plaques or in the cytoplasm of nerve cells. In this study, we demonstrated colocalization of Al and beta-amyloid (Abeta) peptides in amyloid fibers in the cores of senile plaques. The results support the following possibilities in the brains of patients with Alzheimer's disease: Al could be involved in the aggregation of Abeta peptides to form toxic fibrils; Al might induce Abeta peptides into the beta-sheet structure; and Al might facilitate iron-mediated oxidative reactions, which cause severe damage to brain tissues.

  11. Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease.

    Directory of Open Access Journals (Sweden)

    Elena-Raluca Nicoli

    Full Text Available Niemann-Pick type C (NPC disease is a neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 gene. NPC is characterised by storage of multiple lipids in the late endosomal/lysosomal compartment, resulting in cellular and organ system dysfunction. The underlying molecular mechanisms that lead to the range of clinical presentations in NPC are not fully understood. While evaluating potential small molecule therapies in Npc1-/- mice, we observed a consistent pattern of toxicity associated with drugs metabolised by the cytochrome P450 system, suggesting a potential drug metabolism defect in NPC1 disease. Investigation of the P450 system in the context of NPC1 dysfunction revealed significant changes in the gene expression of many P450 associated genes across the full lifespan of Npc1-/- mice, decreased activity of cytochrome P450 reductase, and a global decrease of multiple cytochrome P450 catalysed dealkylation reactions. In vivo drug metabolism studies using a prototypic P450 metabolised drug, midazolam, confirmed dysfunction in drug clearance in the Npc1-/- mouse. Expression of the Phase II enzyme uridinediphosphate-glucuronosyltransferase (UGT was also significantly reduced in Npc1-/- mice. Interestingly, reduced activity within the P450 system was also observed in heterozygous Npc1+/- mice. The reduced activity of P450 enzymes may be the result of bile acid deficiency/imbalance in Npc1-/- mice, as bile acid treatment significantly rescued P450 enzyme activity in Npc1-/- mice and has the potential to be an adjunctive therapy for NPC disease patients. The dysfunction in the cytochrome P450 system were recapitulated in the NPC1 feline model. Additionally, we present the first evidence that there are alterations in the P450 system in NPC1 patients.

  12. A Stochastic Multidimensional Scaling Procedure for the Spatial Representation of Three-Mode, Three-Way Pick Any/"J" Data.

    Science.gov (United States)

    Jedidi, Kamel; DeSarbo, Wayne S.

    1991-01-01

    A stochastic multidimensional scaling procedure is presented for analysis of three-mode, three-way pick any/"J" data. The procedure fits both vector and ideal-point models and characterizes the effect of situations by a set of dimension weights. An application in the area of consumer psychology is discussed. (SLD)

  13. The effects of subthalamic deep brain stimulation on metaphor comprehension and language abilities in Parkinson's disease.

    Science.gov (United States)

    Tremblay, Christina; Macoir, Joël; Langlois, Mélanie; Cantin, Léo; Prud'homme, Michel; Monetta, Laura

    2015-02-01

    The effects of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) on different language abilities are still controversial and its impact on high-level language abilities such as metaphor comprehension has been overlooked. The aim of this study was to determine the effects of STN electrical stimulation on metaphor comprehension and language abilities such as lexical and semantic capacities. Eight PD individuals with bilateral STN-DBS were first evaluated OFF-DBS and, at least seven weeks later, ON-DBS. Performance on metaphor comprehension, lexical decision, word association and verbal fluency tasks were compared ON and OFF-DBS in addition to motor symptoms evaluation. STN stimulation had a significant beneficial effect on motor symptoms in PD. However, this stimulation did not have any effect on metaphor comprehension or any other cognitive ability evaluated in this study. These outcomes suggest that STN stimulation may have dissociable effects on motor and language functions.

  14. Treatment of Chronic Skin-Picking in an Adolescent With Asperger Syndrome and Borderline Intellectual Disability

    NARCIS (Netherlands)

    Lang, R.; Didden, H.C.M.; Sigafoos, J.; Rispoli, M.; Regester, A.; Lancioni, G.E.

    2009-01-01

    We present the case of a 17-year-old girl with Asperger syndrome and borderline intellectual disability with a 5-year history of chronic skin-picking. Our intervention approach included an initial functional assessment to identify variables maintaining skin-picking, followed by evaluation of a

  15. Treatment of Chronic Skin-Picking in an Adolescent With Asperger Syndrome and Borderline Intellectual Disability

    NARCIS (Netherlands)

    Lang, R.; Didden, H.C.M.; Sigafoos, J.; Rispoli, M.; Regester, A.; Lancioni, G.E.

    2009-01-01

    We present the case of a 17-year-old girl with Asperger syndrome and borderline intellectual disability with a 5-year history of chronic skin-picking. Our intervention approach included an initial functional assessment to identify variables maintaining skin-picking, followed by evaluation of a behav

  16. Treatment of Chronic Skin-Picking in an Adolescent With Asperger Syndrome and Borderline Intellectual Disability

    NARCIS (Netherlands)

    Lang, R.; Didden, H.C.M.; Sigafoos, J.; Rispoli, M.; Regester, A.; Lancioni, G.E.

    2009-01-01

    We present the case of a 17-year-old girl with Asperger syndrome and borderline intellectual disability with a 5-year history of chronic skin-picking. Our intervention approach included an initial functional assessment to identify variables maintaining skin-picking, followed by evaluation of a behav

  17. Structure of Dimeric and Tetrameric Complexes of the BAR Domain Protein PICK1 Determined by Small-Angle X-Ray Scattering.

    Science.gov (United States)

    Karlsen, Morten L; Thorsen, Thor S; Johner, Niklaus; Ammendrup-Johnsen, Ina; Erlendsson, Simon; Tian, Xinsheng; Simonsen, Jens B; Høiberg-Nielsen, Rasmus; Christensen, Nikolaj M; Khelashvili, George; Streicher, Werner; Teilum, Kaare; Vestergaard, Bente; Weinstein, Harel; Gether, Ulrik; Arleth, Lise; Madsen, Kenneth L

    2015-07-07

    PICK1 is a neuronal scaffolding protein containing a PDZ domain and an auto-inhibited BAR domain. BAR domains are membrane-sculpting protein modules generating membrane curvature and promoting membrane fission. Previous data suggest that BAR domains are organized in lattice-like arrangements when stabilizing membranes but little is known about structural organization of BAR domains in solution. Through a small-angle X-ray scattering (SAXS) analysis, we determine the structure of dimeric and tetrameric complexes of PICK1 in solution. SAXS and biochemical data reveal a strong propensity of PICK1 to form higher-order structures, and SAXS analysis suggests an offset, parallel mode of BAR-BAR oligomerization. Furthermore, unlike accessory domains in other BAR domain proteins, the positioning of the PDZ domains is flexible, enabling PICK1 to perform long-range, dynamic scaffolding of membrane-associated proteins. Together with functional data, these structural findings are compatible with a model in which oligomerization governs auto-inhibition of BAR domain function.

  18. The relevance of aging-related changes in brain function to rehabilitation in aging-related disease.

    Science.gov (United States)

    Crosson, Bruce; McGregor, Keith M; Nocera, Joe R; Drucker, Jonathan H; Tran, Stella M; Butler, Andrew J

    2015-01-01

    The effects of aging on rehabilitation of aging-related diseases are rarely a design consideration in rehabilitation research. In this brief review we present strong coincidental evidence from these two fields suggesting that deficits in aging-related disease or injury are compounded by the interaction between aging-related brain changes and disease-related brain changes. Specifically, we hypothesize that some aphasia, motor, and neglect treatments using repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) in stroke patients may address the aging side of this interaction. The importance of testing this hypothesis and addressing the larger aging by aging-related disease interaction is discussed. Underlying mechanisms in aging that most likely are relevant to rehabilitation of aging-related diseases also are covered.

  19. The relevance of aging-related changes in brain function to rehabilitation in aging-related disease

    Directory of Open Access Journals (Sweden)

    Bruce eCrosson

    2015-05-01

    Full Text Available The effects of aging on rehabilitation of aging-related diseases are rarely a design consideration in rehabilitation research. In this brief review we present strong coincidental evidence from these two fields suggesting that deficits in aging-related disease or injury are compounded by the interaction between aging-related brain changes and disease-related brain changes. Specifically, we hypothesize that some aphasia, motor, and neglect treatments using repetitive transcranial magnetic stimulation (rTMS or transcranial direct current stimulation (tDCS in stroke patients may address the aging side of this interaction. The importance of testing this hypothesis and addressing the larger aging by aging-related disease interaction is discussed. Underlying mechanisms in aging that most likely are relevant to rehabilitation of aging-related diseases also are covered.

  20. Behavioral Treatment of Chronic Skin-Picking in Individuals with Developmental Disabilities: A Systematic Review

    Science.gov (United States)

    Lang, Russell; Didden, Robert; Machalicek, Wendy; Rispoli, Mandy; Sigafoos, Jeff; Lancioni, Giulio; Mulloy, Austin; Regester, April; Pierce, Nigel; Kang, Soyeon

    2010-01-01

    Skin-picking is a type of self-injurious behavior involving the pulling, scratching, lancing, digging, or gouging of one's own body. It is associated with social impairment, and increased medical and mental health concerns. While there are several reports showing that skin-picking is common in individuals with developmental disabilities, knowledge…

  1. Behavioral treatment of chronic skin-picking in individuals with developmental disabilities: A systematic review

    NARCIS (Netherlands)

    Lang, R.; Didden, H.C.M.; Machalicek, W.A.; Rispoli, M.; Sigafoos, J.; Lancioni, G.E.; Mulloy, A.; Regester, A.; Pierce, N.; Kang, S.Y.

    2010-01-01

    Skin-picking is a type of self-injurious behavior involving the pulling, scratching, lancing, digging, or gouging of one's own body. It is associated with social impairment, and increased medical and mental health concerns. While there are several reports showing that skin-picking is common in indiv

  2. In vivo bioluminescence imaging of neurogenesis - the role of the blood brain barrier in an experimental model of Parkinson's disease.

    Science.gov (United States)

    Fricke, Inga B; Schelhaas, Sonja; Zinnhardt, Bastian; Viel, Thomas; Hermann, Sven; Couillard-Després, Sébastien; Jacobs, Andreas H

    2017-02-13

    Bioluminescence imaging in transgenic mice expressing firefly luciferase in Doublecortin(+) (Dcx) neuroblasts might serve as a powerful tool to study the role of neurogenesis in models of brain injury and neurodegeneration using non-invasive, longitudinal in vivo imaging. Therefore, we aimed to use BLI in B6(Cg)-Tyrc-2J/J Dcx-Luc (Doublecortin-Luciferase, Dcx-Luc) mice to investigate its suitability to assess neurogenesis in a unilateral injection model of Parkinson's disease. We further aimed to assess the blood brain barrier leakage associated with the intranigral 6-OHDA injection to evaluate its impact on substrate delivery and bioluminescence signal intensity. Two weeks after lesion, we observed an increase in bioluminescence signal in the ipsilateral hippocampal region in both, 6-OHDA and vehicle injected Dcx-Luc mice. At the same time, no corresponding increase in Dcx(+) neuroblast numbers could be observed in the dentate gyrus of C57Bl6 mice. Blood brain barrier leakage was observed in the hippocampal region and in the degenerating substantia nigra of C57Bl6 mice in vivo using T1 weighted Magnetic Resonance Imaging with Gadovist(®) and ex vivo using Evans Blue Fluorescence Reflectance Imaging and mouse Immunoglobulin G staining. Our data suggests a BLI signal dependency on blood brain barrier permeability, underlining a major pitfall of substrate/tracer dependent imaging in invasive disease models.

  3. Theory of feedback controlled brain stimulations for Parkinson's disease

    Science.gov (United States)

    Sanzeni, A.; Celani, A.; Tiana, G.; Vergassola, M.

    2016-01-01

    Limb tremor and other debilitating symptoms caused by the neurodegenerative Parkinson's disease are currently treated by administering drugs and by fixed-frequency deep brain stimulation. The latter interferes directly with the brain dynamics by delivering electrical impulses to neurons in the subthalamic nucleus. While deep brain stimulation has shown therapeutic benefits in many instances, its mechanism is still unclear. Since its understanding could lead to improved protocols of stimulation and feedback control, we have studied a mathematical model of the many-body neural network dynamics controlling the dynamics of the basal ganglia. On the basis of the results obtained from the model, we propose a new procedure of active stimulation, that depends on the feedback of the network and that respects the constraints imposed by existing technology. We show by numerical simulations that the new protocol outperforms the standard ones for deep brain stimulation and we suggest future experiments that could further improve the feedback procedure.

  4. Simulating the Evolution of Functional Brain Networks in Alzheimer’s Disease: Exploring Disease Dynamics from the Perspective of Global Activity

    Science.gov (United States)

    Li, Wei; Wang, Miao; Zhu, Wenzhen; Qin, Yuanyuan; Huang, Yue; Chen, Xi

    2016-01-01

    Functional brain connectivity is altered during the pathological processes of Alzheimer’s disease (AD), but the specific evolutional rules are insufficiently understood. Resting-state functional magnetic resonance imaging indicates that the functional brain networks of individuals with AD tend to be disrupted in hub-like nodes, shifting from a small world architecture to a random profile. Here, we proposed a novel evolution model based on computational experiments to simulate the transition of functional brain networks from normal to AD. Specifically, we simulated the rearrangement of edges in a pathological process by a high probability of disconnecting edges between hub-like nodes, and by generating edges between random pair of nodes. Subsequently, four topological properties and a nodal distribution were used to evaluate our model. Compared with random evolution as a null model, our model captured well the topological alteration of functional brain networks during the pathological process. Moreover, we implemented two kinds of network attack to imitate the damage incurred by the brain in AD. Topological changes were better explained by ‘hub attacks’ than by ‘random attacks’, indicating the fragility of hubs in individuals with AD. This model clarifies the disruption of functional brain networks in AD, providing a new perspective on topological alterations. PMID:27677360

  5. The role of free radicals in the aging brain and Parkinson's Disease: convergence and parallelism.

    Science.gov (United States)

    Kumar, Hemant; Lim, Hyung-Woo; More, Sandeep Vasant; Kim, Byung-Wook; Koppula, Sushruta; Kim, In Su; Choi, Dong-Kug

    2012-01-01

    Free radical production and their targeted action on biomolecules have roles in aging and age-related disorders such as Parkinson's disease (PD). There is an age-associated increase in oxidative damage to the brain, and aging is considered a risk factor for PD. Dopaminergic neurons show linear fallout of 5-10% per decade with aging; however, the rate and intensity of neuronal loss in patients with PD is more marked than that of aging. Here, we enumerate the common link between aging and PD at the cellular level with special reference to oxidative damage caused by free radicals. Oxidative damage includes mitochondrial dysfunction, dopamine auto-oxidation, α-synuclein aggregation, glial cell activation, alterations in calcium signaling, and excess free iron. Moreover, neurons encounter more oxidative stress as a counteracting mechanism with advancing age does not function properly. Alterations in transcriptional activity of various pathways, including nuclear factor erythroid 2-related factor 2, glycogen synthase kinase 3β, mitogen activated protein kinase, nuclear factor kappa B, and reduced activity of superoxide dismutase, catalase and glutathione with aging might be correlated with the increased incidence of PD.

  6. Deep brain stimulation and cognitive decline in Parkinson's disease: The predictive value of electroencephalography.

    Science.gov (United States)

    Markser, A; Maier, Franziska; Lewis, C J; Dembek, T A; Pedrosa, D; Eggers, C; Timmermann, L; Kalbe, E; Fink, G R; Burghaus, Lothar

    2015-10-01

    Some Parkinson's disease (PD) patients treated with subthalamic nucleus deep brain stimulation (STN-DBS) develop new-onset cognitive decline. We examined whether clinical EEG recordings can be used to predict cognitive deterioration in PD patients undergoing STN-DBS. In this retrospective study, we used the Grand Total EEG (GTE)-score (short and total) to evaluate pre- and postoperative EEGs. In PD patients undergoing STN-DBS (N = 30), cognitive functioning was measured using Mini-Mental State Test and DemTect before and after surgery. Severity of motor impairment was assessed using the Unified Parkinson's Disease Rating Scale-III. Patients were classified into patients with or without cognitive decline after STN-DBS surgery. Epidemiological data, pre- and postoperative EEG recordings as well as neuropsychological and neurological data, electrode positions and the third ventricle width were compared. A logistic regression model was used to identify predictors of cognitive decline. Motor deficits significantly improved from pre- to post-surgery, while the mean GTE-scores increased significantly. Six patients developed cognitive deterioration 4-12 months postoperatively. These patients had significantly higher preoperative GTE-scores than patients without cognitive deterioration, although preoperative cognitive functioning was comparable. Electrode positions, brain atrophy and neurological data did not differ between groups. Logistic regression analysis identified the GTE-score as a significant predictor of postoperative cognitive deterioration. Data suggest that the preoperative GTE-score can be used to identify PD patients that are at high risk for developing cognitive deterioration after STN-DBS surgery even though their preoperative cognitive state was normal.

  7. [Functional imaging of deep brain stimulation in idiopathic Parkinson's disease].

    Science.gov (United States)

    Hilker, R

    2010-10-01

    Functional brain imaging allows the effects of deep brain stimulation (DBS) on the living human brain to be investigated. In patients with advanced Parkinson's disease (PD), positron emission tomography (PET) studies were undertaken at rest as well as under motor, cognitive or behavioral activation. DBS leads to a reduction of abnormal PD-related network activity in the motor system, which partly correlates with the improvement of motor symptoms. The local increase of energy consumption within the direct target area suggests a predominant excitatory influence of the stimulation current on neuronal tissue. Remote effects of DBS of the subthalamic nucleus (STN) on frontal association cortices indicate an interference of stimulation energy with associative and limbic basal ganglia loops. Taken together, functional brain imaging provides very valuable data for advancement of the DBS technique in PD therapy.

  8. Biomechanics of the brain

    CERN Document Server

    Miller, Karol

    2011-01-01

    With contributions from scientists at major institutions, this book presents an introduction to brain anatomy for engineers and scientists. It provides, for the first time, a comprehensive resource in the field of brain biomechanics.

  9. The Role of the Blood-Brain Barrier in the Pathogenesis of Senile Plaques in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    J. Provias

    2014-01-01

    Full Text Available The accumulation of beta-amyloid [Aβ] within senile plaques [SP] is characteristic of these lesions in Alzheimer’s disease. The accumulation of Aβ42, in particular, in the superior temporal [ST] cortex may result from an inability of the blood brain barrier (BBB to regulate the trans-endothelial transport and clearance of the amyloid. Lipoprotein receptor-related protein [LRP] and P-glycoprotein [P-gp] facilitate the efflux of Aβ out of the brain, whereas receptor for advanced glycation end products [RAGE] facilitates Aβ influx. Additionally, vascular endothelial growth factor [VEGF] and endothelial nitric oxide synthase [eNOS] may influence the trans-BBB transport of Aβ. In this study we examined ST samples and compared SP burden of all types with the capillary expression of LRP, p-gp, RAGE, VEGF, and e-NOS in samples from 15 control and 15 Alzheimer brains. LRP, P-gp, RAGE, VEGF, and eNOS positive capillaries and Aβ42 plaques were quantified and statistical analysis of the nonparametric data was performed using the Mann-Whitney and Kruskal-Wallis tests. In the Alzheimer condition P-gp, VEGF, and eNOS positive capillaries were negatively correlated with SP burden, but LRP and RAGE were positively correlated with SP burden. These results indicate altered BBB function in the pathogenesis of SPs in Alzheimer brains.

  10. Insights into brain function through the examination of art: the influence of neurodegenerative diseases.

    Science.gov (United States)

    Kleiner-Fisman, Galit; Lang, Anthony E

    2004-04-29

    There has been intense interest in determining how the visual brain processes the outside world, and in identifying the neuroanatomical correlates of the ability to create art. Comparing art production before and after illness onset permits some speculation on the function of selective brain regions affected by the neurodegenerative process. In this review of cases of neurodegenerative illness in visual artists, the evolution of abstraction may be argued to either reflect an enhancement of previous skills or, that the emergence of abstraction, when it was previously absent, is a manifestation of cognitive and visuo-spatial decline. We present examples of each, illustrating both perspectives and suggest that the two opposing views may not be mutually exclusive.

  11. Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways

    Directory of Open Access Journals (Sweden)

    Zilka Norbert

    2012-03-01

    Full Text Available Abstract Neurodegeneration, induced by misfolded tau protein, and neuroinflammation, driven by glial cells, represent the salient features of Alzheimer's disease (AD and related human tauopathies. While tau neurodegeneration significantly correlates with disease progression, brain inflammation seems to be an important factor in regulating the resistance or susceptibility to AD neurodegeneration. Previously, it has been shown that there is a reciprocal relationship between the local inflammatory response and neurofibrillary lesions. Numerous independent studies have reported that inflammatory responses may contribute to the development of tau pathology and thus accelerate the course of disease. It has been shown that various cytokines can significantly affect the functional and structural properties of intracellular tau. Notwithstanding, anti-inflammatory approaches have not unequivocally demonstrated that inhibition of the brain immune response can lead to reduction of neurofibrillary lesions. On the other hand, our recent data show that misfolded tau could represent a trigger for microglial activation, suggesting the dual role of misfolded tau in the Alzheimer's disease inflammatory cascade. On the basis of current knowledge, we can conclude that misfolded tau is located at the crossroad of the neurodegenerative and neuroinflammatory pathways. Thus disease-modified tau represents an important target for potential therapeutic strategies for patients with Alzheimer's disease.

  12. Neuroprotective Effect against Alzheimer's Disease of Porcine Brain Extract

    Directory of Open Access Journals (Sweden)

    Wipawee Thukham-Mee

    2012-01-01

    Full Text Available Problem statement: Despite the increasing importance of Alzheimer’s disease, no effective therapeutic strategy is available. Therefore, neuroprotective strategy is still required. Recent findings show that numerous substances possessing antioxidant can improve neurodegeneration and memory impairment. Based on the antioxidant effect and its reputation to serve as brain tonic in traditional folklore, we hypothesized that porcine brain extract could mitigate neurodegeneration and memory impairment. Therefore, this study was set up to determine the effect of porcine brain extract on memory impairment and neurodegeneration in animal models of Alzheimer’s disease. Approach: Male Wistar rats (180-220 g had been orally given porcine brain extract at doses of 0.5 and 2.5 mg kg-1 BW for a period of 4 weeks before and 1 week after the induction of cognitive deficit condition as those found in early phase of Alzheimer’s disease via the intraventricular injection of AF64A, a cholinotoxin. Rats were assessed the spatial memory using Morris water maze test. Then, they were determined neuron density in hippocampus using histological techniques. Moreover, the assessment of acetylcholinesterase (AChE activity and malondialdehyde (MDA level in hippocampus were also performed. Results: It was found that both doses of porcine brain extract could enhance memory, neuron and cholinergic neuron density in all subregions of hippocampus. In addition, the decreased AChE and MDA were also observed. Therefore, our results suggested that the possible underlying mechanism of the extract might occur partly via the decrease in oxidative stress marker, MDA and AChE. Conclusion: This study clearly demonstrates that porcine brain extract can protect against memory impairment and neurodegeneration in animal model of Alzheimer’s disease. Therefore, it should be serve as the potential food supplement or adjuvant therapy against Alzheimer’s disease and other age-related cognitive

  13. Staging of Neurofibrillary Pathology in Alzheimer's Disease: A Study of the BrainNet Europe Consortium

    Science.gov (United States)

    Alafuzoff, Irina; Arzberger, Thomas; Al-Sarraj, Safa; Bodi, Istvan; Bogdanovic, Nenad; Braak, Heiko; Bugiani, Orso; Del-Tredici, Kelly; Ferrer, Isidro; Gelpi, Ellen; Giaccone, Giorgio; Graeber, Manuel B; Ince, Paul; Kamphorst, Wouter; King, Andrew; Korkolopoulou, Penelope; Kovács, Gábor G; Larionov, Sergey; Meyronet, David; Monoranu, Camelia; Parchi, Piero; Patsouris, Efstratios; Roggendorf, Wolfgang; Seilhean, Danielle; Tagliavini, Fabrizio; Stadelmann, Christine; Streichenberger, Nathalie; Thal, Dietmar R; Wharton, Stephen B; Kretzschmar, Hans

    2008-01-01

    It has been recognized that molecular classifications will form the basis for neuropathological diagnostic work in the future. Consequently, in order to reach a diagnosis of Alzheimer's disease (AD), the presence of hyperphosphorylated tau (HP-tau) and β-amyloid protein in brain tissue must be unequivocal. In addition, the stepwise progression of pathology needs to be assessed. This paper deals exclusively with the regional assessment of AD-related HP-tau pathology. The objective was to provide straightforward instructions to aid in the assessment of AD-related immunohistochemically (IHC) detected HP-tau pathology and to test the concordance of assessments made by 25 independent evaluators. The assessment of progression in 7-µm-thick sections was based on assessment of IHC labeled HP-tau immunoreactive neuropil threads (NTs). Our results indicate that good agreement can be reached when the lesions are substantial, i.e., the lesions have reached isocortical structures (stage V–VI absolute agreement 91%), whereas when only mild subtle lesions were present the agreement was poorer (I–II absolute agreement 50%). Thus, in a research setting when the extent of lesions is mild, it is strongly recommended that the assessment of lesions should be carried out by at least two independent observers. PMID:18371174

  14. The Recognition and Treatment of Pathological Skin Picking: A Potential Neurobiological Underpinning of the Efficacy of Pharmacotherapy in Impulse Control Disorders

    OpenAIRE

    David R. Spiegel; Finklea, Lindsey

    2009-01-01

    Pathological skin picking is an impulse control disorder that causes significant anxiety and disfigurement to those afflicted. Standard therapy with a selective serotonin reuptake inhibitor provides variable and often suboptimal responses. We report a case of pathological skin picking treated with paliperidone, a 5-HT2/D2 antagonist.

  15. Network structure of brain atrophy in de novo Parkinson's disease.

    Science.gov (United States)

    Zeighami, Yashar; Ulla, Miguel; Iturria-Medina, Yasser; Dadar, Mahsa; Zhang, Yu; Larcher, Kevin Michel-Herve; Fonov, Vladimir; Evans, Alan C; Collins, D Louis; Dagher, Alain

    2015-09-07

    We mapped the distribution of atrophy in Parkinson's disease (PD) using magnetic resonance imaging (MRI) and clinical data from 232 PD patients and 117 controls from the Parkinson's Progression Markers Initiative. Deformation-based morphometry and independent component analysis identified PD-specific atrophy in the midbrain, basal ganglia, basal forebrain, medial temporal lobe, and discrete cortical regions. The degree of atrophy reflected clinical measures of disease severity. The spatial pattern of atrophy demonstrated overlap with intrinsic networks present in healthy brain, as derived from functional MRI. Moreover, the degree of atrophy in each brain region reflected its functional and anatomical proximity to a presumed disease epicenter in the substantia nigra, compatible with a trans-neuronal spread of the disease. These results support a network-spread mechanism in PD. Finally, the atrophy pattern in PD was also seen in healthy aging, where it also correlated with the loss of striatal dopaminergic innervation.

  16. When "Picking the Right People" Is Not Enough: A Bourdieuian Analysis of Social Justice and Dispositional Change in Pre-Service Teachers

    Science.gov (United States)

    Mills, Carmen

    2012-01-01

    Teacher educators across the world face a daunting task: preparing predominantly White, middle class, pre-service teachers to be effective educators of diverse students. With predispositions arguably more powerful socialising influences than pre-service education (Lortie, 1975), selective recruitment has been advocated: "picking the right…

  17. Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders.

    Directory of Open Access Journals (Sweden)

    Michael Zech

    Full Text Available Niemann-Pick type C (NPC disease is a rare autosomal-recessively inherited lysosomal storage disorder caused by mutations in NPC1 (95% or NPC2. Given the highly variable phenotype, diagnosis is challenging and particularly late-onset forms with predominantly neuropsychiatric presentations are likely underdiagnosed. Pathophysiologically, genetic alterations compromising the endosomal/lysosomal system are linked with age-related neurodegenerative disorders. We sought to examine a possible association of rare sequence variants in NPC1 and NPC2 with Parkinson's disease (PD, frontotemporal lobar degeneration (FTLD and progressive supranuclear palsy (PSP, and to genetically determine the proportion of potentially misdiagnosed NPC patients in these neurodegenerative conditions. By means of high-resolution melting, we screened the coding regions of NPC1 and NPC2 for rare genetic variation in a homogenous German sample of patients clinically diagnosed with PD (n = 563, FTLD (n = 133 and PSP (n = 94, and 846 population-based controls. The frequencies of rare sequence variants in NPC1/2 did not differ significantly between patients and controls. Disease-associated NPC1/2 mutations were found in six PD patients (1.1% and seven control subjects (0.8%, but not in FTLD or PSP. All rare variation was detected in the heterozygous state and no compound heterozygotes were observed. Our data do not support the hypothesis that rare NPC1/2 variants confer susceptibility for PD, FTLD, or PSP in the German population. Misdiagnosed NPC patients were not present in our samples. However, further assessment of NPC disease genes in age-related neurodegeneration is warranted.

  18. Understanding the Role of GPCR Heteroreceptor Complexes in Modulating the Brain Networks in Health and Disease

    Science.gov (United States)

    Borroto-Escuela, Dasiel O.; Carlsson, Jens; Ambrogini, Patricia; Narváez, Manuel; Wydra, Karolina; Tarakanov, Alexander O.; Li, Xiang; Millón, Carmelo; Ferraro, Luca; Cuppini, Riccardo; Tanganelli, Sergio; Liu, Fang; Filip, Malgorzata; Diaz-Cabiale, Zaida; Fuxe, Kjell

    2017-01-01

    The introduction of allosteric receptor–receptor interactions in G protein-coupled receptor (GPCR) heteroreceptor complexes of the central nervous system (CNS) gave a new dimension to brain integration and neuropsychopharmacology. The molecular basis of learning and memory was proposed to be based on the reorganization of the homo- and heteroreceptor complexes in the postjunctional membrane of synapses. Long-term memory may be created by the transformation of parts of the heteroreceptor complexes into unique transcription factors which can lead to the formation of specific adapter proteins. The observation of the GPCR heterodimer network (GPCR-HetNet) indicated that the allosteric receptor–receptor interactions dramatically increase GPCR diversity and biased recognition and signaling leading to enhanced specificity in signaling. Dysfunction of the GPCR heteroreceptor complexes can lead to brain disease. The findings of serotonin (5-HT) hetero and isoreceptor complexes in the brain over the last decade give new targets for drug development in major depression. Neuromodulation of neuronal networks in depression via 5-HT, galanin peptides and zinc involve a number of GPCR heteroreceptor complexes in the raphe-hippocampal system: GalR1-5-HT1A, GalR1-5-HT1A-GPR39, GalR1-GalR2, and putative GalR1-GalR2-5-HT1A heteroreceptor complexes. The 5-HT1A receptor protomer remains a receptor enhancing antidepressant actions through its participation in hetero- and homoreceptor complexes listed above in balance with each other. In depression, neuromodulation of neuronal networks in the raphe-hippocampal system and the cortical regions via 5-HT and fibroblast growth factor 2 involves either FGFR1-5-HT1A heteroreceptor complexes or the 5-HT isoreceptor complexes such as 5-HT1A-5-HT7 and 5-HT1A-5-HT2A. Neuromodulation of neuronal networks in cocaine use disorder via dopamine (DA) and adenosine signals involve A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complexes in the dorsal and

  19. Understanding the Role of GPCR Heteroreceptor Complexes in Modulating the Brain Networks in Health and Disease.

    Science.gov (United States)

    Borroto-Escuela, Dasiel O; Carlsson, Jens; Ambrogini, Patricia; Narváez, Manuel; Wydra, Karolina; Tarakanov, Alexander O; Li, Xiang; Millón, Carmelo; Ferraro, Luca; Cuppini, Riccardo; Tanganelli, Sergio; Liu, Fang; Filip, Malgorzata; Diaz-Cabiale, Zaida; Fuxe, Kjell

    2017-01-01

    The introduction of allosteric receptor-receptor interactions in G protein-coupled receptor (GPCR) heteroreceptor complexes of the central nervous system (CNS) gave a new dimension to brain integration and neuropsychopharmacology. The molecular basis of learning and memory was proposed to be based on the reorganization of the homo- and heteroreceptor complexes in the postjunctional membrane of synapses. Long-term memory may be created by the transformation of parts of the heteroreceptor complexes into unique transcription factors which can lead to the formation of specific adapter proteins. The observation of the GPCR heterodimer network (GPCR-HetNet) indicated that the allosteric receptor-receptor interactions dramatically increase GPCR diversity and biased recognition and signaling leading to enhanced specificity in signaling. Dysfunction of the GPCR heteroreceptor complexes can lead to brain disease. The findings of serotonin (5-HT) hetero and isoreceptor complexes in the brain over the last decade give new targets for drug development in major depression. Neuromodulation of neuronal networks in depression via 5-HT, galanin peptides and zinc involve a number of GPCR heteroreceptor complexes in the raphe-hippocampal system: GalR1-5-HT1A, GalR1-5-HT1A-GPR39, GalR1-GalR2, and putative GalR1-GalR2-5-HT1A heteroreceptor complexes. The 5-HT1A receptor protomer remains a receptor enhancing antidepressant actions through its participation in hetero- and homoreceptor complexes listed above in balance with each other. In depression, neuromodulation of neuronal networks in the raphe-hippocampal system and the cortical regions via 5-HT and fibroblast growth factor 2 involves either FGFR1-5-HT1A heteroreceptor complexes or the 5-HT isoreceptor complexes such as 5-HT1A-5-HT7 and 5-HT1A-5-HT2A. Neuromodulation of neuronal networks in cocaine use disorder via dopamine (DA) and adenosine signals involve A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complexes in the dorsal and

  20. Genetic control of human brain transcript expression in Alzheimer disease.

    Science.gov (United States)

    Webster, Jennifer A; Gibbs, J Raphael; Clarke, Jennifer; Ray, Monika; Zhang, Weixiong; Holmans, Peter; Rohrer, Kristen; Zhao, Alice; Marlowe, Lauren; Kaleem, Mona; McCorquodale, Donald S; Cuello, Cindy; Leung, Doris; Bryden, Leslie; Nath, Priti; Zismann, Victoria L; Joshipura, Keta; Huentelman, Matthew J; Hu-Lince, Diane; Coon, Keith D; Craig, David W; Pearson, John V; Heward, Christopher B; Reiman, Eric M; Stephan, Dietrich; Hardy, John; Myers, Amanda J

    2009-04-01

    We recently surveyed the relationship between the human brain transcriptome and genome in a series of neuropathologically normal postmortem samples. We have now analyzed additional samples with a confirmed pathologic diagnosis of late-onset Alzheimer disease (LOAD; final n = 188 controls, 176 cases). Nine percent of the cortical transcripts that we analyzed had expression profiles correlated with their genotypes in the combined cohort, and approximately 5% of transcripts had SNP-transcript relationships that could distinguish LOAD samples. Two of these transcripts have been previously implicated in LOAD candidate-gene SNP-expression screens. This study shows how the relationship between common inherited genetic variants and brain transcript expression can be used in the study of human brain disorders. We suggest that studying the transcriptome as a quantitative endo-phenotype has greater power for discovering risk SNPs influencing expression than the use of discrete diagnostic categories such as presence or absence of disease.

  1. The metabolic syndrome: a brain disease?

    NARCIS (Netherlands)

    Buijs, R.M.; Kreier, F.

    2006-01-01

    The incidence of obesity with, as consequence, a rise in associated diseases such as diabetes, hypertension and dyslipidemia--the metabolic syndrome--is reaching epidemic proportions in industrialized countries. Here, we provide a hypothesis that the biological clock which normally prepares us each

  2. Examining the Relationship between Heart Rate and Problem Behavior: A Case Study of Severe Skin Picking in Prader-Willi Syndrome

    Science.gov (United States)

    Hall, Scott S.; Hammond, Jennifer L.; Hustyi, Kristin M.

    2013-01-01

    Few studies have examined the relationship between heart rate and self-injurious behavior (SIB) shown by individuals with IDD (intellectual and developmental disabilities). In this single-case study, we simultaneously monitored heart rate and activity levels during a functional analysis of severe skin picking behavior exhibited by a young man with…

  3. Examining the Relationship between Heart Rate and Problem Behavior: A Case Study of Severe Skin Picking in Prader-Willi Syndrome

    Science.gov (United States)

    Hall, Scott S.; Hammond, Jennifer L.; Hustyi, Kristin M.

    2013-01-01

    Few studies have examined the relationship between heart rate and self-injurious behavior (SIB) shown by individuals with IDD (intellectual and developmental disabilities). In this single-case study, we simultaneously monitored heart rate and activity levels during a functional analysis of severe skin picking behavior exhibited by a young man with…

  4. [The blood-brain barrier and neurodegenerative lysosomal storage diseases].

    Science.gov (United States)

    Urayama, Akihiko

    2013-02-01

    Enzyme replacement therapy has been a very effective treatment for several lysosomal storage diseases. However, correcting central nervous system (CNS) storage has been challenging due to the presence of the blood-brain barrier (BBB), which hampers the entry of circulating lysosomal enzymes into the brain. In our previous studies, we discovered that luminally expressed cation-independent mannose 6-phosphate (M6P) receptor is a universal transporter for lysosomal enzymes that contain M6P moieties on the enzyme molecule. This receptor-mediated transport of lysosomal enzymes showed developmental down-regulation that resulted in a failure of delivery of lysosomal enzymes across the BBB in the adult brain. Conceptually, if one can re-induce M6P receptor-mediated transport of lysosomal enzymes in adult BBB, this could provide a novel brain targeting approach for treating abnormal storage in the CNS, regardless of the age of subjects. We found that systemic adrenergic stimuli restored functional transport of β-glucuronidase across the adult BBB. The concept of manipulating BBB transport activity by endogenous characteristics has also been demonstrated by another group who showed effective treatment in a Pompe disease model animal in vivo. It is intriguing that lysosomal enzymes utilize multiple mechanisms for their transport across the BBB. This review explores pharmacological manipulations for the delivery of lysosomal enzymes into the CNS, and the mechanisms of their transport across the BBB, based on existing evidence from studies of β-glucuronidase, sulfamidase, acid α-glucosidase, and arylsulfatase A.

  5. Development of the Young Brain

    Medline Plus

    Full Text Available ... items) Brain Anatomy and Physiology (9 items) RDoC (4 items) Research Funding (2 items) Training (1 item) Other Treatments (11 items) Alzheimer’s Disease (2 items) Coping with Traumatic Events (3 items) Institute Announcements (24 items) Development of the Young Brain May 2, 2011 For ...

  6. [Study on distribution of neural stem cells in the brain of Alzheimer disease transgenic mice through caudal vein transplantation].

    Science.gov (United States)

    Zhan, Yan-qiang; Wang, Fu-rong; Li, Feng-guang; Xing, Bian-zhi; Fang, Xin; Zhang, Su-ming

    2007-07-03

    To observe whether neural stem cells (NSCs) can successfully permeate into the brain through the blood-brain barrier (BBB) of Alzheimer disease (AD) transgenic mice and explore the methods of distribution and migration. NSCs were isolated from 12-day-old fetal mice, cultured, labeled with enhanced green fluorescent protein (eGFP) and then transplanted into 10 AD transgenic mice and normal mice as controls through caudal vein. The mice were killed 48 h, 1 w, 2 w, and 4 w after transplantation respectively. The brains of the mice were made into continual frozen sections, the distribution and migration of the eGFP-labeled NSCs were studied under fluorescence microscope. At different time points after transplantation the eGFP-labeled NSCs were diffusely distributed in the brain: distributed around the blood vessels in the first 48 h, and then migrated gradually towards the hippocampus and cortex until 4 weeks later. There were no obvious abnormal complications occurring after transplantation. NSCs can successfully permeate into the brain through the BBB of AD transgenic mice, and migrate into the brain parenchyma gradually.

  7. Identification of elevated urea as a severe, ubiquitous metabolic defect in the brain of patients with Huntington's disease.

    Science.gov (United States)

    Patassini, Stefano; Begley, Paul; Reid, Suzanne J; Xu, Jingshu; Church, Stephanie J; Curtis, Maurice; Dragunow, Mike; Waldvogel, Henry J; Unwin, Richard D; Snell, Russell G; Faull, Richard L M; Cooper, Garth J S

    Huntington's disease (HD) is a neurodegenerative disorder wherein the aetiological defect is a mutation in the Huntington's gene (HTT), which alters the structure of the huntingtin protein through the lengthening of a polyglutamine tract and initiates a cascade that ultimately leads to dementia and premature death. However, neurodegeneration typically manifests in HD only in middle age, and processes linking the causative mutation to brain disease are poorly understood. Here, our objective was to elucidate further the processes that cause neurodegeneration in HD, by measuring levels of metabolites in brain regions known to undergo varying degrees of damage. We applied gas-chromatography/mass spectrometry-based metabolomics in a case-control study of eleven brain regions in short post-mortem-delay human tissue from nine well-characterized HD patients and nine controls. Unexpectedly, a single major abnormality was evident in all eleven brain regions studied across the forebrain, midbrain and hindbrain, namely marked elevation of urea, a metabolite formed in the urea cycle by arginase-mediated cleavage of arginine. Urea cycle activity localizes primarily in the liver, where it functions to incorporate protein-derived amine-nitrogen into urea for recycling or urinary excretion. It also occurs in other cell-types, but systemic over-production of urea is not known in HD. These findings are consistent with impaired local urea regulation in brain, by up-regulation of synthesis and/or defective clearance. We hypothesize that defective brain urea metabolism could play a substantive role in the pathogenesis of neurodegeneration, perhaps via defects in osmoregulation or nitrogen metabolism. Brain urea metabolism is therefore a target for generating novel monitoring/imaging strategies and/or therapeutic interventions aimed at ameliorating the impact of HD in patients.

  8. Regional analysis of the magnetization transfer ratio of the brain in mild Alzheimer disease and amnestic mild cognitive impairment.

    Science.gov (United States)

    Mascalchi, M; Ginestroni, A; Bessi, V; Toschi, N; Padiglioni, S; Ciulli, S; Tessa, C; Giannelli, M; Bracco, L; Diciotti, S

    2013-01-01

    Manually drawn VOI-based analysis shows a decrease in magnetization transfer ratio in the hippocampus of patients with Alzheimer disease. We investigated with whole-brain voxelwise analysis the regional changes of the magnetization transfer ratio in patients with mild Alzheimer disease and patients with amnestic mild cognitive impairment. Twenty patients with mild Alzheimer disease, 27 patients with amnestic mild cognitive impairment, and 30 healthy elderly control subjects were examined with high-resolution T1WI and 3-mm-thick magnetization transfer images. Whole-brain voxelwise analysis of magnetization transfer ratio maps was performed by use of Statistical Parametric Mapping 8 software and was supplemented by the analysis of the magnetization transfer ratio in FreeSurfer parcellation-derived VOIs. Voxelwise analysis showed 2 clusters of significantly decreased magnetization transfer ratio in the left hippocampus and amygdala and in the left posterior mesial temporal cortex (fusiform gyrus) of patients with Alzheimer disease as compared with control subjects but no difference between patients with amnestic mild cognitive impairment and either patients with Alzheimer disease or control subjects. VOI analysis showed that the magnetization transfer ratio in the hippocampus and amygdala was significantly lower (bilaterally) in patients with Alzheimer disease when compared with control subjects (ANOVA with Bonferroni correction, at P Alzheimer disease. Support vector machine-based classification demonstrated improved classification performance after inclusion of magnetization transfer ratio-related features, especially between patients with Alzheimer disease versus healthy subjects. Bilateral but asymmetric decrease of magnetization transfer ratio reflecting microstructural changes of the residual GM is present not only in the hippocampus but also in the amygdala in patients with mild Alzheimer disease.

  9. Neuroradiology of the Brain.

    Science.gov (United States)

    Yeager, Susan

    2016-03-01

    A variety of imaging modalities are currently used to evaluate the brain. Prior to the 1970s, neurologic imaging involved radiographs, invasive procedures for spinal and carotid artery air and contrast injection, and painful patient manipulation. The brain was considered inaccessible to imaging and referred to as "the dark continent." Since then, advances in neuroradiology have moved the brain from being a dark continent to evaluation techniques that illuminate brain contents and pathology. These advances enable quick acquisition of images for prompt diagnosis and treatment. This article reviews anatomy, diagnostic principles, and clinical application of brain imaging beyond plain radiographs.

  10. Solar cycle variation of interstellar neutral He, Ne, O density and pick-up ions along the Earth's orbit

    Science.gov (United States)

    Sokół, Justyna M.; Bzowski, Maciej; Kubiak, Marzena A.; Möbius, Eberhard

    2016-06-01

    We simulated the modulation of the interstellar neutral (ISN) He, Ne, and O density and pick-up ion (PUI) production rate and count rate along the Earth's orbit over the solar cycle (SC) from 2002 to 2013 to verify if SC-related effects may modify the inferred ecliptic longitude of the ISN inflow direction. We adopted the classical PUI model with isotropic distribution function and adiabatic cooling, modified by time- and heliolatitude-dependent ionization rates and non-zero injection speed of PUIs. We found that the ionization losses have a noticeable effect on the derivation of the ISN inflow longitude based on the Gaussian fit to the crescent and cone peak locations. We conclude that the non-zero radial velocity of the ISN flow and the energy range of the PUI distribution function that is accumulated are of importance for a precise reproduction of the PUI count rate along the Earth orbit. However, the temporal and latitudinal variations of the ionization in the heliosphere, and particularly their variation on the SC time-scale, may significantly modify the shape of PUI cone and crescent and also their peak positions from year to year and thus bias by a few degrees the derived longitude of the ISN gas inflow direction.

  11. Deep brain stimulation of the subthalamic nucleus improves reward-based decision-learning in Parkinson’s disease

    NARCIS (Netherlands)

    Wouwe, N.C. van; Ridderinkhof, K.R.; Wildenberg, W.P.M. van den; Band, G.P.H.; Abisogun, A.; Elias, W.J.; Frysinger, R.; Wylie, S.A.

    2011-01-01

    Recently, the subthalamic nucleus (STN) has been shown to be critically involved in decision-making, action selection, and motor control. Here we investigate the effect of deep brain stimulation (DBS) of the STN on reward-based decision-learning in patients diagnosed with Parkinson’s disease (PD). W

  12. Deep brain stimulation of the subthalamic nucleus improves reward-based decision-learning in Parkinson’s disease

    NARCIS (Netherlands)

    Wouwe, N.C. van; Ridderinkhof, K.R.; Wildenberg, W.P.M. van den; Band, G.P.H.; Abisogun, A.; Elias, W.J.; Frysinger, R.; Wylie, S.A.

    2011-01-01

    Recently, the subthalamic nucleus (STN) has been shown to be critically involved in decision-making, action selection, and motor control. Here we investigate the effect of deep brain stimulation (DBS) of the STN on reward-based decision-learning in patients diagnosed with Parkinson’s disease (PD). W

  13. Lacosamide reduces HDAC levels in the brain and improves memory: Potential for treatment of Alzheimer's disease.

    Science.gov (United States)

    Bang, Shraddha R; Ambavade, Shirishkumar D; Jagdale, Priti G; Adkar, Prafulla P; Waghmare, Arun B; Ambavade, Prashant D

    2015-07-01

    Lacosamide, a histone deacetylase (HDAC) inhibitor, has been approved for the treatment of epilepsy. Some HDAC inhibitors have been proven effective for the treatment of memory disorders. The present investigation was designed to evaluate the effect of lacosamide on memory and brain HDAC levels. The effect on memory was evaluated in animals with scopolamine-induced amnesia using the elevated plus maze, object recognition test, and radial arm maze. The levels of acetylcholinesterase and HDAC in the cerebral cortex were evaluated. Lacosamide at doses of 10 and 30mg/kg significantly reduced the transfer latency in the elevated plus maze. Lacosamide at a dose of 30mg/kg significantly increased the time spent with a familiar object in the object recognition test at the 24h interval and decreased the time spent in the baited arm. Moreover, at this dose, the number of errors in the radial arm maze at 3 and 24h intervals was minimized and a reduction in the level of HDAC1, but not acetylcholinesterase, was observed in the cerebral cortex. These effects of lacosamide are equivalent to those of piracetam at a dose of 300mg/kg. These results suggest that lacosamide at a 30mg/kg dose improves disrupted memory, possibly by inhibiting HDAC, and could be used to treat amnesic symptoms of Alzheimer's disease.

  14. [A Self-Report Instrument for the Assessment of Dermatillomania: Reliability and Validity of the German Skin Picking Scale-Revised].

    Science.gov (United States)

    Gallinat, Christina; Keuthen, Nancy J; Backenstrass, Matthias

    2016-06-01

    At least since the introduction of the official diagnosis Excoriation (Skin-Picking) Disorder in the DSM-5 [1], dermatillomania is an important and growing field of research. Despite the high importance currently a huge lack of German assessment instruments exists. Aim of the present study was the examination of the psychometric properties of the German translation of the Skin Picking Scale-Revised [2]. For this purpose an open online study has been conducted. The analysis of N=2 065 data sets indicated a high internal consistency with Cronbachs Alpha being 0.93. Furthermore positive associations with the 3 problem areas psychological impairment, general physical condition, social problems as well as with reduced competence skills, general life satisfaction and social support indicate a good constructvalidity. Another sign for validity is a significant effect in terms of gender: As expected women showed higher skin picking scores than men. Overall the results of the present study suggest that the German version of the SPS-R can be seen as a reliable and valid instrument for the assessment of dermatillomania.

  15. Grammar improvement following deep brain stimulation of the subthalamic and the pedunculopontine nuclei in advanced Parkinson's disease: a pilot study.

    Science.gov (United States)

    Zanini, Sergio; Moschella, Vincenzo; Stefani, Alessandro; Peppe, Antonella; Pierantozzi, Mariangela; Galati, Salvatore; Costa, Alberto; Mazzone, Paolo; Stanzione, Paolo

    2009-09-01

    Combined deep brain stimulation of the subthalamic (STN) and pedunculopontine (PPN) nuclei has been recently proposed as surgical treatment of advanced Parkinson's disease. STN stimulation alone has been shown to provide selective improvement of the grammatical aspect of language. We studied five advanced Parkinson's disease patients who underwent combined deep brain stimulation (STN + PPN). Overall cognitive profile did not change. On the contrary, an interesting trend towards reduction of ungrammatical errors (particularly substitution of free and inflectional morphemes) was found when stimulating the STN, and also the PPN, when the STN was switched off. These findings replicate previous observations on the STN, and provide the rationale for further investigation of the role of the PPN in processing linguistic grammar.

  16. Solar cycle variation of interstellar neutral He, Ne, O density and pick-up ions along the Earth's orbit

    CERN Document Server

    Sokół, Justyna M; Kubiak, Marzena A; Möbius, Eberhard

    2016-01-01

    We simulated the modulation of the interstellar neutral (ISN) He, Ne, and O density and pick-up ion (PUI) production rate and count rate along the Earth's orbit over the solar cycle from 2002 to 2013 to verify if solar cycle-related effects may modify the inferred ecliptic longitude of the ISN inflow direction. We adopted the classical PUI model with isotropic distribution function and adiabatic cooling, modified by time- and heliolatitude-dependent ionization rates and non-zero injection speed of PUIs. We found that the ionization losses have a noticeable effect on the derivation of the ISN inflow longitude based on the Gaussian fit to the crescent and cone peak locations. We conclude that the non-zero radial velocity of the ISN flow and the energy range of the PUI distribution function that is accumulated are of importance for a precise reproduction of the PUI count rate along the Earth orbit. However, the temporal and latitudinal variations of the ionization in the heliosphere, and particularly their varia...

  17. Street vending and waste picking in developing countries: a long-standing hazardous occupational activity of the urban poor.

    Science.gov (United States)

    Amegah, Adeladza Kofi; Jaakkola, Jouni J K

    2016-07-28

    Uncontrolled urbanization in developing countries has led to widespread urban poverty and increased susceptibility to environmental exposures owing to the hazardous occupational activities of the urban poor. Street vending and waste picking are the dominant works undertaken by the urban poor, and besides the physical hazards, it also exposes them to several pathogens and high levels of air pollutants present in the outdoor environment. The situation has severe consequences for the health of the workers. Eliminating these occupational activities from the urban landscape of developing countries should therefore receive urgent attention from the global health community and governments. In this article, we provide evidence to support this policy recommendation by documenting exposure experiences of the workers, the associated adverse health effects, whilst also outlining measures for addressing the problem sustainably. We conclude that with the adoption of the sustainable development goals (SDG), governments now have a commitment to address poverty and the associated occupational health hazards experienced by the poor through their choices to help achieve the health-related SDG target (3.9) of substantially reducing the number of deaths and illnesses from hazardous chemicals and air, water, and soil pollution and contamination by 2030.

  18. Effect of transcranial brain stimulation for the treatment of Alzheimer disease: a review.

    Science.gov (United States)

    Nardone, Raffaele; Bergmann, Jürgen; Christova, Monica; Caleri, Francesca; Tezzon, Frediano; Ladurner, Gunther; Trinka, Eugen; Golaszewski, Stefan

    2012-01-01

    Available pharmacological treatments for Alzheimer disease (AD) have limited effectiveness, are expensive, and sometimes induce side effects. Therefore, alternative or complementary adjuvant therapeutic strategies have gained increasing attention. The development of novel noninvasive methods of brain stimulation has increased the interest in neuromodulatory techniques as potential therapeutic tool for cognitive rehabilitation in AD. In particular, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are noninvasive approaches that induce prolonged functional changes in the cerebral cortex. Several studies have begun to therapeutically use rTMS or tDCS to improve cognitive performances in patients with AD. However, most of them induced short-duration beneficial effects and were not adequately powered to establish evidence for therapeutic efficacy. Therefore, TMS and tDCS approaches, seeking to enhance cognitive function, have to be considered still very preliminary. In future studies, multiple rTMS or tDCS sessions might also interact, and metaplasticity effects could affect the outcome.

  19. Primary lymphoma of the brain

    Science.gov (United States)

    Brain lymphoma; Cerebral lymphoma; Primary lymphoma of the central nervous system; Lymphoma - brain ... The cause of primary brain lymphoma is not known. People with a weakened immune system are at high risk for primary lymphoma of the brain. ...

  20. Pick病的脑MRI研究%Investigation of Brain MRI in Pick Disease

    Institute of Scientific and Technical Information of China (English)

    卢文甫; 王鲁宁; 贾建军; 汤洪川; 蔡幼铨

    2001-01-01

    目的研究Pick病患者脑萎缩变化的特点,并动态研究脑萎缩变化的程度和病程及临床之间的相互相关系.方法2例Pick病患者分别进行5次和7次脑MRI动态观察,并和6例Alzheimer病患者进行对比分析.结果 Pick病早期以Kluver-Bacy综合征和情感障碍为突出,人格改变、行为异常、语言障碍为显著,而智能减退相对较轻较晚,脑MRI以额或/和颞极萎缩为主,尤其颞上回前1/3为明显,其脑MRI的改变和临床特征及病程相一致."刀片”状、"剪刀”像和"锥柱”样或"蘑菇”状脑萎缩改变可能是Pick病的特点.结论充分认识这些特征,以利于Pick病的早期临床诊断.

  1. O-6 Optical Property Degradation of the Hubble Space Telescope's Wide Field Camera-2 Pick Off Mirror

    Science.gov (United States)

    McNamara, Karen M.; Hughes, D. W.; Lauer, H. V.; Burkett, P. J.; Reed, B. B.

    2011-01-01

    Degradation in the performance of optical components can be greatly affected by exposure to the space environment. Many factors can contribute to such degradation including surface contaminants; outgassing; vacuum, UV, and atomic oxygen exposure; temperature cycling; or combinations of parameters. In-situ observations give important clues to degradation processes, but there are relatively few opportunities to correlate those observations with post-flight ground analyses. The return of instruments from the Hubble Space Telescope (HST) after its final servicing mission in May 2009 provided such an opportunity. Among the instruments returned from HST was the Wide-Field Planetary Camera-2 (WFPC-2), which had been exposed to the space environment for 16 years. This work focuses on the identifying the sources of degradation in the performance of the Pick-off mirror (POM) from WFPC-2. Techniques including surface reflectivity measurements, spectroscopic ellipsometry, FTIR (and ATR-FTIR) analyses, SEM/EDS, X-ray photoelectron spectroscopy (XPS) with and without ion milling, and wet and dry physical surface sampling were performed. Destructive and contact analyses took place only after completion of the non-destructive measurements. Spectroscopic ellipsometry was then repeated to determine the extent of contaminant removal by the destructive techniques, providing insight into the nature and extent of polymerization of the contaminant layer.

  2. T Lymphocytes and Inflammatory Mediators in the Interplay between Brain and Blood in Alzheimer's Disease: Potential Pools of New Biomarkers

    Science.gov (United States)

    Mietelska-Porowska, Anna

    2017-01-01

    Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the main cause of dementia. The disease is among the leading medical concerns of the modern world, because only symptomatic therapies are available, and no reliable, easily accessible biomarkers exist for AD detection and monitoring. Therefore extensive research is conducted to elucidate the mechanisms of AD pathogenesis, which seems to be heterogeneous and multifactorial. Recently much attention has been given to the neuroinflammation and activation of glial cells in the AD brain. Reports also highlighted the proinflammatory role of T lymphocytes infiltrating the AD brain. However, in AD molecular and cellular alterations involving T cells and immune mediators occur not only in the brain, but also in the blood and the cerebrospinal fluid (CSF). Here we review alterations concerning T lymphocytes and related immune mediators in the AD brain, CSF, and blood and the mechanisms by which peripheral T cells cross the blood brain barrier and the blood-CSF barrier. This knowledge is relevant for better AD therapies and for identification of novel biomarkers for improved AD diagnostics in the blood and the CSF. The data will be reviewed with the special emphasis on possibilities for development of AD biomarkers.

  3. Birth of a brain disease: science, the state and addiction neuropolitics.

    Science.gov (United States)

    Vrecko, Scott

    2010-01-01

    This article critically interrogates contemporary forms of addiction medicine that are portrayed by policy-makers as providing a "rational" or politically neutral approach to dealing with drug use and related social problems. In particular, it examines the historical origins of the biological facts that are today understood to provide a foundation for contemporary understandings of addiction as a "disease of the brain." Drawing upon classic and contemporary work on "styles of thought," it documents how, in the period between the mid-1960s and the mid 1970s, such facts emerged in relation to new neurobiological styles of explaining and managing social problems associated with drug abuse, and an alliance between a relatively marginal group of researchers and American policy-makers who were launching the "War on Drugs." Beyond illustrating the political and material conditions necessary for the rise of addiction neuroscience, the article highlights the productivity of neurobiological thought styles, by focusing on the new biological objects, treatments and hopes that have emerged within the field of addiction studies over the last several decades.

  4. Recent advances in the neuroimmunology of cell-surface CNS autoantibody syndromes, Alzheimer's disease, traumatic brain injury and schizophrenia.

    Science.gov (United States)

    Needham, Ed; Zandi, Michael S

    2014-10-01

    In this update, we review recent advances in antibody-associated disorders of the central nervous system, and the immune mechanisms which may contribute to Alzheimer's disease, traumatic brain injury and schizophrenia. The field of neuroimmunology is rapidly developing and has concerned itself with an expanding portfolio of diseases. The core neuroimmunological diseases remain, multiple sclerosis, neuromyelitis optica, primary inflammatory and antibody-associated disorders of the central and peripheral nervous system (including Myasthenia Gravis and other disorders of neuromuscular junction and muscle, paraneoplastic syndromes, paraproteinaemic neuropathies), and the neurological involvement seen in systemic inflammatory diseases including lupus, sarcoidosis and vasculitis. But it is increasingly realised that immune mechanisms may contribute to the pathogenesis of degenerative diseases including Alzheimer's disease, traumatic brain disease and psychiatric diseases including schizophrenia and depression. These common and devastating disorders, often without effective disease-modifying therapies, are yet to be seen in a conventional neuroimmunology clinic, but the immune mechanisms identified have encouraged research into novel therapeutic approaches for them.

  5. Cholesterol supply and SREBPs modulate transcription of the Niemann-Pick C-1 gene in steroidogenic tissues.

    Science.gov (United States)

    Gévry, Nicolas; Schoonjans, Kristina; Guay, Fréderic; Murphy, Bruce D

    2008-05-01

    We tested whether sterol-regulatory element binding proteins (SREBPs) mediate sterol-regulated transactivation of the Niemann-Pick C-1 (NPC-1) gene. Loading granulosa cells with 22- or 25-hydroxycholesterol decreased NPC-1 mRNA, whereas culturing in cholesterol-depleted medium or inhibition of cholesterol biosynthesis increased NPC-1 promoter activity and NPC-1 mRNA abundance. Cotransfection of SREBP1a, SREBP1c, and SREBP2 and the NPC-1 promoter-luciferase reporter into granulosa cell lines increased the transcriptional activity of porcine, human, and mouse NPC-1 promoters. Deletion analysis of the 5' flanking region of the pig NPC-1 gene demonstrated significant promoter activity between fragments -934 and -636 bp upstream from the transcription initiation site. Sequence analysis revealed three sterol-regulatory elements (SREs) clustered between -558 and -650 bp. Each site, along with E-box sequences, bound recombinant SREBP in electromobility shift assays. Mutation of all three sites attenuated the SREBP induction of promoter activity. Chromatin immunoprecipitation (ChIP) assays revealed that cholesterol depletion enriched the association of both SREBP and acetylated histone H3 with the NPC-1 promoter fragment containing the three SREs. ChIP analysis confirmed that SREBP's association with SRE and the E-box was enriched in cells cultured in cholesterol-depleted medium. We conclude that NPC-1 is sterol-regulated, achieved by SREBP acting via SRE and the E-box sequences.

  6. The metabolic syndrome: a brain disease?

    Science.gov (United States)

    Buijs, Ruud M; Kreier, Felix

    2006-09-01

    The incidence of obesity with, as consequence, a rise in associated diseases such as diabetes, hypertension and dyslipidemia--the metabolic syndrome--is reaching epidemic proportions in industrialized countries. Here, we provide a hypothesis that the biological clock which normally prepares us each morning for the coming activity period is altered due to a modern life style of low activity during the day and late-night food intake. Furthermore, we review the anatomical evidence supporting the proposal that an unbalanced autonomic nervous system output may lead to the simultaneous occurrence of diabetes type 2, dyslipidemia, hypertension and visceral obesity.

  7. Cerebral hemodynamics of the aging brain: risk of Alzheimer disease and benefit of aerobic exercise

    OpenAIRE

    Takashi eTarumi; Rong eZhang

    2014-01-01

    Alzheimer disease (AD) and cerebrovascular disease often coexist with advanced age. Mounting evidence indicates that the presence of vascular disease and its risk factors increase the risk of AD, suggesting a potential overlap of the underlying pathophysiological mechanisms. In particular, atherosclerosis, endothelial dysfunction, and stiffening of central elastic arteries have been shown to associate with AD. Currently, there are no effective treatments for the cure and prevention of AD. Vas...

  8. Clearing the corpses: regulatory mechanisms, novel tools, and therapeutic potential of harnessing microglial phagocytosis in the diseased brain

    Directory of Open Access Journals (Sweden)

    Irune Diaz-Aparicio

    2016-01-01

    Full Text Available Apoptosis is a widespread phenomenon that occurs in the brain in both physiological and pathological conditions. Dead cells must be quickly removed to avoid the further toxic effects they exert in the parenchyma, a process executed by microglia, the brain professional phagocytes. Although phagocytosis is critical to maintain tissue homeostasis, it has long been either overlooked or indirectly assessed based on microglial morphology, expression of classical activation markers, or engulfment of artificial phagocytic targets in vitro. Nevertheless, these indirect methods present several limitations and, thus, direct observation and quantification of microglial phagocytosis is still necessary to fully grasp its relevance in the diseased brain. To overcome these caveats and obtain a comprehensive, quantitative picture of microglial phagocytosis we have developed a novel set of parameters. These parameters have allowed us to identify the different strategies utilized by microglia to cope with apoptotic challenges induced by excitotoxicity or inflammation. In contrast, we discovered that in mouse and human epilepsy microglia failed to find and engulf apoptotic cells, resulting in accumulation of debris and inflammation. Herein, we advocate that the efficiency of microglial phagocytosis should be routinely tested in neurodegenerative and neurological disorders, in order to determine the extent to which it contributes to apoptosis and inflammation found in these conditions. Finally, our findings point towards enhancing microglial phagocytosis as a novel therapeutic strategy to control tissue damage and inflammation, and accelerate recovery in brain diseases.

  9. Clearing the corpses:regulatory mechanisms, novel tools, and therapeutic potential of harnessing microglial phagocytosis in the diseased brain

    Institute of Scientific and Technical Information of China (English)

    Irune Diaz-Aparicio; Sol Beccari; Oihane Abiega; Amanda Sierra

    2016-01-01

    Apoptosis is a widespread phenomenon that occurs in the brain in both physiological and pathological conditions. Dead cells must be quickly removed to avoid the further toxic effects they exert in the pa-renchyma, a process executed by microglia, the brain professional phagocytes. Although phagocytosis is critical to maintain tissue homeostasis, it has long been either overlooked or indirectly assessed based on microglial morphology, expression of classical activation markers, or engulfment of artiifcial phagocytic targetsin vitro. Nevertheless, these indirect methods present several limitations and, thus, direct obser-vation and quantiifcation of microglial phagocytosis is still necessary to fully grasp its relevance in the diseased brain. To overcome these caveats and obtain a comprehensive, quantitative picture of microglial phagocytosis we have developed a novel set of parameters. hTese parameters have allowed us to identify the different strategies utilized by microglia to cope with apoptotic challenges induced by excitotoxicity or inlfammation. In contrast, we discovered that in mouse and human epilepsy microglia failed to ifnd and engulf apoptotic cells, resulting in accumulation of debris and inlfammation. Herein, we advocate that the effciency of microglial phagocytosis should be routinely tested in neurodegenerative and neuro-logical disorders, in order to determine the extent to which it contributes to apoptosis and inlfammation found in these conditions. Finally, our ifndings point towards enhancing microglial phagocytosis as a novel therapeutic strategy to control tissue damage and inlfammation, and accelerate recovery in brain diseases.

  10. [The systemic and differential psychoprophylaxis of vascular brain diseases in the workers of an industrial enterprise].

    Science.gov (United States)

    Andreev, A G

    1994-01-01

    Basing on epidemiological, prospective and clinicopsychological data obtained on 1900 industrial workers of Nizhni Novgorod city, the system of psychoprophylaxis and psychotherapy of cerebrovascular diseases has been developed. The system of psychoprophylaxis was used with consideration of the disease stage and phase, psychic and psychosomatic status in risk groups, in subjects with initial and apparent symptoms of cerebrovascular failure. The psychoprophylactic system proved effective in the conditions of a large industrial enterprise.

  11. β-methylamino-L-alanine (BMAA) is not found in the brains of patients with confirmed Alzheimer’s disease

    Science.gov (United States)

    Meneely, Julie P.; Chevallier, Olivier P.; Graham, Stewart; Greer, Brett; Green, Brian D.; Elliott, Christopher T.

    2016-11-01

    Controversy surrounds the proposed hypothesis that exposure to β-methylamino-L-alanine (BMAA) could play a role in various neurodegenerative conditions including Alzheimer’s disease (AD). Here we present the results of the most comprehensive scientific study on BMAA detection ever undertaken on brain samples from patients pathologically confirmed to have suffered from AD, and those from healthy volunteers. Following the full validation of a highly accurate and sensitive mass spectrometric method, no trace of BMAA was detected in the diseased brain or in the control specimens. This contradicts the findings of other reports and calls into question the significance of this compound in neurodegenerative disease. We have attempted to explain the potential causes of misidentification of BMAA in these studies.

  12. Genome sequencing in a case of Niemann-Pick type C.

    Science.gov (United States)

    Dougherty, Max; Lazar, John; Klein, Jason C; Diaz, Karina; Gobillot, Theodore; Grunblatt, Eli; Hasle, Nicholas; Lawrence, Daniel; Maurano, Megan; Nelson, Maria; Olson, Gregory; Srivatsan, Sanjay; Shendure, Jay; Keene, C Dirk; Bird, Thomas; Horwitz, Marshall S; Marshall, Desiree A

    2016-11-01

    Adult-onset Niemann-Pick disease type C (NPC) is an infrequent presentation of a rare neurovisceral lysosomal lipid storage disorder caused by autosomal recessive mutations in NPC1 (∼95%) or NPC2 (∼5%). Our patient was diagnosed at age 33 when he presented with a 10-yr history of difficulties in judgment, concentration, speech, and coordination. A history of transient neonatal jaundice and splenomegaly with bone marrow biopsy suggesting a lipid storage disorder pointed to NPC; biochemical ("variant" level cholesterol esterification) and ultrastructural studies in adulthood confirmed the diagnosis. Genetic testing revealed two different missense mutations in the NPC1 gene-V950M and N1156S. Symptoms progressed over >20 yr to severe ataxia and spasticity, dementia, and dysphagia with aspiration leading to death. Brain autopsy revealed mild atrophy of the cerebrum and cerebellum. Microscopic examination showed diffuse gray matter deposition of balloon neurons, mild white matter loss, extensive cerebellar Purkinje cell loss with numerous "empty baskets," and neurofibrillary tangles predominantly in the hippocampal formation and transentorhinal cortex. We performed whole-genome sequencing to examine whether the patient harbored variants outside of the NPC1 locus that could have contributed to his late-onset phenotype. We focused analysis on genetic modifiers in pathways related to lipid metabolism, longevity, and neurodegenerative disease. We identified no rare coding variants in any of the pathways examined nor was the patient enriched for genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) associated with longevity or altered lipid metabolism. In light of these findings, this case provides support for the V950M variant being sufficient for adult-onset NPC disease.

  13. Genome sequencing in a case of Niemann–Pick type C

    Science.gov (United States)

    Dougherty, Max; Lazar, John; Klein, Jason C.; Diaz, Karina; Gobillot, Theodore; Grunblatt, Eli; Hasle, Nicholas; Lawrence, Daniel; Maurano, Megan; Nelson, Maria; Olson, Gregory; Srivatsan, Sanjay; Shendure, Jay; Keene, C. Dirk; Bird, Thomas; Horwitz, Marshall S.; Marshall, Desiree A.

    2016-01-01

    Adult-onset Niemann–Pick disease type C (NPC) is an infrequent presentation of a rare neurovisceral lysosomal lipid storage disorder caused by autosomal recessive mutations in NPC1 (∼95%) or NPC2 (∼5%). Our patient was diagnosed at age 33 when he presented with a 10-yr history of difficulties in judgment, concentration, speech, and coordination. A history of transient neonatal jaundice and splenomegaly with bone marrow biopsy suggesting a lipid storage disorder pointed to NPC; biochemical (“variant” level cholesterol esterification) and ultrastructural studies in adulthood confirmed the diagnosis. Genetic testing revealed two different missense mutations in the NPC1 gene—V950M and N1156S. Symptoms progressed over >20 yr to severe ataxia and spasticity, dementia, and dysphagia with aspiration leading to death. Brain autopsy revealed mild atrophy of the cerebrum and cerebellum. Microscopic examination showed diffuse gray matter deposition of balloon neurons, mild white matter loss, extensive cerebellar Purkinje cell loss with numerous “empty baskets,” and neurofibrillary tangles predominantly in the hippocampal formation and transentorhinal cortex. We performed whole-genome sequencing to examine whether the patient harbored variants outside of the NPC1 locus that could have contributed to his late-onset phenotype. We focused analysis on genetic modifiers in pathways related to lipid metabolism, longevity, and neurodegenerative disease. We identified no rare coding variants in any of the pathways examined nor was the patient enriched for genome-wide association study (GWAS) single-nucleotide polymorphisms (SNPs) associated with longevity or altered lipid metabolism. In light of these findings, this case provides support for the V950M variant being sufficient for adult-onset NPC disease. PMID:27900365

  14. Targeting of the Subthalamic Nucleus for Deep Brain Stimulation: A Survey Among Parkinson Disease Specialists.

    Science.gov (United States)

    Hamel, Wolfgang; Köppen, Johannes A; Alesch, François; Antonini, Angelo; Barcia, Juan A; Bergman, Hagai; Chabardes, Stephan; Contarino, Maria Fiorella; Cornu, Philippe; Demmel, Walter; Deuschl, Günther; Fasano, Alfonso; Kühn, Andrea A; Limousin, Patricia; McIntyre, Cameron C; Mehdorn, H Maximilian; Pilleri, Manuela; Pollak, Pierre; Rodríguez-Oroz, Maria C; Rumià, Jordi; Samuel, Michael; Timmermann, Lars; Valldeoriola, Francesc; Vesper, Jan; Visser-Vandewalle, Veerle; Volkmann, Jens; Lozano, Andres M

    2017-03-01

    Deep brain stimulation within or adjacent to the subthalamic nucleus (STN) represents the most common stereotactic procedure performed for Parkinson disease. Better STN imaging is often regarded as a requirement for improving stereotactic targeting. However, it is unclear whether there is consensus about the optimal target. To obtain an expert opinion on the site regarded optimal for "STN stimulation," movement disorder specialists were asked to indicate their preferred position for an active contact on hard copies of the Schaltenbrand and Wahren atlas depicting the STN in all 3 planes. This represented an idealized setting, and it mimicked optimal imaging for direct target definition in a perfectly delineated STN. The suggested targets were heterogeneous, although some clustering was observed in the dorsolateral STN and subthalamic area. In particular, in the anteroposterior direction, the intended targets differed to a great extent. Most of the indicated targets are thought to also result in concomitant stimulation of structures adjacent to the STN, including the zona incerta, fields of Forel, and internal capsule. This survey illustrates that most sites regarded as optimal for STN stimulation are close to each other, but there appears to be no uniform perception of the optimal anatomic target, possibly influencing surgical results. The anatomic sweet zone for STN stimulation needs further specification, as this information is likely to make magnetic resonance imaging-based target definition less variable when applied to individual patients. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Structure-modification and oil pick-up ability of PHBV as oil sorbent materials

    Institute of Scientific and Technical Information of China (English)

    Xuwen He; Dayi Qian; Bing Wu; Tong Wang

    2003-01-01

    The PHBV (β-hydroxybutyrate-co-β-hydroxyvalerate) foams as oil sorbent materials, which were prepared by salting out method based on PHBV and chloroform additive and their oil pick-up abilities were investigated. And the oil pick-up abilities of different PHBV foams as oil sorbent materials were compared. The results show that with the amount of chloroform additive and sodium chloride increasing, the oil pick-up rates, the oil-keeping rates and the second oil pick-up rates of PHBV foams can increase to different extent. When the amount of sodium chloride was 92%, the ratio of PHBV to chloroform was 1 (g): 14 (mL), the oil pick-up ability of the PHBV foam was optimal. And their oil pick-up ratios can reach 25.51 (26℃) and 27.51 g/g (17℃) in raw oil, which were 4-5 times more than those of PHBV powder. In addition, the structure-modified PHBV as oil sorbent materials also has some advantages, such as three-dimension structure, bio-degradability and good oil pick-up ability, so this kind of green oil sorbent materials will have great perspective in the future.

  16. Wear Assessment of Conical Pick used in Coal Cutting Operation

    Science.gov (United States)

    Dewangan, Saurabh; Chattopadhyaya, Somnath; Hloch, Sergej

    2015-09-01

    Conical pick is a widely used tool for cutting coal in mines. It has a cemented carbide tip inserted in a steel body. Cemented carbide has been in use for many years for coal/rock cutting because it has the optimum combination of hardness, toughness and resistance against abrasive wear. As coal/rock is a heterogeneous substance, the cutting tool has to undergo various obstructions at the time of excavation that cause the tool to wear out. The cracks and fractures developing in the cemented carbide limit the life of the tool. For a long time, different wear mechanisms have been studied to develop improved grades of cemented carbide with high wear resistance properties. The research is still continuing. Moreover, due to the highly unpredictable nature of coal/rock, it is not easy to understand the wear mechanisms. In the present work, an attempt has been made to understand the wear mechanisms in four conical picks, which were used in a continuous miner machine for underground mining of coal. The wearing pattern of the conical pick indicates damage in its cemented carbide tip as well as the steel body. The worn out parts of the tools have been critically examined using scanning electron microscopy (SEM) and energy dispersive X-ray (EDX) point analysis. Mainly four types of wear mechanisms, namely, coal/rock intermixing, plastic deformation, rock channel formation and crushing and cracking, have been detected. The presence of coal/rock material and their respective concentrations in the selected area of worn out surface were observed using the spectra generated by EDX analysis.

  17. Sodium selenate regulates the brain ionome in a transgenic mouse model of Alzheimer’s disease

    Science.gov (United States)

    Zheng, Lin; Zhu, Hua-Zhang; Wang, Bing-Tao; Zhao, Qiong-Hui; Du, Xiu-Bo; Zheng, Yi; Jiang, Liang; Ni, Jia-Zuan; Zhang, Yan; Liu, Qiong

    2016-01-01

    Many studies have shown that imbalance of mineral metabolism may play an important role in Alzheimer’s disease (AD) progression. It was recently reported that selenium could reverse memory deficits in AD mouse model. We carried out multi-time-point ionome analysis to investigate the interactions among 15 elements in the brain by using a triple-transgenic mouse model of AD with/without high-dose sodium selenate supplementation. Except selenium, the majority of significantly changed elements showed a reduced level after 6-month selenate supplementation, especially iron whose levels were completely reversed to normal state at almost all examined time points. We then built the elemental correlation network for each time point. Significant and specific elemental correlations and correlation changes were identified, implying a highly complex and dynamic crosstalk between selenium and other elements during long-term supplementation with selenate. Finally, we measured the activities of two important anti-oxidative selenoenzymes, glutathione peroxidase and thioredoxin reductase, and found that they were remarkably increased in the cerebrum of selenate-treated mice, suggesting that selenoenzyme-mediated protection against oxidative stress might also be involved in the therapeutic effect of selenate in AD. Overall, this study should contribute to our understanding of the mechanism related to the potential use of selenate in AD treatment. PMID:28008954

  18. Treatment results of brain metastasis from breast cancer. Course of the disease and radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Yamada, Kazunari; Murakami, Masao; Kuroda, Yasumasa [Tenri Hospital, Nara (Japan)

    1997-01-01

    Thirty-nine patients with brain metastasis from breast cancer who were treated in our hospital between 1978 and 1992 and followed up until November 1995 were reviewed. The initial diagnosis of brain metastasis and follow-up were made by MRI and/or CT. Extracranial metastases were found in 90% of the patients and were the cause of death in 89%. Treatments included surgery alone in 2 patients (group S), surgery plus postoperative radiotherapy in 8 (group SR), radiotherapy alone in 28 (group R) and conservative therapy in 1 (group C). Radiotherapy of up to 40 Gy to the whole brain was carried out, but was performed in only 75% of patients in group R. The overall median survival was 5.4 months with a 1-year survival rate of 23% and a two-year rate of 10%. In patients treated with over 40 Gy, the survival time for radiotherapy alone was 5.1 months, with a 1-year survival rate of 9.5%; relief of specific neurologic symptoms was noted in 80%. The longest survival was noted in a patient with a single brain metastasis, who, to date, has survived for five years and two months following 60 Gy of irradiation. Patients with the following clinical conditions should have a good prognosis; no further metastases in other sites, or well controlled if existing, no symptoms of NF (neurological function: RTOG) or slight, and improved NF by treatment, surgical candidate, good response to initial treatment on CT or MRI. Despite a bad prognosis in general, brain metastasis from breast cancer can be treated affirmatively, if these clinical conditions are fulfilled. (author)

  19. The Other Itch That Rashes: a Clinical and Therapeutic Approach to Pruritus and Skin Picking Disorders.

    Science.gov (United States)

    Craig-Müller, Sören A; Reichenberg, Jason S

    2015-06-01

    Patients with skin picking disorders (SPDs) have historically been an under recognized and under treated group. Originally classified an impulse control disorder, skin picking disorder is now considered under the obsessive-compulsive disorder (OCD) and obsessive-compulsive-related disorder (OCRD) spectrum. Workup of SPD concentrates on differentiating this condition from primary skin disorders, systemic conditions associated with pruritus, and psychocutaneous syndromes. It is important to first address any underlying pruritic disorders (if present) that may be a trigger to pick the skin. First-line treatment for SPD is cognitive behavioral therapy. When necessary, pharmacologic therapy can be helpful as well.

  20. Protein interacting with C kinase 1 (PICK1) reduces reinsertion rates of interaction partners sorted to Rab11-dependent slow recycling pathway

    DEFF Research Database (Denmark)

    Madsen, Kenneth Lindegaard; Thorsen, Thor Seneca; Rahbek-Clemmensen, Troels;

    2012-01-01

    of PICK1 co-clusters in Rab11-positive compartments. Furthermore, PICK1 inhibited Rab11-mediated recycling of the receptor in a BAR and PDZ domain-dependent manner. In contrast, transfer of the DAT C terminus to the δ-opioid receptor, which sorts to degradation, did not result in PICK1 co-clusters or any...... primarily sorts to degradation upon internalization, did not form perinuclear clusters with PICK1, and PICK1 did not affect DAT internalization/recycling. However, transfer of the PICK1-binding DAT C terminus to the β(2)-adrenergic receptor, which sorts to recycling upon internalization, led to formation...... change in internalization/recycling. Further support for a role of PICK1 determined by its PDZ cargo was obtained for the PICK1 interaction partner prolactin-releasing peptide receptor (GPR10). GPR10 co-localized with Rab11 and clustered with PICK1 upon constitutive internalization but co...

  1. The rationale for deep brain stimulation in Alzheimer's disease.

    Science.gov (United States)

    Mirzadeh, Zaman; Bari, Ausaf; Lozano, Andres M

    2016-07-01

    Alzheimer's disease is a major worldwide health problem with no effective therapy. Deep brain stimulation (DBS) has emerged as a useful therapy for certain movement disorders and is increasingly being investigated for treatment of other neural circuit disorders. Here we review the rationale for investigating DBS as a therapy for Alzheimer's disease. Phase I clinical trials of DBS targeting memory circuits in Alzheimer's disease patients have shown promising results in clinical assessments of cognitive function, neurophysiological tests of cortical glucose metabolism, and neuroanatomical volumetric measurements showing reduced rates of atrophy. These findings have been supported by animal studies, where electrical stimulation of multiple nodes within the memory circuit have shown neuroplasticity through stimulation-enhanced hippocampal neurogenesis and improved performance in memory tasks. The precise mechanisms by which DBS may enhance memory and cognitive functions in Alzheimer's disease patients and the degree of its clinical efficacy continue to be examined in ongoing clinical trials.

  2. Quantitative magnetic resonance imaging and studies of degenerative diseases of the developing human brain

    Energy Technology Data Exchange (ETDEWEB)

    Caviness, V.S. Jr. (Massachusetts General Hospital, Boston, MA (United States)); Phil, D.; Filipek, P.A.; Kennedy, D.N.

    1992-05-01

    The Rett syndrome is a progressive disorder which is associated with regression of psychomotor development and precipitous deceleration of brain growth during the first year of life. General histopathological surveys in postmortem specimens have identified degeneration of subpopulations of neurons of the nigrostriatal system but no other evidence of degenerative process. Magnetic resonance imaging-based morphometry may usefully guide application of rigorous but demanding quantitative histologic search for evidence of neuronal degeneration. The volumes of the principal set of cortical and nuclear structures of principal interest in the disorder may be measured by currently avaiable MRI-based methods. Opimized levels of precision now allow detection of volumetric changes over time in the same brain of approximately 10% at the 95% confidence level. (author).

  3. The sweet branch of metabolic engineering: cherry-picking the low-hanging sugary fruits.

    Science.gov (United States)

    Chen, Rachel

    2015-12-09

    In the first science review on the then nascent Metabolic Engineering field in 1991, Dr. James E. Bailey described how improving erythropoietin (EPO) glycosylation can be achieved via metabolic engineering of Chinese hamster ovary (CHO) cells. In the intervening decades, metabolic engineering has brought sweet successes in glycoprotein engineering, including antibodies, vaccines, and other human therapeutics. Today, not only eukaryotes (CHO, plant, insect, yeast) are being used for manufacturing protein therapeutics with human-like glycosylation, newly elucidated bacterial glycosylation systems are enthusiastically embraced as potential breakthrough to revolutionize the biopharmaceutical industry. Notwithstanding these excitement in glycoprotein, the sweet metabolic engineering reaches far beyond glycoproteins. Many different types of oligo- and poly-saccharides are synthesized with metabolically engineered cells. For example, several recombinant hyaluronan bioprocesses are now in commercial production, and the titer of 2'-fucosyllactose, the most abundant fucosylated trisaccharide in human milk, reaches over 20 g/L with engineered E. coli cells. These successes represent only the first low hanging fruits, which have been appreciated scientifically, medically and fortunately, commercially as well. As one of the four building blocks of life, sugar molecules permeate almost all aspects of life. They are also unique in being intimately associated with all major types of biopolymers (including DNA/RNA, proteins, lipids) meanwhile they stand alone as bioactive polysaccharides, or free soluble oligosaccharides. As such, all sugar moieties in biological components, small or big and free or bound, are important targets for metabolic engineering. Opportunities abound at the interface of glycosciences and metabolic engineering. Continued investment and successes in this branch of metabolic engineering will make vastly diverse sugar-containing molecules (a

  4. Excoriation (skin-picking disorder: a systematic review of treatment options

    Directory of Open Access Journals (Sweden)

    Lochner C

    2017-07-01

    Full Text Available Christine Lochner,1 Annerine Roos,1 Dan J Stein2 1SU/UCT MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry, Stellenbosch University, South Africa; 2SU/UCT MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Mental Health, University of Cape Town, South Africa Abstract: Although pathological skin-picking has been documented in the medical literature since the 19th century, it has only recently been included as a distinct entity in psychiatric classification systems. In the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition and the proposed International Classification of Diseases, Eleventh Revision, excoriation (skin-picking disorder (ED, also known as neurotic excoriation, psychogenic excoriation, or dermatillomania, is described as recurrent picking of skin, leading to skin lesions and significant distress or functional impairment. ED is listed as one of the obsessive–compulsive and related disorders, given its overlap with conditions such as trichotillomania (hair-pulling disorder. Arguably, its inclusion and delineation in the diagnostic nomenclature will lead to increased awareness of the condition, more research, and ultimately in treatment advances. This systematic review aims to provide readers with an up-to-date view of current treatment options for ED. A MEDLINE search of the ED treatment literature was conducted to collate relevant articles published between 1996 and 2017. The findings indicate that a number of randomized controlled trails on ED have now been published, and that current management options include behavioral therapy (habit reversal or acceptance-enhanced behavior therapy, and medication (selective serotonin reuptake inhibitors or N-acetyl cysteine. Keywords: excoriation, skin-picking, treatment, habit reversal therapy, behavioral therapy, pharmacotherapy, systematic review

  5. Brain Plasticity and Disease: A Matter of Inhibition

    Directory of Open Access Journals (Sweden)

    Laura Baroncelli

    2011-01-01

    Full Text Available One major goal in Neuroscience is the development of strategies promoting neural plasticity in the adult central nervous system, when functional recovery from brain disease and injury is limited. New evidence has underscored a pivotal role for cortical inhibitory circuitries in regulating plasticity both during development and in adulthood. This paper summarizes recent findings showing that the inhibition-excitation balance controls adult brain plasticity and is at the core of the pathogenesis of neurodevelopmental disorders like autism, Down syndrome, and Rett syndrome.

  6. Picking the right tool for the job--Phosphoproteomics of egg activation.

    Science.gov (United States)

    Wessel, Gary M

    2015-12-01

    Eggs are the rarest cell in the human body, yet their study is essential for the fields of fertility, reproduction, and fetal health. Guo et al. (Proteomics 2015, 15, 4080-4095) use a "surrogate" animal to discover the phosphoproteomic pathways involved in egg activation. With datasets of several thousand phosphosites on 2500 different proteins, these investigators have defined new pathways, connections to pathways, and priorities in searches for how eggs are activated at fertilization. These results in a sea urchin are now transposable to mammals for testing on a per candidate strategy.

  7. Picking the right tool for the job – phosphor-proteomics of egg activation

    Science.gov (United States)

    Wessel, Gary M.

    2016-01-01

    Eggs are the rarest cell in the human body, yet their study is essential for the fields of fertility, reproduction, and fetal health. Guo et al use a “surrogate” animal to discover the phophoproteomic pathways involved in egg activation. With datasets of several thousand phophosites on 2500 different proteins, these investigators have defined new pathways, connections to pathways, and priorities in searches for how eggs are activated at fertilization. These results in a sea urchin are now transposable to mammals for testing on a per candidate strategy. PMID:26573262

  8. PICK1 expression in the Drosophila central nervous system primarily occurs in the neuroendocrine system

    DEFF Research Database (Denmark)

    Jansen, Anna M; Nässel, Dick R; Madsen, Kenneth L

    2009-01-01

    in the adult and larval Drosophila central nervous system. PICK1 was found in cell bodies in the subesophageal ganglion, the antennal lobe, the protocerebrum, and the neuroendocrine center pars intercerebralis. The cell types that express PICK1 were identified using GAL4 enhancer trap lines. The PICK1...... (AMPA) receptor subunit GluR2 and the dopamine transporter. PICK1 is strongly implicated in GluR2 trafficking and synaptic plasticity. In mammals, PICK1 has been characterized extensively in cell culture studies. To study PICK1 in an intact system, we characterized PICK1 expression immunohistochemically...... neurons in the neuroendocrine system, which express the transcription factor DIMM and the amidating enzyme peptidylglycine-alpha-hydroxylating monooxygenase (PHM). The PICK1-positive cells include neurosecretory cells that produce the insulin-like peptide dILP2. PICK1 expression in insulin-producing cells...

  9. Reducing iron in the brain: a novel pharmacologic mechanism of huperzine A in the treatment of Alzheimer's disease.

    Science.gov (United States)

    Huang, Xiao-Tian; Qian, Zhong-Ming; He, Xuan; Gong, Qi; Wu, Ka-Chun; Jiang, Li-Rong; Lu, Li-Na; Zhu, Zhou-Jing; Zhang, Hai-Yan; Yung, Wing-Ho; Ke, Ya

    2014-05-01

    Huperzine A (HupA), a natural inhibitor of acetylcholinesterase derived from a plant, is a licensed anti-Alzheimer's disease (AD) drug in China and a nutraceutical in the United States. In addition to acting as an acetylcholinesterase inhibitor, HupA possesses neuroprotective properties. However, the relevant mechanism is unknown. Here, we showed that the neuroprotective effect of HupA was derived from a novel action on brain iron regulation. HupA treatment reduced insoluble and soluble beta amyloid levels, ameliorated amyloid plaques formation, and hyperphosphorylated tau in the cortex and hippocampus of APPswe/PS1dE9 transgenic AD mice. Also, HupA decreased beta amyloid oligomers and amyloid precursor protein levels, and increased A Disintegrin And Metalloprotease Domain 10 (ADAM10) expression in these treated AD mice. However, these beneficial effects of HupA were largely abolished by feeding the animals with a high iron diet. In parallel, we found that HupA decreased iron content in the brain and demonstrated that HupA also has a role to reduce the expression of transferrin-receptor 1 as well as the transferrin-bound iron uptake in cultured neurons. The findings implied that reducing iron in the brain is a novel mechanism of HupA in the treatment of Alzheimer's disease.

  10. Equine preantral follicles obtained via the Biopsy Pick-Up method: histological evaluation and validation of a mechanical isolation technique.

    Science.gov (United States)

    Haag, K T; Magalhães-Padilha, D M; Fonseca, G R; Wischral, A; Gastal, M O; King, S S; Jones, K L; Figueiredo, J R; Gastal, E L

    2013-03-15

    The aims of this study in mares were to: (1) compare preantral follicle parameters between in vitro Biopsy Pick-Up (BPU) and scalpel blade collection methods and between histological and mechanical isolation processing (experiment 1); (2) histologically evaluate preantral follicles (experiment 2); and (3) compare histological analysis with a previously established mechanical isolation technique using a tissue chopper (experiment 3) for ovarian cortical fragments obtained in vivo using a BPU instrument. In experiment 1, preantral follicles were analyzed (N = 220; 90% primordial and 10% primary). Proportions of primordial and primary follicles did not differ (P > 0.05) between tissue collection (BPU vs. scalpel blade dissection) or processing (mechanical isolation vs. histology) methods. Follicle viability and morphology rates were similar (P > 0.05) between tissue collection methods, but mechanical isolation produced more (P 0.05) by processing methods. In conclusion, most parameters evaluated for preantral follicles were sim