WorldWideScience

Sample records for niemann-pick disease patients

  1. Niemann-Pick disease

    Science.gov (United States)

    NPD; Sphingomyelinase deficiency; Lipid storage disorder - Niemann-Pick disease; Lysosomal storage disease - Niemann-Pick ... lipofuscinoses or Batten disease (Wolman disease, cholesteryl ... metabolism of lipids. In: Kliegman RM, Stanton BF, St. Geme JW, ...

  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. National Niemann-Pick Disease Foundation

    Science.gov (United States)

    ... nor does it host or receive funding from advertising or from the display of commercial content. This site complies to the HONcode standard for trustworthy health information: verify here . The National Niemann-Pick Disease Foundation ...

  4. Genetics Home Reference: Niemann-Pick disease

    Science.gov (United States)

    ... are compartments within cells that break down and recycle different types of molecules. Acid sphingomyelinase is responsible ... A, Brodie SE, Desnick RJ, Wasserstein MP. Natural history of Type A Niemann-Pick disease: possible endpoints ...

  5. Niemann-Pick type C disease: molecular mechanisms and potential therapeutic approaches

    OpenAIRE

    Rosenbaum, Anton I.; Maxfield, Frederick R.

    2011-01-01

    Cholesterol is an important lipid of mammalian cells. Its unique physicochemical properties modulate membrane behavior and it serves as the precursor for steroid hormones, oxysterols and vitamin D. Cholesterol is effluxed from the late endosomes/lysosomes via the concerted action of at least two distinct proteins: Niemann-Pick C1 and Niemann-Pick C2. Mutations in these two proteins manifest as Niemann-Pick type C disease – a very rare, usually fatal, autosomal, recessive, neurovisceral, lysos...

  6. Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease

    Directory of Open Access Journals (Sweden)

    Sandra Torres

    2017-11-01

    Full Text Available Lysosomal storage disorders (LSD are characterized by the accumulation of diverse lipid species in lysosomes. Niemann-Pick type A/B (NPA/B and type C diseases Niemann-Pick type C (NPC are progressive LSD caused by loss of function of distinct lysosomal-residing proteins, acid sphingomyelinase and NPC1, respectively. While the primary cause of these diseases differs, both share common biochemical features, including the accumulation of sphingolipids and cholesterol, predominantly in endolysosomes. Besides these alterations in lysosomal homeostasis and function due to accumulation of specific lipid species, the lysosomal functional defects can have far-reaching consequences, disrupting intracellular trafficking of sterols, lipids and calcium through membrane contact sites (MCS of apposed compartments. Although MCS between endoplasmic reticulum and mitochondria have been well studied and characterized in different contexts, emerging evidence indicates that lysosomes also exhibit close proximity with mitochondria, which translates in their mutual functional regulation. Indeed, as best illustrated in NPC disease, alterations in the lysosomal-mitochondrial liaisons underlie the secondary accumulation of specific lipids, such as cholesterol in mitochondria, resulting in mitochondrial dysfunction and defective antioxidant defense, which contribute to disease progression. Thus, a better understanding of the lysosomal and mitochondrial interactions and trafficking may identify novel targets for the treatment of Niemann-Pick disease.

  7. 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. Copyright © 2016 Elsevier B.V. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. In Vivo Assessment of Neurodegeneration in Type C Niemann-Pick Disease by IDEAL-IQ.

    Science.gov (United States)

    Guo, Ruo-Mi; Li, Qing-Ling; Luo, Zhong-Xing; Tang, Wen; Jiao, Ju; Wang, Jin; Kang, Zhuang; Chen, Shao-Qiong; Zhang, Yong

    2018-01-01

    To noninvasively assess the neurodegenerative changes in the brain of patients with Niemann-Pick type C (NPC) disease by measuring the lesion tissue with the iterative decomposition of water and fat with echo asymmetry and least square estimation-iron quantification (IDEAL-IQ). Routine brain MRI, IDEAL-IQ and 1 H-proton magnetic resonance spectroscopy ( 1 H-MRS, served as control) were performed on 12 patients with type C Niemann-Pick disease (4 males and 8 females; age range, 15-61 years; mean age, 36 years) and 20 healthy subjects (10 males and 10 females; age range, 20-65 years; mean age, 38 years). The regions with lesion and the normal appearing regions (NARs) of patients were measured and analyzed based on the fat/water signal intensity on IDEAL-IQ and the lipid peak on 1 H-MRS. Niemann-Pick type C patients showed a higher fat/water signal intensity ratio with IDEAL-IQ on T2 hyperintensity lesions and NARs (3.7-4.9%, p IQ instead of 1 H-MRS. The findings of this study suggested that IDEAL-IQ may be useful as a noninvasive and objective method in the evaluation of patients with NPC; additionally, IDEAL-IQ can be used to quantitatively measure the brain parenchymal adipose content and monitor patient follow-up after treatment of NPC.

  10. 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.

  11. Immune dysfunction in Niemann?Pick disease type C

    OpenAIRE

    Platt, Nick; Speak, Annelise O.; Colaco, Alexandria; Gray, James; Smith, David A.; Williams, Ian M.; Wallom, Kerri?Lee; Platt, Frances M.

    2015-01-01

    Abstract Lysosomal storage diseases are inherited monogenic disorders in which lysosome function is compromised. Although individually very rare, they occur at a collective frequency of approximately one in five thousand live births and usually have catastrophic consequences for health. The lysosomal storage diseases Niemann?Pick disease type C (NPC) is caused by mutations predominantly in the lysosomal integral membrane protein NPC1 and clinically presents as a progressive neurodegenerative ...

  12. 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

  13. Type a niemann-pick disease. Description of three cases with delayed myelination.

    Science.gov (United States)

    D'Amico, A; Sibilio, M; Caranci, F; Bartiromo, F; Taurisano, R; Balivo, F; Melis, D; Parenti, G; Cirillo, S; Elefante, R; Brunetti, A

    2008-06-03

    We describe three patients with type A Niemann-Pick disease (NPD-A). NPD-A is an autosomal recessive neuronal storage disease classified among the sphingolipidoses, characterized by accumulation of sphingomyelin in various tissues and in the brain. Magnetic Resonance imaging (MRI) of our three patients showed a marked delay of myelination with frontal atrophy. Few descriptions of this MRI pattern of delayed myelination have been published to date.

  14. Cataplexy leading to the diagnosis of Niemann-Pick disease type C.

    Science.gov (United States)

    Smit, Liesbeth S; Lammers, Gert Jan; Catsman-Berrevoets, Coriene E

    2006-07-01

    Cataplexy in childhood is a rare and often misdiagnosed symptom. It is described as a brief episode of bilateral loss of muscle tone with intact consciousness, triggered by a variety of strong emotions and in particular with unexpected laughter. This report presents a 9-year old male with progressive cerebellar and pyramidal symptoms and a cognitive decline since the age of 4. His recently developed "drop attacks" on laughter were recognized as cataplexy and led to the diagnosis of Niemann-Pick type C disease. With biochemical studies this diagnosis, a lysosomal storage disease, was confirmed. With cataplexy narcolepsy, Niemann-Pick type C disease, Norrie disease, Prader-Willi syndrome, and Coffin-Lowry syndrome are associated disorders. Recognition of cataplexy in children with concomitant neurologic symptoms may lead to an early and straight diagnosis of one of these disorders.

  15. Hematopoietic stem cell transplantation in Niemann-Pick disease type B monitored by chitotriosidase activity.

    Science.gov (United States)

    Quarello, Paola; Spada, Marco; Porta, Francesco; Vassallo, Elena; Timeus, Fabio; Fagioli, Franca

    2018-02-01

    Here, we report a patient with Niemann-Pick disease type B, with early severe onset of disease and pulmonary involvement, treated with hematopoietic stem cell transplant (HSCT) from a bone marrow matched unrelated donor. We confirm that HSCT is feasible and potentially beneficial for patients with severe phenotype. Noteworthy, we discussed the potential usefulness of the activity of peripheral chitotriosidase for the longitudinal evaluation of HSCT success and effectiveness. © 2017 Wiley Periodicals, Inc.

  16. Vestibular function in patients with Niemann-Pick type C disease.

    Science.gov (United States)

    Bremova, Tatiana; Krafczyk, Siegbert; Bardins, Stanislavs; Reinke, Jörg; Strupp, Michael

    2016-11-01

    We investigated whether vestibular dysfunction may cause or contribute to postural imbalance and falls in patients with Niemann-Pick type C disease (NP-C). Eight patients with NP-C disease and 20 healthy controls were examined using the video-based head impulse test (vHIT) and caloric irrigation to investigate horizontal canal function as well as ocular- and cervical vestibular evoked myogenic potentials (o- and cVEMP), and binocular subjective visual vertical estimation (SVV) for otolith function, and static posturography. There were no significant differences in vestibulo-ocular gain, caloric excitability, o-/cVEMP measures or SVV between the two groups. Posturographic total sway path (tSP) and root mean square (RMS) were significantly higher in NP-C than in controls in 3 out of 4 conditions. The Romberg quotient (RQ) to assess the amount of visual stabilization was significantly lower in the NP-C than in the HC group. In contrast to other inherited metabolic disorders, such as Morbus Gaucher type 3, we did not find any evidence for an impairment of canal or otolith function in patients with NP-C as their cause of postural imbalance. Since RQ was low in NP-C patients, indicating proper sensory input, the observed increased postural sway is most likely due to a cerebellar dysfunction in NP-C, which may therefore, explain postural imbalance.

  17. 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

  18. Distinct Niemann-Pick Disease Type C Clinical, Cytological, and Biochemical Phenotype in an Adult Patient With 1 Mutated, Overexpressed Allele

    Directory of Open Access Journals (Sweden)

    Julia Jecel MD

    2015-11-01

    Full Text Available Niemann-Pick disease type C (NP-C is a rare autosomal-recessive neurovisceral lysosomal storage disease. We report on a juvenile onset, now 25-year-old female patient with typical neurologic symptoms, including vertical gaze palsy, of NP-C. The diagnosis was supported by a positive filipin test (“variant biochemical phenotype” of cholesterol accumulation in cultured fibroblasts, high numbers of “Niemann-Pick cells” in the bone marrow, and 1 positive out of 3 NP-C biomarkers tested, but NP-C was not definitely confirmed genetically. She showed only 1 known NPC1 variant (3 bp deletion in exon 18; p.N916del; this allele, however, being distinctly overexpressed at the messenger RNA level as compared to the wild-type allele, as a not as yet clarified (copathogenic? phenomenon. The patient’s mother, also carrying the p.N916del allele but without overexpression, has a chronic inflammatory disease of the central nervous system classified as multiple sclerosis. However, her severe clinical phenotype includes some signs also consistent with NP-C. The laboratory diagnosis of NP-C can be challenging in detecting novel disease constellations.

  19. Adult onset Niemann-Pick type C disease: A clinical, neuroimaging and molecular genetic study.

    Science.gov (United States)

    Battisti, Carla; Tarugi, Patrizla; Dotti, Maria Teresa; De Stefano, Nicola; Vattimo, Angelo; Chierichetti, Francesea; Calandra, Sebastiano; Federico, Antonio

    2003-11-01

    We report on a patient with adult-onset Niemann-Pick type C (NPC) disease, carrying the mutations P1007 and I1061T in the NPC1 gene, presenting with marked psychiatric changes followed by dystonia and cognitive impairment. Filipin staining, single photon emission computed tomography perfusional, positron emission tomography metabolic, conventional magnetic resonance imaging, and magnetic resonance spectroscopy findings suggested a pathophysiological correlation with phenotype expression. This case expands the clinical and genetic spectrum of the rare adult-onset NPC disease phenotype.

  20. Liver and Skin Histopathology in Adults with Acid Sphingomyelinase Deficiency (Niemann-Pick Disease Type B)

    OpenAIRE

    Thurberg, Beth L.; Wasserstein, Melissa P.; Schiano, Thomas; O’Brien, Fanny; Richards, Susan; Cox, Gerald F.; McGovern, Margaret M.

    2012-01-01

    Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder characterized by the pathologic accumulation of sphingomyelin in multiple cells types, and occurs most prominently within the liver, spleen and lungs, leading to significant clinical disease. Seventeen ASMD patients underwent a liver biopsy during baseline screening for a Phase 1 trial of recombinant human acid sphingomyelinase (rhASM) in adults with Niemann-Pick disease type B. Eleven of the 17 were enrolled in the trial...

  1. 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. © 2016 Wiley Periodicals, Inc.

  2. Development of a Suspicion Index to aid diagnosis of Niemann-Pick disease type C

    NARCIS (Netherlands)

    Wijburg, F. A.; Sedel, F.; Pineda, M.; Hendriksz, C. J.; Fahey, M.; Walterfang, M.; Patterson, M. C.; Wraith, J. E.; Kolb, S. A.

    2012-01-01

    Objectives: Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive lysosomal lipid storage disorder that is invariably fatal. NP-C diagnosis can be delayed for years due to heterogeneous presentation; adult-onset NP-C can be particularly difficult to diagnose. We developed a Suspicion

  3. Impact of miglustat on evolution of atypical presentation of late-infantile-onset Niemann?Pick disease type C with early cognitive impairment, behavioral dysfunction, epilepsy, ophthalmoplegia, and cerebellar involvement: a case report

    OpenAIRE

    Cuisset, Jean-Marie; Sukno, S.; Trauffler, A.; Latour, P.; Dobbelaere, D.; Michaud, L.; Vall?e, L.

    2016-01-01

    Background Niemann?Pick disease type C is a rare inherited neurodegenerative disease involving impaired intracellular lipid trafficking and accumulation of glycolipids in various tissues, including the brain. Miglustat, a reversible inhibitor of glucosylceramide synthase, has been shown to be effective in the treatment of progressive neurological manifestations in pediatric and adult patients with Niemann?Pick disease type C, and has been used in that indication in Europe since 2010. Case pre...

  4. Impaired Autophagy in the Lipid-Storage Disorder Niemann-Pick Type C1 Disease

    OpenAIRE

    Sarkar, Sovan; Carroll, Bernadette; Buganim, Yosef; Maetzel, Dorothea; Ng, Alex H.M.; Cassady, John P.; Cohen, Malkiel A.; Chakraborty, Souvik; Wang, Haoyi; Spooner, Eric; Ploegh, Hidde; Gsponer, Joerg; Korolchuk, Viktor I.; Jaenisch, Rudolf

    2013-01-01

    Autophagy dysfunction has been implicated in misfolded protein accumulation and cellular toxicity in several diseases. Whether alterations in autophagy also contribute to the pathology of lipid-storage disorders is not clear. Here, we show defective autophagy in Niemann-Pick type C1 (NPC1) disease associated with cholesterol accumulation, where the maturation of autophagosomes is impaired because of defective amphisome formation caused by failure in SNARE machinery, whereas the lysosomal prot...

  5. Plasma chitotriosidase and CCL18: Early biochemical surrogate markers in type B Niemann-Pick disease

    NARCIS (Netherlands)

    Brinkman, J.; Wijburg, F. A.; Hollak, C. E.; Groener, J. E.; Verhoek, M.; Scheij, S.; Aten, J.; Boot, R. G.; Aerts, J. M.

    2005-01-01

    Type B Niemann-Pick disease (NPD) is a nonneuronopathic lysosomal storage disorder which is characterized by accumulation of sphingomyelin-laden macrophages. The availability of plasma markers for storage cells may be of great value in facilitating therapeutic decisions. Given the similarity of the

  6. Niemann-Pick disease type C

    Directory of Open Access Journals (Sweden)

    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

  7. Complex lipid trafficking in Niemann-Pick disease type C.

    Science.gov (United States)

    Vanier, Marie T

    2015-01-01

    Niemann-Pick disease type C (NPC) is an atypical lysosomal storage disease resulting from mutations in one of two genes, either NPC1 or NPC2. Although a neurovisceral disorder, it is above all a neurodegenerative disease in the vast majority of patients. Not an enzyme deficiency, it is currently conceived as a lipid trafficking disorder. Impaired egress of cholesterol from the late endosomal/lysosomal (LE/L) compartment is a specific and key element of the pathogenesis, but other lipids, more specially sphingolipids, are also involved, and there are indications for further abnormalities. The full function of the NPC1 and NPC2 proteins is still unclear. This review provides a reappraisal of lipid storage and lysosomal enzymes activities in tissues/cells from NPC patients and animal models. It summarizes the current knowledge on the NPC1 and NPC2 proteins and their function in transport of cholesterol within the late endosomal-lysosomal compartment, with emphasis on differences between systemic organs and the brain; it also discusses regulation by membrane lipids of the NPC2-mediated cholesterol trafficking, interplay between cholesterol and sphingomyelin, the metabolic origin of glycosphingolipids stored in brain, and the putative role of free sphingoid bases in pathogenesis. Brief mention is finally made of diseases affecting other genes that were very recently shown to impact the "NPC pathway".

  8. Adult Niemann-Pick disease type B with myositis ossificans: a case report

    Directory of Open Access Journals (Sweden)

    Russka Shumnalieva

    2016-07-01

    Full Text Available Niemann-Pick Disease (NPD is a rare autosomal recessive lysosomal lipid storage disorder. The disease is caused by gene mutations that affect the metabolism of sphingolipids. The dysfunctions cause sphingomyelin to accumulate in different organs. NPD includes forms with low and high levels of sphingomyelin. We report a case of a 34 year-old man with a family history of NPD type B who presented with hepatosplenomegaly, neurological deficiency, bone abnormalities, and myositis ossificans. The clinical, biochemical, and imaging data confirmed the combined diagnosis of NPD type B with myositis ossificans.

  9. Sphingomyelin lipidosis (Niemann-Pick disease) in a juvenile raccoon (Procyon lotor).

    Science.gov (United States)

    Vapniarsky, N; Wenger, D A; Scheenstra, D; Mete, A

    2013-01-01

    A wild caught juvenile male raccoon with neurological disease was humanely destroyed due to poor prognosis. Necropsy examination revealed hepatomegaly, splenomegaly and multicentric lymphadenomegaly with diffuse hepatic pallor and pulmonary consolidation with pinpoint pale subpleural foci. Microscopically, there was marked pale cytoplasmic swelling of the central and peripheral neurons as well as the glial cells in the brain, accompanied by multiorgan infiltration by abundant foamy macrophages. Ultrastructural investigation revealed accumulation of concentrically arranged lamellar material within lysosomes of the affected neurons, macrophages and endothelial cells. Biochemical enzymatic analysis detected sphingomyelinase deficiency and lysosomal storage disease consistent with sphingomyelin lipidosis (Niemann-Pick disease [NPD]) was diagnosed. This is the first report of NPD in a raccoon. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Peripheral neuropathy in type A Niemann-Pick disease. A morphological study.

    Science.gov (United States)

    Landrieu, P; Saïd, G

    1984-01-01

    A black boy had a severe neuropathic form of Niemann-Pick disease (NPD) with a pronounced sphingomyelinase deficiency in the fibroblasts. Nerve conduction velocities were diminished, and a nerve biopsy was performed. Isolated fibers showed segmental demyelination and numerous dense bodies in the Schwann cells (SC). Electron microscopy revealed two categories of inclusions: the first was made up of lysosomal inclusions usually described in NPD. The second comprised myelin inclusions--sometimes still connected to the original myelin sheath--indicating severe myelinopathy. Both myelin debris and NPD inclusions were found in axoplasms and probably came from SC cytoplasm through axolemma lesions. NPD is a unique example of myelinopathy due to sphingomyelinase deficiency.

  11. Oxidative Stress: A Pathogenic Mechanism for Niemann-Pick Type C Disease

    Directory of Open Access Journals (Sweden)

    Mary Carmen Vázquez

    2012-01-01

    Full Text Available Niemann-Pick type C (NPC disease is a neurovisceral atypical lipid storage disorder involving the accumulation of cholesterol and other lipids in the late endocytic pathway. The pathogenic mechanism that links the accumulation of intracellular cholesterol with cell death in NPC disease in both the CNS and the liver is currently unknown. Oxidative stress has been observed in the livers and brains of NPC mice and in different NPC cellular models. Moreover, there is evidence of an elevation of oxidative stress markers in the serumof NPC patients. Recent evidence strongly suggests that mitochondrial dysfunction plays an important role in NPC pathogenesis and that mitochondria could be a significant source of oxidative stress in this disease. In this context, the accumulation of vitamin E in the late endosomal/lysosomal compartments in NPC could lead to a potential decrease of its bioavailability and could be another possible cause of oxidative damage. Another possible source of reactive species in NPC is the diminished activity of different antioxidant enzymes. Moreover, because NPC is mainly caused by the accumulation of free cholesterol, oxidized cholesterol derivatives produced by oxidative stress may contribute to the pathogenesis of the disease.

  12. 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.

  13. 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.

  14. Probable Diagnosis of a Patient with Niemann-Pick Disease Type C: Managing Pitfalls of Exome Sequencing.

    Science.gov (United States)

    Zeiger, William A; Jamal, Nasheed I; Scheuner, Maren T; Pittman, Patricia; Raymond, Kimiyo M; Morra, Massimo; Mishra, Shri K

    2018-02-17

    Here, we present a case of a 31-year-old man with progressive cognitive decline, ataxia, and dystonia. Extensive laboratory, radiographic, and targeted genetic studies over the course of several years failed to yield a diagnosis. Initial whole exome sequencing through a commercial laboratory identified several variants of uncertain significance; however, follow-up clinical examination and testing ruled each of these out. Eventually, repeat whole exome sequencing identified a known pathogenic intronic variant in the NPC1 gene (NM_000271.4, c.1554-1009G>A) and an additional heterozygous exonic variant of uncertain significance in the NPC1 gene (NM_000271.4, c.2524T>C). Follow-up biochemical testing was consistent with a diagnosis of probable Niemann-Pick disease Type C (NP-C). This case illustrates the potential of whole exome sequencing for diagnosing rare complex neurologic diseases. It also identifies several potential common pitfalls that must be navigated by clinicians when interpreting commercial whole exome sequencing results.

  15. 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

    2017-10-09

    Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease that should be recognised 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.

  16. Impaired Autophagy in the Lipid-Storage Disorder Niemann-Pick Type C1 Disease

    Directory of Open Access Journals (Sweden)

    Sovan Sarkar

    2013-12-01

    Full Text Available Autophagy dysfunction has been implicated in misfolded protein accumulation and cellular toxicity in several diseases. Whether alterations in autophagy also contribute to the pathology of lipid-storage disorders is not clear. Here, we show defective autophagy in Niemann-Pick type C1 (NPC1 disease associated with cholesterol accumulation, where the maturation of autophagosomes is impaired because of defective amphisome formation caused by failure in SNARE machinery, whereas the lysosomal proteolytic function remains unaffected. Expression of functional NPC1 protein rescues this defect. Inhibition of autophagy also causes cholesterol accumulation. Compromised autophagy was seen in disease-affected organs of Npc1 mutant mice. Of potential therapeutic relevance is that HP-β-cyclodextrin, which is used for cholesterol-depletion treatment, impedes autophagy, whereas stimulating autophagy restores its function independent of amphisome formation. Our data suggest that a low dose of HP-β-cyclodextrin that does not perturb autophagy, coupled with an autophagy inducer, may provide a rational treatment strategy for NPC1 disease.

  17. Miglustat therapy in the French cohort of paediatric patients with Niemann-Pick disease type C

    Directory of Open Access Journals (Sweden)

    Héron Bénédicte

    2012-06-01

    Full Text Available Abstract Background Niemann-Pick disease type C (NP-C is a rare neurovisceral lysosomal lipid storage disease characterized by progressive neurological deterioration. Published data on the use of miglustat in paediatric patients in clinical practice settings are limited. We report findings from a prospective open-label study in the French paediatric NP-C cohort. Methods Data on all paediatric NP-C patients treated with miglustat in France between October 2006 and December 2010 were compiled. All patients had a confirmed diagnosis of NP-C, and received miglustat therapy according to manufacturer’s recommendations. Pre-treatment and follow-up assessments were conducted according to a standardized protocol. Results Twenty children were enrolled; 19 had NPC1 gene mutations and 1 had NPC2 gene mutations. The median age at diagnosis was 1.5 years, and the median age at miglustat initiation was 6.0 years. Eight NPC1 patients had the early-infantile, eight had the late-infantile, and three had the juvenile-onset forms of NP-C. A history of hepatosplenomegaly and/or other cholestatic symptoms was recorded in all 8 early-infantile onset patients, 3/8 late-infantile patients, and 1/3 juvenile onset patients. Brain imaging indicated white matter abnormalities in most patients. The median (range duration of miglustat therapy was 1.3 (0.6–2.3 years in early-infantile, 1.0 (0.8–5.0 year in late-infantile, and 1.0 (0.6–2.5 year in juvenile onset patients. NP-C disability scale scores indicated either stabilization or improvement of neurological manifestations in 1/8, 6/8, and 1/3 NPC1 patients in these subgroups, respectively. There were no correlations between brain imaging findings and disease course. Mild-to-moderate gastrointestinal disturbances were frequent during the first 3 months of miglustat therapy, but were easily managed with dietary modifications and/or anti-propulsive medication. Conclusions Miglustat can improve or stabilize neurological

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

    Directory of Open Access Journals (Sweden)

    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.

  19. Impaired autophagy in the lipid-storage disorder Niemann-Pick type C1 disease.

    Science.gov (United States)

    Sarkar, Sovan; Carroll, Bernadette; Buganim, Yosef; Maetzel, Dorothea; Ng, Alex H M; Cassady, John P; Cohen, Malkiel A; Chakraborty, Souvik; Wang, Haoyi; Spooner, Eric; Ploegh, Hidde; Gsponer, Joerg; Korolchuk, Viktor I; Jaenisch, Rudolf

    2013-12-12

    Autophagy dysfunction has been implicated in misfolded protein accumulation and cellular toxicity in several diseases. Whether alterations in autophagy also contribute to the pathology of lipid-storage disorders is not clear. Here, we show defective autophagy in Niemann-Pick type C1 (NPC1) disease associated with cholesterol accumulation, where the maturation of autophagosomes is impaired because of defective amphisome formation caused by failure in SNARE machinery, whereas the lysosomal proteolytic function remains unaffected. Expression of functional NPC1 protein rescues this defect. Inhibition of autophagy also causes cholesterol accumulation. Compromised autophagy was seen in disease-affected organs of Npc1 mutant mice. Of potential therapeutic relevance is that HP-β-cyclodextrin, which is used for cholesterol-depletion treatment, impedes autophagy, whereas stimulating autophagy restores its function independent of amphisome formation. Our data suggest that a low dose of HP-β-cyclodextrin that does not perturb autophagy, coupled with an autophagy inducer, may provide a rational treatment strategy for NPC1 disease. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Mitochondrial G8292A and C8794T mutations in patients with Niemann-Pick disease type C.

    Science.gov (United States)

    Masserrat, Abbas; Sharifpanah, Fatemeh; Akbari, Leila; Tonekaboni, Seyed Hasan; Karimzadeh, Parvaneh; Asharafi, Mahmood Reza; Mazouei, Safoura; Sauer, Heinrich; Houshmand, Massoud

    2018-07-01

    Niemann-Pick disease type C (NP-C) is a neurovisceral lipid storage disorder. At the cellular level, the disorder is characterized by accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system. NP-C is transmitted in an autosomal recessive manner and is caused by mutations in either the NPC1 (95% of families) or NPC2 gene. The estimated disease incidence is 1 in 120,000 live births, but this likely represents an underestimate, as the disease may be under-diagnosed due to its highly heterogeneous presentation. Variants of adenosine triphosphatase (ATPase) subunit 6 and ATPase subunit 8 ( ATPase6/8 ) in mitochondrial DNA (mtDNA) have been reported in different types of genetic diseases including NP-C. In the present study, the blood samples of 22 Iranian patients with NP-C and 150 healthy subjects as a control group were analyzed. The DNA of the blood samples was extracted by the salting out method and analyzed for ATPase6/8 mutations using polymerase chain reaction sequencing. Sequence variations in mitochondrial genome samples were determined via the Mitomap database. Analysis of sequencing data confirmed the existence of 11 different single nucleotide polymorphisms (SNPs) in patients with NP-C1. One of the most prevalent polymorphisms was the A8860G variant, which was observed in both affected and non-affected groups and determined to have no significant association with NP-C incidence. Amongst the 11 polymorphisms, only one was identified in the ATPase8 gene, while 9 including A8860G were observed in the ATPase6 gene. Furthermore, two SNPs, G8292A and C8792A, located in the non-coding region of mtDNA and the ATPase6 gene, respectively, exhibited significantly higher prevalence rates in NP-C1 patients compared with the control group (PC disease. In addition, the mitochondrial SNPs identified maybe pathogenic mutations involved in the development and prevalence of NP-C. Furthermore, these results suggest a higher occurrence of

  1. Case Report: Ursodeoxycholic acid treatment in Niemann-Pick disease type C; clinical experience in four cases

    Science.gov (United States)

    Movsesyan, Nina; Platt, Frances M.

    2017-01-01

    In this case series, we demonstrate that Ursodeoxycholic acid (UDCA) improves liver dysfunction in Niemann-Pick type C (NPC) and may restore a suppressed cytochrome p450 system. NPC disease is a progressive neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 genes. Liver disease is a common feature presenting either acutely as cholestatic jaundice in the neonatal period, or in later life as elevated liver enzymes indicative of liver dysfunction. Recently, an imbalance in bile acid synthesis in a mouse model of NPC disease was linked to suppression of the P450 detoxification system and was corrected by UDCA treatment. UDCA (3α, 7β-dihydroxy-5β-cholanic acid), a hydrophilic bile acid, is used to treat various cholestatic disorders. In this report we summarise the findings from four independent cases of NPC, three with abnormal liver enzyme levels at baseline, that were subsequently treated with UDCA. The patients differed in age and clinical features, they all tolerated the drug well, and in those with abnormal liver function, there were significant improvements in their liver enzyme parameters. PMID:29119141

  2. Oculomotor abnormalities in children with Niemann-Pick type C.

    Science.gov (United States)

    Blundell, James; Frisson, Steven; Chakrapani, Anupam; Gissen, Paul; Hendriksz, Chris; Vijay, Suresh; Olson, Andrew

    2018-02-01

    Niemann-Pick type C (NP-C) is a rare recessive disorder associated with progressive supranuclear gaze palsy. Degeneration occurs initially for vertical saccades and later for horizontal saccades. There are studies of oculomotor degeneration in adult NP-C patients [1, 2] but no comparable studies in children. We used high-resolution video-based eye tracking to record monocular vertical and horizontal eye movements in 2 neurological NP-C patients (children with clinically observable oculomotor abnormalities) and 3 pre-neurological NP-C patients (children without clinically observable oculomotor abnormalities). Saccade onset latency, saccade peak velocity and saccade curvature were compared to healthy controls (N=77). NP-C patients had selective impairments of vertical saccade peak velocity and vertical saccade curvature, with slower peak velocities and greater curvature. Changes were more pronounced in neurological than pre-neurological patients, showing that these measures are sensitive to disease progress, but abnormal curvature and slowed downward saccades were present in both groups, showing that eye-tracking can register disease-related changes before these are evident in a clinical exam. Both slowing, curvature and the detailed characteristics of the curvature we observed are predicted by the detailed characteristics of RIMLF population codes. Onset latencies were not different from healthy controls. High-resolution video-based eye tracking is a promising sensitive and objective method to measure NP-C disease severity and neurological onset. It may also help evaluate responses to therapeutic interventions. Copyright © 2017. Published by Elsevier Inc.

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

    Science.gov (United States)

    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.

  4. Case Report: Genetic analysis and anesthetic management of a child with Niemann-Pick disease Type A [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Priti G. Dalal

    2015-12-01

    Full Text Available A 14-month-old child, recently diagnosed with Niemann-Pick disease type A, presented for a laparoscopic placement of a gastrostomy tube under general anesthesia. The disease was confirmed and further characterized by genetic testing, which revealed evidence of the presence of two known pathogenic mutations in the SMPD1 gene, and enzyme studies showed a corresponding very low level of enzymatic activity of acidic sphingomyelinase. The anesthetic management involved strategies to manage an anticipated difficult intubation and avoid post-operative ventilation.

  5. Dietary cholesterol induces trafficking of intestinal Niemann-Pick Type C1 Like 1 from the brush border to endosomes

    DEFF Research Database (Denmark)

    Skov, Marianne; Tønnesen, Carina K; Hansen, Gert H

    2011-01-01

    The transmembrane protein Niemann-Pick C1 Like 1 (NPC1L1) belongs to the Niemann-Pick C1 (NPC1) family of cholesterol transporters and is mainly expressed in the liver and the small intestine. NPC1L1 is believed to be the main transporter responsible for the absorption of dietary cholesterol. Lik...

  6. 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.

  7. 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.

  8. Treatment of cataplexy in Niemann-Pick disease type C with the use of miglustat.

    Science.gov (United States)

    Zarowski, Marcin; Steinborn, Barbara; Gurda, Barbara; Dvorakova, Lenka; Vlaskova, Hana; Kothare, Sanjeev V

    2011-01-01

    Cataplexy is the sudden muscle weakness brought on by strong emotions, particularly joking, laughter, or anger. Cataplexy may involve only certain group of muscles or the entire voluntary musculature. In rare cases, symptoms of cataplexy can be seen during the course of some inherited diseases (Niemann-Pick type C (NPC), Prader-Willi syndrome, myotonic dystrophy, Norrie disease). We report the successful use of miglustat, a reversible inhibitor of the enzyme glucosylceramide synthase, approved for use in Gaucher's disease, and which catalyses the first step in the biosynthesis of most glycosphingolipid, in a boy with NPC with cataplexy. A 9-year-old boy was admitted for assessments of frequent "drop attacks" while laughing. The filipin fluorescence tests of cultured skin fibroblasts revealed massive accumulation of unesterified cholesterol, confirming the diagnosis of NPC disease. Molecular studies confirmed the diagnosis of NPC too. After approval from the bioethics committee, miglustat was initiated on the child at 100mg three times a day. Cataplectic attacks disappeared completely after 6 months on treatment, and patient continues to be in remission from the cataplectic attacks at 16 months follow-up. There was no further progression of neurological signs or symptoms or splenomegaly, with some improvement in cognitive function as well as social, affective and attention problems, up-gaze, and gait. Miglustat was well tolerated with no side effects observed. In summary, this is the first report of miglustat treatment of cataplexy in NPC. Long-term follow-up for continuing efficacy and tolerability in a larger cohort with NPC is needed to substantiate our observation. © 2010 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

  9. PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder

    OpenAIRE

    Brown, Anna; Patel, Siddharth; Ward, Carl; Lorenz, Anna; Ortiz, Mauren; DuRoss, Allison; Wieghardt, Fabian; Esch, Amanda; Otten, Elsje G.; Heiser, Laura M.; Korolchuk, Viktor I.; Sun, Conroy; Sarkar, Sovan; Sahay, Gaurav

    2016-01-01

    2-Hydroxy-propyl-?-cyclodextrin (HP?CD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HP?CD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (e...

  10. Ataxia, dystonia and myoclonus in adult patients with Niemann-Pick type C.

    Science.gov (United States)

    Koens, L H; Kuiper, A; Coenen, M A; Elting, J W J; de Vries, J J; Engelen, M; Koelman, J H T M; van Spronsen, F J; Spikman, J M; de Koning, T J; Tijssen, M A J

    2016-09-01

    Niemann-Pick type C (NP-C) is a rare autosomal recessive progressive neurodegenerative disorder caused by mutations in the NP-C 1 or 2 gene. Besides visceral symptoms, presentation in adolescent and adult onset variants is often with neurological symptoms. The most frequently reported presenting symptoms of NP-C in adulthood are psychiatric symptoms (38 %), cognitive decline (23 %) and ataxia (20 %). Myoclonus can be present, but its value in early diagnosis and the evolving clinical phenotype in NP-C is unclear. In this paper we present eight Dutch cases of NP-C of whom five with myoclonus. Eight patients with genetically confirmed NP-C were recruited from two Dutch University Medical Centers. A structured interview and neuropsychological tests (for working and verbal memory, attention and emotion recognition) were performed. Movement disorders were assessed using a standardized video protocol. Quality of life was evaluated by questionnaires (Rand-36, SIP-68, HAQ). In four of the five patients with myoclonic jerks simultaneous EEG with EMG was performed. A movement disorder was the initial neurological symptom in six patients: three with myoclonus and three with ataxia. Two others presented with psychosis. Four experienced cognitive deficits early in the course of the disease. Patients showed cognitive deficits in all investigated domains. Five patients showed myoclonic jerks, including negative myoclonus. In all registered patients EEG-EMG coherence analysis and/or back-averaging proved a cortical origin of myoclonus. Patients with more severe movement disorders experienced significantly more physical disabilities. Presenting neurological symptoms of NP-C include movement disorders, psychosis and cognitive deficits. At current neurological examination movement disorders were seen in all patients. The incidence of myoclonus in our cohort was considerably higher (63 %) than in previous publications and it was the presenting symptom in 38 %. A cortical origin

  11. 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.

  12. 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.

  13. Liver and Skin Histopathology in Adults with Acid Sphingomyelinase Deficiency (Niemann-Pick Disease Type B)

    Science.gov (United States)

    Thurberg, Beth L.; Wasserstein, Melissa P.; Schiano, Thomas; O’Brien, Fanny; Richards, Susan; Cox, Gerald F.; McGovern, Margaret M.

    2012-01-01

    Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder characterized by the pathologic accumulation of sphingomyelin in multiple cells types, and occurs most prominently within the liver, spleen and lungs, leading to significant clinical disease. Seventeen ASMD patients underwent a liver biopsy during baseline screening for a Phase 1 trial of recombinant human acid sphingomyelinase (rhASM) in adults with Niemann-Pick disease type B. Eleven of the 17 were enrolled in the trial and each received a single dose of rhASM and underwent a repeat liver biopsy on Day 14. Biopsies were evaluated for fibrosis, sphingomyelin accumulation and macrophage infiltration by light and electron microscopy. When present, fibrosis was periportal and pericellular, predominantly surrounding affected Kupffer cells. Two baseline biopsies exhibited frank cirrhosis. Sphingomyelin was localized to isolated Kupffer cells in mildly affected biopsies and was present in both Kupffer cells and hepatocytes in more severely affected cases. Morphometric quantification of sphingomyelin storage in liver biopsies ranged from 4–44% of the microscopic field. Skin biopsies were also performed at baseline and Day 14 in order to compare the sphingomyelin distribution in a peripheral tissue to that of liver. Sphingomyelin storage was present at lower levels in multiple cell types of the skin, including dermal fibroblasts, macrophages, vascular endothelial cells, vascular smooth muscle cells and Schwann cells. This Phase 1 trial of rhASM in adults with ASMD provided a unique opportunity for a prospective assessment of hepatic and skin pathology in this rare disease and their potential usage as pharmacodynamic biomarkers. PMID:22613999

  14. Genetic dissection of a cell-autonomous neurodegenerative disorder: lessons learned from mouse models of Niemann-Pick disease type C

    Directory of Open Access Journals (Sweden)

    Manuel E. Lopez

    2013-09-01

    Full Text Available Understanding neurodegenerative disease progression and its treatment requires the systematic characterization and manipulation of relevant cell types and molecular pathways. The neurodegenerative lysosomal storage disorder Niemann-Pick disease type C (NPC is highly amenable to genetic approaches that allow exploration of the disease biology at the organismal, cellular and molecular level. Although NPC is a rare disease, genetic analysis of the associated neuropathology promises to provide insight into the logic of disease neural circuitry, selective neuron vulnerability and neural-glial interactions. The ability to control the disorder cell-autonomously and in naturally occurring spontaneous animal models that recapitulate many aspects of the human disease allows for an unparalleled dissection of the disease neurobiology in vivo. Here, we review progress in mouse-model-based studies of NPC disease, specifically focusing on the subtype that is caused by a deficiency in NPC1, a sterol-binding late endosomal membrane protein involved in lipid trafficking. We also discuss recent findings and future directions in NPC disease research that are pertinent to understanding the cellular and molecular mechanisms underlying neurodegeneration in general.

  15. 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.

  16. Genetic and Chemical Correction of Cholesterol Accumulation and Impaired Autophagy in Hepatic and Neural Cells Derived from Niemann-Pick Type C Patient-Specific iPS Cells

    Directory of Open Access Journals (Sweden)

    Dorothea Maetzel

    2014-06-01

    Full Text Available Niemann-Pick type C (NPC disease is a fatal inherited lipid storage disorder causing severe neurodegeneration and liver dysfunction with only limited treatment options for patients. Loss of NPC1 function causes defects in cholesterol metabolism and has recently been implicated in deregulation of autophagy. Here, we report the generation of isogenic pairs of NPC patient-specific induced pluripotent stem cells (iPSCs using transcription activator-like effector nucleases (TALENs. We observed decreased cell viability, cholesterol accumulation, and dysfunctional autophagic flux in NPC1-deficient human hepatic and neural cells. Genetic correction of a disease-causing mutation rescued these defects and directly linked NPC1 protein function to impaired cholesterol metabolism and autophagy. Screening for autophagy-inducing compounds in disease-affected human cells showed cell type specificity. Carbamazepine was found to be cytoprotective and effective in restoring the autophagy defects in both NPC1-deficient hepatic and neuronal cells and therefore may be a promising treatment option with overall benefit for NPC disease.

  17. 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

    2010-09-01

    Full Text Available 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.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.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.

  18. 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.

  19. 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.

  20. Annexins as organizers of cholesterol- and sphingomyelin-enriched membrane microdomains in Niemann-Pick type C disease.

    Science.gov (United States)

    Domon, Magdalena; Nasir, Mehmet Nail; Matar, Gladys; Pikula, Slawomir; Besson, Françoise; Bandorowicz-Pikula, Joanna

    2012-06-01

    Growing evidence suggests that membrane microdomains enriched in cholesterol and sphingomyelin are sites for numerous cellular processes, including signaling, vesicular transport, interaction with pathogens, and viral infection, etc. Recently some members of the annexin family of conserved calcium and membrane-binding proteins have been recognized as cholesterol-interacting molecules and suggested to play a role in the formation, stabilization, and dynamics of membrane microdomains to affect membrane lateral organization and to attract other proteins and signaling molecules onto their territory. Furthermore, annexins were implicated in the interactions between cytosolic and membrane molecules, in the turnover and storage of cholesterol and in various signaling pathways. In this review, we focus on the mechanisms of interaction of annexins with lipid microdomains and the role of annexins in membrane microdomains dynamics including possible participation of the domain-associated forms of annexins in the etiology of human lysosomal storage disease called Niemann-Pick type C disease, related to the abnormal storage of cholesterol in the lysosome-like intracellular compartment. The involvement of annexins and cholesterol/sphingomyelin-enriched membrane microdomains in other pathologies including cardiac dysfunctions, neurodegenerative diseases, obesity, diabetes mellitus, and cancer is likely, but is not supported by substantial experimental observations, and therefore awaits further clarification.

  1. 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; 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 Science (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. PMID:24283970

  2. 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.

  3. Enfermedad de Niemann Pick tipo-A. Presentación de 12 casos

    Directory of Open Access Journals (Sweden)

    Jorge Zarco-Román

    2017-05-01

    Full Text Available INTRODUCCIÓN: la enfermedad de Niemann Pick tipo A es una enfermedad hereditaria de depósito lisosomal, debida a un déficit de la enzima esfingomielinasa ácida, lo que da lugar a la acumulación de esfingomielina en las células del sistema reticuloendotelial y nervioso central. OBJETIVO: se describe el curso de la enfermedad de Niemann Pick tipo A en 12 pacientes: tres niños y nueve niñas, con edades entre 3 a 33 meses. MATERIAL Y MÉTODOS: estudio retrospectivo efectuado con base en la información de los expedientes de 12 pacientes, evaluados mediante un examen físico completo, oftalmológico, análisis de laboratorio, ultrasonido de abdomen, tomografía axial computarizada o resonancia magnética nuclear cerebral, radiografías de tórax, ecocardiograma, electroencefalograma, potenciales evocados auditivos y visuales, serie esofagogastroduodenal y serie ósea. Se obtuvo información sobre enfermedades intercurrentes y causas de muerte. RESULTADOS: la sintomatología comenzó en promedio a los 5.9 meses (2 a 16 meses y el diagnóstico definitivo se realizó a la edad de los 15.6 meses (3 a 33 meses a través del cuadro clínico sugestivo, con presencia de células espumosas en el aspirado de médula ósea 12/12 (100% y deficiencia de la enzima esfingomielinasa ácida en 12/12 pacientes (100%; la biopsia hepática fue sugestiva de enfermedad por atesoramiento en 5/12 (41.6%. Las manifestaciones clínicas por orden de frecuencia fueron: hepatoesplenomegalia y afección neurológica en 12/12 (100%, alteración pulmonar 11/12 (91.6%, hematológica 9/12 (80%, oftalmológica con mancha rojo cereza 9/12 (75%, ósea 6/12 (50%, y cardiaca 4/12 (33.3%. Únicamente hubo antecedente de consanguinidad en 4 familias (33.3%. CONCLUSIONES: el curso clínico de la enfermedad de Niemann Pick tipo A es muy similar entre los pacientes afectados, el primer dato clínico detectado es la hepatoesplenomegalia. Los pacientes están asintomáticos los primeros

  4. Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway.

    Science.gov (United States)

    Fineran, Paul; Lloyd-Evans, Emyr; Lack, Nathan A; Platt, Nick; Davis, Lianne C; Morgan, Anthony J; Höglinger, Doris; Tatituri, Raju Venkata V; Clark, Simon; Williams, Ian M; Tynan, Patricia; Al Eisa, Nada; Nazarova, Evgeniya; Williams, Ann; Galione, Antony; Ory, Daniel S; Besra, Gurdyal S; Russell, David G; Brenner, Michael B; Sim, Edith; Platt, Frances M

    2016-11-18

    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 persistent 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. 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. Macrophages infected with persistent 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 persistent 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 promoting clearance of mycobacteria

  5. Differential response of the liver to bile acid treatment in a mouse model of Niemann-Pick disease type C [version 2; referees: 2 approved, 1 not approved

    Directory of Open Access Journals (Sweden)

    Elena-Raluca Nicoli

    2018-04-01

    Full Text Available Niemann-Pick disease type C (NPC disease is a neurodegenerative lysosomal storage disease caused by mutations in the NPC1 or NPC2 genes. Liver disease is also a common feature of NPC that can present as cholestatic jaundice in the neonatal period. Liver enzymes can remain elevated above the normal range in some patients as they age. We recently reported suppression of the P450 detoxification system in a mouse model of NPC disease and also in post-mortem liver from NPC patients. We demonstrated the ability of the hydrophobic bile acid ursodeoxycholic acid (UDCA (3α, 7β-dihydroxy-5β-cholanic acid to correct the P450 system suppression. UDCA is used to treat several cholestatic disorders and was tested in NPC due to the P450 system being regulated by bile acids. Here, we compare the effect of UDCA and cholic acid (CA, another bile acid, in the NPC mouse model. We observed unexpected hepatotoxicity in response to CA treatment of NPC mice. No such hepatotoxicity was associated with UDCA treatment. These results suggest that CA treatment is contraindicated in NPC patients, whilst supporting the use of UDCA as an adjunctive therapy in NPC patients.

  6. Plasma lysosphingomyelin demonstrates great potential as a diagnostic biomarker for Niemann-Pick disease type C in a retrospective study.

    Directory of Open Access Journals (Sweden)

    Richard W D Welford

    Full Text Available Niemann-Pick disease type C (NP-C is a devastating, neurovisceral lysosomal storage disorder which is characterised by variable manifestation of visceral signs, progressive neuropsychiatric deterioration and premature death, caused by mutations in the NPC1 and NPC2 genes. Due to the complexity of diagnosis and the availability of an approved therapy in the EU, improved detection of NP-C may have a huge impact on future disease management. At the cellular level dysfunction or deficiency of either the NPC1 or NPC2 protein leads to a complex intracellular endosomal/lysosomal trafficking defect, and organ specific patterns of sphingolipid accumulation. Lysosphingolipids have been shown to be excellent biomarkers of sphingolipidosis in several enzyme deficient lysosomal storage disorders. Additionally, in a recent study the lysosphingolipids, lysosphingomyelin (SPC and glucosylsphingosine (GlcSph, appeared to be elevated in the plasma of three adult NP-C patients. In order to investigate the clinical utility of SPC and GlcSph as diagnostic markers, an in-depth fit for purpose biomarker assay validation for measurement of these biomarkers in plasma by liquid chromatography-tandem mass spectrometry was performed. Plasma SPC and GlcSph are stable and can be measured accurately, precisely and reproducibly. In a retrospective analysis of 57 NP-C patients and 70 control subjects, median plasma SPC and GlcSph were significantly elevated in NP-C by 2.8-fold and 1.4-fold respectively. For miglustat-naïve NP-C patients, aged 2-50 years, the area under the ROC curve was 0.999 for SPC and 0.776 for GlcSph. Plasma GlcSph did not correlate with SPC levels in NP-C patients. The data indicate excellent potential for the use of lysosphingomyelin in NP-C diagnosis, where it could be used to identify NP-C patients for confirmatory genetic testing.

  7. 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

    2009-09-01

    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.

  8. Modeling Niemann Pick type C1 using human embryonic and induced pluripotent stem cells.

    Science.gov (United States)

    Ordoñez, M Paulina; Steele, John W

    2017-02-01

    Data generated in Niemann Pick type C1 (NPC1) human embryonic and human induced pluripotent stem cell derived neurons complement on-going studies in animal models and provide the first example, in disease-relevant human cells, of processes that underlie preferential neuronal defects in a NPC1. Our work and that of other investigators in human neurons derived from stem cells highlight the importance of performing rigorous mechanistic studies in relevant cell types to guide drug discovery and therapeutic development, alongside of existing animal models. Through the use of human stem cell-derived models of disease, we can identify and discover or repurpose drugs that revert early events that lead to neuronal failure in NPC1. Together with the study of disease pathogenesis and efficacy of therapies in animal models, these strategies will fulfill the promise of stem cell technology in the development of new treatments for human diseases. This article is part of a Special Issue entitled SI: Exploiting human neurons. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Molecular and biochemical biomarkers for diagnosis and therapy monitorization of Niemann-Pick type C patients.

    Science.gov (United States)

    Hammerschmidt, Tatiane Grazieli; de Oliveira Schmitt Ribas, Graziela; Saraiva-Pereira, Maria Luiza; Bonatto, Márcia Polese; Kessler, Rejane Gus; Souza, Fernanda Timm Seabra; Trapp, Franciele; Michelin-Tirelli, Kristiane; Burin, Maira Graeff; Giugliani, Roberto; Vargas, Carmen Regla

    2018-05-01

    Niemann-Pick type C (NP-C), one of 50 inherited lysosomal storage disorders, is caused by NPC protein impairment that leads to unesterified cholesterol accumulation in late endosomal/lysosomal compartments. The clinical manifestations of NP-C include hepatosplenomegaly, neurological and psychiatric symptoms. Current diagnosis for NP-C is based on observation of the accumulated cholesterol in fibroblasts of affected individuals, using an invasive and time expensive test, called Filipin staining. Lately, two metabolites that are markedly increased in NP-C patients are arising as biomarkers for this disease screening: 7-ketocholesterol and cholestane-3β,5α,6β-triol, both oxidized cholesterol products. In this work, we aimed to evaluate the performance of cholestane-3β,5α,6β-triol analysis for the screening and monitoring of NPC patients, correlating it with chitotriosidase levels, Filipin staining and molecular analysis. It was investigated 76 non-treated individuals with NP-C suspicion and also 7 patients with previous NP-C diagnosis under treatment with miglustat, in order to verify the cholestane-3β,5α,6β-triol value as a tool for therapy monitoring. Considering molecular assay as golden standard, it was verified that cholestane-3β,5α,6β-triol analysis presented 88% of sensitivity, 96.08% of specificity, a positive and negative predictive value calculated in 91.67% and 94.23%, respectively, for the diagnosis of NP-C. Chitotriosidase levels were increased in patients with positive molecular analysis for NP-C. For Filipin staining, it was found 1 false positive, 7 false negative and 24 inconclusive cases, showing that this assay has important limitations for NP-C diagnosis. Besides, we found a significant decrease in cholestane-3β,5α,6β-triol concentrations in NP-C patients under therapy with miglustat when compared to non-treated patients. Taken together, the present data show that cholestane-3β,5α,6β-triol analysis has a high potential to be an

  10. Reducing GBA2 Activity Ameliorates Neuropathology in Niemann-Pick Type C Mice.

    Directory of Open Access Journals (Sweden)

    André R A Marques

    Full Text Available The enzyme glucocerebrosidase (GBA hydrolyses glucosylceramide (GlcCer in lysosomes. Markedly reduced GBA activity is associated with severe manifestations of Gaucher disease including neurological involvement. Mutations in the GBA gene have recently also been identified as major genetic risk factor for Parkinsonism. Disturbed metabolism of GlcCer may therefore play a role in neuropathology. Besides lysosomal GBA, cells also contain a non-lysosomal glucosylceramidase (GBA2. Given that the two β-glucosidases share substrates, we speculated that over-activity of GBA2 during severe GBA impairment might influence neuropathology. This hypothesis was studied in Niemann-Pick type C (Npc1-/- mice showing secondary deficiency in GBA in various tissues. Here we report that GBA2 activity is indeed increased in the brain of Npc1-/- mice. We found that GBA2 is particularly abundant in Purkinje cells (PCs, one of the most affected neuronal populations in NPC disease. Inhibiting GBA2 in Npc1-/- mice with a brain-permeable low nanomolar inhibitor significantly improved motor coordination and extended lifespan in the absence of correction in cholesterol and ganglioside abnormalities. This trend was recapitulated, although not to full extent, by introducing a genetic loss of GBA2 in Npc1-/- mice. Our findings point to GBA2 activity as therapeutic target in NPC.

  11. Niemann-Pick C1-deficient mice lacking sterol O-acyltransferase 2 have less hepatic cholesterol entrapment and improved liver function.

    Science.gov (United States)

    Lopez, Adam M; Jones, Ryan Dale; Repa, Joyce J; Turley, Stephen D

    2018-06-07

    Cholesteryl esters are generated at multiple sites in the body by sterol O-acyltransferase 1 (SOAT1) or sterol O-acyltransferase 2 (SOAT2) in various cell types, and lecithin cholesterol acyltransferase (LCAT) in plasma. Esterified cholesterol (EC) and triacylglycerol (TAG) contained in lipoproteins cleared from the circulation via receptor-mediated or bulk-phase endocytosis are hydrolyzed by lysosomal acid lipase (LAL) within the late endosomal/lysosomal (E/L) compartment. Then, through the successive actions of Niemann-Pick C2 (NPC2) and Niemann-Pick C1 (NPC1), unesterified cholesterol (UC) is exported from the E/L compartment to the cytosol. Mutations in either NPC1 or NPC2 lead to continuing entrapment of UC in all organs, resulting in multisystem disease which includes hepatic dysfunction and in some cases liver failure. These studies investigated primarily whether elimination of SOAT2 in NPC1-deficient mice impacted hepatic UC sequestration, inflammation, and transaminase activities. Measurements were made in 7 wk-old mice fed a low-cholesterol chow diet or one enriched with cholesterol starting 2 wk before study. In the chow-fed mice, NPC1:SOAT2 double knockouts, compared to their littermates lacking only NPC1, had 20% less liver mass, 28% lower hepatic UC concentrations, and plasma ALT and AST activities that were decreased by 48% and 36%, respectively. mRNA expression levels for several markers of inflammation were all significantly lower in the NPC1 mutants lacking SOAT2. The existence of a new class of potent and selective SOAT2 inhibitors provides an opportunity for exploring if suppression of this enzyme could potentially become an adjunctive therapy for liver disease in NPC1 deficiency.

  12. Seven novel mutations of the SMPD1 gene in four Chinese patients with Niemann-Pick disease type A and prenatal diagnosis for four fetuses.

    Science.gov (United States)

    Ding, Yuan; Li, Xiyuan; Liu, Yupeng; Hua, Ying; Song, Jinqing; Wang, Liwen; Li, Mengqiu; Qin, Yaping; Yang, Yanling

    2016-04-01

    Niemann-Pick disease type A (NPD-A) is a rare autosomal recessive lysosomal storage disorder caused by acid sphingomyelinase deficiency. Only a few cases have been documented in mainland China, and prenatal diagnosis has not been performed to date. In this study, the clinical and laboratory features of four Chinese patients with early-onset NPD-A were summarized. Four patients with NPD-A were the firstborns of non-consanguineous parents from four unrelated Chinese families. Bone marrow analysis, acid sphingomyelinase assay and genetic studies were performed. SMPD1 gene studies on amniocytes were performed for the prenatal diagnosis of four fetuses from three families. Four patients were admitted at the age of 1-10 months due to jaundice, hepatosplenomegaly and psychomotor retardation. Liver histopathological analysis revealed glucolipid accumulation. Massive foamy histiocytes were found in the bone marrow. Acid sphingomyelinase activities of peripheral blood leukocytes were significantly decreased (4.05-21.9 nmol/h/mg protein, normal range 216.1-950.9 nmol/h/mg protein). Seven novel mutations (c.518-519insT, c.562_563insC, c.792Gdel, c.949G>A, c.1487_1499delACCGTGTGTACCA, c.1495T>C and c.1670T>C) of the SMPD1 gene were identified in four patients. Only one fetus had two mutations of the SMPD1 gene of amniocytes. The results suggested that the fetus was affected by NPD-A. The mother chose artificial abortion. The other three fetuses were not affected by NPD-A. No mutation of the SMPD1 gene was detected in the cultured amniocytes from the mothers. Postnatal genetic analysis and normal development of the three infants confirmed the prenatal diagnosis. Seven novel mutations associated with NPD-A were identified in the Chinese population. Prenatal diagnosis for four fetuses of three families was successfully performed by amniocyte gene analysis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  13. Use of complementary and alternative medicine by patients with lysosomal storage diseases.

    Science.gov (United States)

    Balwani, Manisha; Fuerstman, Laura; Desnick, Robert J; Buckley, Brian; McGovern, Margaret M

    2009-10-01

    To evaluate the extent of complementary and alternative medicine use and perceived effectiveness in patients with lysosomal storage diseases. A 26-item survey was distributed to 495 patients with type 1 Gaucher, Fabry, and type B Niemann-Pick diseases who were seen at the Lysosomal Storage Disease Program at the Mount Sinai School of Medicine. Survey responses were entered into an access database and analyzed using descriptive statistics. Surveys were completed by 167 respondents with an overall response rate of 34%. Complementary and alternative medicines were used by 45% of patients with type 1 Gaucher disease, 41% of patients with Fabry disease, and 47% of patients with type B Niemann-Pick for symptoms related to their disease. Complementary and alternative medicines were used most frequently by adult females (55%), in patients who reported having one or more invasive procedures due to their disease, patients who use one or more conventional medical therapies, or those with depression and/or anxiety. Overall perceived effectiveness of complementary and alternative medicine supplements was low; however, complementary and alternative medicine therapies were perceived as effective. Complementary and alternative medicines are commonly used among patients with lysosomal storage diseases. Assessment of the effectiveness of these approaches in the lysosomal storage diseases is needed, and physicians should be aware of complementary and alternative medicine therapies used by patients to evaluate safety and possible drug interactions.

  14. Quantitative Analysis of the Proteome Response to the Histone Deacetylase Inhibitor (HDACi) Vorinostat in Niemann-Pick Type C1 disease.

    Science.gov (United States)

    Subramanian, Kanagaraj; Rauniyar, Navin; Lavalleé-Adam, Mathieu; Yates, John R; Balch, William E

    2017-11-01

    Niemann-Pick type C (NPC) disease is an inherited, progressive neurodegenerative disorder principally caused by mutations in the NPC1 gene. NPC disease is characterized by the accumulation of unesterified cholesterol in the late endosomes (LE) and lysosomes (Ly) (LE/Ly). Vorinostat, a histone deacetylase inhibitor (HDACi), restores cholesterol homeostasis in fibroblasts derived from NPC patients; however, the exact mechanism by which Vorinostat restores cholesterol level is not known yet. In this study, we performed comparative proteomic profiling of the response of NPC1 I1061T fibroblasts to Vorinostat. After stringent statistical criteria to filter identified proteins, we observed 202 proteins that are differentially expressed in Vorinostat-treated fibroblasts. These proteins are members of diverse cellular pathways including the endomembrane dependent protein folding-stability-degradation-trafficking axis, energy metabolism, and lipid metabolism. Our study shows that treatment of NPC1 I1061T fibroblasts with Vorinostat not only enhances pathways promoting the folding, stabilization and trafficking of NPC1 (I1061T) mutant to the LE/Ly, but alters the expression of lysosomal proteins, specifically the lysosomal acid lipase (LIPA) involved in the LIPA->NPC2->NPC1 based flow of cholesterol from the LE/Ly lumen to the LE/Ly membrane. We posit that the Vorinostat may modulate numerous pathways that operate in an integrated fashion through epigenetic and post-translational modifications reflecting acetylation/deacetylation balance to help manage the defective NPC1 fold, the function of the LE/Ly system and/or additional cholesterol metabolism/distribution pathways, that could globally contribute to improved mitigation of NPC1 disease in the clinic based on as yet uncharacterized principles of cellular metabolism dictating cholesterol homeostasis. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. Delivery of acid sphingomyelinase in normal and niemann-pick disease mice using intercellular adhesion molecule-1-targeted polymer nanocarriers.

    Science.gov (United States)

    Garnacho, Carmen; Dhami, Rajwinder; Simone, Eric; Dziubla, Thomas; Leferovich, John; Schuchman, Edward H; Muzykantov, Vladimir; Muro, Silvia

    2008-05-01

    Type B Niemann-Pick disease (NPD) is a multiorgan system disorder caused by a genetic deficiency of acid sphingomyelinase (ASM), for which lung is an important and challenging therapeutic target. In this study, we designed and evaluated new delivery vehicles for enzyme replacement therapy of type B NPD, consisting of polystyrene and poly(lactic-coglycolic) acid polymer nanocarriers targeted to intercellular adhesion molecule (ICAM)-1, an endothelial surface protein up-regulated in many pathologies, including type B NPD. Real-time vascular imaging using intravital microscopy and postmortem imaging of mouse organs showed rapid, uniform, and efficient binding of fluorescently labeled ICAM-1-targeted ASM nanocarriers (anti-ICAM/ASM nanocarriers) to endothelium after i.v. injection in mice. Fluorescence microscopy of lung alveoli actin, tissue histology, and 125I-albumin blood-to-lung transport showed that anti-ICAM nanocarriers cause neither detectable lung injury, nor abnormal vascular permeability in animals. Radioisotope tracing showed rapid disappearance from the circulation and enhanced accumulation of anti-ICAM/125I-ASM nanocarriers over the nontargeted naked enzyme in kidney, heart, liver, spleen, and primarily lung, both in wild-type and ASM knockout mice. These data demonstrate that ICAM-1-targeted nanocarriers may enhance enzyme replacement therapy for type B NPD and perhaps other lysosomal storage disorders.

  16. Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: disease spectrum and natural course in attenuated patients.

    Science.gov (United States)

    Hollak, C E M; de Sonnaville, E S V; Cassiman, D; Linthorst, G E; Groener, J E; Morava, E; Wevers, R A; Mannens, M; Aerts, J M F G; Meersseman, W; Akkerman, E; Niezen-Koning, K E; Mulder, M F; Visser, G; Wijburg, F A; Lefeber, D; Poorthuis, B J H M

    2012-11-01

    Niemann-Pick disease (NPD) is a neurovisceral lysosomal storage disorder caused by acid sphingomyelinase (ASM) deficiency, which can be categorized as either Niemann-Pick disease type A [NPD-A], with progressive neurological disease and death in early childhood, or as Niemann-Pick disease type B [NPD-B], with a more variable spectrum of manifestations. Enzyme replacement therapy (ERT) with recombinant sphingomyelinase is currently studied as potential treatment for NPD-B patients. The objective of this study is to characterize the clinical features of patients with ASM deficiency in the Netherlands and Belgium with focus on the natural disease course of NPD-B patients. Prospective and retrospective data on ASM deficient patients were collected in The Netherlands and part of Belgium. Patients with NPD-B that could be followed prospectively were evaluated every 6-12 months for pulmonary function tests, 6 minute walk test (6 MWT), imaging (bone marrow infiltration measured by QCSI, organ volumes by MRI and CT scan of the lungs) and biochemical markers. Twenty-five patients with ASM deficiency were identified (13 males, 12 females, median age 13years, range 1-59 years). Nine patients had died at the time of the study, including four NPD-A patients at the age of 1,1, 2, 3 and five NPDB patents at the age of 5, 6, 43, 56 and 60 years. There was a high prevalence of homozygosity and compound heterozygosity for the common p.Arg608del mutation in 43% and 19% of NPD-B patients, respectively. In NPD-B patients, thrombocytopenia was present in most, while anemia and leucopenia were less common (33% and 6 % respectively). HDL cholesterol was reduced in most patients. Pulmonary disease was severe in several patients. Follow-up up to 11 years revealed a gradual decrease in platelet count. Detailed investigations in 6 NPD-B patients with follow-up in 4 patients revealed remarkable stable disease parameters up to 6 years, with some decline in pulmonary function and 6 MWT. Bone

  17. 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.

  18. Structural Insights into the Niemann-Pick C1 (NPC1)-Mediated Cholesterol Transfer and Ebola Infection.

    Science.gov (United States)

    Gong, Xin; Qian, Hongwu; Zhou, Xinhui; Wu, Jianping; Wan, Tao; Cao, Pingping; Huang, Weiyun; Zhao, Xin; Wang, Xudong; Wang, Peiyi; Shi, Yi; Gao, George F; Zhou, Qiang; Yan, Nieng

    2016-06-02

    Niemann-Pick disease type C (NPC) is associated with mutations in NPC1 and NPC2, whose gene products are key players in the endosomal/lysosomal egress of low-density lipoprotein-derived cholesterol. NPC1 is also the intracellular receptor for Ebola virus (EBOV). Here, we present a 4.4 Å structure of full-length human NPC1 and a low-resolution reconstruction of NPC1 in complex with the cleaved glycoprotein (GPcl) of EBOV, both determined by single-particle electron cryomicroscopy. NPC1 contains 13 transmembrane segments (TMs) and three distinct lumenal domains A (also designated NTD), C, and I. TMs 2-13 exhibit a typical resistance-nodulation-cell division fold, among which TMs 3-7 constitute the sterol-sensing domain conserved in several proteins involved in cholesterol metabolism and signaling. A trimeric EBOV-GPcl binds to one NPC1 monomer through the domain C. Our structural and biochemical characterizations provide an important framework for mechanistic understanding of NPC1-mediated intracellular cholesterol trafficking and Ebola virus infection. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Normalization of Hepatic Homeostasis in the Npc1nmf164 Mouse Model of Niemann-Pick Type C Disease Treated with the Histone Deacetylase Inhibitor Vorinostat.

    Science.gov (United States)

    Munkacsi, Andrew B; Hammond, Natalie; Schneider, Remy T; Senanayake, Dinindu S; Higaki, Katsumi; Lagutin, Kirill; Bloor, Stephen J; Ory, Daniel S; Maue, Robert A; Chen, Fannie W; Hernandez-Ono, Antonio; Dahlson, Nicole; Repa, Joyce J; Ginsberg, Henry N; Ioannou, Yiannis A; Sturley, Stephen L

    2017-03-17

    Niemann-Pick type C (NP-C) disease is a fatal genetic lipidosis for which there is no Food and Drug Administration (FDA)-approved therapy. Vorinostat, an FDA-approved inhibitor of histone deacetylases, ameliorates lysosomal lipid accumulation in cultured NP-C patient fibroblasts. To assess the therapeutic potential of histone deacetylase inhibition, we pursued these in vitro observations in two murine models of NP-C disease. Npc1 nmf164 mice, which express a missense mutation in the Npc1 gene, were treated intraperitoneally, from weaning, with the maximum tolerated dose of vorinostat (150 mg/kg, 5 days/week). Disease progression was measured via gene expression, liver function and pathology, serum and tissue lipid levels, body weight, and life span. Transcriptome analyses of treated livers indicated multiple changes consistent with reversal of liver dysfunction that typifies NP-C disease. Significant improvements in liver pathology and function were achieved by this treatment regimen; however, NPC1 protein maturation and levels, disease progression, weight loss, and animal morbidity were not detectably altered. Vorinostat concentrations were >200 μm in the plasma compartment of treated animals but were almost 100-fold lower in brain tissue. Apolipoprotein B metabolism and the expression of key components of lipid homeostasis in primary hepatocytes from null ( Npc1 -/- ) and missense ( Npc1 nmf164 ) mutant mice were altered by vorinostat treatment, consistent with a response by these cells independent of the status of the Npc1 locus. These results suggest that HDAC inhibitors have utility to treat visceral NP-C disease. However, it is clear that improved blood-brain barrier penetration will be required to alleviate the neurological symptoms of human NP-C disease. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. Normalization of Hepatic Homeostasis in the Npc1nmf164 Mouse Model of Niemann-Pick Type C Disease Treated with the Histone Deacetylase Inhibitor Vorinostat*

    Science.gov (United States)

    Munkacsi, Andrew B.; Hammond, Natalie; Schneider, Remy T.; Senanayake, Dinindu S.; Higaki, Katsumi; Lagutin, Kirill; Bloor, Stephen J.; Ory, Daniel S.; Maue, Robert A.; Chen, Fannie W.; Hernandez-Ono, Antonio; Dahlson, Nicole; Repa, Joyce J.; Ginsberg, Henry N.; Ioannou, Yiannis A.; Sturley, Stephen L.

    2017-01-01

    Niemann-Pick type C (NP-C) disease is a fatal genetic lipidosis for which there is no Food and Drug Administration (FDA)-approved therapy. Vorinostat, an FDA-approved inhibitor of histone deacetylases, ameliorates lysosomal lipid accumulation in cultured NP-C patient fibroblasts. To assess the therapeutic potential of histone deacetylase inhibition, we pursued these in vitro observations in two murine models of NP-C disease. Npc1nmf164 mice, which express a missense mutation in the Npc1 gene, were treated intraperitoneally, from weaning, with the maximum tolerated dose of vorinostat (150 mg/kg, 5 days/week). Disease progression was measured via gene expression, liver function and pathology, serum and tissue lipid levels, body weight, and life span. Transcriptome analyses of treated livers indicated multiple changes consistent with reversal of liver dysfunction that typifies NP-C disease. Significant improvements in liver pathology and function were achieved by this treatment regimen; however, NPC1 protein maturation and levels, disease progression, weight loss, and animal morbidity were not detectably altered. Vorinostat concentrations were >200 μm in the plasma compartment of treated animals but were almost 100-fold lower in brain tissue. Apolipoprotein B metabolism and the expression of key components of lipid homeostasis in primary hepatocytes from null (Npc1−/−) and missense (Npc1nmf164) mutant mice were altered by vorinostat treatment, consistent with a response by these cells independent of the status of the Npc1 locus. These results suggest that HDAC inhibitors have utility to treat visceral NP-C disease. However, it is clear that improved blood-brain barrier penetration will be required to alleviate the neurological symptoms of human NP-C disease. PMID:28031458

  1. Cyclodextrin alleviates neuronal storage of cholesterol in Niemann-Pick C disease without evidence of detectable blood-brain barrier permeability.

    Science.gov (United States)

    Pontikis, Charles C; Davidson, Cristin D; Walkley, Steven U; Platt, Frances M; Begley, David J

    2013-05-01

    Niemann-Pick type C disease is an inherited autosomal recessive neurodegenerative disorder characterised by the accumulation of unesterified cholesterol and sphingolipids within the endosomal/lysosomal compartments. It has been observed that the administration of hydroxypropyl-β-cyclodextrin (HPBCD) delays onset of clinical symptoms and reduces accumulation of cholesterol and gangliosides within neuronal cells. It was assumed that HPBCD exerts its action by readily entering the CNS and directly interacting with neurones and other brain cells to facilitate removal of stored cholesterol from the late endosomal/lysosomal compartment. Here, we present evidence that refutes this hypothesis. We use two well established techniques for accurately measuring brain uptake of solutes from blood and show that there is no significant crossing of HPBCD into the brain. The two techniques are brain in situ perfusion and intraperitoneal injection followed by multi-time-point regression analysis. Neither study demonstrates significant, time-dependent uptake of HPBCD in either adult or neonatal mice. However, the volume of distribution available to HPBCD (0.113 ± 0.010 ml/g) exceeds the accepted values for plasma and vascular volume of the brain. In fact, it is nearly three times larger than that for sucrose (0.039 ± 0.006 ml/g). We propose that this indicates cell surface binding of HPBCD to the endothelium of the cerebral vasculature and may provide a mechanism for the mobilisation and clearance of cholesterol from the CNS.

  2. Neuroimaging Findings in a Brain With Niemann–Pick Type C Disease

    Directory of Open Access Journals (Sweden)

    Jei-Yie Huang

    2011-08-01

    Full Text Available Niemann-Pick type C disease (NPC is a rare autosomal recessive lipid storage disorder caused by impaired cellular functions in processing and transporting low-density lipoprotein-cholesterol. In this report, we present magnetic resonance imaging (MRI, magnetic resonance spectrography (MRS and 18-fluoro-2-deoxyglucose positron emission tomography (PET imaging results for a 22-year-old male NPC patient. The patient's two MRI studies (at age 19 years and 22 years demonstrated progressive changes of brain atrophy that were more prominent at the frontal lobes, and hyperintense signals in bilateral parietal-occipital periventricular white matter. MRS (at age 19 years revealed no significant decrease in N-acetyl aspartate/choline ratio in the left frontal central white matter. PET (at age 22 years showed significant bilateral hypometabolism in the prefrontal cortex and dorsomedial thalamus, and hypermetabolism in the parietal-occipital white matter, lenticular nucleus of the basal ganglia, cerebellum and pons. The imaging findings noted by MRI, MRS and 18-fluoro-2-deoxyglucose PET offered a possible supplementary explanation for the clinical neurological symptoms of this NPC patient.

  3. Pick disease

    Science.gov (United States)

    Semantic dementia; Dementia - semantic; Frontotemporal dementia; FTD; Arnold Pick disease; 3R tauopathy ... doctors tell Pick disease apart from Alzheimer disease. (Memory loss is often the main, and earliest, symptom ...

  4. Cholesterol pathways affected by small molecules that decrease sterol levels in Niemann-Pick type C mutant cells.

    Directory of Open Access Journals (Sweden)

    Madalina Rujoi

    2010-09-01

    Full Text Available Niemann-Pick type C (NPC disease is a genetically inherited multi-lipid storage disorder with impaired efflux of cholesterol from lysosomal storage organelles.The effect of screen-selected cholesterol lowering compounds on the major sterol pathways was studied in CT60 mutant CHO cells lacking NPC1 protein. Each of the selected chemicals decreases cholesterol in the lysosomal storage organelles of NPC1 mutant cells through one or more of the following mechanisms: increased cholesterol efflux from the cell, decreased uptake of low-density lipoproteins, and/or increased levels of cholesteryl esters. Several chemicals promote efflux of cholesterol to extracellular acceptors in both non-NPC and NPC1 mutant cells. The uptake of low-density lipoprotein-derived cholesterol is inhibited by some of the studied compounds.Results herein provide the information for prioritized further studies in identifying molecular targets of the chemicals. This approach proved successful in the identification of seven chemicals as novel inhibitors of lysosomal acid lipase (Rosenbaum et al, Biochim. Biophys. Acta. 2009, 1791:1155-1165.

  5. Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1.

    Science.gov (United States)

    Wang, Han; Shi, Yi; Song, Jian; Qi, Jianxun; Lu, Guangwen; Yan, Jinghua; Gao, George F

    2016-01-14

    Filoviruses, including Ebola and Marburg, cause fatal hemorrhagic fever in humans and primates. Understanding how these viruses enter host cells could help to develop effective therapeutics. An endosomal protein, Niemann-Pick C1 (NPC1), has been identified as a necessary entry receptor for this process, and priming of the viral glycoprotein (GP) to a fusion-competent state is a prerequisite for NPC1 binding. Here, we have determined the crystal structure of the primed GP (GPcl) of Ebola virus bound to domain C of NPC1 (NPC1-C) at a resolution of 2.3 Å. NPC1-C utilizes two protruding loops to engage a hydrophobic cavity on head of GPcl. Upon enzymatic cleavage and NPC1-C binding, conformational change in the GPcl further affects the state of the internal fusion loop, triggering membrane fusion. Our data therefore provide structural insights into filovirus entry in the late endosome and the molecular basis for design of therapeutic inhibitors of viral entry. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1.

    Science.gov (United States)

    Park, Walter D; O'Brien, John F; Lundquist, Patrick A; Kraft, Daniel L; Vockley, Cate Walsh; Karnes, Pamela S; Patterson, Marc C; Snow, Karen

    2003-10-01

    The two known complementation groups of Niemann-Pick Type C disease, NPC1 and NPC2, result from non-allelic protein defects. Both the NPC1 and NPC2 (HE1) gene products are intimately involved in cholesterol and glycolipid trafficking and/or transport. We describe mutation analysis on samples from 143 unrelated affected NPC patients using conformation sensitive gel electrophoresis and DNA sequencing as the primary mutation screening methods for NPC1 and NPC2, respectively. These methods are robust, sensitive, and do not require any specialized laboratory equipment. Analyses identified two NPC1 mutations for 115 (80.4%) patients, one NPC1 mutation for 10 (7.0%) patients, two NPC2 mutations for five (3.5%) patients, one NPC2 mutation for one (0.7%) patient, and no mutations for 12 (8.4%) patients. Thus, mutations were identified on 251 of 286 (88%) disease alleles, including 121 different mutations (114 in NPC1 and seven in NPC2), 58 of which are previously unreported. The most common NPC1 mutation, I1061T, was detected on 18% of NPC alleles. Other NPC1 mutations were mostly private, missense mutations located throughout the gene with clustering in the cysteine-rich luminal domain. Correlation with biochemical data suggests classification of several mutations as severe and others as moderate or variable. The region between amino acids 1038 and 1253, which shares 35% identity with Patched 1, appears to be a hot spot for mutations. Additionally, a high percentage of mutations were located at amino acids identical to the NPC1 homolog, NPC1L1. Biochemical complementation analysis of cases negative for mutations revealed a high percentage of equivocal results where the complementation group appeared to be non-NPC1 and non-NPC2. This raises the possibilities of an additional NPC complementation group(s) or non-specificity of the biochemical testing for NPC. These caveats must be considered when offering mutation testing as a clinical service. Copyright 2003 Wiley-Liss, Inc.

  7. Small molecule inhibitors reveal Niemann-Pick C1 is essential for Ebola virus infection.

    Science.gov (United States)

    Côté, Marceline; Misasi, John; Ren, Tao; Bruchez, Anna; Lee, Kyungae; Filone, Claire Marie; Hensley, Lisa; Li, Qi; Ory, Daniel; Chandran, Kartik; Cunningham, James

    2011-08-24

    Ebola virus (EboV) is a highly pathogenic enveloped virus that causes outbreaks of zoonotic infection in Africa. The clinical symptoms are manifestations of the massive production of pro-inflammatory cytokines in response to infection and in many outbreaks, mortality exceeds 75%. The unpredictable onset, ease of transmission, rapid progression of disease, high mortality and lack of effective vaccine or therapy have created a high level of public concern about EboV. Here we report the identification of a novel benzylpiperazine adamantane diamide-derived compound that inhibits EboV infection. Using mutant cell lines and informative derivatives of the lead compound, we show that the target of the inhibitor is the endosomal membrane protein Niemann-Pick C1 (NPC1). We find that NPC1 is essential for infection, that it binds to the virus glycoprotein (GP), and that antiviral compounds interfere with GP binding to NPC1. Combined with the results of previous studies of GP structure and function, our findings support a model of EboV infection in which cleavage of the GP1 subunit by endosomal cathepsin proteases removes heavily glycosylated domains to expose the amino-terminal domain, which is a ligand for NPC1 and regulates membrane fusion by the GP2 subunit. Thus, NPC1 is essential for EboV entry and a target for antiviral therapy.

  8. Neuronal and epithelial cell rescue resolves chronic systemic inflammation in the lipid storage disorder Niemann-Pick C.

    Science.gov (United States)

    Lopez, Manuel E; Klein, Andrés D; Hong, Jennifer; Dimbil, Ubah J; Scott, Matthew P

    2012-07-01

    Chronic systemic inflammation is thought to be a major contributor to metabolic and neurodegenerative diseases. Since inflammatory components are shared among different disorders, targeting inflammation is an attractive option for mitigating disease. To test the significance of inflammation in the lipid storage disorder (LSD) Niemann-Pick C (NPC), we deleted the macrophage inflammatory gene Mip1a/Ccl3 from NPC diseased mice. Deletion of Ccl3 had been reported to delay neuronal loss in Sandhoff LSD mice by inhibiting macrophage infiltration. For NPC mice, in contrast, deleting Ccl3 did not retard neurodegeneration and worsened the clinical outcome. Depletion of visceral tissue macrophages also did not alter central nervous system (CNS) pathology and instead increased liver injury, suggesting a limited macrophage infiltration response into the CNS and a beneficial role of macrophage activity in visceral tissue. Prevention of neuron loss or liver injury, even at late stages in the disease, was achieved through specific rescue of NPC disease in neurons or in liver epithelial cells, respectively. Local epithelial cell correction was also sufficient to reduce the macrophage-associated pathology in lung tissue. These results demonstrate that elevated inflammation and macrophage activity does not necessarily contribute to neurodegeneration and tissue injury, and LSD defects in immune cells may not preclude an appropriate inflammatory response. We conclude that inflammation remains secondary to neuronal and epithelial cell dysfunction and does not irreversibly contribute to the pathogenic cascade in NPC disease. Without further exploration of possible beneficial roles of inflammatory mediators, targeting inflammation may not be therapeutically effective at ameliorating disease severity.

  9. Four Novel p.N385K, p.V36A, c.1033–1034insT and c.1417–1418delCT Mutations in the Sphingomyelin Phosphodiesterase 1 (SMPD1 Gene in Patients with Types A and B Niemann-Pick Disease (NPD

    Directory of Open Access Journals (Sweden)

    Masoumeh Dehghan Manshadi

    2015-03-01

    Full Text Available Background: Types A and B Niemann-Pick disease (NPD are autosomal-recessive lysosomal storage disorders caused by the deficient activity of acid sphingomyelinase due to mutations in the sphingomyelin phosphodiesterase 1 (SMPD1 gene. Methods: In order to determine the prevalence and distribution of SMPD1 gene mutations, the genomic DNA of 15 unrelated Iranian patients with types A and B NPD was examined using PCR, DNA sequencing and bioinformatics analysis. Results: Of 8 patients with the p.G508R mutation, 5 patients were homozygous, while the other 3 were heterozygous. One patient was heterozygous for both the p.N385K and p.G508R mutations. Another patient was heterozygous for both the p.A487V and p.G508R mutations. Two patients (one homozygous and one heterozygous showed the p.V36A mutation. One patient was homozygous for the c.1033–1034insT mutation. One patient was homozygous for the c.573delT mutation, and 1 patient was homozygous for the c.1417–1418delCT mutation. Additionally, bioinformatics analysis indicated that two new p.V36A and p.N385K mutations decreased the acid sphingomyelinase (ASM protein stability, which might be evidence to suggest the pathogenicity of these mutations. Conclusion: with detection of these new mutations, the genotypic spectrum of types A and B NPD is extended, facilitating the definition of disease-related mutations. However, more research is essential to confirm the pathogenic effect of these mutations.

  10. 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

  11. Lysosomal pH-inducible supramolecular dissociation of polyrotaxanes possessing acid-labile N-triphenylmethyl end groups and their therapeutic potential for Niemann-Pick type C disease

    Science.gov (United States)

    Tamura, Atsushi; Nishida, Kei; Yui, Nobuhiko

    2016-01-01

    Niemann-Pick type C (NPC) disease is characterized by the accumulation of cholesterol in lysosomes. We have previously reported that biocleavable polyrotaxanes (PRXs) composed of β-cyclodextrins (β-CDs) threaded onto a linear polymer capped with bulky stopper molecules via intracellularly cleavable linkers show remarkable cholesterol reducing effects in NPC disease patient-derived fibroblasts owing to the stimuli-responsive intracellular dissociation of PRXs and subsequent β-CD release from the PRXs. Herein, we describe a series of novel acid-labile 2-(2-hydroxyethoxy)ethyl group-modified PRXs (HEE-PRXs) bearing terminal N-triphenylmethyl (N-Trt) groups as a cleavable component for the treatment of NPC disease. The N-Trt end groups of the HEE-PRXs underwent acidic pH-induced cleavage and led to the dissociation of their supramolecular structure. A kinetic study revealed that the number of HEE groups on the PRX did not affect the cleavage kinetics of the N-Trt end groups of the HEE-PRXs. The effect of the number of HEE groups of the HEE-PRXs, which was modified to impart water solubility to the PRXs, on cellular internalization efficiency, lysosomal localization efficiency, and cholesterol reduction ability in NPC disease-derived fibroblasts (NPC1 fibroblasts) was also investigated. The cellular uptake and lysosomal localization efficiency were almost equivalent for HEE-PRXs with different numbers of HEE groups. However, the cholesterol reducing ability of the HEE-PRXs in NPC1 fibroblasts was affected by the number of HEE groups, and HEE-PRXs with a high number of HEE groups were unable to reduce lysosomal cholesterol accumulation. This deficiency is most likely due to the cholesterol-solubilizing ability of HEE-modified β-CDs released from the HEE-PRXs. We conclude that the N-Trt group acts as a cleavable component to induce the lysosomal dissociation of HEE-PRXs, and acid-labile HEE-PRXs with an optimal number of HEE groups (4.1 to 5.4 HEE groups per single

  12. PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder

    Science.gov (United States)

    Brown, Anna; Patel, Siddharth; Ward, Carl; Lorenz, Anna; Ortiz, Mauren; Duross, Allison; Wieghardt, Fabian; Esch, Amanda; Otten, Elsje G.; Heiser, Laura M.; Korolchuk, Viktor I.; Sun, Conroy; Sarkar, Sovan; Sahay, Gaurav

    2016-08-01

    2-Hydroxy-propyl-β-cyclodextrin (HPβCD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HPβCD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (ethylene glycol) (PEG)-lipid conjugate enables cholesterol clearance from endo/lysosomes of Npc1 mutant (Npc1-/-) cells. Herein, we show that distearyl-phosphatidylethanolamine-PEG (DSPE-PEG), which forms 12-nm micelles above the critical micelle concentration, accumulates heavily inside cholesterol-rich late endosomes in Npc1-/- cells. This potentially results in cholesterol solubilization and leakage from lysosomes. High-throughput screening revealed that DSPE-PEG, in combination with HPβCD, acts synergistically to efflux cholesterol without significantly aggravating autophagy defects. These well-known excipients can be used as admixtures to treat NPC1 disorder. Increasing PEG chain lengths from 350 Da-30 kDa in DSPE-PEG micelles, or increasing DSPE-PEG content in an array of liposomes packaged with HPβCD, improved cholesterol egress, while Pluronic block copolymers capable of micelle formation showed slight effects at high concentrations. We postulate that PEG-lipid based nanocarriers can serve as bioactive drug delivery systems for effective treatment of lysosomal storage disorders.

  13. PEG-lipid micelles enable cholesterol efflux in Niemann-Pick Type C1 disease-based lysosomal storage disorder

    Science.gov (United States)

    Brown, Anna; Patel, Siddharth; Ward, Carl; Lorenz, Anna; Ortiz, Mauren; DuRoss, Allison; Wieghardt, Fabian; Esch, Amanda; Otten, Elsje G.; Heiser, Laura M.; Korolchuk, Viktor I.; Sun, Conroy; Sarkar, Sovan; Sahay, Gaurav

    2016-01-01

    2-Hydroxy-propyl-β-cyclodextrin (HPβCD), a cholesterol scavenger, is currently undergoing Phase 2b/3 clinical trial for treatment of Niemann Pick Type C-1 (NPC1), a fatal neurodegenerative disorder that stems from abnormal cholesterol accumulation in the endo/lysosomes. Unfortunately, the extremely high doses of HPβCD required to prevent progressive neurodegeneration exacerbates ototoxicity, pulmonary toxicity and autophagy-based cellular defects. We present unexpected evidence that a poly (ethylene glycol) (PEG)-lipid conjugate enables cholesterol clearance from endo/lysosomes of Npc1 mutant (Npc1−/−) cells. Herein, we show that distearyl-phosphatidylethanolamine-PEG (DSPE-PEG), which forms 12-nm micelles above the critical micelle concentration, accumulates heavily inside cholesterol-rich late endosomes in Npc1−/− cells. This potentially results in cholesterol solubilization and leakage from lysosomes. High-throughput screening revealed that DSPE-PEG, in combination with HPβCD, acts synergistically to efflux cholesterol without significantly aggravating autophagy defects. These well-known excipients can be used as admixtures to treat NPC1 disorder. Increasing PEG chain lengths from 350 Da-30 kDa in DSPE-PEG micelles, or increasing DSPE-PEG content in an array of liposomes packaged with HPβCD, improved cholesterol egress, while Pluronic block copolymers capable of micelle formation showed slight effects at high concentrations. We postulate that PEG-lipid based nanocarriers can serve as bioactive drug delivery systems for effective treatment of lysosomal storage disorders. PMID:27572704

  14. A new simple and rapid LC-ESI-MS/MS method for quantification of plasma oxysterols as dimethylaminobutyrate esters. Its successful use for the diagnosis of Niemann-Pick type C disease.

    Science.gov (United States)

    Boenzi, Sara; Deodato, Federica; Taurisano, Roberta; Martinelli, Diego; Verrigni, Daniela; Carrozzo, Rosalba; Bertini, Enrico; Pastore, Anna; Dionisi-Vici, Carlo; Johnson, David W

    2014-11-01

    Two oxysterols, cholestan-3β,5α,6β-triol (C-triol) and 7-ketocholesterol (7-KC), have been recently proposed as diagnostic markers of Niemann-Pick type C (NP-C) disease, representing a potential alternative diagnostic tool to the more invasive and time consuming filipin test in cultured fibroblasts. Usually, the oxysterols are detected and quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using atmospheric pressure chemical ionization (APCI) or electro-spray-ionization (ESI) sources, after a variety of derivatization procedures to enhance sensitivity. We developed a sensitive LC-MS/MS method to quantify the oxysterols in plasma as dimethylaminobutyrate ester, suitable for ESI analysis. This method, with an easy liquid-phase extraction and a short derivatization procedure, has been validated to demonstrate specificity, linearity, recovery, lowest limit of quantification, accuracy and precision. The assay was linear over a concentration range of 0.5-200ng/mL for C-triol and 1.0-200ng/mL for 7-KC. Intra-day and inter-day coefficients of variation (CV%) were <15% for both metabolites. Receiver operating characteristic analysis estimates that the area under curve was 0.998 for C-triol, and 0.972 for 7-KC, implying a significant discriminatory power for the method in this patient population of both oxysterols. In summary, our method provides a simple, rapid and non-invasive diagnostic tool for the biochemical diagnosis of NP-C disease. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Reduction of VLDL secretion decreases cholesterol excretion in niemann-pick C1-like 1 hepatic transgenic mice.

    Directory of Open Access Journals (Sweden)

    Stephanie M Marshall

    Full Text Available An effective way to reduce LDL cholesterol, the primary risk factor of atherosclerotic cardiovascular disease, is to increase cholesterol excretion from the body. Our group and others have recently found that cholesterol excretion can be facilitated by both hepatobiliary and transintestinal pathways. However, the lipoprotein that moves cholesterol through the plasma to the small intestine for transintestinal cholesterol efflux (TICE is unknown. To test the hypothesis that hepatic very low-density lipoproteins (VLDL support TICE, antisense oligonucleotides (ASO were used to knockdown hepatic expression of microsomal triglyceride transfer protein (MTP, which is necessary for VLDL assembly. While maintained on a high cholesterol diet, Niemann-Pick C1-like 1 hepatic transgenic (L1Tg mice, which predominantly excrete cholesterol via TICE, and wild type (WT littermates were treated with control ASO or MTP ASO. In both WT and L1Tg mice, MTP ASO decreased VLDL triglyceride (TG and cholesterol secretion. Regardless of treatment, L1Tg mice had reduced biliary cholesterol compared to WT mice. However, only L1Tg mice treated with MTP ASO had reduced fecal cholesterol excretion. Based upon these findings, we conclude that VLDL or a byproduct such as LDL can move cholesterol from the liver to the small intestine for TICE.

  16. Mitotic spindle defects and chromosome mis-segregation induced by LDL/cholesterol-implications for Niemann-Pick C1, Alzheimer's disease, and atherosclerosis.

    Directory of Open Access Journals (Sweden)

    Antoneta Granic

    Full Text Available Elevated low-density lipoprotein (LDL-cholesterol is a risk factor for both Alzheimer's disease (AD and Atherosclerosis (CVD, suggesting a common lipid-sensitive step in their pathogenesis. Previous results show that AD and CVD also share a cell cycle defect: chromosome instability and up to 30% aneuploidy-in neurons and other cells in AD and in smooth muscle cells in atherosclerotic plaques in CVD. Indeed, specific degeneration of aneuploid neurons accounts for 90% of neuronal loss in AD brain, indicating that aneuploidy underlies AD neurodegeneration. Cell/mouse models of AD develop similar aneuploidy through amyloid-beta (Aß inhibition of specific microtubule motors and consequent disruption of mitotic spindles. Here we tested the hypothesis that, like upregulated Aß, elevated LDL/cholesterol and altered intracellular cholesterol homeostasis also causes chromosomal instability. Specifically we found that: 1 high dietary cholesterol induces aneuploidy in mice, satisfying the hypothesis' first prediction, 2 Niemann-Pick C1 patients accumulate aneuploid fibroblasts, neurons, and glia, demonstrating a similar aneugenic effect of intracellular cholesterol accumulation in humans 3 oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL, induce chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors, indicating that LDL/cholesterol directly affects the cell cycle, 4 LDL-induced aneuploidy requires the LDL receptor, but not Aß, showing that LDL works differently than Aß, with the same end result, 5 cholesterol treatment disrupts the structure of the mitotic spindle, providing a cell biological mechanism for its aneugenic activity, and 6 ethanol or calcium chelation attenuates lipoprotein-induced chromosome mis-segregation, providing molecular insights into cholesterol's aneugenic mechanism, specifically through its rigidifying effect on the cell membrane, and potentially explaining why ethanol

  17. Cholesterol accumulation in Niemann Pick type C (NPC) model cells causes a shift in APP localization to lipid rafts

    International Nuclear Information System (INIS)

    Kosicek, Marko; Malnar, Martina; Goate, Alison; Hecimovic, Silva

    2010-01-01

    It has been suggested that cholesterol may modulate amyloid-β (Aβ) formation, a causative factor of Alzheimer's disease (AD), by regulating distribution of the three key proteins in the pathogenesis of AD (β-amyloid precursor protein (APP), β-secretase (BACE1) and/or presenilin 1 (PS1)) within lipid rafts. In this work we tested whether cholesterol accumulation upon NPC1 dysfunction, which causes Niemann Pick type C disease (NPC), causes increased partitioning of APP into lipid rafts leading to increased CTF/Aβ formation in these cholesterol-rich membrane microdomains. To test this we used CHO NPC1 -/- cells (NPC cells) and parental CHOwt cells. By sucrose density gradient centrifugation we observed a shift in fl-APP/CTF compartmentalization into lipid raft fractions upon cholesterol accumulation in NPC vs. wt cells. Furthermore, γ-secretase inhibitor treatment significantly increased fl-APP/CTF distribution in raft fractions in NPC vs. wt cells, suggesting that upon cholesterol accumulation in NPC1-null cells increased formation of APP-CTF and its increased processing towards Aβ occurs in lipid rafts. Our results support that cholesterol overload, such as in NPC disease, leads to increased partitioning of APP/CTF into lipid rafts resulting in increased amyloidogenic processing of APP in these cholesterol-rich membranes. This work adds to the mechanism of the cholesterol-effect on APP processing and the pathogenesis of Alzheimer's disease and supports the role of lipid rafts in these processes.

  18. Trafficking of cholesterol from cell bodies to distal axons in Niemann Pick C1-deficient neurons.

    Science.gov (United States)

    Karten, Barbara; Vance, Dennis E; Campenot, Robert B; Vance, Jean E

    2003-02-07

    Niemann Pick type C (NPC) disease is a progressive neurodegenerative disorder. In cells lacking functional NPC1 protein, endocytosed cholesterol accumulates in late endosomes/lysosomes. We utilized primary neuronal cultures in which cell bodies and distal axons reside in separate compartments to investigate the requirement of NPC1 protein for transport of cholesterol from cell bodies to distal axons. We have recently observed that in NPC1-deficient neurons compared with wild-type neurons, cholesterol accumulates in cell bodies but is reduced in distal axons (Karten, B., Vance, D. E., Campenot, R. B., and Vance, J. E. (2002) J. Neurochem. 83, 1154-1163). We now show that NPC1 protein is expressed in both cell bodies and distal axons. In NPC1-deficient neurons, cholesterol delivered to cell bodies from low density lipoproteins (LDLs), high density lipoproteins, or cyclodextrin complexes was transported into axons in normal amounts, whereas transport of endogenously synthesized cholesterol was impaired. Inhibition of cholesterol synthesis with pravastatin in wild-type and NPC1-deficient neurons reduced axonal growth. However, LDLs restored a normal rate of growth to wild-type but not NPC1-deficient neurons treated with pravastatin. Thus, although LDL cholesterol is transported into axons of NPC1-deficient neurons, this source of cholesterol does not sustain normal axonal growth. Over the lifespan of NPC1-deficient neurons, these defects in cholesterol transport might be responsible for the observed altered distribution of cholesterol between cell bodies and axons and, consequently, might contribute to the neurological dysfunction in NPC disease.

  19. Are Niemann-Pick type C proteins key players in cnidarian-dinoflagellate endosymbioses?

    Science.gov (United States)

    Dani, Vincent; Ganot, Philippe; Priouzeau, Fabrice; Furla, Paola; Sabourault, Cecile

    2014-09-01

    The symbiotic interaction between cnidarians, such as corals and sea anemones, and the unicellular algae Symbiodinium is regulated by yet poorly understood cellular mechanisms, despite the ecological importance of coral reefs. These mechanisms, including host-symbiont recognition and metabolic exchange, control symbiosis stability under normal conditions, but also lead to symbiosis breakdown (bleaching) during stress. This study describes the repertoire of the sterol-trafficking proteins Niemann-Pick type C (NPC1 and NPC2) in the symbiotic sea anemone Anemonia viridis. We found one NPC1 gene in contrast to the two genes (NPC1 and NPC1L1) present in vertebrate genomes. While only one NPC2 gene is present in many metazoans, this gene has been duplicated in cnidarians, and we detected four NPC2 genes in A. viridis. However, only one gene (AvNPC2-d) was upregulated in symbiotic relative to aposymbiotic sea anemones and displayed higher expression in the gastrodermis (symbiont-containing tissue) than in the epidermis. We performed immunolabelling experiments on tentacle cross sections and demonstrated that the AvNPC2-d protein was closely associated with symbiosomes. In addition, AvNPC1 and AvNPC2-d gene expression was strongly downregulated during stress. These data suggest that AvNPC2-d is involved in both the stability and dysfunction of cnidarian-dinoflagellate symbioses. © 2014 John Wiley & Sons Ltd.

  20. Niemann-pick type C1 (NPC1) overexpression alters cellular cholesterol homeostasis.

    Science.gov (United States)

    Millard, E E; Srivastava, K; Traub, L M; Schaffer, J E; Ory, D S

    2000-12-08

    The Niemann-Pick type C1 (NPC1) protein is a key participant in intracellular trafficking of low density lipoprotein cholesterol, but its role in regulation of sterol homeostasis is not well understood. To characterize further the function of NPC1, we generated stable Chinese hamster ovary (CHO) cell lines overexpressing the human NPC1 protein (CHO/NPC1). NPC1 overexpression increases the rate of trafficking of low density lipoprotein cholesterol to the endoplasmic reticulum and the rate of delivery of endosomal cholesterol to the plasma membrane (PM). CHO/NPC1 cells exhibit a 1.5-fold increase in total cellular cholesterol and up to a 2.9-fold increase in PM cholesterol. This increase in PM cholesterol is closely paralleled by a 3-fold increase in de novo cholesterol synthesis. Inhibition of cholesterol synthesis results in marked redistribution of PM cholesterol to intracellular sites, suggesting an unsuspected role for NPC1 in internalization of PM cholesterol. Despite elevated total cellular cholesterol, CHO/NPC1 cells exhibit increased cholesterol synthesis, which may be attributable to both resistance to oxysterol suppression of sterol-regulated gene expression and to reduced endoplasmic reticulum cholesterol levels under basal conditions. Taken together, these studies provide important new insights into the role of NPC1 in the determination of the levels and distribution of cellular cholesterol.

  1. Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway [version 1; referees: 2 approved, 1 approved with reservations

    Directory of Open Access Journals (Sweden)

    Paul Fineran

    2016-11-01

    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 persistent 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 persistent intracellular mycobacteria phenocopied NPC cells, exhibiting accumulation of multiple lipid types, reduced lysosomal Ca2+ 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 persistent intracellular mycobacteria inhibit the NPC pathway, likely via inhibition of the NPC1 protein, and subsequently induce altered acidic store Ca2+ 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

  2. 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

  3. Cholesterol-dependent energy transfer between fluorescent proteins-insights into protein proximity of APP and BACE1 in different membranes in Niemann-Pick type C disease cells.

    Science.gov (United States)

    von Einem, Bjoern; Weber, Petra; Wagner, Michael; Malnar, Martina; Kosicek, Marko; Hecimovic, Silva; Arnim, Christine A F von; Schneckenburger, Herbert

    2012-11-26

    Förster resonance energy transfer (FRET) -based techniques have recently been applied to study the interactions between β-site APP-cleaving enzyme-GFP (BACE1-GFP) and amyloid precursor protein-mRFP (APP-mRFP) in U373 glioblastoma cells. In this context, the role of APP-BACE1 proximity in Alzheimer's disease (AD) pathogenesis has been discussed. FRET was found to depend on intracellular cholesterol levels and associated alterations in membrane stiffness. Here, NPC1 null cells (CHO-NPC1-/-), exhibiting increased cholesterol levels and disturbed cholesterol transport similar to that observed in Niemann-Pick type C disease (NPC), were used to analyze the influence of altered cholesterol levels on APP-BACE1 proximity. Fluorescence lifetime measurements of whole CHO-wild type (WT) and CHO-NPC1-/- cells (EPI-illumination microscopy), as well as their plasma membranes (total internal reflection fluorescence microscopy, TIRFM), were performed. Additionally, generalized polarization (GP) measurements of CHO-WT and CHO-NPC1-/- cells incubated with the fluorescence marker laurdan were performed to determine membrane stiffness of plasma- and intracellular-membranes. CHO-NPC1-/- cells showed higher membrane stiffness at intracellular- but not plasma-membranes, equivalent to cholesterol accumulation in late endosomes/lysosomes. Along with higher membrane stiffness, the FRET efficiency between BACE1-GFP and APP-mRFP was reduced at intracellular membranes, but not within the plasma membrane of CHO-NPC1-/-. Our data show that FRET combined with TIRF is a powerful technique to determine protein proximity and membrane fluidity in cellular models of neurodegenerative diseases.

  4. Intracellular transport of low density lipoprotein-derived cholesterol is defective in Niemann-Pick type C fibroblasts

    International Nuclear Information System (INIS)

    Liscum, L.; Ruggiero, R.M.; Faust, J.R.

    1989-01-01

    Niemann-Pick disease type C (NPC) is characterized by substantial intracellular accumulation of unesterified cholesterol. The accumulation of unesterified cholesterol in NPC fibroblasts cultured with low density lipoprotein (LDL) appears to result from the inability of LDL to stimulate cholesterol esterification in addition to impaired LDL-mediated downregulation of LDL receptor activity and cellular cholesterol synthesis. Although a defect in cholesterol transport in NPC cells has been inferred from previous studies, no experiments have been reported that measure the intracellular movement of LDL-cholesterol specifically. We have used four approaches to assess intracellular cholesterol transport in normal and NPC cells and have determined the following: (a) mevinolin-inhibited NPC cells are defective in using LDL-cholesterol for growth. However, exogenously added mevalonate restores cell growth equally in normal and NPC cells; (b) the transport of LDL-derived [3H]cholesterol to the plasma membrane is slower in NPC cells, while the rate of appearance of [3H]acetate-derived, endogenously synthesized [3H]cholesterol at the plasma membrane is the same for normal and NPC cells; (c) in NPC cells, LDL-derived [3H]cholesterol accumulates in lysosomes to higher levels than normal, resulting in defective movement to other cell membranes; and (d) incubation of cells with LDL causes an increase in cholesterol content of NPC lysosomes that is threefold greater than that observed in normal lysosomes. Our results indicate that a cholesterol transport defect exists in NPC that is specific for LDL-derived cholesterol

  5. Pharmacologic Treatment Assigned for Niemann Pick Type C1 Disease Partly Changes Behavioral Traits in Wild-Type Mice.

    Science.gov (United States)

    Schlegel, Victoria; Thieme, Markus; Holzmann, Carsten; Witt, Martin; Grittner, Ulrike; Rolfs, Arndt; Wree, Andreas

    2016-11-09

    Niemann-Pick Type C1 (NPC1) is an autosomal recessive inherited disorder characterized by accumulation of cholesterol and glycosphingolipids. Previously, we demonstrated that BALB/c-npc1 nih Npc1 -/- mice treated with miglustat, cyclodextrin and allopregnanolone generally performed better than untreated Npc1 -/- animals. Unexpectedly, they also seemed to accomplish motor tests better than their sham-treated wild-type littermates. However, combination-treated mutant mice displayed worse cognition performance compared to sham-treated ones. To evaluate effects of these drugs in healthy BALB/c mice, we here analyzed pharmacologic effects on motor and cognitive behavior of wild-type mice. For combination treatment mice were injected with allopregnanolone/cyclodextrin weekly, starting at P7. Miglustat injections were performed daily from P10 till P23. Starting at P23, miglustat was embedded in the chow. Other mice were treated with miglustat only, or sham-treated. The battery of behavioral tests consisted of accelerod, Morris water maze, elevated plus maze, open field and hot-plate tests. Motor capabilities and spontaneous motor behavior were unaltered in both drug-treated groups. Miglustat-treated wild-type mice displayed impaired spatial learning compared to sham- and combination-treated mice. Both combination- and miglustat-treated mice showed enhanced anxiety in the elevated plus maze compared to sham-treated mice. Additionally, combination treatment as well as miglustat alone significantly reduced brain weight, whereas only combination treatment reduced body weight significantly. Our results suggest that allopregnanolone/cyclodextrin ameliorate most side effects of miglustat in wild-type mice.

  6. Pharmacologic Treatment Assigned for Niemann Pick Type C1 Disease Partly Changes Behavioral Traits in Wild-Type Mice

    Directory of Open Access Journals (Sweden)

    Victoria Schlegel

    2016-11-01

    Full Text Available Niemann-Pick Type C1 (NPC1 is an autosomal recessive inherited disorder characterized by accumulation of cholesterol and glycosphingolipids. Previously, we demonstrated that BALB/c-npc1nihNpc1−/− mice treated with miglustat, cyclodextrin and allopregnanolone generally performed better than untreated Npc1−/− animals. Unexpectedly, they also seemed to accomplish motor tests better than their sham-treated wild-type littermates. However, combination-treated mutant mice displayed worse cognition performance compared to sham-treated ones. To evaluate effects of these drugs in healthy BALB/c mice, we here analyzed pharmacologic effects on motor and cognitive behavior of wild-type mice. For combination treatment mice were injected with allopregnanolone/cyclodextrin weekly, starting at P7. Miglustat injections were performed daily from P10 till P23. Starting at P23, miglustat was embedded in the chow. Other mice were treated with miglustat only, or sham-treated. The battery of behavioral tests consisted of accelerod, Morris water maze, elevated plus maze, open field and hot-plate tests. Motor capabilities and spontaneous motor behavior were unaltered in both drug-treated groups. Miglustat-treated wild-type mice displayed impaired spatial learning compared to sham- and combination-treated mice. Both combination- and miglustat-treated mice showed enhanced anxiety in the elevated plus maze compared to sham-treated mice. Additionally, combination treatment as well as miglustat alone significantly reduced brain weight, whereas only combination treatment reduced body weight significantly. Our results suggest that allopregnanolone/cyclodextrin ameliorate most side effects of miglustat in wild-type mice.

  7. Niemann-Pick C1 like 1 gene expression is down-regulated by LXR activators in the intestine

    International Nuclear Information System (INIS)

    Duval, Caroline; Touche, Veronique; Tailleux, Anne; Fruchart, Jean-Charles; Fievet, Catherine; Clavey, Veronique; Staels, Bart; Lestavel, Sophie

    2006-01-01

    Niemann-Pick C1 like 1 (NPC1L1) is a protein critical for intestinal cholesterol absorption. The nuclear receptors peroxisome proliferator-activated receptor alpha (PPARα) and liver X receptors (LXRα and LXRβ) are major regulators of cholesterol homeostasis and their activation results in a reduced absorption of intestinal cholesterol. The goal of this study was to define the role of PPARα and LXR nuclear receptors in the regulation of NPC1L1 gene expression. We show that LXR activators down-regulate NPC1L1 mRNA levels in the human enterocyte cell line Caco-2/TC7, whereas PPARα ligands have no effect. Furthermore, NPC1L1 mRNA levels are decreased in vivo, in duodenum of mice treated with the LXR agonist T0901317. In conclusion, the present study identifies NPC1L1 as a novel LXR target gene further supporting a crucial role of LXR in intestinal cholesterol homeostasis

  8. Disruption in connexin-based communication is associated with intracellular Ca²⁺ signal alterations in astrocytes from Niemann-Pick type C mice.

    Directory of Open Access Journals (Sweden)

    Pablo J Sáez

    Full Text Available Reduced astrocytic gap junctional communication and enhanced hemichannel activity were recently shown to increase astroglial and neuronal vulnerability to neuroinflammation. Moreover, increasing evidence suggests that neuroinflammation plays a pivotal role in the development of Niemann-Pick type C (NPC disease, an autosomal lethal neurodegenerative disorder that is mainly caused by mutations in the NPC1 gene. Therefore, we investigated whether the lack of NPC1 expression in murine astrocytes affects the functional state of gap junction channels and hemichannels. Cultured cortical astrocytes of NPC1 knock-out mice (Npc1⁻/⁻ showed reduced intercellular communication via gap junctions and increased hemichannel activity. Similarly, astrocytes of newborn Npc1⁻/⁻ hippocampal slices presented high hemichannel activity, which was completely abrogated by connexin 43 hemichannel blockers and was resistant to inhibitors of pannexin 1 hemichannels. Npc1⁻/⁻ astrocytes also showed more intracellular Ca²⁺ signal oscillations mediated by functional connexin 43 hemichannels and P2Y₁ receptors. Therefore, Npc1⁻/⁻ astrocytes present features of connexin based channels compatible with those of reactive astrocytes and hemichannels might be a novel therapeutic target to reduce neuroinflammation in NPC disease.

  9. Disruption in connexin-based communication is associated with intracellular Ca²⁺ signal alterations in astrocytes from Niemann-Pick type C mice.

    Science.gov (United States)

    Sáez, Pablo J; Orellana, Juan A; Vega-Riveros, Natalia; Figueroa, Vania A; Hernández, Diego E; Castro, Juan F; Klein, Andrés D; Jiang, Jean X; Zanlungo, Silvana; Sáez, Juan C

    2013-01-01

    Reduced astrocytic gap junctional communication and enhanced hemichannel activity were recently shown to increase astroglial and neuronal vulnerability to neuroinflammation. Moreover, increasing evidence suggests that neuroinflammation plays a pivotal role in the development of Niemann-Pick type C (NPC) disease, an autosomal lethal neurodegenerative disorder that is mainly caused by mutations in the NPC1 gene. Therefore, we investigated whether the lack of NPC1 expression in murine astrocytes affects the functional state of gap junction channels and hemichannels. Cultured cortical astrocytes of NPC1 knock-out mice (Npc1⁻/⁻) showed reduced intercellular communication via gap junctions and increased hemichannel activity. Similarly, astrocytes of newborn Npc1⁻/⁻ hippocampal slices presented high hemichannel activity, which was completely abrogated by connexin 43 hemichannel blockers and was resistant to inhibitors of pannexin 1 hemichannels. Npc1⁻/⁻ astrocytes also showed more intracellular Ca²⁺ signal oscillations mediated by functional connexin 43 hemichannels and P2Y₁ receptors. Therefore, Npc1⁻/⁻ astrocytes present features of connexin based channels compatible with those of reactive astrocytes and hemichannels might be a novel therapeutic target to reduce neuroinflammation in NPC disease.

  10. Niemann-Pick C1 (NPC1/NPC1-like1 Chimeras Define Sequences Critical for NPC1’s Function as a Filovirus Entry Receptor

    Directory of Open Access Journals (Sweden)

    Esther Ndungo

    2012-10-01

    Full Text Available We recently demonstrated that Niemann-Pick C1 (NPC1, a ubiquitous 13-pass cellular membrane protein involved in lysosomal cholesterol transport, is a critical entry receptor for filoviruses. Here we show that Niemann-Pick C1-like1 (NPC1L1, an NPC1 paralog and hepatitis C virus entry factor, lacks filovirus receptor activity. We exploited the structural similarity between NPC1 and NPC1L1 to construct and analyze a panel of chimeras in which NPC1L1 sequences were replaced with cognate sequences from NPC1. Only one chimera, NPC1L1 containing the second luminal domain (C of NPC1 in place of its own, bound to the viral glycoprotein, GP. This engineered protein mediated authentic filovirus infection nearly as well as wild-type NPC1, and more efficiently than did a minimal NPC1 domain C-based receptor recently described by us. A reciprocal chimera, NPC1 containing NPC1L1’s domain C, was completely inactive. Remarkably, an intra-domain NPC1L1-NPC1 chimera bearing only a ~130-amino acid N–terminal region of NPC1 domain C could confer substantial viral receptor activity on NPC1L1. Taken together, these findings account for the failure of NPC1L1 to serve as a filovirus receptor, highlight the central role of the luminal domain C of NPC1 in filovirus entry, and reveal the direct involvement of N–terminal domain C sequences in NPC1’s function as a filovirus receptor.

  11. Lycopene reduces cholesterol absorption through the downregulation of Niemann-Pick C1-like 1 in Caco-2 cells.

    Science.gov (United States)

    Zou, Jun; Feng, Dan

    2015-11-01

    Elevated blood cholesterol is an important risk factor associated with atherosclerosis and coronary heart disease. Tomato lycopene has been found to have a hypocholesterolemic effect, and the effect was considered to be related to inhibition of cholesterol synthesis. However, since plasma cholesterol levels are also influenced by the absorption of cholesterol in the gut, the present study is to investigate whether lycopene affects cholesterol absorption in the intestinal Caco-2 cells. The Caco-2 cells were pretreated with lycopene at different concentrations for 24 h and then incubated with radioactive micellar cholesterol for 2 h. The absorption of radioactive cholesterol was quantified by liquid scintillation. The expression of Niemann-Pick C1-like 1 (NPC1L1) and liver X receptor α (LXRα) was analyzed by Western blot and qPCR. We found that lycopene dose dependently inhibited cholesterol absorption and the expression of NPC1L1 protein and NPC1L1 mRNA. The inhibitory effects of lycopene on cholesterol absorption and NPC1L1 expression could be prevented by blockade of the LXRα pathway. This study provides the first evidence that lycopene inhibits cholesterol absorption in the intestinal cells and this inhibitory effect of lycopene is mediated, at least in part, by LXRα-NPC1L1 signaling pathway. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. 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.

  13. Alteration of gene expression profile in Niemann-Pick type C mice correlates with tissue damage and oxidative stress.

    Directory of Open Access Journals (Sweden)

    Mary C Vázquez

    Full Text Available BACKGROUND: Niemann-Pick type C disease (NPC is a neurovisceral lipid storage disorder mainly characterized by unesterified cholesterol accumulation in lysosomal/late endosomal compartments, although there is also an important storage for several other kind of lipids. The main tissues affected by the disease are the liver and the cerebellum. Oxidative stress has been described in various NPC cells and tissues, such as liver and cerebellum. Although considerable alterations occur in the liver, the pathological mechanisms involved in hepatocyte damage and death have not been clearly defined. Here, we assessed hepatic tissue integrity, biochemical and oxidative stress parameters of wild-type control (Npc1(+/+; WT and homozygous-mutant (Npc1(-/-; NPC mice. In addition, the mRNA abundance of genes encoding proteins associated with oxidative stress, copper metabolism, fibrosis, inflammation and cholesterol metabolism were analyzed in livers and cerebella of WT and NPC mice. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed various oxidative stress parameters in the liver and hepatic and cerebellum gene expression in 7-week-old NPC1-deficient mice compared with control animals. We found signs of inflammation and fibrosis in NPC livers upon histological examination. These signs were correlated with increased levels of carbonylated proteins, diminished total glutathione content and significantly increased total copper levels in liver tissue. Finally, we analyzed liver and cerebellum gene expression patterns by qPCR and microarray assays. We found a correlation between fibrotic tissue and differential expression of hepatic as well as cerebellar genes associated with oxidative stress, fibrosis and inflammation in NPC mice. CONCLUSIONS/SIGNIFICANCE: In NPC mice, liver disease is characterized by an increase in fibrosis and in markers associated with oxidative stress. NPC is also correlated with altered gene expression, mainly of genes involved in oxidative stress

  14. A comparative study of Alzheimer's disease and Pick's disease by CT

    International Nuclear Information System (INIS)

    Ichimiya, Yosuke; Kobayashi, Kazunari; Arai, Heii; Ikeda, Kenji; Kosaka, Kenji

    1984-01-01

    17 patients with clinically diagnosed Alzheimer's disease, 11 patients with clinically diagnosed Pick's disease and 13 healthy age-matched subjects as the control were studied by computed tomography (CT). In order to study cerebral atrophy, volumetric measurement was performed. Subarachnoid Space Volume Index (SVI). Frontal, Temporal, and Parieto-Occipital Subarachnoid Space Volume Indices (SfVI, StVI, and SpoVI, respectively) as well as Ventricle Volume Index (VVI), The volume indices of anterior horn, inferior horn, and posterior horn of the lateral ventricles (VaVI, ViVI, and VpVI, respectively) were calculated as the indices for the atrophy of the cerebral cortex and white matter. Furthermore, to evaluate lobar atrophy, SfVI+VaVI (FA), StVI+ViVI (TA), and SpoVI+VpVI (POA) were defined as the indices of frontal lobe atrophy, temporal lobe atrophy, and parieto-occipital lobe atrophy respectively. In Alzheimer's patients, FA and POA were significantly large (p<0.001) in stage I group and TA was significantly enlarged (p<0.001) in stage II group. In Pick's patients, FA and TA were significantly large (FA : p<0.001, TA : p<0.01) in stage I group and POA became significantly prominent (p<0.001) in stage III group. Pick's patients showed significantly larger SfVI (p<0.2 in stage I group and p<0.001 in stage II group) and FA (p<0.01 in stage II group) than Alzheimer's patients. The results in this study give us the following suggestions; 1) Alzheimer's patients show a diffuse cerebral atrophy in the early stage. 2) Pick's patients have a localized atrophy of frontal and temporal lobes already in the early stage. 3) Compared with Alzheimer's patients, Pick's patients show significantly more severe atrophy in frontal lobe at the early stage. (J.P.N.)

  15. Synthesis, characterization, and evaluation of pluronic-based β-cyclodextrin polyrotaxanes for mobilization of accumulated cholesterol from Niemann-Pick type C fibroblasts.

    Science.gov (United States)

    Collins, Christopher J; McCauliff, Leslie A; Hyun, Seok-Hee; Zhang, Zhaorui; Paul, Lake N; Kulkarni, Aditya; Zick, Klaus; Wirth, Mary; Storch, Judith; Thompson, David H

    2013-05-14

    Several lines of evidence suggest that β-cyclodextrin (β-CD) derivatives initiate the efflux of accumulated, unesterified cholesterol from the late endosomal/lysosomal compartment in Niemann Pick C (NPC) disease models. Unfortunately, repeated injections or continuous infusions of current β-CD therapies are required to sustain suppression of symptoms and prolong life. In an effort to make CD treatment a more viable option by boosting efficacy and improving pharmacokinetics, a library of Pluronic surfactant-based β-CD polyrotaxanes has been developed using biocompatible poly(ethylene glycol) (PEG)-polypropylene glycol (PPG)-PEG triblock copolymers. These compounds carry multiple copies of β-CD as shown by (1)H NMR, 2D nuclear Overhouser effect spectroscopy, gel permeation chromatography/multiangle light scattering, analytical ultracentrifugation analysis, matrix assisted laser desorption/ionization mass spectrometry, and diffusion-ordered spectroscopy. Analyses of free β-cyclodextrin contamination in the compounds were made by reverse phase high pressure liquid chromatography and hydrophilic interaction liquid chromatography. Dethreading kinetics were studied by reverse phase high pressure liquid chromatography, UV/vis, and (1)H NMR analysis. Filipin staining studies using npc2(-/-) fibroblasts show significant reversal of cholesterol accumulation after treatment with polyrotaxane compounds. The rate and efficacy of reversal is similar to that achieved by equivalent amounts of monomeric β-CD alone.

  16. Alterations in gene expression in mutant amyloid precursor protein transgenic mice lacking Niemann-Pick type C1 protein.

    Directory of Open Access Journals (Sweden)

    Mahua Maulik

    Full Text Available Niemann-Pick type C (NPC disease, a rare autosomal recessive disorder caused mostly by mutation in NPC1 gene, is pathologically characterized by the accumulation of free cholesterol in brain and other tissues. This is accompanied by gliosis and loss of neurons in selected brain regions, including the cerebellum. Recent studies have shown that NPC disease exhibits intriguing parallels with Alzheimer's disease, including the presence of neurofibrillary tangles and increased levels of amyloid precursor protein (APP-derived β-amyloid (Aβ peptides in vulnerable brain neurons. To evaluate the role of Aβ in NPC disease, we determined the gene expression profile in selected brain regions of our recently developed bigenic ANPC mice, generated by crossing APP transgenic (Tg mice with heterozygous Npc1-deficient mice. The ANPC mice exhibited exacerbated neuronal and glial pathology compared to other genotypes [i.e., APP-Tg, double heterozygous (Dhet, Npc1-null and wild-type mice]. Analysis of expression profiles of 86 selected genes using real-time RT-PCR arrays showed a wide-spectrum of alterations in the four genotypes compared to wild-type controls. The changes observed in APP-Tg and Dhet mice are limited to only few genes involved mostly in the regulation of cholesterol metabolism, whereas Npc1-null and ANPC mice showed alterations in the expression profiles of a number of genes regulating cholesterol homeostasis, APP metabolism, vesicular trafficking and cell death mechanism in both hippocampus and cerebellum compared to wild-type mice. Intriguingly, ANPC and Npc1-null mice, with some exceptions, exhibited similar changes, although more genes were differentially expressed in the affected cerebellum than the relatively spared hippocampus. The altered gene profiles were found to match with the corresponding protein levels. These results suggest that lack of Npc1 protein can alter the expression profile of selected transcripts as well as proteins, and

  17. Loss of Niemann-Pick C1 or C2 protein results in similar biochemical changes suggesting that these proteins function in a common lysosomal pathway.

    Directory of Open Access Journals (Sweden)

    Sayali S Dixit

    Full Text Available Niemann-Pick Type C (NPC disease is a lysosomal storage disorder characterized by accumulation of unesterified cholesterol and other lipids in the endolysosomal system. NPC disease results from a defect in either of two distinct cholesterol-binding proteins: a transmembrane protein, NPC1, and a small soluble protein, NPC2. NPC1 and NPC2 are thought to function closely in the export of lysosomal cholesterol with both proteins binding cholesterol in vitro but they may have unrelated lysosomal roles. To investigate this possibility, we compared biochemical consequences of the loss of either protein. Analyses of lysosome-enriched subcellular fractions from brain and liver revealed similar decreases in buoyant densities of lysosomes from NPC1 or NPC2 deficient mice compared to controls. The subcellular distribution of both proteins was similar and paralleled a lysosomal marker. In liver, absence of either NPC1 or NPC2 resulted in similar alterations in the carbohydrate processing of the lysosomal protease, tripeptidyl peptidase I. These results highlight biochemical alterations in the lysosomal system of the NPC-mutant mice that appear secondary to lipid storage. In addition, the similarity in biochemical phenotypes resulting from either NPC1 or NPC2 deficiency supports models in which the function of these two proteins within lysosomes are linked closely.

  18. Pre-symptomatic activation of antioxidant responses and alterations in glucose and pyruvate metabolism in Niemann-Pick Type C1-deficient murine brain.

    Directory of Open Access Journals (Sweden)

    Barry E Kennedy

    Full Text Available Niemann-Pick Type C (NPC disease is an autosomal recessive neurodegenerative disorder caused in most cases by mutations in the NPC1 gene. NPC1-deficiency is characterized by late endosomal accumulation of cholesterol, impaired cholesterol homeostasis, and a broad range of other cellular abnormalities. Although neuronal abnormalities and glial activation are observed in nearly all areas of the brain, the most severe consequence of NPC1-deficiency is a near complete loss of Purkinje neurons in the cerebellum. The link between cholesterol trafficking and NPC pathogenesis is not yet clear; however, increased oxidative stress in symptomatic NPC disease, increases in mitochondrial cholesterol, and alterations in autophagy/mitophagy suggest that mitochondria play a role in NPC disease pathology. Alterations in mitochondrial function affect energy and neurotransmitter metabolism, and are particularly harmful to the central nervous system. To investigate early metabolic alterations that could affect NPC disease progression, we performed metabolomics analyses of different brain regions from age-matched wildtype and Npc1 (-/- mice at pre-symptomatic, early symptomatic and late stage disease by (1H-NMR spectroscopy. Metabolic profiling revealed markedly increased lactate and decreased acetate/acetyl-CoA levels in Npc1 (-/- cerebellum and cerebral cortex at all ages. Protein and gene expression analyses indicated a pre-symptomatic deficiency in the oxidative decarboxylation of pyruvate to acetyl-CoA, and an upregulation of glycolytic gene expression at the early symptomatic stage. We also observed a pre-symptomatic increase in several indicators of oxidative stress and antioxidant response systems in Npc1 (-/- cerebellum. Our findings suggest that energy metabolism and oxidative stress may present additional therapeutic targets in NPC disease, especially if intervention can be started at an early stage of the disease.

  19. Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor

    Science.gov (United States)

    Sainz, Bruno; Barretto, Naina; Martin, Danyelle N.; Hiraga, Nobuhiko; Imamura, Michio; Hussain, Snawar; Marsh, Katherine A.; Yu, Xuemei; Chayama, Kazuaki; Alrefai, Waddah A.; Uprichard, Susan L.

    2011-01-01

    Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. With ~170 million individuals infected and current interferon-based treatment having toxic side-effects and marginal efficacy, more effective antivirals are critically needed1. Although HCV protease inhibitors were just FDA approved, analogous to HIV therapy, optimal HCV therapy likely will require a combination of antivirals targeting multiple aspects of the viral lifecycle. Viral entry represents a promising multi-faceted target for antiviral intervention; however, to date FDA-approved inhibitors of HCV cell entry are unavailable. Here we show that the cellular Niemann-Pick C1-Like 1 (NPC1L1) cholesterol uptake receptor is an HCV entry factor amendable to therapeutic intervention. Specifically, NPC1L1 expression is necessary for HCV infection as silencing or antibody-mediated blocking of NPC1L1 impairs cell-cultured-derived HCV (HCVcc) infection initiation. In addition, the clinically-available FDA-approved NPC1L1 antagonist ezetimibe2,3 potently blocks HCV uptake in vitro via a virion cholesterol-dependent step prior to virion-cell membrane fusion. Importantly, ezetimibe inhibits infection of all major HCV genotypes in vitro, and in vivo delays the establishment of HCV genotype 1b infection in mice with human liver grafts. Thus, we have not only identified NPC1L1 as an HCV cell entry factor, but also discovered a new antiviral target and potential therapeutic agent. PMID:22231557

  20. Newborn screening for six lysosomal storage disorders in a cohort of Mexican patients: Three-year findings from a screening program in a closed Mexican health system.

    Science.gov (United States)

    Navarrete-Martínez, Juana Inés; Limón-Rojas, Ana Elena; Gaytán-García, Maria de Jesús; Reyna-Figueroa, Jesús; Wakida-Kusunoki, Guillermo; Delgado-Calvillo, Ma Del Rocío; Cantú-Reyna, Consuelo; Cruz-Camino, Héctor; Cervantes-Barragán, David Eduardo

    2017-05-01

    To evaluate the results of a lysosomal newborn screening (NBS) program in a cohort of 20,018 Mexican patients over the course of 3years in a closed Mexican Health System (Petróleos Mexicanos [PEMEX] Health Services). Using dried blood spots (DBS), we performed a multiplex tandem mass spectrometry enzymatic assay for six lysosomal storage disorders (LSDs) including Pompe disease, Fabry disease, Gaucher disease, mucopolysaccharidosis type I (MPS-I), Niemann-Pick type A/B, and Krabbe disease. Screen-positive cases were confirmed using leukocyte enzymatic activity and DNA molecular analysis. From July 2012 to April 2016, 20,018 patients were screened; 20 patients were confirmed to have an LSD phenotype (99.9 in 100,000 newborns). Final distributions include 11 Pompe disease, five Fabry disease, two MPS-I, and two Niemann-Pick type A/B patients. We did not find any Gaucher or Krabbe patients. A final frequency of 1 in 1001 LSD newborn phenotypes was established. NBS is a major public health achievement that has decreased the morbidity and mortality of inborn errors of metabolism. The introduction of NBS for LSD presents new challenges. This is the first multiplex Latin-American study of six LSDs detected through NBS. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Multiple cationic amphiphiles induce a Niemann-Pick C phenotype and inhibit Ebola virus entry and infection.

    Directory of Open Access Journals (Sweden)

    Charles J Shoemaker

    Full Text Available Ebola virus (EBOV is an enveloped RNA virus that causes hemorrhagic fever in humans and non-human primates. Infection requires internalization from the cell surface and trafficking to a late endocytic compartment, where viral fusion occurs, providing a conduit for the viral genome to enter the cytoplasm and initiate replication. In a concurrent study, we identified clomiphene as a potent inhibitor of EBOV entry. Here, we screened eleven inhibitors that target the same biosynthetic pathway as clomiphene. From this screen we identified six compounds, including U18666A, that block EBOV infection (IC(50 1.6 to 8.0 µM at a late stage of entry. Intriguingly, all six are cationic amphiphiles that share additional chemical features. U18666A induces phenotypes, including cholesterol accumulation in endosomes, associated with defects in Niemann-Pick C1 protein (NPC1, a late endosomal and lysosomal protein required for EBOV entry. We tested and found that all six EBOV entry inhibitors from our screen induced cholesterol accumulation. We further showed that higher concentrations of cationic amphiphiles are required to inhibit EBOV entry into cells that overexpress NPC1 than parental cells, supporting the contention that they inhibit EBOV entry in an NPC1-dependent manner. A previously reported inhibitor, compound 3.47, inhibits EBOV entry by blocking binding of the EBOV glycoprotein to NPC1. None of the cationic amphiphiles tested had this effect. Hence, multiple cationic amphiphiles (including several FDA approved agents inhibit EBOV entry in an NPC1-dependent fashion, but by a mechanism distinct from that of compound 3.47. Our findings suggest that there are minimally two ways of perturbing NPC1-dependent pathways that can block EBOV entry, increasing the attractiveness of NPC1 as an anti-filoviral therapeutic target.

  2. Synthesis, Characterization, In Vitro Evaluation, and Preclinical Profiling of beta-Cyclodextrin Polyrotaxane Families for Use As Potential Niemann-Pick Type C Therapeutics

    Science.gov (United States)

    Collins, Christopher J.

    Niemann-Pick Disease Type C (NPC) is a rare, autosomal recessive genetic disorder featuring a loss of proteins responsible for unesterified cholesterol (UC) trafficking through the late endosomes/lysosomes (LE/LY) of every cell of the body. Disruption of this pathway leads to abnormal accumulation and storage of UC and other lipids. A broad range of visceral and neurological symptoms result from this accumulation exhibiting a variable age of onset and a disease progression that is ultimately fatal. The disease has an incidence of approximately 1 in 120,000 live births and has no known effective treatment. beta-Cyclodextrin (beta-CD) are natural small molecules macrocycles composed of glucose units with a hydrophobic inner cavity and hydrophilic outer rims. beta-CD derivatives have recently been shown to be effective therapeutics for NPC in cellular and animal models. In the mouse model of the disease, beta-CD therapy increases overall lifetime by as much as 50% and slows the progression of neurodegeneration. The progress has led to the initiation of a National Institutes of Health phase I clinical trial. A main drawback of beta-CD administration is the poor pharmacokinetic profile characterized by rapid renal clearance of the drug through the urine. Libraries of beta-CD derivative carrying high molecular weight polyrotaxane (PR) systems have been designed to prevent glomerular filtration of the injected beta-CD dose. An initial family of unmodified beta-CD PRs was synthesized, characterized, and their therapeutic efficacy was tested in NPC fibroblasts. This was followed by screening of PRs consisting of mixed beta-CD derivative threading featuring charged sulfobutylether beta-CD. Finally, we sought to define PR structure-property effects on in vivo pharmacokinetics, biodistribution, toxicity, immunogenicity, and protein hard corona composition. This was accomplished using a family of gadolinium carrying PRs composed of triblock Pluronic co-polymers of varying

  3. Imaging of macrophage-related lung diseases

    International Nuclear Information System (INIS)

    Marten, Katharina; Hansell, David M.

    2005-01-01

    Macrophage-related pulmonary diseases are a heterogeneous group of disorders characterized by macrophage accumulation, activation or dysfunction. These conditions include smoking-related interstitial lung diseases, metabolic disorders such as Niemann-Pick or Gaucher disease, and rare primary lung tumors. High-resolution computed tomography abnormalities include pulmonary ground-glass opacification secondary to infiltration by macrophages, centrilobular nodules or interlobular septal thickening reflecting peribronchiolar or septal macrophage accumulation, respectively, emphysema caused by macrophage dysfunction, and honeycombing following macrophage-related lung matrix remodeling. (orig.)

  4. Chitotriosidase activity as additional biomarker in the diagnosis of lysosomal storage diseases

    Directory of Open Access Journals (Sweden)

    N. V. Olkhovych

    2016-02-01

    Full Text Available To date, several genetic variants that lead to a deficiency of chitotriosidase activity have been described. The duplication of 24 bp (dup24bp in exon 10 of the CHIT1 gene, which causes a complete loss of enzymatic activity of the gene product, is the most common among the European population. The aim of the study was to evaluate the possibility of using chitotriosidase activity as an additional biomarker in diagnosis of lysosomal storage diseases (LSDs in Ukraine, to determine this parameter in blood plasma of the patients with various lysosomal diseases and to assess the effect of the presence of dup24bp in the CHIT1 gene on this parameter. It has been shown that chitotriosidase activity in blood plasma is a convenient additional biochemical marker in the diagnosis of some LSDs, namely Gaucher disease, Niemann-Pick disease A, B, C and GM1-gangliosidosis. Reference ranges of the normal chitotriosidase activity were determined in blood plasma of Ukrainian population and found to be 8.0-53.1 nmol 4-methylumbelliferone/h·ml of plasma. The total allele frequency of the dup24bp in the CHIT1 gene in Ukrainian population was determined, which amounted to 0.26 (323/1244 that is higher than in European population. It was indicated that molecular-genetic screening of dup24bp in the CHIT1 gene is a necessary stage in a protocol for the laboratory diagnosis of Gaucher disease, Niemann-Pick disease A, B, C as well as GM1-gangliosidosis to avoid incorrect diagnosis.

  5. Rapid screening for lipid storage disorders using biochemical markers. Expert center data and review of the literature.

    Science.gov (United States)

    Voorink-Moret, M; Goorden, S M I; van Kuilenburg, A B P; Wijburg, F A; Ghauharali-van der Vlugt, J M M; Beers-Stet, F S; Zoetekouw, A; Kulik, W; Hollak, C E M; Vaz, F M

    2018-02-01

    In patients suspected of a lipid storage disorder (sphingolipidoses, lipidoses), confirmation of the diagnosis relies predominantly on the measurement of specific enzymatic activities and genetic studies. New UPLC-MS/MS methods have been developed to measure lysosphingolipids and oxysterols, which, combined with chitotriosidase activity may represent a rapid first tier screening for lipid storage disorders. A lysosphingolipid panel consisting of lysoglobotriaosylceramide (LysoGb3), lysohexosylceramide (LysoHexCer: both lysoglucosylceramide and lysogalactosylceramide), lysosphingomyelin (LysoSM) and its carboxylated analogue lysosphingomyelin-509 (LysoSM-509) was measured in control subjects and plasma samples of predominantly untreated patients affected with lipid storage disorders (n=74). In addition, the oxysterols cholestane-3β,5α,6β-triol and 7-ketocholesterol were measured in a subset of these patients (n=36) as well as chitotriosidase activity (n=43). A systematic review of the literature was performed to assess the usefulness of these biochemical markers. Specific elevations of metabolites, i.e. without overlap between controls and other lipid storage disorders, were found for several lysosomal storage diseases: increased LysoSM levels in acid sphingomyelinase deficiency (Niemann-Pick disease type A/B), LysoGb3 levels in males with classical phenotype Fabry disease and LysoHexCer (i.e. lysoglucosylceramide/lysogalactosylceramide) in Gaucher and Krabbe diseases. While elevated levels of LysoSM-509 and cholestane-3β,5α,6β-triol did not discriminate between Niemann Pick disease type C and acid sphingomyelinase deficiency, LysoSM-509/LysoSM ratio was specifically elevated in Niemann-Pick disease type C. In Gaucher disease type I, mild increases in several lysosphingolipids were found including LysoGb3 with levels in the range of non-classical Fabry males and females. Chitotriosidase showed specific elevations in symptomatic Gaucher disease, and was mildly

  6. Stem Cell Transplant for Inborn Errors of Metabolism

    Science.gov (United States)

    2017-12-03

    Adrenoleukodystrophy; Metachromatic Leukodystrophy; Globoid Cell Leukodystrophy; Gaucher's Disease; Fucosidosis; Wolman Disease; Niemann-Pick Disease; Batten Disease; GM1 Gangliosidosis; Tay Sachs Disease; Sandhoff Disease

  7. Lysosomal enzyme delivery by ICAM-1-targeted nanocarriers bypassing glycosylation- and clathrin-dependent endocytosis.

    Science.gov (United States)

    Muro, Silvia; Schuchman, Edward H; Muzykantov, Vladimir R

    2006-01-01

    Enzyme replacement therapy, a state-of-the-art treatment for many lysosomal storage disorders, relies on carbohydrate-mediated binding of recombinant enzymes to receptors that mediate lysosomal delivery via clathrin-dependent endocytosis. Suboptimal glycosylation of recombinant enzymes and deficiency of clathrin-mediated endocytosis in some lysosomal enzyme-deficient cells limit delivery and efficacy of enzyme replacement therapy for lysosomal disorders. We explored a novel delivery strategy utilizing nanocarriers targeted to a glycosylation- and clathrin-independent receptor, intercellular adhesion molecule (ICAM)-1, a glycoprotein expressed on diverse cell types, up-regulated and functionally involved in inflammation, a hallmark of many lysosomal disorders. We targeted recombinant human acid sphingomyelinase (ASM), deficient in types A and B Niemann-Pick disease, to ICAM-1 by loading this enzyme to nanocarriers coated with anti-ICAM. Anti-ICAM/ASM nanocarriers, but not control ASM or ASM nanocarriers, bound to ICAM-1-positive cells (activated endothelial cells and Niemann-Pick disease patient fibroblasts) via ICAM-1, in a glycosylation-independent manner. Anti-ICAM/ASM nanocarriers entered cells via CAM-mediated endocytosis, bypassing the clathrin-dependent pathway, and trafficked to lysosomes, where delivered ASM displayed stable activity and alleviated lysosomal lipid accumulation. Therefore, lysosomal enzyme targeting using nanocarriers targeted to ICAM-1 bypasses defunct pathways and may improve the efficacy of enzyme replacement therapy for lysosomal disorders, such as Niemann-Pick disease.

  8. PATIENT-REPORTED OUTCOMES IN RARE LYSOSOMAL STORAGE DISEASES: KEY INFORMANT INTERVIEWS AND A SYSTEMATIC REVIEW PROTOCOL.

    Science.gov (United States)

    Miller, Patricia A; Mulla, Sohail M; Adams-Webber, Thomasin; Sivji, Yasmin; Guyatt, Gordon H; Johnston, Bradley C

    2016-01-01

    To investigate the use, challenges and opportunities associated with using patient-reported outcomes (PROs) in studies with patients with rare lysosomal storage diseases (LSDs), we conducted interviews with researchers and health technology assessment (HTA) experts, and developed the methods for a systematic review of the literature. The purpose of the review is to identify the psychometrically sound generic and disease-specific PROs used in studies with patients with five LSDs of interest: Fabry, Gaucher (Type I), Niemann-Pick (Type B) and Pompe diseases, and mucopolysaccharidosis (Types I and II). Researchers and HTA experts who responded to an email invitation participated in a telephone interview. We used qualitative content analysis to analyze the anonymized transcripts. We conducted a comprehensive literature search for studies that used PROs to investigate burden of disease or to assess the impact of interventions across the five LSDs of interest. Interviews with seven researchers and six HTA experts representing eight countries revealed five themes. These were: (i) the importance of using psychometrically sound PROs in studies with rare diseases, (ii) the paucity of disease-specific PROs, (iii) the importance of having PRO data for economic analyses, (iv) practical and psychometric limitations of existing PROs, and (v) suggestions for new PROs. The systematic review has been completed. The interviews highlight current challenges and opportunities experienced by researchers and HTA experts involved in work with rare LSDs. The ongoing systematic review will highlight the experience, opportunities, and limitations of PROs in LSDs and provide suggestions for future research.

  9. Intracellular trafficking of the free cholesterol derived from LDL cholesteryl ester is defective in vivo in Niemann-Pick C disease: insights on normal metabolism of HDL and LDL gained from the NP-C mutation.

    Science.gov (United States)

    Shamburek, R D; Pentchev, P G; Zech, L A; Blanchette-Mackie, J; Carstea, E D; VandenBroek, J M; Cooper, P S; Neufeld, E B; Phair, R D; Brewer, H B; Brady, R O; Schwartz, C C

    1997-12-01

    Niemann-Pick C disease (NP-C) is a rare inborn error of metabolism with hepatic involvement and neurological sequelae that usually manifest in childhood. Although in vitro studies have shown that the lysosomal distribution of LDL-derived cholesterol is defective in cultured cells of NP-C subjects, no unusual characteristics mark the plasma lipoprotein profiles. We set out to determine whether anomalies exist in vivo in the cellular distribution of newly synthesized, HDL-derived or LDL-derived cholesterol under physiologic conditions in NP-C subjects. Three affected and three normal male subjects were administered [14C]mevalonate as a tracer of newly synthesized cholesterol and [3H]cholesteryl linoleate in either HDL or LDL to trace the distribution of lipoprotein-derived free cholesterol. The rate of appearance of free [14C]- and free [3H]cholesterol in the plasma membrane was detected indirectly by monitoring their appearance in plasma and bile. The plasma disappearance of [3H]cholesteryl linoleate was slightly faster in NP-C subjects regardless of its lipoprotein origin. Appearance of free [14C] cholesterol ill the plasma (and in bile) was essentially identical in normal and affected individuals as was the initial appearance of free [3H]cholesterol derived from HDL, observed before extensive exchange occurred of the [3H]cholesteryl linoleate among lipoproteins. In contrast, the rate of appearance of LDL-derived free [3H]cholesterol in the plasma membrane of NP-C subjects, as detected in plasma and bile, was retarded to a similar extent that LDL cholesterol metabolism was defective in cultured fibroblasts of these affected subjects. These findings show that intracellular distribution of both newly synthesized and HDL-derived cholesterol are essentially unperturbed by the NP-C mutation, and therefore occur by lysosomal-independent paths. In contrast, in NP-C there is defective trafficking of LDL-derived cholesterol to the plasma membrane in vivo as well as in vitro

  10. Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders

    Science.gov (United States)

    2017-11-15

    Hurler Syndrome (MPS I); Hurler-Scheie Syndrome; Hunter Syndrome (MPS II); Sanfilippo Syndrome (MPS III); Krabbe Disease (Globoid Leukodystrophy); Metachromatic Leukodystrophy (MLD); Adrenoleukodystrophy (ALD and AMN); Sandhoff Disease; Tay Sachs Disease; Pelizaeus Merzbacher (PMD); Niemann-Pick Disease; Alpha-mannosidosis

  11. Genetic Characterization of Movement Disorders and Dementias

    Science.gov (United States)

    2018-04-27

    Ataxia; Dystonia; Parkinson's Disease; Amyotrophic Lateral Sclerosis; Corticobasal Degeneration; Multiple System Atrophy; Alzheimer's Disease; Lewy Body Dementia; Parkinson Disease-Dementia; Dentatorubral-pallidoluysian Atrophy; Creutzfeldt-Jakob Disease and Fatal Familial Insomnia; Fragile X-associated Tremor/Ataxia Syndrome; Krabbe's Disease; Niemann-Pick Disease, Type C; Neuronal Ceroid Lipofuscinosis

  12. Nibbling and picking in obese patients with Binge Eating Disorder.

    Science.gov (United States)

    Masheb, Robin M; Roberto, Christina A; White, Marney A

    2013-12-01

    The goal of this study was to examine the clinical utility of nibbling behavior, defined as eating in an unplanned and repetitious manner between meals and snacks without a sense of loss of control, in obese patients with Binge Eating Disorder (BED). Two-hundred seventeen (N = 217) consecutive, treatment-seeking, obese patients with BED were assessed with the Eating Disorder Examination (EDE). Nibbling frequency was examined in relation to current weight, eating disorder psychopathology and eating patterns. Results found that nibbling/picking was not related to body mass index, objective bulimic, subjective bulimic, or overeating episodes, food avoidance, sensitivity to weight gain, or any subscales of the EDE. However, nibbling/picking was significantly related to frequency of morning and afternoon snacking (r = .21, p = .002; r = .27, p < .001). The assessment of nibbling/picking behaviors among individuals with BED might not provide clinically significant information. © 2013.

  13. A Comparative Study on the Alterations of Endocytic Pathways in Multiple Lysosomal Storage Disorders.

    Science.gov (United States)

    Rappaport, Jeff; Manthe, Rachel L; Solomon, Melani; Garnacho, Carmen; Muro, Silvia

    2016-02-01

    Many cellular activities and pharmaceutical interventions involve endocytosis and delivery to lysosomes for processing. Hence, lysosomal processing defects can cause cell and tissue damage, as in lysosomal storage diseases (LSDs) characterized by lysosomal accumulation of undegraded materials. This storage causes endocytic and trafficking alterations, which exacerbate disease and hinder treatment. However, there have been no systematic studies comparing different endocytic routes in LSDs. Here, we used genetic and pharmacological models of four LSDs (type A Niemann-Pick, type C Niemann-Pick, Fabry, and Gaucher diseases) and evaluated the pinocytic and receptor-mediated activity of the clathrin-, caveolae-, and macropinocytic routes. Bulk pinocytosis was diminished in all diseases, suggesting a generic endocytic alteration linked to lysosomal storage. Fluid-phase (dextran) and ligand (transferrin) uptake via the clathrin route were lower for all LSDs. Fluid-phase and ligand (cholera toxin B) uptake via the caveolar route were both affected but less acutely in Fabry or Gaucher diseases. Epidermal growth factor-induced macropinocytosis was altered in Niemann-Pick cells but not other LSDs. Intracellular trafficking of ligands was also distorted in LSD versus wild-type cells. The extent of these endocytic alterations paralleled the level of cholesterol storage in disease cell lines. Confirming this, pharmacological induction of cholesterol storage in wild-type cells disrupted endocytosis, and model therapeutics restored uptake in proportion to their efficacy in attenuating storage. This suggests a proportional and reversible relationship between endocytosis and lipid (cholesterol) storage. By analogy, the accumulation of biological material in other diseases, or foreign material from drugs or their carriers, may cause similar deficits, warranting further investigation.

  14. Evaluation of plasma cholestane-3β,5α,6β-triol and 7-ketocholesterol in inherited disorders related to cholesterol metabolism[S

    Science.gov (United States)

    Boenzi, Sara; Deodato, Federica; Taurisano, Roberta; Goffredo, Bianca Maria; Rizzo, Cristiano; Dionisi-Vici, Carlo

    2016-01-01

    Oxysterols are intermediates of cholesterol metabolism and are generated from cholesterol via either enzymatic or nonenzymatic pathways under oxidative stress conditions. Cholestan-3β,5α,6β-triol (C-triol) and 7-ketocholesterol (7-KC) have been proposed as new biomarkers for the diagnosis of Niemann-Pick type C (NP-C) disease, representing an alternative tool to the invasive and time-consuming method of fibroblast filipin test. To test the efficacy of plasma oxysterol determination for the diagnosis of NP-C, we systematically screened oxysterol levels in patients affected by different inherited disorders related with cholesterol metabolism, which included Niemann-Pick type B (NP-B) disease, lysosomal acid lipase (LAL) deficiency, Smith-Lemli-Opitz syndrome (SLOS), congenital familial hypercholesterolemia (FH), and sitosterolemia (SITO). As expected, NP-C patients showed significant increase of both C-triol and 7-KC. Strong increase of both oxysterols was observed in NP-B and less pronounced in LAL deficiency. In SLOS, only 7-KC was markedly increased, whereas in both FH and in SITO, oxysterol concentrations were normal. Interestingly, in NP-C alone, we observed that plasma oxysterols correlate negatively with patient’s age and positively with serum total bilirubin, suggesting the potential relationship between oxysterol levels and hepatic disease status. Our results indicate that oxysterols are reliable and sensitive biomarkers of NP-C. PMID:26733147

  15. Protein complexes and cholesterol in the control of late endosomal dynamicsCholesterol and multi-protein complexes in the control of late endosomal dynamics

    NARCIS (Netherlands)

    Kant, Rik Henricus Nicolaas van der

    2013-01-01

    Late endosomal transport is disrupted in several diseases such as Niemann-Pick type C, ARC syndrome and Alzheimer’s disease. This thesis describes the regulation of late endosomal dynamics by cholesterol and multi-protein complexes. We find that cholesterol acts as a cellular tomtom that steers the

  16. Longitudinal Study of Neurodegenerative Disorders

    Science.gov (United States)

    2018-01-31

    MLD; Krabbe Disease; ALD; MPS I; MPS II; MPS III; Vanishing White Matter Disease; GM3 Gangliosidosis; PKAN; Tay-Sachs Disease; NP Deficiency; Osteopetrosis; Alpha-Mannosidosis; Sandhoff Disease; Niemann-Pick Diseases; MPS IV; Gaucher Disease; GAN; GM1 Gangliosidoses; Morquio Disease; S-Adenosylhomocysteine Hydrolase Deficiency; Batten Disease; Pelizaeus-Merzbacher Disease; Leukodystrophy; Lysosomal Storage Diseases; Purine Nucleoside Phosphorylase Deficiency; Multiple Sulfatase Deficiency Disease

  17. Evaluation of plasma cholestane-3β,5α,6β-triol and 7-ketocholesterol in inherited disorders related to cholesterol metabolism.

    Science.gov (United States)

    Boenzi, Sara; Deodato, Federica; Taurisano, Roberta; Goffredo, Bianca Maria; Rizzo, Cristiano; Dionisi-Vici, Carlo

    2016-03-01

    Oxysterols are intermediates of cholesterol metabolism and are generated from cholesterol via either enzymatic or nonenzymatic pathways under oxidative stress conditions. Cholestan-3β,5α,6β-triol (C-triol) and 7-ketocholesterol (7-KC) have been proposed as new biomarkers for the diagnosis of Niemann-Pick type C (NP-C) disease, representing an alternative tool to the invasive and time-consuming method of fibroblast filipin test. To test the efficacy of plasma oxysterol determination for the diagnosis of NP-C, we systematically screened oxysterol levels in patients affected by different inherited disorders related with cholesterol metabolism, which included Niemann-Pick type B (NP-B) disease, lysosomal acid lipase (LAL) deficiency, Smith-Lemli-Opitz syndrome (SLOS), congenital familial hypercholesterolemia (FH), and sitosterolemia (SITO). As expected, NP-C patients showed significant increase of both C-triol and 7-KC. Strong increase of both oxysterols was observed in NP-B and less pronounced in LAL deficiency. In SLOS, only 7-KC was markedly increased, whereas in both FH and in SITO, oxysterol concentrations were normal. Interestingly, in NP-C alone, we observed that plasma oxysterols correlate negatively with patient's age and positively with serum total bilirubin, suggesting the potential relationship between oxysterol levels and hepatic disease status. Our results indicate that oxysterols are reliable and sensitive biomarkers of NP-C. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

  18. Lysosomal lipid storage diseases.

    Science.gov (United States)

    Schulze, Heike; Sandhoff, Konrad

    2011-06-01

    Lysosomal lipid storage diseases, or lipidoses, are inherited metabolic disorders in which typically lipids accumulate in cells and tissues. Complex lipids, such as glycosphingolipids, are constitutively degraded within the endolysosomal system by soluble hydrolytic enzymes with the help of lipid binding proteins in a sequential manner. Because of a functionally impaired hydrolase or auxiliary protein, their lipid substrates cannot be degraded, accumulate in the lysosome, and slowly spread to other intracellular membranes. In Niemann-Pick type C disease, cholesterol transport is impaired and unesterified cholesterol accumulates in the late endosome. In most lysosomal lipid storage diseases, the accumulation of one or few lipids leads to the coprecipitation of other hydrophobic substances in the endolysosomal system, such as lipids and proteins, causing a "traffic jam." This can impair lysosomal function, such as delivery of nutrients through the endolysosomal system, leading to a state of cellular starvation. Therapeutic approaches are currently restricted to mild forms of diseases with significant residual catabolic activities and without brain involvement.

  19. Modulation of the maladaptive stress response to manage diseases of protein folding.

    Directory of Open Access Journals (Sweden)

    Daniela Martino Roth

    2014-11-01

    Full Text Available Diseases of protein folding arise because of the inability of an altered peptide sequence to properly engage protein homeostasis components that direct protein folding and function. To identify global principles of misfolding disease pathology we examined the impact of the local folding environment in alpha-1-antitrypsin deficiency (AATD, Niemann-Pick type C1 disease (NPC1, Alzheimer's disease (AD, and cystic fibrosis (CF. Using distinct models, including patient-derived cell lines and primary epithelium, mouse brain tissue, and Caenorhabditis elegans, we found that chronic expression of misfolded proteins not only triggers the sustained activation of the heat shock response (HSR pathway, but that this sustained activation is maladaptive. In diseased cells, maladaptation alters protein structure-function relationships, impacts protein folding in the cytosol, and further exacerbates the disease state. We show that down-regulation of this maladaptive stress response (MSR, through silencing of HSF1, the master regulator of the HSR, restores cellular protein folding and improves the disease phenotype. We propose that restoration of a more physiological proteostatic environment will strongly impact the management and progression of loss-of-function and gain-of-toxic-function phenotypes common in human disease.

  20. Skin Picking Disorder

    Directory of Open Access Journals (Sweden)

    Pinar Cetinay Aydin

    2014-08-01

    Full Text Available Skin picking disorder is not a dermatological disorder and it is a table characterized with picking skin excessively and repetitively, leading to damage in skin tissue. Unlike normal picking behaviour, psychogenic skin picking is repetitive and it can lead to severe damage in the skin and even complications which constitute vital danger. While some patients define frequent but short lasting picking attacks, others define rarer attacks which last a few hours. Skin picking disorder, which is not included in the classification systems up to DSM-5 as a separate diagnosis category, is included as an independent diagnosis in Obsessive Compulsive Disorder and Associated Disorders category in DSM-5. In case reports, open label studies and double blind studies selective serotonin reuptake inhibitors are shown to be effective in the treatment of skin picking disorder. Mostly, cognitive-behaviourial techniques are used and have been proven to be useful in psychotherapy. Habit reversal is one of the behaviourial techniques which are frequently applied, give positive results in which well-being state can be maintained. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2014; 6(4.000: 401-428

  1. Dataset and standard operating procedure for newborn screening of six lysosomal storage diseases: By tandem mass spectrometry

    Directory of Open Access Journals (Sweden)

    Susan Elliott

    2016-09-01

    Full Text Available In this data article we provide a detailed standard operating procedure for performing a tandem mass spectrometry, multiplex assay of 6 lysosomal enzymes for newborn screening of the lysosomal storage diseases Mucopolysaccharidosis-I, Pompe, Fabry, Niemann-Pick-A/B, Gaucher, and Krabbe, (Elliott, et al., 2016 [1]. We also provide the mass spectrometry peak areas for the product and internal standard ions typically observed with a dried blood spot punch from a random newborn, and we provide the daily variation of the daily mean activities for all 6 enzymes.

  2. Exploring the role of picker personality in predicting picking performance with pick by voice, pick to light and RF-terminal picking

    NARCIS (Netherlands)

    de Vries, J.; de Koster, R.; Stam, D.

    2016-01-01

    Order pickers and individual differences between them could have a substantial impact on picking performance, but are largely ignored in studies on order picking. This paper explores the role of individual differences in picking performance with various picking tools (pick by voice, RF-terminal

  3. Evaluation by statistical brain perfusion SPECT analysis on MRI findings, kana pick-out test and Mini-Mental State Examination results in patients with forgetfulness

    International Nuclear Information System (INIS)

    Nakatsuka, Hiroki; Matsubara, Ichirou; Ohtani, Haruhiko

    2003-01-01

    The aim of this single photon emission computed tomography (SPECT) study was to determine the abnormality of the regional cerebral blood flow (rCBF) using a three-dimensional stereotactic surface projection (3D-SSP) in 18 patients who were referred to the hospital because of forgetfulness. Two intergroup comparison by 3D-SSP analysis was conducted based on MRI, kana pick-out test and Mini-Mental State Examination (MMSE) results. Of the MRI findings, in the brain atrophy group, rCBF was decreased in the posterior cingulate gyrus, medial temporal structure and parieto-temporal association cortex; these rCBF-decreased areas are similar to the Alzheimer disease pattern. In the group where the MMSE was normal but the kana pick-out test was abnormal, rCBF was decreased in the posterior cingulate gyrus and cinguloparietal transitional area. In the group where both the MMSE and kana pick-out test were abnormal, rCBF was decreased in the parieto-temporal association cortex, temporal cortex and medial temporal structure. These results suggest that 3D-SSP analysis of the SPECT with MMSE and the kana pick-out test provides the possibility of early diagnosis of initial stage of Alzheimer's disease. (author)

  4. 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.

  5. Making the Right Pick: Aligning Order Picking Methods, Incentive Systems and Regulatory Focus to Increase Picking Performance

    NARCIS (Netherlands)

    J. de Vries (Jelle); M.B.M. de Koster (René); D.A. Stam (Daan)

    2015-01-01

    textabstractA unique controlled field experiment investigates order picking performance (in terms of productivity, quality, and job satisfaction). We examined three manual picker-to-parts order picking methods (parallel, zone, and dynamic zone picking) under two different incentive systems

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

    Science.gov (United States)

    Özten, Eylem; Sayar, Gökben Hızlı; Eryılmaz, Gül; Kağan, Gaye; Işık, Sibel; Karamustafalıoğlu, Oğuz

    2015-01-01

    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. 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. 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. 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 developing trichotillomania or skin picking symptoms helps the patient to cope with intrusive thoughts related to trauma. Future longitudinal research must focus on whether trauma and post-traumatic stress or trichotillomania and skin picking precede the development of mental disorder.

  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. Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly

    Science.gov (United States)

    Niemann-Pick C1-like 1 protein (NPC1L1) plays a critical role in intestinal cholesterol absorption. Our objective was to examine whether five variants (-133A>G, -18A>C, L272L, V1296V, and U3_28650A>G) at the NPC1L1 gene have effects on lipid levels, prevalence, and incidence of coronary heart diseas...

  9. Lysosomal storage diseases

    Science.gov (United States)

    Ferreira, Carlos R.; Gahl, William A.

    2016-01-01

    Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage can be caused not by the enzymatic deficiency of one of the hydrolases, but by the deficiency of an activator protein, as occurs in the AB variant of GM2 gangliosidosis. Still other times, the accumulated lysosomal material results from failed egress of a small molecule as a consequence of a deficient transporter, as in cystinosis or Salla disease. In the last couple of decades, enzyme replacement therapy has become available for a number of lysosomal storage diseases. Examples include imiglucerase, taliglucerase and velaglucerase for Gaucher disease, laronidase for Hurler disease, idursulfase for Hunter disease, elosulfase for Morquio disease, galsulfase for Maroteaux-Lamy disease, alglucosidase alfa for Pompe disease, and agalsidase alfa and beta for Fabry disease. In addition, substrate reduction therapy has been approved for certain disorders, such as eliglustat for Gaucher disease. The advent of treatment options for some of these disorders has led to newborn screening pilot studies, and ultimately to the addition of Pompe disease and Hurler disease to the Recommended Uniform Screening Panel (RUSP) in 2015 and 2016, respectively. PMID:29152458

  10. Autophagic dysfunction in a lysosomal storage disorder due to impaired proteolysis

    OpenAIRE

    Elrick, Matthew J.; Lieberman, Andrew P.

    2013-01-01

    Alterations in macroautophagy (hereafter referred to as “autophagy”) are a common feature of lysosomal storage disorders, and have been hypothesized to play a major role in the pathogenesis of these diseases. We have recently reported multiple defects in autophagy contributing to the lysosomal storage disorder Niemann-Pick type C (NPC). These include increased formation of autophagosomes, slowed turnover of autophagosomes secondary to impaired lysosomal proteolysis, and delivery of stored lip...

  11. 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

  12. 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.

  13. Gaucher disease and other storage disorders.

    Science.gov (United States)

    Grabowski, Gregory A

    2012-01-01

    In 1882, Philippe Gaucher described a 32-year-old woman with massive splenomegaly and unusually large cells in the spleen, which he called a "primary epithelioma of the spleen." The systemic nature and inheritance of the disease and its variants involving the viscera and CNS were described over the next century. The delineation of the causal enzymatic defects, genetics, molecular pathology, and genomics have provided pathogenic insights into the phenotypic spectrum and the bases for development of specific therapies for what is now known as Gaucher disease. As a prototype, the clinically and economically successful intracellular enzyme therapy provided the impetus for the expansion of similar research and therapeutic developments for other lysosomal storage diseases (LSDs) and orphan diseases, including Fabry, Pompe, and Niemann-Pick diseases, as well as several mucopolysaccharidoses. Continuing studies of such LSDs, which occur as a group in more than 7000 live births, have revealed the complex molecular interdigitation with the autophagy and apoptotic pathways and proteostasis and the impact of disruptions of the lysosomal/autophagy and proteostasis systems on more common diseases has been recognized. Examples include age-related neurodegenerative diseases (eg, Parkinson disease and Gaucher disease), idiopathic hypertrophic myocardiopathies, stroke and renal failure (eg, Fabry disease), and Nonalcoholic Fatty Liver Disease/Nonalcoholic SteatoHepatitis (NAFLD/NASH) and atherosclerosis (eg, lysosomal acid lipase deficiencies). Although perceived as rare, the availability of treatment and the impact of the LSDs on more common diseases require their integration into routine clinical practice.

  14. 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.

  15. 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.

  16. Application of closed queueing network in the performance of a pick-and-pass order picking system

    NARCIS (Netherlands)

    Gaast, van der J.P.; Koster, de M.B.M.; Adan, I.J.B.F.; Resing, J.A.C.

    2011-01-01

    This paper presents a method for obtaining approximate solutions for pick-and-pass order picking systems with multiple classes of orders. The pick-and-pass system is decomposed into an entrance station, conveyor nodes and pick stations. A customer order needs to visit multiple pick stations, but the

  17. 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

    Heat shock protein 70 (Hsp70) is an evolutionarily highly conserved molecular chaperone that promotes the survival of stressed cells by inhibiting lysosomal membrane permeabilization, a hallmark of stress-induced cell death. Clues to its molecular mechanism of action may lay in the recently...... reported stress- and cancer-associated translocation of a small portion of Hsp70 to the lysosomal compartment. Here we show that Hsp70 stabilizes lysosomes by binding to an endolysosomal anionic phospholipid bis(monoacylglycero)phosphate (BMP), an essential co-factor for lysosomal sphingomyelin metabolism......-is also associated with a marked decrease in lysosomal stability, and this phenotype can be effectively corrected by treatment with recombinant Hsp70. Taken together, these data open exciting possibilities for the development of new treatments for lysosomal storage disorders and cancer with compounds...

  18. Feather-picking psittacines: histopathology and species trends.

    Science.gov (United States)

    Garner, M M; Clubb, S L; Mitchell, M A; Brown, L

    2008-05-01

    Histologic findings are described for 408 feather-picking or self-mutilating psittacines with the use of biopsies from clinically affected and unaffected skin. Inflammatory skin disease was diagnosed in 210 birds, and traumatic skin disease was diagnosed in 198 birds. Criteria used for the diagnosis of inflammatory skin disease included the presence of perivascular inflammation in the superficial or deep dermis of clinically affected and unaffected sites. The primary histologic criteria for the diagnosis of traumatic skin disease were superficial dermal scarring with or without inflammation in the affected sites and an absence of inflammation in the unaffected sites. The inflammatory cells associated with the lesions were typically lymphocytes and occasionally plasma cells, histiocytes, and granulocytes. A preponderance of inflammatory skin disease was seen in macaws (Ara spp.) and Amazon parrots (Amazona spp.). A preponderance of traumatic skin disease was seen in cockatoos (Cacatua spp.) and African grey parrots (Psittacus erithacus). The prevalence of each was approximately equal in several other species, including conures (Aratinga and Pyrrhura spp.), eclectus parrots (Eclectus roratus), quaker parrots (Myiopsitta monachus), cockatiels (Nymphicus hollandicus), parakeets (Cyanorhamphus and Psittacula spp.), and caiques (Pionites spp.). No geographic or gender-based trends were identified. These findings could be helpful for identifying and treating birds with feather-picking disorders.

  19. Alterations in membrane trafficking and pathophysiological implications in lysosomal storage disorders.

    Science.gov (United States)

    Kuech, Eva-Maria; Brogden, Graham; Naim, Hassan Y

    2016-11-01

    Lysosomal storage disorders are a heterogeneous group of more than 50 distinct inborn metabolic diseases affecting about 1 in 5000 to 7000 live births. The diseases often result from mutations followed by functional deficiencies of enzymes or transporters within the acidic environment of the lysosome, which mediate the degradation of a wide subset of substrates, including glycosphingolipids, glycosaminoglycans, cholesterol, glycogen, oligosaccharides, peptides and glycoproteins, or the export of the respective degradation products from the lysosomes. The progressive accumulation of uncleaved substrates occurs in multiple organs and finally causes a broad spectrum of different pathologies including visceral, neurological, skeletal and hematologic manifestations. Besides deficient lysosomal enzymes and transporters other defects may lead to lysosomal storage disorders, including activator defects, membrane defects or defects in modifier proteins. In this review we concentrate on four different lysosomal storage disorders: Niemann-Pick type C, Fabry disease, Gaucher disease and Pompe disease. While the last three are caused by defective lysosomal hydrolases, Niemann-Pick type C is caused by the inability to export LDL-derived cholesterol out of the lysosome. We want to emphasise potential implications of membrane trafficking defects on the pathology of these diseases, as many mutations interfere with correct lysosomal protein trafficking and alter cellular lipid homeostasis. Current therapeutic strategies are summarised, including substrate reduction therapy as well as pharmacological chaperone therapy which directly aim to improve folding and lysosomal transport of misfolded mutant proteins. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  20. Picking Robot Arm Trajectory Planning Method

    Directory of Open Access Journals (Sweden)

    Zhang Zhiyong

    2014-01-01

    Full Text Available The picking robot arm is scheduled to complete picking tasks in the working space, to overcome the shaking vibration to improve the picking stability, its movement should follow specific consistence trajectory points. Usually we should give definite multiple feature picking points, map their inverse kinematics to the joint space, establish motion equation for the corresponding point in the joint space, then follow these equations motion for the interpolation on the joint so that we can meet the movement requirements. Trajectory planning is decisive significance for accuracy and stability of controlling robot arm. The key issue that picking arm complete picking task will be come true by trajectory planning, namely, robot arm track the desired trajectory. which based on kinematics and statics picking analysis in a joint space according to the requirements of picking tasks, and obtain the position and orientation for picking robot arm, study and calculate the theory of trajectory parameters timely.

  1. Put order picking system

    Directory of Open Access Journals (Sweden)

    Đurđević Dragan D.

    2014-01-01

    Full Text Available Nowadays the warehouse is very important logistic component of the supply chain, where order-picking systems have important role. Due to the significant impact on logistics performance permanent goals are to increase efficiency and reduce the cost of these systems. To achieve these goals, there are different researches, and their success is determined by the achieved performances. Performances order picking process are dependent on the applied technology concepts of order-picking system, as well as the ways in which it is organized and managed. In addition to the standard conceptions (the man to good and good to the man is one of the newer, so-called. 'put' system - the inverse order-picking. The aim of this paper is to describe this concept, point out its core strengths and weaknesses and provide a basis that may be of importance in the development of warehouse technological solutions and application of this order-picking systems concept.

  2. Investor Outlook: Gene Therapy Picking up Steam; At a Crossroads.

    Science.gov (United States)

    Schimmer, Joshua; Breazzano, Steven

    2016-09-01

    The gene therapy field continues to pick up steam with recent successes in a number of different therapeutic indications that highlight the potential for the platform. As the field continues to make progress, a growing data set of long-term safety and efficacy data will continue to define gene therapy's role, determining ultimately how widely it may be used beyond rare, serious diseases with high unmet needs. New technologies often take unanticipated twists and turns as patient exposure accumulates, and gene therapy may be no exception. That said, with many diseases that have no other treatment options beyond gene therapy and that present considerable morbidity and mortality, the field appears poised to withstand some minor and even major bumps in the road should they emerge.

  3. A REVIEW OF ORDER PICKING IMPROVEMENT METHODS

    Directory of Open Access Journals (Sweden)

    Johan Oscar Ong

    2014-09-01

    Full Text Available As a crucial and one of the most important parts of warehousing, order picking often raises discussion between warehousing professionals, resulting in various studies aiming to analyze how order picking activity can be improved from various perspective. This paper reviews various past researches on order picking improvement, and the various methods those studies analyzed or developed. This literature review is based on twenty research articles on order picking improvement viewed from four different perspectives: Automation (specifically, stock-to-picker system, storage assignment policy, order batching, and order picking sequencing. By reviewing these studies, we try to identify the most prevalent order picking improvement approach to order picking improvement. Keywords: warehousing; stock-to-picker; storage assignment; order batching; order picking sequencing; improvement

  4. Prenatal-Onset Niemann–Pick Type C Disease with Nonimmune Hydrops Fetalis

    Directory of Open Access Journals (Sweden)

    Ozge Surmeli-Onay

    2013-10-01

    Full Text Available Niemann–Pick type C (NPC; OMIM 257219 disease is a neurodegenerative lysosomal storage disorder characterized by accumulation of unesterified cholesterol in the lysosomal/late endosomal system. This autosomal recessive disorder occurs in approximately 1/150,000 births. The broad clinical spectrum ranges from a prenatal severe presentation to an adult-onset chronic neurodegenerative disease. Data about prenatal presentation of NPC are limited. A female newborn was born at 342 weeks' gestation with a birth weight of 3070 g, and transferred to the Neonatal Intensive Care Unit because of nonimmune hydrops fetalis (NIHF and respiratory distress. On admission, a physical examination revealed skin edema, mild respiratory distress, and abdominal distention due to massive ascites. Hepatosplenomegaly and cholestasis increased progressively and bleeding diathesis occurred. Results of an abdominal ultrasonography showed hepatosplenomegaly and segmental multicystic dysplastic left kidney. Foamy cells with a lysosomal phospholipid storage pattern compatible with NPC were found in the bone marrow smear. Cultured fibroblasts showed a strongly elevated filipin staining (classical NPC cellular phenotype, establishing the diagnosis of NPC. The infant died on the 52nd day of life because of respiratory distress due to lung involvement of NPC, massive ascites, and progressive liver failure. Results of an autopsy showed multiorgan storage disease involving the liver, spleen, lymph nodes, thymus, lungs, and brain. Here, we present a preterm infant with NIHF as a sign of severe prenatal-onset NPC and review the literature.

  5. Outline of metabolic diseases in adult neurology.

    Science.gov (United States)

    Mochel, F

    2015-01-01

    Inborn errors of metabolism (IEM) are traditionally defined by enzymatic deficiencies or defects in proteins involved in cellular metabolism. Historically discovered and characterized in children, a growing number of IEM are described in adults, and especially in the field of neurology. In daily practice, it is important to recognize emergency situations as well as neurodegenerative diseases for which a metabolic disease is likely, especially when therapeutic interventions are available. Here, the goal is to provide simple clinical, imaging and biochemical tools that can first orientate towards and then confirm the diagnosis of IEM. General guidelines are presented to treat the most common IEM during metabolic crises - acute encephalopathies with increased plasma ammonia, lactate or homocystein, as well as rhabdomyolysis. Examples of therapeutic strategies currently applied to chronic neurometabolic diseases are also provided - GLUT1 deficiency, adrenoleukodystrophy, cerebrotendinous xanthomatosis, Niemann-Pick type C and Wilson disease. Genetic counseling is mandatory in some X-linked diseases - ornithine transcarbamylase deficiency and adrenoleukodystrophy - and recommended in maternally inherited mitochondrial diseases - mutations of mitochondrial DNA. Besides these practical considerations, the contribution of metabolism to the field of adult neurology and neurosciences is much greater: first, with the identification of blood biomarkers that are progressively changing our diagnostic strategies thanks to lipidomic approaches, as illustrated in the field of spastic paraplegia and atypical psychiatric presentations; and second, through the understanding of pathophysiological mechanisms involved in common neurological diseases thanks to the study of these rare diseases. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  6. Steryl ester synthesis, storage and hydrolysis: A contribution to sterol homeostasis.

    Science.gov (United States)

    Korber, Martina; Klein, Isabella; Daum, Günther

    2017-12-01

    Sterols are essential lipids of all eukaryotic cells, appearing either as free sterols or steryl esters. Besides other regulatory mechanisms, esterification of sterols and hydrolysis of steryl esters serve to buffer both an excess and a lack of free sterols. In this review, the esterification process, the storage of steryl esters and their mobilization will be described. Several model organisms are discussed but the focus was set on mammals and the yeast Saccharomyces cerevisiae. The contribution of imbalanced cholesterol homeostasis to several human diseases, namely Wolman disease, cholesteryl ester storage disease, atherosclerosis and Alzheimer's disease, Niemann-Pick type C and Tangier disease is described. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV.

    Science.gov (United States)

    Park, Soonhong; Ahuja, Malini; Kim, Min Seuk; Brailoiu, G Cristina; Jha, Archana; Zeng, Mei; Baydyuk, Maryna; Wu, Ling-Gang; Wassif, Christopher A; Porter, Forbes D; Zerfas, Patricia M; Eckhaus, Michael A; Brailoiu, Eugen; Shin, Dong Min; Muallem, Shmuel

    2016-02-01

    Mutations in TRPML1 cause the lysosomal storage disease mucolipidosis type IV (MLIV). The role of TRPML1 in cell function and how the mutations cause the disease are not well understood. Most studies focus on the role of TRPML1 in constitutive membrane trafficking to and from the lysosomes. However, this cannot explain impaired neuromuscular and secretory cells' functions that mediate regulated exocytosis. Here, we analyzed several forms of regulated exocytosis in a mouse model of MLIV and, opposite to expectations, we found enhanced exocytosis in secretory glands due to enlargement of secretory granules in part due to fusion with lysosomes. Preliminary exploration of synaptic vesicle size, spontaneous mEPSCs, and glutamate secretion in neurons provided further evidence for enhanced exocytosis that was rescued by re-expression of TRPML1 in neurons. These features were not observed in Niemann-Pick type C1. These findings suggest that TRPML1 may guard against pathological fusion of lysosomes with secretory organelles and suggest a new approach toward developing treatment for MLIV. © 2015 The Authors.

  8. Phytosterol and cholesterol precursor levels indicate increased cholesterol excretion and biosynthesis in gallstone disease.

    Science.gov (United States)

    Krawczyk, Marcin; Lütjohann, Dieter; Schirin-Sokhan, Ramin; Villarroel, Luis; Nervi, Flavio; Pimentel, Fernando; Lammert, Frank; Miquel, Juan Francisco

    2012-05-01

    In hepatocytes and enterocytes sterol uptake and secretion is mediated by Niemann-Pick C1-like 1 (NPC1L1) and ATP-binding cassette (ABC)G5/8 proteins, respectively. Whereas serum levels of phytosterols represent surrogate markers for intestinal cholesterol absorption, cholesterol precursors reflect cholesterol biosynthesis. Here we compare serum and biliary sterol levels in ethnically different populations of patients with gallstone disease (GSD) and stone-free controls to identify differences in cholesterol transport and synthesis between these groups. In this case-control study four cohorts were analyzed: 112 German patients with GSD and 152 controls; two distinct Chilean ethnic groups: Hispanics (100 GSD, 100 controls), and Amerindians (20 GSD, 20 controls); additionally an 8-year follow-up of 70 Hispanics was performed. Serum sterols were measured by gas chromatography / mass spectrometry. Gallbladder bile sterol levels were analyzed in cholesterol GSD and controls. Common ABCG5/8 variants were genotyped. Comparison of serum sterols showed lower levels of phytosterols and higher levels of cholesterol precursors in GSD patients than in controls. The ratios of phytosterols to cholesterol precursors were lower in GSD patients, whereas biliary phytosterol and cholesterol concentrations were elevated as compared with controls. In the follow-up study, serum phytosterol levels were significantly lower even before GSD was detectable by ultrasound. An ethnic gradient in the ratios of phytosterols to cholesterol precursors was apparent (Germans > Hispanics > Amerindians). ABCG5/8 variants did not fully explain the sterol metabolic trait of GSD in any of the cohorts. Individuals predisposed to GSD display increased biliary output of cholesterol in the setting of relatively low intestinal cholesterol absorption, indicating enhanced whole-body sterol clearance. This metabolic trait precedes gallstone formation and is a feature of ethnic groups at higher risk of cholesterol

  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. '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.

  11. Successful pregnancy and delivery in a patient with Niemaoh-Pick disease after liver transplantation: report of one case and literature review%尼曼匹克病肝移植术后成功妊娠分娩1例并文献复习

    Institute of Scientific and Technical Information of China (English)

    郝庆春; 曾强; 刘保旺; 滕亮; 窦剑

    2017-01-01

    Objective To summarize the clinical experience of patient diagnosed with Niemaoh-Pick disease being pregnant after liver transplantation. Methods Clinical data of one case of type B Niemaoh-Pick disease being pregnant after liver transplantation were retrospectively analyzed. Results The patient successfully underwent liver transplantation combined with splenic artery ligation on July 8, 2011. She was well recovered postoperatively. After surgery, she received conventional anti-rejection treatment, and gradually switched to use of tacrolimus at a dosage of 2.5 mg/d. The serum drug concentration was maintained at 2 ng/mL. In September 2015, she was successfully pregnant. On June 2, 2016, she delivered a male infant through cesarean section. She could breastfeed the infant in a low quantity early after delivery. Both the mother and infant were followed up until submission date. The mother was physically stable and the infant grew normally. Conclusions Patients diagnosed with Niemaoh-Pick disease can obtain favorable clinical outcomes of pregnancy and delivery after liver transplantation.%目的 总结尼曼匹克病肝移植患者术后妊娠的临床经验.方法 回顾性分析1例尼曼匹克病B型患者接受肝移植后成功妊娠分娩的临床资料.结果 该例患者于2011年7月8日行肝移植术,同时行脾动脉结扎,手术及术后恢复顺利,术后常规抗排斥治疗,后逐渐改为单用他克莫司,剂量2.5 mg/d,血药浓度维持在2 ng/mL.2015年9月该患者成功妊娠,于2016年6月2日行剖宫产分娩一男婴.分娩后短期内少量母乳喂养,产妇及新生儿随访至投稿日,母亲正常,婴儿生长发育正常.结论 尼曼匹克病患者肝移植术后妊娠分娩可取得良好结局.

  12. Determining stress fields of shearer-loader picks

    Energy Technology Data Exchange (ETDEWEB)

    Luszczkiewicz, J; Sikora, W

    1987-06-01

    Analyzes factors which influence stress distribution in the NK-4 shearer-loader picks during coal cutting. The AFT optically active cover, 0.0015 mm thick, was used. The pick with the AFT cover was loaded using a force of 33 kN. Isoclinic lines showing stress distribution were photographed. Effects of pick design and its holder type on stress distribution were investigated. Investigations showed that distribution of normal stresses in a pick shaft has a non-linear character. The hole in a pick shaft increased stress concentration in that shaft section. Eliminating the hole reduced stress concentration. Reducing shaft length by about 20 mm did not increase stresses in that shaft zone. 15 refs.

  13. Automatic traveltime picking using instantaneous traveltime

    KAUST Repository

    Saragiotis, Christos; Alkhalifah, Tariq Ali; Fomel, Sergey

    2013-01-01

    Event picking is used in many steps of seismic processing. We present an automatic event picking method that is based on a new attribute of seismic signals, instantaneous traveltime. The calculation of the instantaneous traveltime consists of two separate but interrelated stages. First, a trace is mapped onto the time-frequency domain. Then the time-frequency representation is mapped back onto the time domain by an appropriate operation. The computed instantaneous traveltime equals the recording time at those instances at which there is a seismic event, a feature that is used to pick the events. We analyzed the concept of the instantaneous traveltime and demonstrated the application of our automatic picking method on dynamite and Vibroseis field data.

  14. Automatic traveltime picking using instantaneous traveltime

    KAUST Repository

    Saragiotis, Christos

    2013-02-08

    Event picking is used in many steps of seismic processing. We present an automatic event picking method that is based on a new attribute of seismic signals, instantaneous traveltime. The calculation of the instantaneous traveltime consists of two separate but interrelated stages. First, a trace is mapped onto the time-frequency domain. Then the time-frequency representation is mapped back onto the time domain by an appropriate operation. The computed instantaneous traveltime equals the recording time at those instances at which there is a seismic event, a feature that is used to pick the events. We analyzed the concept of the instantaneous traveltime and demonstrated the application of our automatic picking method on dynamite and Vibroseis field data.

  15. Niemann-Pick type C2 protein supplementation in experimental non-alcoholic fatty liver disease

    DEFF Research Database (Denmark)

    Christensen, Claus Uhrenholt; Glavind, Emilie; Thomsen, Karen Louise

    2018-01-01

    the last two weeks or the entire four weeks. End-points were liver/body- and spleen/body weight ratios, histopathological NASH scores, fibrosis, serum liver enzymes, cholesterol, lipoproteins, cytokines, and quantitative polymerase chain reaction derived hepatic gene expression related to cholesterol...... metabolism, inflammation, and fibrosis. RESULTS: HFHC rats developed hepatomegaly, non-fibrotic NASH histopathology, elevated liver enzymes, serum cholesterol, and pro-inflammatory cytokines. Their sterol regulatory element binding factor 2 (SREBF2) and low-density lipoprotein receptor (LDL-R) mRNAs were...... down-regulated compared with rats on standard chow. NPC2 did not improve liver weight, histopathology, levels of serum liver enzymes or pro-inflammatory tumor necrosis factor-α (TNFα), Interleukin (IL)-6, or IL-1β in HFHC rats. Two weeks of NPC2 treatment lowered hepatic TNFα and COL1A1 mRNA expression...

  16. Semi-Automated Digital Image Analysis of Pick's Disease and TDP-43 Proteinopathy.

    Science.gov (United States)

    Irwin, David J; Byrne, Matthew D; McMillan, Corey T; Cooper, Felicia; Arnold, Steven E; Lee, Edward B; Van Deerlin, Vivianna M; Xie, Sharon X; Lee, Virginia M-Y; Grossman, Murray; Trojanowski, John Q

    2016-01-01

    Digital image analysis of histology sections provides reliable, high-throughput methods for neuropathological studies but data is scant in frontotemporal lobar degeneration (FTLD), which has an added challenge of study due to morphologically diverse pathologies. Here, we describe a novel method of semi-automated digital image analysis in FTLD subtypes including: Pick's disease (PiD, n=11) with tau-positive intracellular inclusions and neuropil threads, and TDP-43 pathology type C (FTLD-TDPC, n=10), defined by TDP-43-positive aggregates predominantly in large dystrophic neurites. To do this, we examined three FTLD-associated cortical regions: mid-frontal gyrus (MFG), superior temporal gyrus (STG) and anterior cingulate gyrus (ACG) by immunohistochemistry. We used a color deconvolution process to isolate signal from the chromogen and applied both object detection and intensity thresholding algorithms to quantify pathological burden. We found object-detection algorithms had good agreement with gold-standard manual quantification of tau- and TDP-43-positive inclusions. Our sampling method was reliable across three separate investigators and we obtained similar results in a pilot analysis using open-source software. Regional comparisons using these algorithms finds differences in regional anatomic disease burden between PiD and FTLD-TDP not detected using traditional ordinal scale data, suggesting digital image analysis is a powerful tool for clinicopathological studies in morphologically diverse FTLD syndromes. © The Author(s) 2015.

  17. Multidisciplinary Pharmacotherapeutic Options for Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Kei Nakajima

    2012-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD and non-alcoholic steatohepatitis (NASH are multidisciplinary liver diseases that often accompany type 2 diabetes or metabolic syndrome, which are characterized by insulin resistance. Therefore, effective treatment of type 2 diabetes and metabolic syndrome should target not only the cardiometabolic abnormalities, but also the associated liver disorders. In the last decade, it has been shown that metformin, thiazolidinediones, vitamin E, ezetimibe, n-3 polyunsaturated fatty acids, renin-angiotensin system (RAS blockers, and antiobesity drugs may improve hepatic pathophysiological disorders as well as clinical parameters. Accordingly, insulin sensitizers, antioxidative agents, Niemann-Pick C1-like 1 (NPC1L1 inhibitors, RAS blockers, and drugs that target the central nervous system may represent candidate pharmacotherapies for NAFLD and possibly NASH. However, the efficacy, safety, and tolerability of long-term treatment (potentially for many years with these drugs have not been fully established. Furthermore, clinical trials have not comprehensively examined the efficacy of lipid-lowering drugs (i.e., statins, fibrates, and NPC1L1 inhibitors for the treatment of NAFLD. Although clinical evidence for RAS blockers and incretin-based agents (GLP-1 analogs and dipeptidyl peptidase-4 inhibitors is also lacking, these agents are promising in terms of their insulin-sensitizing and anti-inflammatory effects without causing weight gain.

  18. Large-scale computational drug repositioning to find treatments for rare diseases.

    Science.gov (United States)

    Govindaraj, Rajiv Gandhi; Naderi, Misagh; Singha, Manali; Lemoine, Jeffrey; Brylinski, Michal

    2018-01-01

    Rare, or orphan, diseases are conditions afflicting a small subset of people in a population. Although these disorders collectively pose significant health care problems, drug companies require government incentives to develop drugs for rare diseases due to extremely limited individual markets. Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning. In order to find new targets for known drugs ultimately leading to drug repositioning, we recently developed e MatchSite, a new computer program to compare drug-binding sites. In this study, e MatchSite is combined with virtual screening to systematically explore opportunities to reposition known drugs to proteins associated with rare diseases. The effectiveness of this integrated approach is demonstrated for a kinase inhibitor, which is a confirmed candidate for repositioning to synapsin Ia. The resulting dataset comprises 31,142 putative drug-target complexes linked to 980 orphan diseases. The modeling accuracy is evaluated against the structural data recently released for tyrosine-protein kinase HCK. To illustrate how potential therapeutics for rare diseases can be identified, we discuss a possibility to repurpose a steroidal aromatase inhibitor to treat Niemann-Pick disease type C. Overall, the exhaustive exploration of the drug repositioning space exposes new opportunities to combat orphan diseases with existing drugs. DrugBank/Orphanet repositioning data are freely available to research community at https://osf.io/qdjup/.

  19. Picking at waste facilities – scavenging or entrepreneurshipPicking at waste facilities – scavenging or entrepreneurship

    CSIR Research Space (South Africa)

    Oelofse, Suzanna HH

    2010-10-01

    Full Text Available Picking at landfills is a reality at most landfills in South Africa. It is often the poorest community members that resolve to picking as a way of making a living, typically under conditions that are not conducive to their health or safety. However...

  20. White matter abnormalities in skin picking disorder

    DEFF Research Database (Denmark)

    Grant, Jon E; Odlaug, Brian Lawrence; Hampshire, Adam

    2013-01-01

    Skin picking disorder (SPD) is characterized by the repetitive and compulsive picking of skin, resulting in tissue damage. Neurocognitive findings in SPD implicate difficulty with response inhibition (suppression of pre-potent motor responses). This function is dependent on the integrity of the r......Skin picking disorder (SPD) is characterized by the repetitive and compulsive picking of skin, resulting in tissue damage. Neurocognitive findings in SPD implicate difficulty with response inhibition (suppression of pre-potent motor responses). This function is dependent on the integrity...... remarkably similar to those previously reported in trichotillomania. This study adds considerable support to the notion that-in addition to the phenomenological and comorbid overlap between SPD and trichotillomania-these disorders likely share overlapping neurobiology....

  1. Wavefront picking for 3D tomography and full-waveform inversion

    KAUST Repository

    AlTheyab, Abdullah

    2016-09-08

    We have developed an efficient approach for picking firstbreak wavefronts on coarsely sampled time slices of 3D shot gathers. Our objective was to compute a smooth initial velocity model for multiscale full-waveform inversion (FWI). Using interactive software, first-break wavefronts were geometrically modeled on time slices with a minimal number of picks. We picked sparse time slices, performed traveltime tomography, and then compared the predicted traveltimes with the data in-between the picked slices. The picking interval was refined with iterations until the errors in traveltime predictions fell within the limits necessary to avoid cycle skipping in early arrivals FWI. This approach was applied to a 3D ocean-bottom-station data set. Our results indicate that wavefront picking has 28% fewer data slices to pick compared with picking traveltimes in shot gathers. In addition, by using sparse time samples for picking, data storage is reduced by 88%, and therefore allows for a faster visualization and quality control of the picks. Our final traveltime tomogram is sufficient as a starting model for early arrival FWI. © 2016 Society of Exploration Geophysicists.

  2. Skin picking disorder in university students

    DEFF Research Database (Denmark)

    Odlaug, Brian Lawrence; Lust, Katherine; Schreiber, Liana R N

    2013-01-01

    This study sought to examine the prevalence of skin picking disorder (SPD) in a university sample and assess associated physical and mental health correlates.......This study sought to examine the prevalence of skin picking disorder (SPD) in a university sample and assess associated physical and mental health correlates....

  3. PICK1 regulates the trafficking of ASIC1a and acidotoxicity in a BAR domain lipid binding-dependent manner

    Directory of Open Access Journals (Sweden)

    Jin Wenying

    2010-12-01

    Full Text Available Abstract Background Acid-sensing ion channel 1a (ASIC1a is the major ASIC subunit determining acid-activated currents in brain neurons. Recent studies show that ASIC1a play critical roles in acid-induced cell toxicity. While these studies raise the importance of ASIC1a in diseases, mechanisms for ASIC1a trafficking are not well understood. Interestingly, ASIC1a interacts with PICK1 (protein interacting with C-kinase 1, an intracellular protein that regulates trafficking of several membrane proteins. However, whether PICK1 regulates ASIC1a surface expression remains unknown. Results Here, we show that PICK1 overexpression increases ASIC1a surface level. A BAR domain mutant of PICK1, which impairs its lipid binding capability, blocks this increase. Lipid binding of PICK1 is also required for PICK1-induced clustering of ASIC1a. Consistent with the effect on ASIC1a surface levels, PICK1 increases ASIC1a-mediated acidotoxicity and this effect requires both the PDZ and BAR domains of PICK1. Conclusions Taken together, our results indicate that PICK1 regulates trafficking and function of ASIC1a in a lipid binding-dependent manner.

  4. Disease: H01449 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available which causes tissue damage. Patients spend a significant amount of time each day picking their skin, that causes psychosocial...for this disease has largely focused on cognitive behavioral therapy and pharmacology. Early psychosocial tr

  5. Autophagic dysfunction in a lysosomal storage disorder due to impaired proteolysis.

    Science.gov (United States)

    Elrick, Matthew J; Lieberman, Andrew P

    2013-02-01

    Alterations in macroautophagy (hereafter referred to as "autophagy") are a common feature of lysosomal storage disorders, and have been hypothesized to play a major role in the pathogenesis of these diseases. We have recently reported multiple defects in autophagy contributing to the lysosomal storage disorder Niemann-Pick type C (NPC). These include increased formation of autophagosomes, slowed turnover of autophagosomes secondary to impaired lysosomal proteolysis, and delivery of stored lipids to the lysosome via autophagy. The study summarized here describes novel methods for the interrogation of individual stages of the autophagic pathway, and suggests mechanisms by which lipid storage may result in broader lysosomal dysfunction.

  6. High frequency permeameter with semi-rigid pick-up coil

    International Nuclear Information System (INIS)

    Shin, Sung-Yong; Shin, Kwang-Ho . E-mail : khshin@star.ks.ac.kr; Kim, Jong-sung; Kim, Young-Hak; Lim, Sang-Ho; Sa-gong, Geon

    2006-01-01

    In this study, we propose the application of semi-rigid cable loop as a single turn shielded loop pick-up coil for the high frequency permeameter. Since the semi-rigid cable pick-up coil has simple structure, it is very easy to make the pick-up coil with bending and conventional soldering. The permeability of cobalt base amorphous ribbon was investigated using the developed permeameter for demonstrating its performance. The permeability of the amorphous ribbon was driven from the S-parameters measured using a network analyzer and permameter having the semi-rigid pick-up coil

  7. Performance of diamond and point attack coal cutter picks

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Y. [CSIRO, Brisbane, Qld. (Australia). Division of Exploration and Mining

    1996-12-31

    This paper presents results of laboratory experiments and field trials of PDC (Polycrystalline Diamond Compact) and PA (Point Attack) coal cutter picks. Laboratory cutting tests included linear rock and coal cutting and turning rock cutting. The following parameters were measured to assess performance of PDC and PA cutter picks: cutting force, normal force, specific energy consumption, yield, dust generation and ignitional characteristics (temperature rise). Field trials were conducted on a longwall shearer. Performance of both types of pick interims of pick life and dust generation were assessed. 3 refs., 18 figs., 3 tabs.

  8. 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...

  9. A Proposed Analytical Model for Integrated Pick-and-Sort Systems

    Directory of Open Access Journals (Sweden)

    Recep KIZILASLAN

    2013-11-01

    Full Text Available In this study we present an analytical approach for integration of order picking and sortation operations which are the most important, labour intensive and costly activity for warehouses. Main aim is to investigate order picking and sorting efficiencies under different design issues as a function of order wave size. Integrated analytical model is proposed to estimate the optimum order picking and order sortation efficiency. The model, which has been tested by simulations with different illustrative examples, calculates the optimum wave size that solves the trade-off between picking and sorting operations and makes the order picking and sortations efficiency maximum. Our model also allow system designer to predict the order picking and sorting capacity for different system configurations. This study presents an innovative approach for integrated warehouse operations.

  10. 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

  11. PICK1 interacts with ABP/GRIP to regulate AMPA receptor trafficking.

    Science.gov (United States)

    Lu, Wei; Ziff, Edward B

    2005-08-04

    PICK1 and ABP/GRIP bind to the AMPA receptor (AMPAR) GluR2 subunit C terminus. Transfer of the receptor from ABP/GRIP to PICK1, facilitated by GluR2 S880 phosphorylation, may initiate receptor trafficking. Here we report protein interactions that regulate these steps. The PICK1 BAR domain interacts intermolecularly with the ABP/GRIP linker II region and intramolecularly with the PICK1 PDZ domain. Binding of PKCalpha or GluR2 to the PICK1 PDZ domain disrupts the intramolecular interaction and facilitates the PICK1 BAR domain association with ABP/GRIP. Interference with the PICK1-ABP/GRIP interaction impairs S880 phosphorylation of GluR2 by PKC and decreases the constitutive surface expression of GluR2, the NMDA-induced endocytosis of GluR2, and recycling of internalized GluR2. We suggest that the PICK1 interaction with ABP/GRIP is a critical step in controlling GluR2 trafficking.

  12. 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.

  13. Warehouse Order-Picking Process. Review

    Directory of Open Access Journals (Sweden)

    E. V. Korobkov

    2015-01-01

    Full Text Available This article describes basic warehousing activities, namely: movement, information storage and transfer, as well as connections between typical warehouse operations (reception, transfer, assigning storage position and put-away, order-picking, hoarding and sorting, cross-docking, shipping. It presents a classification of the warehouse order-picking systems in terms of manual labor on offer as well as external (marketing channels, consumer’s demand structure, supplier’s replenishment structure and inventory level, total production demand, economic situation and internal (mechanization level, information accessibility, warehouse dimensionality, method of dispatch for shipping, zoning, batching, storage assignment method, routing method factors affecting the designing systems complexity. Basic optimization considerations are described. There is a literature review on the following sub-problems of planning and control of orderpicking processes.A layout design problem has been taken in account at two levels — external (facility layout problem and internal (aisle configuration problem. For a problem of distributing goods or stock keeping units the following methods are emphasized: random, nearest open storage position, and dedicated (COI-based, frequency-based distribution, as well as class-based and familygrouped (complimentary- and contact-based one. Batching problem can be solved by two main methods, i.e. proximity order batching (seed and saving algorithms and time-window order batching. There are two strategies for a zoning problem: progressive and synchronized, and also a special case of zoning — bucket brigades method. Hoarding/sorting problem is briefly reviewed. Order-picking routing problem will be thoroughly described in the next article of the cycle “Warehouse order-picking process”.

  14. Fast and Reliable Mouse Picking Using Graphics Hardware

    Directory of Open Access Journals (Sweden)

    Hanli Zhao

    2009-01-01

    Full Text Available Mouse picking is the most commonly used intuitive operation to interact with 3D scenes in a variety of 3D graphics applications. High performance for such operation is necessary in order to provide users with fast responses. This paper proposes a fast and reliable mouse picking algorithm using graphics hardware for 3D triangular scenes. Our approach uses a multi-layer rendering algorithm to perform the picking operation in linear time complexity. The objectspace based ray-triangle intersection test is implemented in a highly parallelized geometry shader. After applying the hardware-supported occlusion queries, only a small number of objects (or sub-objects are rendered in subsequent layers, which accelerates the picking efficiency. Experimental results demonstrate the high performance of our novel approach. Due to its simplicity, our algorithm can be easily integrated into existing real-time rendering systems.

  15. 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

  16. Intracellular sphingosine releases calcium from lysosomes.

    Science.gov (United States)

    Höglinger, Doris; Haberkant, Per; Aguilera-Romero, Auxiliadora; Riezman, Howard; Porter, Forbes D; Platt, Frances M; Galione, Antony; Schultz, Carsten

    2015-11-27

    To elucidate new functions of sphingosine (Sph), we demonstrate that the spontaneous elevation of intracellular Sph levels via caged Sph leads to a significant and transient calcium release from acidic stores that is independent of sphingosine 1-phosphate, extracellular and ER calcium levels. This photo-induced Sph-driven calcium release requires the two-pore channel 1 (TPC1) residing on endosomes and lysosomes. Further, uncaging of Sph leads to the translocation of the autophagy-relevant transcription factor EB (TFEB) to the nucleus specifically after lysosomal calcium release. We confirm that Sph accumulates in late endosomes and lysosomes of cells derived from Niemann-Pick disease type C (NPC) patients and demonstrate a greatly reduced calcium release upon Sph uncaging. We conclude that sphingosine is a positive regulator of calcium release from acidic stores and that understanding the interplay between Sph homeostasis, calcium signaling and autophagy will be crucial in developing new therapies for lipid storage disorders such as NPC.

  17. 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.

  18. NOISY DISPERSION CURVE PICKING (NDCP): a Matlab friendly suite package for fully control dispersion curve picking

    Science.gov (United States)

    Granados, I.; Calo, M.; Ramos, V.

    2017-12-01

    We developed a Matlab suite package (NDCP, Noisy Dispersion Curve Picking) that allows a full control over parameters to identify correctly group velocity dispersion curves in two types of datasets: correlograms between two stations or surface wave records from earthquakes. Using the frequency-time analysis (FTAN), the procedure to obtain the dispersion curves from records with a high noise level becomes difficult, and sometimes, the picked curve result in a misinterpreted character. For correlogram functions, obtained with cross-correlation of noise records or earthquake's coda, a non-homogeneous noise sources distribution yield to a non-symmetric Green's function (GF); to retrieve the complete information contained in there, NDCP allows to pick the dispersion curve in the time domain both in the causal and non-causal part of the GF. Then the picked dispersion curve is displayed on the FTAN diagram to in order to check if it matches with the maximum of the signal energy avoiding confusion with overtones or spike of noise. To illustrate how NDCP performs, we show exemple using: i) local correlograms functions obtained from sensors deployed into a volcanic caldera (Los Humeros, in Puebla, Mexico), ii) regional correlograms functions between two stations of the National Seismological Service (SSN, Servicio Sismológico Nacional in Spanish), and iii) surface wave seismic record for an earthquake located in the Pacific Ocean coast of Mexico and recorded by the SSN. This work is supported by the GEMEX project (Geothermal Europe-Mexico consortium).

  19. The relationship between adolescents' academic stress, impulsivity, anxiety, and skin picking behavior.

    Science.gov (United States)

    Yeo, Sun Kyung; Lee, Woo Kyeong

    2017-08-01

    Skin picking behavior involves an individual picking or biting their skin repeatedly. Although this behavior commonly occurs at a young age, little research has addressed its harmful effects among the Korean population. Therefore, we examined the characteristics of South Korean adolescents who reported skin picking behavior. South Korean students aged 12-16 years participated (N=410, females=52.2%). They completed questionnaires that addressed skin picking behavior, academic stress, impulsivity, and anxiety. The survey was conducted in Seoul and Gyeonggi-do from February-March 2016. Among participants, 66.8% reported that they had picked their skin and 15.4% did so currently. Skin picking was positively correlated with academic stress, impulsivity, and anxiety. Students who picked their skin more often displayed more anxiety, academic stress, and impulsivity. Future studies should address skin picking adolescents' characteristics, especially regarding anxiety and academic stress. Educational programs should be implemented to help adolescents decrease their anxiety and academic stress and prevent the worsening of skin picking behavior. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Order Picking Optimization in Carousels Storage System

    Directory of Open Access Journals (Sweden)

    Xiong-zhi Wang

    2013-01-01

    Full Text Available This paper addresses the order picking problem in a material handling system consisting of multiple carousels and one picker. Carousels are rotatable closed-loop storage systems for small items, where items are stored in bins along the loop. An order at carousels consists of n different items stored there. The objective is to find an optimal picking sequence to minimizing the total order picking time. After proving the problem to be strongly NP-hard and deriving two characteristics, we develop a dynamic programming algorithm (DPA for a special case (two-carousel storage system and an improved nearest items heuristics (INIH for the general problem. Experimental results verify that the solutions are quickly and steadily achieved and show their better performance.

  1. Tracked "Pick-Up" Ultrasound for Robot-Assisted Minimally Invasive Surgery.

    Science.gov (United States)

    Schneider, Caitlin; Nguan, Christopher; Rohling, Robert; Salcudean, Septimiu

    2016-02-01

    We present a novel "pick-up" ultrasound transducer for intraabdominal robot-assisted minimally invasive surgery. Such a "pick-up" ultrasound transducer is inserted through an abdominal incision at the beginning of the procedure and remains in the abdominal cavity throughout, eliminating the need for a dedicated port or a patient bedside surgical assistant. The transducer has a handle that can be grasped in a repeatable manner using a da Vinci Prograsp tool, allowing the transducer to be accurately manipulated by the surgeon using the da Vinci Robot. This is one way to enable 3-D tracking of the transducer, and, thus, mapping of the vasculature. The 3-D vascular images can be used to register preoperative CT to intraoperative camera images. To demonstrate the feasibility of the approach, we use an ultrasound vessel phantom to register a CT surface model to extracted ultrasound vessel models. The 3-D vascular phantom images are generated by segmenting B-mode images and tracking the pick-up ultrasound transducer with the da Vinci kinematics, internal electromagnetic sensor, or visible fiducials suitable for camera tracking. Reconstruction results using da Vinci kinematics for tracking give a target registration error of 5.4 ± 1.7 mm.

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

    Directory of Open Access Journals (Sweden)

    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.

  3. Bayesian Peak Picking for NMR Spectra

    KAUST Repository

    Cheng, Yichen

    2014-02-01

    Protein structure determination is a very important topic in structural genomics, which helps people to understand varieties of biological functions such as protein-protein interactions, protein–DNA interactions and so on. Nowadays, nuclear magnetic resonance (NMR) has often been used to determine the three-dimensional structures of protein in vivo. This study aims to automate the peak picking step, the most important and tricky step in NMR structure determination. We propose to model the NMR spectrum by a mixture of bivariate Gaussian densities and use the stochastic approximation Monte Carlo algorithm as the computational tool to solve the problem. Under the Bayesian framework, the peak picking problem is casted as a variable selection problem. The proposed method can automatically distinguish true peaks from false ones without preprocessing the data. To the best of our knowledge, this is the first effort in the literature that tackles the peak picking problem for NMR spectrum data using Bayesian method.

  4. Automatic microseismic event picking via unsupervised machine learning

    Science.gov (United States)

    Chen, Yangkang

    2018-01-01

    Effective and efficient arrival picking plays an important role in microseismic and earthquake data processing and imaging. Widely used short-term-average long-term-average ratio (STA/LTA) based arrival picking algorithms suffer from the sensitivity to moderate-to-strong random ambient noise. To make the state-of-the-art arrival picking approaches effective, microseismic data need to be first pre-processed, for example, removing sufficient amount of noise, and second analysed by arrival pickers. To conquer the noise issue in arrival picking for weak microseismic or earthquake event, I leverage the machine learning techniques to help recognizing seismic waveforms in microseismic or earthquake data. Because of the dependency of supervised machine learning algorithm on large volume of well-designed training data, I utilize an unsupervised machine learning algorithm to help cluster the time samples into two groups, that is, waveform points and non-waveform points. The fuzzy clustering algorithm has been demonstrated to be effective for such purpose. A group of synthetic, real microseismic and earthquake data sets with different levels of complexity show that the proposed method is much more robust than the state-of-the-art STA/LTA method in picking microseismic events, even in the case of moderately strong background noise.

  5. Automatic seed picking for brachytherapy postimplant validation with 3D CT images.

    Science.gov (United States)

    Zhang, Guobin; Sun, Qiyuan; Jiang, Shan; Yang, Zhiyong; Ma, Xiaodong; Jiang, Haisong

    2017-11-01

    Postimplant validation is an indispensable part in the brachytherapy technique. It provides the necessary feedback to ensure the quality of operation. The ability to pick implanted seed relates directly to the accuracy of validation. To address it, an automatic approach is proposed for picking implanted brachytherapy seeds in 3D CT images. In order to pick seed configuration (location and orientation) efficiently, the approach starts with the segmentation of seed from CT images using a thresholding filter which based on gray-level histogram. Through the process of filtering and denoising, the touching seed and single seed are classified. The true novelty of this approach is found in the application of the canny edge detection and improved concave points matching algorithm to separate touching seeds. Through the computation of image moments, the seed configuration can be determined efficiently. Finally, two different experiments are designed to verify the performance of the proposed approach: (1) physical phantom with 60 model seeds, and (2) patient data with 16 cases. Through assessment of validated results by a medical physicist, the proposed method exhibited promising results. Experiment on phantom demonstrates that the error of seed location and orientation is within ([Formula: see text]) mm and ([Formula: see text])[Formula: see text], respectively. In addition, the most seed location and orientation error is controlled within 0.8 mm and 3.5[Formula: see text] in all cases, respectively. The average process time of seed picking is 8.7 s per 100 seeds. In this paper, an automatic, efficient and robust approach, performed on CT images, is proposed to determine the implanted seed location as well as orientation in a 3D workspace. Through the experiments with phantom and patient data, this approach also successfully exhibits good performance.

  6. Performance approximation of pick-to-belt orderpicking systems

    NARCIS (Netherlands)

    M.B.M. de Koster (René)

    1994-01-01

    textabstractIn this paper, an approximation method is discussed for the analysis of pick-to-belt orderpicking systems. The aim of the approximation method is to provide an instrument for obtaining rapid insight in the performance of designs of pick-to-belt orderpicking systems. It can be used to

  7. Selective visualization of fluorescent sterols in Caenorhabditis elegans by bleach-rate-based image segmentation

    DEFF Research Database (Denmark)

    Wüstner, Daniel; Landt Larsen, Ane; Færgeman, Nils J.

    2010-01-01

    The nematode Caenorhabditis elegans is a genetically tractable model organism to investigate sterol transport. In vivo imaging of the fluorescent sterol, dehydroergosterol (DHE), is challenged by C. elegans' high autofluorescence in the same spectral region as emission of DHE. We present a method....... Bleach-rate constants were determined for DHE in vivo and confirmed in model membranes. Using this method, we could detect enrichment of DHE in specific tissues like the nerve ring, the spermateca and oocytes. We confirm these results in C. elegans gut-granule-loss (glo) mutants with reduced...... homologues of Niemann-Pick C disease proteins. Our approach is generally useful for identifying fluorescent probes in the presence of high cellular autofluorescence....

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

    KAUST Repository

    Saragiotis, Christos; Alkhalifah, Tariq Ali

    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

  9. 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.

  10. Polymorphisms in the glucocerebrosidase gene and pseudogene urge caution in clinical analysis of Gaucher disease allele c.1448T>C (L444P

    Directory of Open Access Journals (Sweden)

    Lahey Cora

    2006-08-01

    Full Text Available Abstract Background Gaucher disease is a potentially severe lysosomal storage disorder caused by mutations in the human glucocerebrosidase gene (GBA. We have developed a multiplexed genetic assay for eight diseases prevalent in the Ashkenazi population: Tay-Sachs, Gaucher type I, Niemann-Pick types A and B, mucolipidosis type IV, familial dysautonomia, Canavan, Bloom syndrome, and Fanconi anemia type C. This assay includes an allelic determination for GBA allele c.1448T>C (L444P. The goal of this study was to clinically evaluate this assay. Methods Biotinylated, multiplex PCR products were directly hybridized to capture probes immobilized on fluorescently addressed microspheres. After incubation with streptavidin-conjugated fluorophore, the reactions were analyzed by Luminex IS100. Clinical evaluations were conducted using de-identified patient DNA samples. Results We evaluated a multiplexed suspension array assay that includes wild-type and mutant genetic determinations for Gaucher disease allele c.1448T>C. Two percent of samples reported to be wild-type by conventional methods were observed to be c.1448T>C heterozygous using our assay. Sequence analysis suggested that this phenomenon was due to co-amplification of the functional gene and a paralogous pseudogene (ΨGBA due to a polymorphism in the primer-binding site of the latter. Primers for the amplification of this allele were then repositioned to span an upstream deletion in the pseudogene, yielding a much longer amplicon. Although it is widely reported that long amplicons negatively impact amplification or detection efficiency in recently adopted multiplex techniques, this assay design functioned properly and resolved the occurrence of false heterozygosity. Conclusion Although previously available sequence information suggested GBA gene/pseudogene discrimination capabilities with a short amplified product, we identified common single-nucleotide polymorphisms in the pseudogene that

  11. Assignment of stock keeping units to parallel undirectional picking

    Directory of Open Access Journals (Sweden)

    Matthews, Jason

    2015-05-01

    Full Text Available An order picking system consisting of a number of parallel unidirectional picking lines is investigated. Stock keeping units (SKUs that are grouped by product type into distributions (DBNs are assigned daily to available picking lines. A mathematical programming formulation and its relaxations is presented. A greedy insertion and a greedy phased insertion are further introduced to obtain feasible results within usable computation times for all test cases. The walking distance of the pickers was shown to decrease by about 22 per cent compared with the current assignment approach. However, product handling and operational risk increases.

  12. Adaptive Motion Planning in Bin-Picking with Object Uncertainties

    DEFF Research Database (Denmark)

    Iversen, Thomas Fridolin; Ellekilde, Lars-Peter; Miró, Jaime Valls

    2017-01-01

    Doing motion planning for bin-picking with object uncertainties requires either a re-grasp of picked objects or an online sensor system. Using the latter is advantageous in terms of computational time, as no time is wasted doing an extra pick and place action. It does, however, put extra...... requirements on the motion planner, as the target position may change on-the-fly. This paper solves that problem by using a state adjusting Partial Observable Markov Decision Process, where the state space is modified between runs, to better fit earlier solved problems. The approach relies on a set...

  13. Methodology of Evaluation of the Impact of Picking Area Location on the Total Costs of Warehouse

    Directory of Open Access Journals (Sweden)

    Apsalons Raitis

    2017-12-01

    Full Text Available The picking system and the layout of the picking area are the key drivers for the evaluation of a warehouse picking cost. There are five variants for organizing the picking process of orders in a warehouse. The choice of a specific variant depends on the total cost of picking. The picking cost is evaluated within an uninterrupted picking process. It means that no stock out occurs in the time period of the picking process. The storing area and the picking area are created as two separate zones for picking quantities of the customer’s orders; the principle of division of orders is observed strictly. Referring to the locations of stock keeping units (SKU, two approaches of the layout of SKU in the picking area can be estimated. The first one is the single picking location for each single SKU, where replenishment is realized in the picking process. The second one - various picking locations for each single SKU, and the replenishment here is realized just only prior to a picking process or after it. The main benefits of the economy of the picking cost as far as these two approaches are concerned are the shortest picking route in the first case and one common replenishment option in the second case.

  14. Aligning Order Picking Methods, Incentive Systems, and Regulatory Focus to Increase Performance

    NARCIS (Netherlands)

    de Vries, J.; de Koster, R.; Stam, D.

    2016-01-01

    A controlled field experiment investigates order picking performance in terms of productivity. We examined three manual picker-to-parts order picking methods (parallel, zone, and dynamic zone picking) under two different incentive systems (competition-based vs. cooperation-based) for pickers with

  15. Aligning order picking methods, incentive systems, and regulatory focus to increase performance

    NARCIS (Netherlands)

    J. de Vries (Jelle); M.B.M. de Koster (René); D.A. Stam (Daan)

    2015-01-01

    textabstractA unique controlled field experiment investigates order picking performance (in terms of productivity and quality). We examined three manual picker-to-parts order picking methods (parallel, zone, and dynamic zone picking) under two different incentive systems (competition- based versus

  16. Excoriation (skin-picking) disorder in adults

    DEFF Research Database (Denmark)

    Leibovici, Vera; Koran, Lorrin M; Murad, Sari

    2015-01-01

    OBJECTIVE: We sought to estimate the lifetime prevalence of Excoriation (Skin-Picking) Disorder (SPD) in the Israeli adult population as a whole and compare SPD prevalence in the Jewish and Arab communities. We also explored demographic, medical and psychological correlates of SPD diagnosis. METH......-reported medical and psychiatric comorbidities between the Jewish and Arab subsamples suggest the possibility of cross-cultural variation in the correlates of this disorder.......OBJECTIVE: We sought to estimate the lifetime prevalence of Excoriation (Skin-Picking) Disorder (SPD) in the Israeli adult population as a whole and compare SPD prevalence in the Jewish and Arab communities. We also explored demographic, medical and psychological correlates of SPD diagnosis...

  17. Estimating order-picking times for return heuristic - equations and simulations

    Directory of Open Access Journals (Sweden)

    Grzegorz Tarczyński

    2015-09-01

    Full Text Available Background: A key element of the evaluation of warehouse operation is the average order-picking time. In warehouses where the order-picking process is carried out according to the "picker-to-part" rule the order-picking time is usually proportional to the distance covered by the picker while picking items. This distance can by estimated by simulations or using mathematical equations. In the paper only the best described in the literature one-block rectangular warehouses are considered. Material and methods: For the one-block rectangular warehouses there are well known five routing heuristics. In the paper the author considers the return heuristic in two variants. The paper presents well known Hall's and De Koster's equations for the average distance traveled by the picker while completing items from one pick list. The author presents own proposals for calculating the expected distance. Results: the results calculated by the use of mathematical equations (the formulas of Hall, De Koster and own propositions were compared with the average values obtained using computer simulations. For the most cases the average error does not exceed 1% (except for Hall's equations. To carry out simulation the computer software Warehouse Real-Time Simulator was used. Conclusions: the order-picking time is a function of many variables and its optimization is not easy. It can be done in two stages: firstly using mathematical equations the set of the potentially best variants is established, next the results are verified using simulations. The results calculated by the use of equations are not precise, but possible to achieve immediately. The simulations are more time-consuming, but allow to analyze the order-picking process more accurately.

  18. The assessment of skin picking in adolescence: psychometric properties of the Skin Picking Scale-Revised (German version).

    Science.gov (United States)

    Gallinat, Christina; Keuthen, Nancy J; Stefini, Annette; Backenstrass, Matthias

    2017-02-01

    Skin picking disorder has received growing attention since the release of DSM-5, yet there are no evidence-based assessment instruments for adolescent samples. The present study examines the psychometric properties of the Skin Picking Scale-Revised (SPS-R, German version) in adolescents. A total of 76 adolescents (96% female) completed the SPS-R, the Clinical Psychological Diagnostic System (KPD-38), and a questionnaire assessing demographics and clinical characteristics online. The SPS-R had high internal consistency (α = 0.89) and significant small-to-medium correlations with reduced competence skills, psychological impairment, general life satisfaction, social support, and social problems on the KPD-38. Similar to prior findings for adults, an exploratory factor analysis suggested a two-factor model for the SPS-R in adolescents. Group comparisons failed to show significant differences on SPS-R scores between participants with and without dermatological conditions. The current results suggest that the SPS-R can be useful in adolescent samples as a reliable and valid instrument for the assessment of skin picking severity. Future research investigating scale validity and factor structure in a clinical sample of adolescent skin pickers is warranted.

  19. 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...

  20. 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.

  1. A Drosophila Genome-Wide Screen Identifies Regulators of Steroid Hormone Production and Developmental Timing

    DEFF Research Database (Denmark)

    Thomas Danielsen, E.; E. Møller, Morten; Yamanaka, Naoki

    2016-01-01

    Steroid hormones control important developmental processes and are linked to many diseases. To systematically identify genes and pathways required for steroid production, we performed a Drosophila genome-wide in vivo RNAi screen and identified 1,906 genes with potential roles in steroidogenesis...... and developmental timing. Here, we use our screen as a resource to identify mechanisms regulating intracellular levels of cholesterol, a substrate for steroidogenesis. We identify a conserved fatty acid elongase that underlies a mechanism that adjusts cholesterol trafficking and steroidogenesis with nutrition...... and developmental programs. In addition, we demonstrate the existence of an autophagosomal cholesterol mobilization mechanism and show that activation of this system rescues Niemann-Pick type C1 deficiency that causes a disorder characterized by cholesterol accumulation. These cholesterol-trafficking mechanisms...

  2. Lysosomal degradation of membrane lipids.

    Science.gov (United States)

    Kolter, Thomas; Sandhoff, Konrad

    2010-05-03

    The constitutive degradation of membrane components takes place in the acidic compartments of a cell, the endosomes and lysosomes. Sites of lipid degradation are intralysosomal membranes that are formed in endosomes, where the lipid composition is adjusted for degradation. Cholesterol is sorted out of the inner membranes, their content in bis(monoacylglycero)phosphate increases, and, most likely, sphingomyelin is degraded to ceramide. Together with endosomal and lysosomal lipid-binding proteins, the Niemann-Pick disease, type C2-protein, the GM2-activator, and the saposins sap-A, -B, -C, and -D, a suitable membrane lipid composition is required for degradation of complex lipids by hydrolytic enzymes. Copyright 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  3. Stock Picking via Nonsymmetrically Pruned Binary Decision Trees

    OpenAIRE

    Anton Andriyashin

    2008-01-01

    Stock picking is the field of financial analysis that is of particular interest for many professional investors and researchers. In this study stock picking is implemented via binary classification trees. Optimal tree size is believed to be the crucial factor in forecasting performance of the trees. While there exists a standard method of tree pruning, which is based on the cost-complexity tradeoff and used in the majority of studies employing binary decision trees, this paper introduces a no...

  4. Order Picking Process in Warehouse: Case Study of Dairy Industry in Croatia

    Directory of Open Access Journals (Sweden)

    Josip Habazin

    2017-02-01

    Full Text Available The proper functioning of warehouse processes is fundamental for operational improvement and overall logistic supply chain improvement. Order picking is considered one of the most important from the group. Throughout picking orders in warehouses, the presence of human work is highly reflected, with the main goal to reduce the process time as much as possible, that is, to the very minimum. There are several different order picking methods, and nowadays, the most common ones are being developed and are significantly dependent on the type of goods, the warehouse equipment, etc., and those that stand out are scanning and picking by voice. This paper will provide information regarding the dairy industry in the Republic of Croatia with the analysis of order picking process in the observed company. Overall research highlighted the problem and resulted in proposals of solutions.

  5. Studies of generalized elemental imbalances in neurological disease patients using INAA [instrumental neutron activation analysis

    International Nuclear Information System (INIS)

    Ehmann, W.D.; Vance, D.E.; Khare, S.S.; Kasarskis, E.J.; Markesbery, W.R.

    1988-01-01

    Evidence has been presented in the literature to implicate trace elements in the etiology of several age-related neurological diseases. Most of these studies are based on brain analyses. Using instrumental neutron activation analysis (INAA), we have observed trace element imbalances in brains of patients with Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Picks's disease. The most prevalent elemental imbalances found in the brain were for bromine, mercury, and the alkali metals. In this study the authors report INAA studies of trace elements in nonneural tissues from Alzheimer's disease and ALS patients. Samples from household relatives were collected for use as controls wherever possible. Hair samples were washed according to the International Atomic Energy Agency recommended procedure. Fingernail samples were scraped with a quartz knife prior to washing by the same procedure. For ALS patients, blood samples were also collected. These data indicate that elemental imbalances in Alzheimer's disease and ALS are not restricted to the brain. Many elements perturbed in the brain are also altered in the several nonneural tissues examined to date. The imbalances in different tissues, however, are not always in the same direction. The changes observed may represent causes, effects, or simply epiphenomena. Longitudinal studies of nonneural tissues and blood, as well as tissue microprobe analyses at the cellular and subcellular level, will be required in order to better assess the role of trace elements in the etiology of these diseases

  6. Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency

    Directory of Open Access Journals (Sweden)

    Bret M. Evers

    2017-09-01

    Full Text Available Defective lysosomal function defines many neurodegenerative diseases, such as neuronal ceroid lipofuscinoses (NCL and Niemann-Pick type C (NPC, and is implicated in Alzheimer’s disease (AD and frontotemporal lobar degeneration (FTLD-TDP with progranulin (PGRN deficiency. Here, we show that PGRN is involved in lysosomal homeostasis and lipid metabolism. PGRN deficiency alters lysosome abundance and morphology in mouse neurons. Using an unbiased lipidomic approach, we found that brain lipid composition in humans and mice with PGRN deficiency shows disease-specific differences that distinguish them from normal and other pathologic groups. PGRN loss leads to an accumulation of polyunsaturated triacylglycerides, as well as a reduction of diacylglycerides and phosphatidylserines in fibroblast and enriched lysosome lipidomes. Transcriptomic analysis of PGRN-deficient mouse brains revealed distinct expression patterns of lysosomal, immune-related, and lipid metabolic genes. These findings have implications for the pathogenesis of FTLD-TDP due to PGRN deficiency and suggest lysosomal dysfunction as an underlying mechanism.

  7. 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.

  8. Functional neuroimaging of Alzheimer's disease and other dementias

    International Nuclear Information System (INIS)

    Wang Ruimin

    2001-01-01

    Dementing illnesses comprise Alzheimer's disease (AD), Pick's disease, Multi-infarct dementia (MID) and other neurological disorders. These diseases have different clinical characters respectively. Neuropsychological examinations can help to diagnose and differential diagnose dementias. The development of neuroimaging dementias is more and more rapid. 18 F-FDG PET method shows neo-cortical hypometabolism occurring in the biparietal-temporal lobes and left-right asymmetry of AD patients in the early stage. It can also differential diagnose Ad from other dementias

  9. PAL-XFEL cavity beam position monitor pick-up design and beam test

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Sojeong, E-mail: sojung8681@postech.ac.kr; Park, Young Jung; Kim, Changbum; Kim, Seung Hwan; Shin, Dong Cheol; Han, Jang-Hui; Ko, In Soo

    2016-08-11

    As an X-ray Free Electron Laser, PAL-XFEL is about to start beam commissioning. X-band cavity beam position monitor (BPM) is used in the PAL-XFEL undulator beam line. Prototypes of cavity BPM pick-up were designed and fabricated to test the RF characteristics. Also, the beam test of a cavity BPM pick-up was done in the Injector Test Facility (ITF). In the beam test, the raw signal properties of the cavity BPM pick-up were measured at a 200 pC bunch charge. According to the RF test and beam test results, the prototype cavity BPM pick-up design was confirmed to meet the requirements of the PAL-XFEL cavity BPM system.

  10. Efficacy of the “pick and roll” offense in top level European basketball teams

    Science.gov (United States)

    Marmarinos, Christos; Kostopoulos, Nikolaos; Apostolidis, Alexandros

    2016-01-01

    Abstract 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 the “pick 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. PMID:28149375

  11. Efficacy of the “pick 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 the “pick 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.

  12. 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…

  13. Skin Picking in Turkish Students: Prevalence, Characteristics, and Gender Differences

    Science.gov (United States)

    Calikusu, Celal; Kucukgoncu, Suat; Tecer, Ozlem; Bestepe, Emrem

    2012-01-01

    The aim of this study is to investigate the prevalence, characteristics, triggers, and consequences of skin picking (SP) in a sample of Turkish university students, with an emphasis on gender differences. A total of 245 students from two universities in Turkey were assessed by using the Skin Picking Inventory. In total, 87.8% of the students…

  14. Increased Regenerative Capacity of the Olfactory Epithelium in Niemann–Pick Disease Type C1

    Directory of Open Access Journals (Sweden)

    Anja Meyer

    2017-04-01

    Full Text Available Niemann–Pick disease type C1 (NPC1 is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is one of the earliest symptoms in many neurodegenerative disorders, we focused on alterations of the olfactory epithelium in an NPC1 mouse model. Previous findings revealed severe morphological and immunohistochemical alterations in the olfactory system of NPC1−/− mutant mice compared with healthy controls (NPC1+/+. Based on immunohistochemical evaluation of the olfactory epithelium, we analyzed the impact of neurodegeneration in the olfactory epithelium of NPC1−/− mice and observed considerable loss of mature olfactory receptor neurons as well as an increased number of proliferating and apoptotic cells. Additionally, after administration of two different therapy approaches using either a combination of miglustat, 2-hydroxypropyl-β-cyclodextrin (HPβCD and allopregnanolone or a monotherapy with HPβCD, we recorded a remarkable reduction of morphological damages in NPC1−/− mice and an up to four-fold increase of proliferating cells within the olfactory epithelium. Numbers of mature olfactory receptor neurons doubled after both therapy approaches. Interestingly, we also observed therapy-induced alterations in treated NPC1+/+ controls. Thus, olfactory testing may provide useful information to monitor pharmacologic treatment approaches in human NPC1.

  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. 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.

  17. Membrane Localization is Critical for Activation of the PICK1 BAR Domain

    Science.gov (United States)

    Madsen, Kenneth L.; Eriksen, Jacob; Milan-Lobo, Laura; Han, Daniel S.; Niv, Masha Y.; Ammendrup-Johnsen, Ina; Henriksen, Ulla; Bhatia, Vikram K.; Stamou, Dimitrios; Sitte, Harald H.; McMahon, Harvey T.; Weinstein, Harel; Gether, Ulrik

    2013-01-01

    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 α-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-terminus transferred to the single transmembrane protein Tac or the dopamine transporter C-terminus transferred to Tac. In contrast, transfer of the GluR2 C-terminus to cyan fluorescent protein, a cytosolic protein, did not elicit BAR domain-dependent clustering. Instead, localizing PICK1 to the membrane by introducing an N-terminal myristoylation site produced BAR domain-dependent, but ligand-independent, PICK1 clustering. The data support that in the absence of PDZ ligand, the PICK1 BAR domain is inhibited through a PDZ domain-dependent and linker-dependent mechanism. Moreover, they suggest that unmasking of the BAR domain’s membrane-binding capacity is not a consequence of ligand binding to the PDZ domain per se but results from, and coincides with, recruitment of PICK1 to a membrane compartment. PMID:18466293

  18. Normative values and the effects of age, gender, and handedness on the Moberg Pick-Up Test.

    Science.gov (United States)

    Amirjani, Nasim; Ashworth, Nigel L; Gordon, Tessa; Edwards, David C; Chan, K Ming

    2007-06-01

    The Moberg Pick-Up Test is a standardized test for assessing hand dexterity. Although reduction of sensation in the hand occurs with aging, the effect of age on a subject's performance of the Moberg Pick-Up Test has not been examined. The primary goal of this study was to examine the impact of aging and, secondarily, the impact of gender and handedness, on performance of the Moberg Pick-Up Test in 116 healthy subjects. The average time to complete each of the four subsets of the test was analyzed using the Kruskal-Wallis, Mann-Whitney U, and Wilcoxon signed-rank tests. The results show that hand dexterity of the subjects was significantly affected by age, with young subjects being the fastest and elderly subjects the slowest. Women accomplished the test faster than men, and task performance with the dominant hand was faster than with the non-dominant hand. Use of normative values established based on age and gender is a valuable objective tool to gauge hand function in patients with different neurologic disorders.

  19. How 'ground-picked' olive fruits affect virgin olive oil ethanol content, ethyl esters and quality.

    Science.gov (United States)

    Beltran, Gabriel; Sánchez, Raquel; Sánchez-Ortiz, Araceli; Aguilera, Maria P; Bejaoui, Mohamed A; Jimenez, Antonio

    2016-08-01

    Olives dropped on the ground naturally sometimes are not separated from those fresh and healthy collected from the tree for harvest and processing. In this work we compared the quality, ethanol content and bioactive components of virgin olive oils from ground-picked olives, tree-picked fruits and their mixture. Ground-picked olives produced 'Lampante' virgin olive oils; these are of a lower quality category, because of important alterations in chemical and sensory characteristics. Ethyl esters showed the highest values, although under the regulated limit. The mixture of ground and tree-picked olives gave oils classified as 'virgin' because of sensory defects, although the quality parameters did not exceed the limits for the 'extra' category. Ethanol content showed a significant increase in the oils from ground- picked olives and their mixture with respect to those from tree-picked fruits. Furthermore, bioactive compounds showed a significant decrease as fruit quality was poorer. Ground-picked olives must be harvested and processed separately since they produce low-quality virgin olive oils with sensory defects and lower concentrations of bioactive compounds. The higher acidity and ethanol concentration observed in oils from ground-picked fruits or their mixture may help ethyl ester synthesis during storage. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

  20. The correlation between cherry picking and the distance that consumers travel to do grocery shopping

    Directory of Open Access Journals (Sweden)

    Louise Van Scheers

    2013-04-01

    Full Text Available Retailers often use price promotions to discriminate between consumers who can shift purchases over time and those who cannot. Retailers consistently tend to charge lower prices than necessary, pricing defensively to prevent loyal customers from cherry picking, or shifting to competitors. Knowledge about cherry picking behaviour will enable retailers to obtain a higher share of disposable income from even price-sensitive shoppers, while at the same time charging higher prices. Recent studies indicate that effective cherry picking entails saving costs through price searching over time, price searching across stores, or both. This study examines the relationship between cherry picking and the distance that consumers travel to do grocery shopping. Interviews were conducted at ten different retail outlets over three days, and the results show that there is a highly significant correlation between cherry picking and the distance that consumers travel to do grocery shopping.These results should help retailers to benefit from cherry picking by taking a proactive approach to store switching and store location, two of the main influences on cherry picking behaviour.

  1. 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. © 2014 American Academy of Forensic Sciences.

  2. Diagnostic challenges and treatment difficulties in a patient with excoriated acne conglobata

    Directory of Open Access Journals (Sweden)

    Simona R. Georgescu

    2017-04-01

    Full Text Available Acne conglobata is a rare and severe form of acne vulgaris, characterized by the presence of comedones, papules, pustules, nodules and sometimes hematic or meliceric crusts. Acne excoriée is a form of self-inflicted skin condition in which the patient picks on imaginary or real acne lesions. We report the case of a 16 year old Caucasian female patient from the urban area who addressed our dermatology department for erythematous, edematous plaques covered by pustules and crusts, located on the face. The anamnesis revealed that during the last weeks she had had a depressive mood after ending a relationship with her boyfriend and started scratching and picking on the lesions. The patient's depressive mood prior to the worsening of the disease was probably aggravated by the condition. This might have determined the picking of the skin which could have impeded the response to standard treatment. The selfexcoriative behavior could also be regarded as an appeal for help.

  3. Automated Peak Picking and Peak Integration in Macromolecular NMR Spectra Using AUTOPSY

    Science.gov (United States)

    Koradi, Reto; Billeter, Martin; Engeli, Max; Güntert, Peter; Wüthrich, Kurt

    1998-12-01

    A new approach for automated peak picking of multidimensional protein NMR spectra with strong overlap is introduced, which makes use of the program AUTOPSY (automatedpeak picking for NMRspectroscopy). The main elements of this program are a novel function for local noise level calculation, the use of symmetry considerations, and the use of lineshapes extracted from well-separated peaks for resolving groups of strongly overlapping peaks. The algorithm generates peak lists with precise chemical shift and integral intensities, and a reliability measure for the recognition of each peak. The results of automated peak picking of NOESY spectra with AUTOPSY were tested in combination with the combined automated NOESY cross peak assignment and structure calculation routine NOAH implemented in the program DYANA. The quality of the resulting structures was found to be comparable with those from corresponding data obtained with manual peak picking.

  4. CD1d-mediated presentation of endogenous lipid antigens by adipocytes requires microsomal triglyceride transfer protein (MTP)

    DEFF Research Database (Denmark)

    Rakhshandehroo, Maryam; Gijzel, Sanne M W; Siersbæk, Rasmus

    2014-01-01

    -dependent fashion, but little is known about the lipid antigen presentation machinery in adipocytes. Here we show that CD1d, as well as the lipid antigen loading machinery genes pro-saposin (Psap), Niemann Pick type C2 (Npc2), α-galactosidase (Gla), are upregulated in early adipogenesis, and are transcriptionally...... presenting cells (APCs), which may present an important aspect of adipocyte-immune cell communication in the regulation of whole body energy metabolism and immune homeostasis....

  5. Cholesterol: Its Regulation and Role in Central Nervous System Disorders

    Directory of Open Access Journals (Sweden)

    Matthias Orth

    2012-01-01

    Full Text Available Cholesterol is a major constituent of the human brain, and the brain is the most cholesterol-rich organ. Numerous lipoprotein receptors and apolipoproteins are expressed in the brain. Cholesterol is tightly regulated between the major brain cells and is essential for normal brain development. The metabolism of brain cholesterol differs markedly from that of other tissues. Brain cholesterol is primarily derived by de novo synthesis and the blood brain barrier prevents the uptake of lipoprotein cholesterol from the circulation. Defects in cholesterol metabolism lead to structural and functional central nervous system diseases such as Smith-Lemli-Opitz syndrome, Niemann-Pick type C disease, and Alzheimer’s disease. These diseases affect different metabolic pathways (cholesterol biosynthesis, lipid transport and lipoprotein assembly, apolipoproteins, lipoprotein receptors, and signaling molecules. We review the metabolic pathways of cholesterol in the CNS and its cell-specific and microdomain-specific interaction with other pathways such as the amyloid precursor protein and discuss potential treatment strategies as well as the effects of the widespread use of LDL cholesterol-lowering drugs on brain functions.

  6. 21 CFR 872.6650 - Massaging pick or tip for oral hygiene.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Massaging pick or tip for oral hygiene. 872.6650 Section 872.6650 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES... hygiene. (a) Identification. A massaging pick or tip for oral hygiene is a rigid, pointed device intended...

  7. Automatic Grasp Generation and Improvement for Industrial Bin-Picking

    DEFF Research Database (Denmark)

    Kraft, Dirk; Ellekilde, Lars-Peter; Rytz, Jimmy Alison

    2014-01-01

    and achieve comparable results and that our learning approach can improve system performance significantly. Automatic bin-picking is an important industrial process that can lead to significant savings and potentially keep production in countries with high labour cost rather than outsourcing it. The presented......This paper presents work on automatic grasp generation and grasp learning for reducing the manual setup time and increase grasp success rates within bin-picking applications. We propose an approach that is able to generate good grasps automatically using a dynamic grasp simulator, a newly developed...

  8. Grasp Densities for Grasp Refinement in Industrial Bin Picking

    DEFF Research Database (Denmark)

    Hupfauf, Benedikt; Hahn, Heiko; Bodenhagen, Leon

    in terms of object-relative gripper pose, can be learned from empirical experience, and allow the automatic choice of optimal grasps in a given scene context (object pose, workspace constraints, etc.). We will show grasp densities extracted from empirical data in a real industrial bin picking context...... generated in industrial bin-picking for grasp learning. This aim is achieved by using the novel concept of grasp densities (Detry et al., 2010). Grasp densities can describe the full variety of grasps that apply to specific objects using specific grippers. They represent the likelihood of grasp success...

  9. Niemann-Pick C2 protein regulates sterol transport between plasma membrane and late endosomes in human fibroblasts

    DEFF Research Database (Denmark)

    Berzina, Zane; Solanko, Lukasz M; Mehadi, Ahmed S

    2018-01-01

    /LYSs is currently unknown. We show that the close cholesterol analog dehydroergosterol (DHE), when delivered to the plasma membrane (PM) accumulates in LE/LYSs of human fibroblasts lacking functional NPC2. We measured two different time scales of sterol diffusion; while DHE rich LE/LYSs moved by slow anomalous...... but not of DHE is reduced 10-fold in disease fibroblasts compared to control cells. Internalized NPC2 rescued the sterol storage phenotype and strongly expanded the dynamic sterol pool seen in FRAP experiments. Together, our study shows that cholesterol esterification and trafficking of sterols between the PM...

  10. PICK1 deficiency impairs secretory vesicle biogenesis and leads to growth retardation and decreased glucose tolerance.

    Directory of Open Access Journals (Sweden)

    Birgitte Holst

    Full Text Available Secretory vesicles in endocrine cells store hormones such as growth hormone (GH and insulin before their release into the bloodstream. The molecular mechanisms governing budding of immature secretory vesicles from the trans-Golgi network (TGN and their subsequent maturation remain unclear. Here, we identify the lipid binding BAR (Bin/amphiphysin/Rvs domain protein PICK1 (protein interacting with C kinase 1 as a key component early in the biogenesis of secretory vesicles in GH-producing cells. Both PICK1-deficient Drosophila and mice displayed somatic growth retardation. Growth retardation was rescued in flies by reintroducing PICK1 in neurosecretory cells producing somatotropic peptides. PICK1-deficient mice were characterized by decreased body weight and length, increased fat accumulation, impaired GH secretion, and decreased storage of GH in the pituitary. Decreased GH storage was supported by electron microscopy showing prominent reduction in secretory vesicle number. Evidence was also obtained for impaired insulin secretion associated with decreased glucose tolerance. PICK1 localized in cells to immature secretory vesicles, and the PICK1 BAR domain was shown by live imaging to associate with vesicles budding from the TGN and to possess membrane-sculpting properties in vitro. In mouse pituitary, PICK1 co-localized with the BAR domain protein ICA69, and PICK1 deficiency abolished ICA69 protein expression. In the Drosophila brain, PICK1 and ICA69 co-immunoprecipitated and showed mutually dependent expression. Finally, both in a Drosophila model of type 2 diabetes and in high-fat-diet-induced obese mice, we observed up-regulation of PICK1 mRNA expression. Our findings suggest that PICK1, together with ICA69, is critical during budding of immature secretory vesicles from the TGN and thus for vesicular storage of GH and possibly other hormones. The data link two BAR domain proteins to membrane remodeling processes in the secretory pathway of

  11. Dyslipidaemia--hepatic and intestinal cross-talk.

    LENUS (Irish Health Repository)

    Tomkin, Gerald H

    2010-06-01

    Cholesterol metabolism is tightly regulated with the majority of de novo cholesterol synthesis occurring in the liver and intestine. 3 Hydroxy-3-methylglutaryl coenzyme A reductase, a major enzyme involved in cholesterol synthesis, is raised in both liver and intestine in diabetic animals. Niemann PickC1-like1 protein regulates cholesterol absorption in the intestine and facilitates cholesterol transport through the liver. There is evidence to suggest that the effect of inhibition of Niemann PickC1-like1 lowers cholesterol through its effect not only in the intestine but also in the liver. ATP binding cassette proteins G5\\/G8 regulate cholesterol re-excretion in the intestine and in the liver, cholesterol excretion into the bile. Diabetes is associated with reduced ATP binding cassette protein G5\\/G8 expression in both the liver and intestine in animal models. Microsomal triglyceride transfer protein is central to the formation of the chylomicron in the intestine and VLDL in the liver. Microsomal triglyceride transfer protein mRNA is increased in diabetes in both the intestine and liver. Cross-talk between the intestine and liver is poorly documented in humans due to the difficulty in obtaining liver biopsies but animal studies are fairly consistent in showing relationships that explain in part mechanisms involved in cholesterol homeostasis.

  12. Belt for picking up liquids

    Energy Technology Data Exchange (ETDEWEB)

    Sewell, R B.H.; Nelson, S P

    1973-05-18

    This belt for picking up liquids consists of a layer of strong material, e.g., coarse cloth, sewed on at least one layer of absorbing material, e.g., sponge cloth, the stitching being disposed along chevrons with their apexes along the central axis of the belt; the edges do not contain any other marks. This arrangement facilitates the expulsion of the absorbed liquid when the belt passes between compression rollers.

  13. Psychosocial dysfunction associated with skin picking disorder and trichotillomania

    DEFF Research Database (Denmark)

    Grant, Jon E.; Redden, Sarah A.; Leppink, Eric W.

    2016-01-01

    Skin picking disorder (SPD) and trichotillomania (TTM) are common and oftentimes disabling disorders. 125 Participants with SPD and 152 with TTM undertook clinical and neurocognitive evaluation, and were grouped according to mild, moderate, or severe levels of psychosocial dysfunction. Relationsh......Skin picking disorder (SPD) and trichotillomania (TTM) are common and oftentimes disabling disorders. 125 Participants with SPD and 152 with TTM undertook clinical and neurocognitive evaluation, and were grouped according to mild, moderate, or severe levels of psychosocial dysfunction...... that levels of self-reported psychosocial dysfunction have a strong association with specific clinical aspects of SPD and TTM....

  14. Arrival-time picking method based on approximate negentropy for microseismic data

    Science.gov (United States)

    Li, Yue; Ni, Zhuo; Tian, Yanan

    2018-05-01

    Accurate and dependable picking of the first arrival time for microseismic data is an important part in microseismic monitoring, which directly affects analysis results of post-processing. This paper presents a new method based on approximate negentropy (AN) theory for microseismic arrival time picking in condition of much lower signal-to-noise ratio (SNR). According to the differences in information characteristics between microseismic data and random noise, an appropriate approximation of negentropy function is selected to minimize the effect of SNR. At the same time, a weighted function of the differences between maximum and minimum value of AN spectrum curve is designed to obtain a proper threshold function. In this way, the region of signal and noise is distinguished to pick the first arrival time accurately. To demonstrate the effectiveness of AN method, we make many experiments on a series of synthetic data with different SNR from -1 dB to -12 dB and compare it with previously published Akaike information criterion (AIC) and short/long time average ratio (STA/LTA) methods. Experimental results indicate that these three methods can achieve well picking effect when SNR is from -1 dB to -8 dB. However, when SNR is as low as -8 dB to -12 dB, the proposed AN method yields more accurate and stable picking result than AIC and STA/LTA methods. Furthermore, the application results of real three-component microseismic data also show that the new method is superior to the other two methods in accuracy and stability.

  15. Herbert L. Pick Jr. (1930-2012).

    Science.gov (United States)

    Rieser, John J; Lockman, Jeffrey J

    2013-01-01

    Presents an obituary for Herbert L. Pick Jr. For 49 years at the University of Minnesota's Institute of Child Development, new students were often greeted by an unassuming guy who rode to work on his bike, helped them carry boxes of books to their offices, and turned out to be a famous professor. Herbert L. Pick Jr. was a fabulous mentor, teacher, and developmental scientist. His work on perception and perceptual development spanned basic and applied science, laboratory and real-world settings. He was honored with the Division 7 (Developmental Psychology) Mentor Award from the American Psychological Association in 1998. He was honored again in 2002, jointly with his wife Anne D. Pick, with a volume of the Minnesota Symposium on Child Psychology based on a central theme of their work and titled "Action as an Organizer of Learning and Development." Two weeks before his death he was honored yet again with a Festschrift titled "Realism to Relevance: An Ecological Approach to Perception, Action and Cognition." Former students and academic admirers gave talks focused on the scientific themes Herb championed, namely, effects of experience on learning and development, organism-environment fit, environmental structure, and societal applications of research about basic psychological processes. He gave the final talk, and after thanking everyone in his typically humble way, he discussed his new research on visual-locomotor coordination. Herb died on June 18, 2012. He is greatly missed by Anne, his wife of 50 years; his sister Barbara; his daughters (and their husbands) Cindy (Jon), Karen (John), and Gretchen (Michael); and his grandchildren Alex, Ted, Katy, Joe, Eva, Sam, Rowan, and Culley. He is also missed by his many students, colleagues, friends, and admirers.

  16. Robotic vision system for random bin picking with dual-arm robots

    Directory of Open Access Journals (Sweden)

    Kang Sangseung

    2016-01-01

    Full Text Available Random bin picking is one of the most challenging industrial robotics applications available. It constitutes a complicated interaction between the vision system, robot, and control system. For a packaging operation requiring a pick-and-place task, the robot system utilized should be able to perform certain functions for recognizing the applicable target object from randomized objects in a bin. In this paper, we introduce a robotic vision system for bin picking using industrial dual-arm robots. The proposed system recognizes the best object from randomized target candidates based on stereo vision, and estimates the position and orientation of the object. It then sends the result to the robot control system. The system was developed for use in the packaging process of cell phone accessories using dual-arm robots.

  17. Use of ergonomic principles in manual order picking systems

    Directory of Open Access Journals (Sweden)

    Labus Nina

    2018-02-01

    Full Text Available Successful companies are continually striving to streamline costs and optimize processes, enabling them to grow progress, develop and ensure competitiveness on the market. A large part of the costs arises in warehouses, where up to 55% of total costs are generated by order-picking, which makes it important and interesting in terms of research. The paper explores “picker to part” order-picking concept, which enables flexible work and is the optimal choice for most companies. The concept is associated with a high level of work-related injuries and work-related illnesses. Work requires physical efforts resulting from handling heavy goods, performing repetitive movements and using manipulative means. Human as the main actor of the concept affects the costs caused by picking and the quality of work done, which depends on technological support, physically and psychologically capable and motivated people. Due to the high costs of service, the focus on time planning and productivity increases. Contrary, the lack of attention is paid to the working conditions and the health status of the pickers. To overcome this gab, a review of scientific and professional literature on ergonomic principles in picking concept »picker to part« was carried out, followed by a quantitative survey of ergonomic properties in warehousing activities. Results revealed that more than 60% of the surveyed order-pickers associate problems with health with the characteristics of work, about 24% of them associate health problems with the use of a particular means of transport, and all agree that provided measures to reduce physical effort and greater support of technologies influence on increased speed of work and better health status of order-pickers.

  18. An assessment of the efficacy and safety of cross technique with 100% TCA in the management of ice pick acne scars

    Directory of Open Access Journals (Sweden)

    Deepali Bhardwaj

    2010-01-01

    Full Text Available Background : Chemical reconstruction of skin scars (CROSS is a technique using high concentrations of trichloroacetic acid (TCA focally on atrophic acne scars to induce inflammation followed by collagenisation. This can lead to reduction in the appearance of scars and cosmetic improvement. Aims : The aim of this pilot study is to investigate the safety of the CROSS technique, using 100% TCA, for atrophic ice pick acne scars. Settings and Design : Open prospective study. Materials and Methods : Twelve patients with predominant atrophic ice pick post acne scars were treated with the CROSS technique, using 100% TCA, applied with a wooden toothpick, at two weekly intervals for four sittings. Efficacy was assessed on the basis of the physician′s clinical assessment, photographic evaluation at each sitting and patient′s feedback after the fourth treatment, and at the three-month and six-month follow-up period, after the last treatment. Results : More than 70% improvement was seen in eight out of ten patients evaluated and good results (50 - 70% improvement were observed in the remaining two patients. No significant side effects were noted. Transient hypopigmentation and hyperpigmentation was observed in one patient each. Physician′s findings were in conformity with the patient′s assessment. Three months after the last treatment, one patient noted a decrease in improvement with no further improvement even at the six-month follow-up period. Conclusion : The CROSS technique with 100% TCA is a safe, efficacious, cost-effective and minimally invasive technique for the management of ice pick acne scars that are otherwise generally difficult to treat. In few patients the improvement may not be sustained, probably due to inadequate or delayed collagenisation.

  19. Development of a doorframe-typed swinging seedling pick-up device for automatic field transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Han, H.; Mao, H.; Hu, J.; Tian, K.

    2015-07-01

    A doorframe-typed swing seedling pick-up device for automatic field transplanters was developed and evaluated in a laboratory. The device, consisting of a path manipulator and two grippers, can move the pins slowly to extract seedlings from the tray cells and return quickly to the pick-up point for the next extraction. The path manipulator was constructed with the creative design of type-Ⅱ mechanism combination in series. It consists of an oscillating guide linkage mechanism and a grooved globoidal cam mechanism. The gripper is a pincette-type mechanism using the pick-up pins to penetrate into the root mass for seedling extraction. The dynamic analysis of the designed seedling pick-up device was simulated with ADAMS software. Being the first prototype, various performance tests under local production conditions were conducted to find out the optimal machine operation parameters and transplant production conditions. As the gripper with multiple fine pins was moved by the swing pick-up device, it can effectively complete the transplanting work cycle of extracting, transferring, and discharging a seedling. The laboratory evaluation showed that the pick-up device equipped with two grippers can extract 80 seedlings/min with a 90% success and a 3% failure in discharging seedlings, using 42-day-old tomato plantlets. The quality of extracting seedlings was satisfactory. (Author)

  20. Solenoid pick-up problem in the CREN-K Triga Mark 2 reactor

    International Nuclear Information System (INIS)

    Malu wa Kalenga; Kobakozete Itono; Diazengwa Mpaka; Mampaka Mana Mouiny; Itio Momba

    1981-01-01

    During a lazy susan forty irradiation tube inspection with the specimen lifting device, the solenoid-operated specimen pick-up tool happened to be locked in the number fourteen position loading tube. The present paper describes the successful experiment which was carried out to solve a potential damaging situation for the safe and useful operation of the reactor. The first step in the investigation process was to ascertain what has indeed occurred in the reactor core to avoid any ill advised step which will worsen the situation. The alternatives were the following: a) The specimen tube was not lined with the loading tube; b) The lazy susan was not working properly due example to the fact that a roll pin in a drive shaft coupling inside the drive shaft tube has been broken; c) The pick-up tool has produced through the cleanout hole in the bottom of the specimen tube and engage the hole; d) The pick-up tool might have slided most of the way between the lazy susan and its housing. By moving up and down the pick-up tool and rotating back and forth the lazy susan it was possible to come to the conclusion that alternative c) was the most likely. It was not possible to release the pick-up tool because its engaging arms could not be activated as was often the case when lifting aluminium container

  1. Solenoid pick-up problem in the CREN-K Triga Mark 2 reactor

    Energy Technology Data Exchange (ETDEWEB)

    Malu wa Kalenga; Kobakozete Itono; Diazengwa Mpaka; Mampaka Mana Mouiny; Itio Momba (Commissariat des Sciences Nucleaires, Kinshasa (Zaire). Centre Regional d' Etudes Nucleaires)

    1981-01-01

    During a lazy susan forty irradiation tube inspection with the specimen lifting device, the solenoid-operated specimen pick-up tool happened to be locked in the number fourteen position loading tube. The present paper describes the successful experiment which was carried out to solve a potential damaging situation for the safe and useful operation of the reactor. The first step in the investigation process was to ascertain what has indeed occurred in the reactor core to avoid any ill advised step which will worsen the situation. The alternatives were the following: a) The specimen tube was not lined with the loading tube; b) The lazy susan was not working properly due example to the fact that a roll pin in a drive shaft coupling inside the drive shaft tube has been broken; c) The pick-up tool has produced through the cleanout hole in the bottom of the specimen tube and engage the hole; d) The pick-up tool might have slided most of the way between the lazy susan and its housing. By moving up and down the pick-up tool and rotating back and forth the lazy susan it was possible to come to the conclusion that alternative c) was the most likely. It was not possible to release the pick-up tool because its engaging arms could not be activated as was often the case when lifting aluminium container.

  2. Habit Reversal as a Treatment for Chronic Skin Picking: A Pilot Investigation

    Science.gov (United States)

    Teng, Ellen J.; Woods, Douglas W.; Twohig, Michael P.

    2006-01-01

    The purpose of this study was to compare the effectiveness of habit reversal (HR) to a wait-list control as a treatment for chronic skin picking in adults. Twenty-five adults with a chronic skin-picking problem were randomly assigned to a wait-list control or HR group. At pretreatment, posttreatment, and a 3-month follow-up, self-reported skin…

  3. The Relationship Between Treatment Adherence and Non-picked Up Medications in Community Pharmacies

    Directory of Open Access Journals (Sweden)

    Vu Phan Hoang Nguyen

    2016-10-01

    Full Text Available Medication adherence is one of the major factors that determine an outcome of a treatment. Despite the effort of healthcare providers to improve the adherence rate, it still remains a serious issue in our health care system today. Many patients do not take their medications as directed or just simply do not want to fill or refill their prescriptions. A small survey performed by pharmacy students at Temple School of Pharmacy showed that there is a significant number of patients did not pick up their medications. Cardiovascular medications are the most common non-picked up drugs. There are various reasons that patients use to justify for this non-adherence behavior. However, they are unaware that their actions create a tremendous negative effect not only on the treatment itself but also on the entire health care system. The consequences include expensive therapies, inaccurate research data, and poor treatment outcomes. Many solutions have been utilized to solve this problem, but it is still the major problem for healthcare providers to keep in mind when planning a drug regimen. Although many people believed that pharmacists are responsible for solving this problem, it should be a multidisciplinary effort of all healthcare providers to improve the medication adherence. Conflict of Interest We declare no conflicts of interest or financial interests that the authors or members of their immediate families have in any product or service discussed in the manuscript, including grants (pending or received, employment, gifts, stock holdings or options, honoraria, consultancies, expert testimony, patents and royalties.   Type: Student Project

  4. Derivados de aminociclitoles, procedimiento de obtención y usos

    OpenAIRE

    Díaz Bueno, Lucía; Casas Brugulat, Josefina; Bujons Vilàs, Jordi; Egido Gabás, Meritxell; Delgado Cirilo, Antonio; Llebaria, Amadeu

    2009-01-01

    La presente invención se refiere a los compuestos de fórmula general (1) ya sus usos como composiciones farmacéuticas para el tratamiento de enfermedades relacionadas con la acumulación lisosomal de esfingolípidos, tales como la enfermedad de Gaucher, la enfermedad de TaySachs, la enfermedad de Sandhoff, la enfermedad de Fabry, la enfermedad de Niemann-Pick, leucodistrofia metacromática y la enfermedad de Krabbe. Además, la invención se refiere al procedimiento de obte...

  5. A multi-objective approach to the assignment of stock keeping units to unidirectional picking lines

    Directory of Open Access Journals (Sweden)

    Le Roux, G. J.

    2017-05-01

    Full Text Available An order picking system in a distribution centre consisting of parallel unidirectional picking lines is considered. The objectives are to minimise the walking distance of the pickers, the largest volume of stock on a picking line over all picking lines, the number of small packages, and the total penalty incurred for late distributions. The problem is formulated as a multi-objective multiple knapsack problem that is not solvable in a realistic time. Population-based algorithms, including the artificial bee colony algorithm and the genetic algorithm, are also implemented. The results obtained from all algorithms indicate a substantial improvement on all objectives relative to historical assignments. The genetic algorithm delivers the best performance.

  6. An interactive tool for CT volume rendering and sagittal plane-picking of the prostate for radiotherapy treatment planning

    International Nuclear Information System (INIS)

    Jani, Ashesh B.; Pelizzari, Charles A.; Chen, George T.Y.; Grzezcszuk, Robert P.; Vijayakumar, Srinivasan

    1997-01-01

    Objective: Accurate and precise target volume and critical structure definition is a basic necessity in radiotherapy. The prostate, particularly the apex (an important potential site of recurrence in prostate cancer patients), is a challenging structure to define using any modality, including conventional axial CT. Invasive or expensive techniques, such as retrograde urethrography or MRI, could be avoided if localization of the prostate were possible using information already available on the planning CT. Our primary objective was to build a software tool to determine whether volume rendering and sagittal plane-picking, which are CT-based, noninvasive visualization techniques, were of utility in radiotherapy treatment planning for the prostate. Methods: Using AVS (Application Visualization System) on a Silicon Graphics Indigo 2 High Impact workstation, we have developed a tool that enables the clinician to efficiently navigate a CT volume and to use volume rendering and sagittal plane-picking to better define structures at any anatomic site. We applied the tool to the specific example of the prostate to compare the two visualization techniques with the current standard of axial CT. The prostate was defined on 80-slice CT scans (scanning thickness 4mm, pixel size 2mm x 2mm) of prostate cancer patients using axial CT images, volume-rendered CT images, and sagittal plane-picked images. Results: The navigation of the prostate using the different visualization techniques qualitatively demonstrated that the sagittal plane-picked images, and even more so the volume-rendered images, revealed the prostate (particularly the lower border) better in relationship to the surrounding regional anatomy (bladder, rectum, pelvis, and penile structures) than did the axial images. A quantitative comparison of the target volumes obtained by navigating using the different visualization techniques demonstrated that, when compared to the prostate volume defined on axial CT, a larger volume

  7. 75 FR 22423 - Pick-Sloan Missouri Basin Program, Eastern and Western Division Proposed Project Use Power Rate

    Science.gov (United States)

    2010-04-28

    ...: Reopening of comment period for review of the Pick-Sloan Missouri Basin Program, Eastern and Western... reopening the comment period for the Pick-Sloan Missouri Basin Program, Eastern and Western Division... DEPARTMENT OF THE INTERIOR Bureau of Reclamation Pick-Sloan Missouri Basin Program, Eastern and...

  8. 75 FR 1408 - Pick-Sloan Missouri Basin Program, Eastern and Western Division Proposed Project Use Power Rate

    Science.gov (United States)

    2010-01-11

    ... of Proposed Pick-Sloan Missouri Basin Program, Eastern and Western Divisions, Project Use Power Rate...) for Project Use Power for the Pick-Sloan Missouri Basin Program (P-SMBP), Eastern and Western... DEPARTMENT OF THE INTERIOR Bureau of Reclamation Pick-Sloan Missouri Basin Program, Eastern and...

  9. Climate Change and Fruit-Picking Tourism: Impact and Adaptation

    Directory of Open Access Journals (Sweden)

    Jun Liu

    2016-01-01

    Full Text Available The purpose of this work is to present phenology as a valid indicator and methodology for monitoring and assessing the impact of climate change on plant-based tourist activities. Fruit-picking has become a popular rural tourism activity worldwide. However, fruit maturity dates (FMD have been affected by climate change (CC, which has in turn profoundly affected fruit-picking tourism activities (FPTA. In this paper, phenological data on the FMD for 45 types of plants in 1980–2012, dates for more than 200 fruit-picking festivals, and data on monthly average air temperature in 1980–2013 were used to assess the impact of CC on FPTA by wavelet and correlation analyses. The findings indicated that the study area had been significantly affected by CC. Prevailing temperatures at one or three months prior have a decisive influence on FMD. Among the 11 plants directly related to FPTA, the FMD of four were significantly advanced, while 6-7 were significantly delayed owning to increased temperature. Of the 11 FPTA, only two had realized the impact of CC and had adjusted festival opening dates based on dynamic changes. However, a considerable number of festival activities remained fixed or scheduled on the weekends.

  10. Warehouse order-picking process. Order-picker routing problem

    Directory of Open Access Journals (Sweden)

    E. V. Korobkov

    2015-01-01

    Full Text Available This article continues “Warehouse order-picking process” cycle and describes order-picker routing sub-problem of a warehouse order-picking process. It draws analogies between the orderpickers’ routing problem and traveling salesman’s problem, shows differences between the standard problem statement of a traveling salesman and routing problem of warehouse orderpickers, and gives the particular Steiner’s problem statement of a traveling salesman.Warehouse layout with a typical order is represented by a graph, with some its vertices corresponding to mandatory order-picker’s visits and some other ones being noncompulsory. The paper describes an optimal Ratliff-Rosenthal algorithm to solve order-picker’s routing problem for the single-block warehouses, i.e. warehouses with only two crossing aisles, defines seven equivalent classes of partial routing sub-graphs and five transitions used to have an optimal routing sub-graph of a order-picker. An extension of optimal Ratliff-Rosenthal order-picker routing algorithm for multi-block warehouses is presented and also reasons for using the routing heuristics instead of exact optimal algorithms are given. The paper offers algorithmic description of the following seven routing heuristics: S-shaped, return, midpoint, largest gap, aisle-by-aisle, composite, and combined as well as modification of combined heuristics. The comparison of orderpicker routing heuristics for one- and two-block warehouses is to be described in the next article of the “Warehouse order-picking process” cycle.

  11. Detection of interstellar pick-up hydrogen in the solar system

    Science.gov (United States)

    Gloeckler, G.; Geiss, J.; Balsiger, H.; Fisk, L. A.; Galvin, A. B.; Ipavich, F. M.; Ogilvie, K. W.; Von Steiger, R.; Wilken, B.

    1993-01-01

    Interstellar hydrogen ionized primarily by the solar wind has been detected by the Solar Wind Ion Composition Spectrometer instrument on the Ulysses spacecraft at a distance of 4.8 AUs from the sun. This 'pick-up' hydrogen is identified by its distinct velocity distribution function, which drops abruptly at twice the local solar wind speed. From the measured fluxes of pick-up protons and singly charged helium, the number densities of neutral hydrogen and helium in the distant regions of the solar system are estimated to be 0.077 +/- 0.015 and 0.013 +/- 0.003 per cu cm, respectively.

  12. Benchmarking motion planning algorithms for bin-picking applications

    DEFF Research Database (Denmark)

    Iversen, Thomas Fridolin; Ellekilde, Lars-Peter

    2017-01-01

    Purpose For robot motion planning there exists a large number of different algorithms, each appropriate for a certain domain, and the right choice of planner depends on the specific use case. The purpose of this paper is to consider the application of bin picking and benchmark a set of motion...... planning algorithms to identify which are most suited in the given context. Design/methodology/approach The paper presents a selection of motion planning algorithms and defines benchmarks based on three different bin-picking scenarios. The evaluation is done based on a fixed set of tasks, which are planned...... and executed on a real and a simulated robot. Findings The benchmarking shows a clear difference between the planners and generally indicates that algorithms integrating optimization, despite longer planning time, perform better due to a faster execution. Originality/value The originality of this work lies...

  13. Fifteen Minutes of Fame? The Market Impact of Internet Stock Picks

    OpenAIRE

    Peter Antunovich; Asani Sarkar

    2006-01-01

    We examine 120 Nasdaq and Over-the-Counter "buy" recommendations made by Internet sites from April 1999 to June 2001. The stock picks show substantial short- and long-run price and liquidity gains, although no new information is revealed about them. For example, liquidity one year after the pick day remains higher for these stocks than for a sample matched according to size, book-to-market value, and liquidity in the preceding year. In addition, after controlling for fundamental and microstru...

  14. A Semiautomated Multilayer Picking Algorithm for Ice-sheet Radar Echograms Applied to Ground-Based Near-Surface Data

    Science.gov (United States)

    Onana, Vincent De Paul; Koenig, Lora Suzanne; Ruth, Julia; Studinger, Michael; Harbeck, Jeremy P.

    2014-01-01

    Snow accumulation over an ice sheet is the sole mass input, making it a primary measurement for understanding the past, present, and future mass balance. Near-surface frequency-modulated continuous-wave (FMCW) radars image isochronous firn layers recording accumulation histories. The Semiautomated Multilayer Picking Algorithm (SAMPA) was designed and developed to trace annual accumulation layers in polar firn from both airborne and ground-based radars. The SAMPA algorithm is based on the Radon transform (RT) computed by blocks and angular orientations over a radar echogram. For each echogram's block, the RT maps firn segmented-layer features into peaks, which are picked using amplitude and width threshold parameters of peaks. A backward RT is then computed for each corresponding block, mapping the peaks back into picked segmented-layers. The segmented layers are then connected and smoothed to achieve a final layer pick across the echogram. Once input parameters are trained, SAMPA operates autonomously and can process hundreds of kilometers of radar data picking more than 40 layers. SAMPA final pick results and layer numbering still require a cursory manual adjustment to correct noncontinuous picks, which are likely not annual, and to correct for inconsistency in layer numbering. Despite the manual effort to train and check SAMPA results, it is an efficient tool for picking multiple accumulation layers in polar firn, reducing time over manual digitizing efforts. The trackability of good detected layers is greater than 90%.

  15. Necessity and complexity of order picking routing optimisation based on pallet loading features

    Directory of Open Access Journals (Sweden)

    Bódis Tamás

    2017-12-01

    Full Text Available Order picking is the most labour-intensive and costly activity of warehouses. The main challenges of its improvement are the synchronisation of warehouse layout, storage assignment policy, routing, zoning, and batching. Furthermore, the competitiveness of the warehouse depends on how it adapts to the unique customer demands and product parameters and the changes. The operators usually have to manage the picking sequence based on best practices taking into consideration the product stacking factors and minimising the lead time. It is usually necessary to support the operators by making e ective decisions. Researchers of the pallet loading problem, bin packing problem, and order picking optimisation provide a wide horizon of solutions but their results are rarely synchronised.

  16. Using Robot Skills for Flexible Reprogramming of Pick Operations in Industrial Scenarios

    DEFF Research Database (Denmark)

    Andersen, Rasmus S.; Nalpantidis, Lazaros; Krüger, Volker

    2014-01-01

    objects on tabletops and pick them up in a user-specified manner. The programming itself is primarily done through kinesthetic teaching. We show that the skill has robustness towards the location and shape of the object to pick, and that objects from a real industrial production line can be handled. Also......, preliminary tests indicate that non-expert users can learn to use the skill after only a short introduction....

  17. NMRNet: A deep learning approach to automated peak picking of protein NMR spectra.

    Science.gov (United States)

    Klukowski, Piotr; Augoff, Michal; Zieba, Maciej; Drwal, Maciej; Gonczarek, Adam; Walczak, Michal J

    2018-03-14

    Automated selection of signals in protein NMR spectra, known as peak picking, has been studied for over 20 years, nevertheless existing peak picking methods are still largely deficient. Accurate and precise automated peak picking would accelerate the structure calculation, and analysis of dynamics and interactions of macromolecules. Recent advancement in handling big data, together with an outburst of machine learning techniques, offer an opportunity to tackle the peak picking problem substantially faster than manual picking and on par with human accuracy. In particular, deep learning has proven to systematically achieve human-level performance in various recognition tasks, and thus emerges as an ideal tool to address automated identification of NMR signals. We have applied a convolutional neural network for visual analysis of multidimensional NMR spectra. A comprehensive test on 31 manually-annotated spectra has demonstrated top-tier average precision (AP) of 0.9596, 0.9058 and 0.8271 for backbone, side-chain and NOESY spectra, respectively. Furthermore, a combination of extracted peak lists with automated assignment routine, FLYA, outperformed other methods, including the manual one, and led to correct resonance assignment at the levels of 90.40%, 89.90% and 90.20% for three benchmark proteins. The proposed model is a part of a Dumpling software (platform for protein NMR data analysis), and is available at https://dumpling.bio/. michaljerzywalczak@gmail.compiotr.klukowski@pwr.edu.pl. Supplementary data are available at Bioinformatics online.

  18. Interaction of intersteller pick-up ions with the solar wind

    International Nuclear Information System (INIS)

    Mobius, E.; Klecker, B.; Hovestadt, D.; Scholer, M.

    1988-01-01

    The interaction of interstellar pick-up ions with the solar wind is studied by comparing a model for the velocity distribution function of pick-up ions with actual measurements of He + ions in the solar wind. The model includes the effects of pitch-angle diffusion due to interplanetary Alfven waves, adiabatic deceleration in the expanding solar wind and the radial variation of the source function. It is demonstrated that the scattering mean free path is in the range ≤0.1 AU and that energy diffusion can be neglected as compared with adiabatic deceleration. The effects of adiabatic focusing, of the radial variation of the neutral density and of an variation of the solar wind velocity with distance from the Sun are investigated. With the correct choice of these parameters the authors can model the measured energy spectra of the pick-up ions does not vary with the solar wind velocity and the direction of the interplanetary magnetic field for a given local neutral gas density and ionization rate. Therefore, the comparison of the model distributions with the measurements leads to a quantitative determination of the local interstellar gas density

  19. Stemcell Information: SKIP000982 [SKIP Stemcell Database[Archive

    Lifescience Database Archive (English)

    Full Text Available ion and the complete removal of the selection cassette, and restorating this mutation. NPC患者由来皮膚線維芽細胞にCreで排除...可能な特定の配列(loxP-TetO-OKSM, loxP-FUW-M2rtTA)をのせたレンチウイルスを用いてトランスジーンが残存しないiPSCを樹立した。|NPC1-2xは同一ヒト皮膚線維芽細胞...emcr.2014.03.014 Genetic and chemical correction of cholesterol accumulation and impaired autophagy in hepatic and neural cell...s derived from Niemann-Pick Type C patient-specific iPS cells. Maetzel D, Sarkar S, Wang H

  20. Derivatives of aminocyclitols, obtainment procedure and uses

    OpenAIRE

    Llebaria, Amadeu; Casas Brugulat, Josefina; Egido Gabás, Meritxell; Díaz Bueno, Lucía; Bujons Vilàs, Jordi

    2009-01-01

    [ES] La presente invención se refiere a los compuestos de fórmula general (I) y a sus usos como composiciones farmacéuticas para el tratamiento de enfermedades relacionadas con la acumulación lisosomal de esfingolípidos, tales como la enfermedad de Gaucher, la enfermedad de Tay-Sachs, la enfermedad de Sandhoff, la enfermedad de Fabry, la enfermedad de Niemann- Pick, leucodistrofia metacromática y la enfermedad de Krabbe. Además, la invención se refiere al procedimiento de obtenció...

  1. 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 (te...

  2. 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

    , 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...... in vesicle number and size, whereas the fusion competence of generated vesicles was unaffected by the absence of PICK1. Viral rescue experiments demonstrated that long-term re-expression of PICK1 is necessary to restore normal vesicular content and secretion, while short-term overexpression is ineffective...

  3. Membrane Localization is Critical for Activation of the PICK1 BAR Domain

    OpenAIRE

    Madsen, Kenneth L.; Eriksen, Jacob; Milan-Lobo, Laura; Han, Daniel S.; Niv, Masha Y.; Ammendrup-Johnsen, Ina; Henriksen, Ulla; Bhatia, Vikram K.; Stamou, Dimitrios; Sitte, Harald H.; McMahon, Harvey T.; Weinstein, Harel; Gether, Ulrik

    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 redis...

  4. Generalized fragment picking in Rosetta: design, protocols and applications.

    Directory of Open Access Journals (Sweden)

    Dominik Gront

    Full Text Available The Rosetta de novo structure prediction and loop modeling protocols begin with coarse grained Monte Carlo searches in which the moves are based on short fragments extracted from a database of known structures. Here we describe a new object oriented program for picking fragments that greatly extends the functionality of the previous program (nnmake and opens the door for new approaches to structure modeling. We provide a detailed description of the code design and architecture, highlighting its modularity, and new features such as extensibility, total control over the fragment picking workflow and scoring system customization. We demonstrate that the program provides at least as good building blocks for ab-initio structure prediction as the previous program, and provide examples of the wide range of applications that are now accessible.

  5. 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...

  6. Metaheuristic approaches to order sequencing on a unidirectional picking line

    Directory of Open Access Journals (Sweden)

    AP de Villiers

    2013-06-01

    Full Text Available In this paper the sequencing of orders on a unidirectional picking line is considered. The aim of the order sequencing is to minimise the number of cycles travelled by a picker within the picking line to complete all orders. A tabu search, simulated annealing, genetic algorithm, generalised extremal optimisation and a random local search are presented as possible solution approaches. Computational results based on real life data instances are presented for these metaheuristics and compared to the performance of a lower bound and the solutions used in practise. The random local search exhibits the best overall solution quality, however, the generalised extremal optimisation approach delivers comparable results in considerably shorter computational times.

  7. Material flow enhancement in production assembly lines under application of zoned order picking systems

    Directory of Open Access Journals (Sweden)

    D. Živanić

    2014-10-01

    Full Text Available Introduced research work relates to the possibility of material flow enhancement in production systems, with the apostrophe on material order picking in production assembly lines. The paper presents basic rules and the results related to formed computer models of zoned order picking systems under the application of developed bound cavities method.

  8. 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.

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

    NARCIS (Netherlands)

    Lang, R.B.; 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

  10. How to reliably deliver narrow individual-patient error bars for optimization of pacemaker AV or VV delay using a "pick-the-highest" strategy with haemodynamic measurements.

    Science.gov (United States)

    Francis, Darrel P

    2013-03-10

    Intuitive and easily-described, "pick-the-highest" is often recommended for quantitative optimization of AV and especially VV delay settings of biventricular pacemakers (BVP; cardiac resynchronization therapy, CRT). But reliable selection of the optimum setting is challenged by beat-to-beat physiological variation, which "pick-the-highest" combats by averaging multiple heartbeats. Optimization is not optimization unless the optimum is identified confidently. This document shows how to calculate how many heartbeats must be averaged to optimize reliably by pick-the-highest. Any reader, by conducting a few measurements, can calculate for locally-available methods (i) biological scatter between replicate measurements, and (ii) curvature of the biological response. With these, for any clinically-desired precision of optimization, the necessary number of heartbeats can be calculated. To achieve 95% confidence of getting within ±∆x of the true optimum, the number of heartbeats needed is 2(scatter/curvature)(2)/∆x(4) per setting. Applying published scatter/curvature values (which readers should re-evaluate locally) indicates that optimizing AV, even coarsely with a 40ms-wide band of precision, requires many thousand beats. For VV delay, the number approaches a million. Moreover, identifying the optimum twice as precisely requires 30-fold more beats. "Pick the highest" is quick to say but slow to do. We must not expect staff to do the impossible; nor criticise them for not doing so. Nor should we assume recommendations and published protocols are well-designed. Reliable AV or VV optimization, using "pick-the-highest" on commonly-recommended manual measurements, is unrealistic. Improving time-efficiency of the optimization process to become clinically realistic may need a curve-fitting strategy instead, with all acquired data marshalled conjointly. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  11. Renal disease in patients with celiac disease.

    Science.gov (United States)

    Boonpheng, Boonphiphop; Cheungpasitporn, Wisit; Wijarnpreecha, Karn

    2018-04-01

    Celiac disease, an inflammatory disease of small bowel caused by sensitivity to dietary gluten and related protein, affects approximately 0.5-1% of the population in the Western world. Extra-intestinal symptoms and associated diseases are increasingly recognized including diabetes mellitus type 1, thyroid disease, dermatitis herpetiformis and ataxia. There have also been a number of reports of various types of renal involvement in patients with celiac disease including diabetes nephropathy, IgA nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis, nephrotic syndrome related to malabsorption, oxalate nephropathy, and associations of celiac disease with chronic kidney disease and end-stage kidney disease. This review aims to present the current literature on possible pathologic mechanisms underlying renal disease in patients with celiac disease.

  12. Sensitivity of Velocity Picking on 4th Order Non Hyperbolic Move out Correction

    International Nuclear Information System (INIS)

    Enuma, C.; Hope, R.; Idoko, P.

    2003-01-01

    Long offset processing has become the standard for TotaFinaElf in the Deep Offshore Nigeria. The advantage of having longer offsets are numerous; higher fold of coverage, improved S/N improved AVA analysis, less multiple contamination etc. A key element in successful long offset processing is the higher order velocity picking. In classical processing of seismic data with standard 2nd order terms for NMO correction, and outer mute at approximately 27 degrees, not to include non flattened events is required. By applying 3 terms 4th order anisotropic non hyperbolic corrections, angles out to 50-60 degrees may be flattened and can be very useful. Typically in modern 3D seismic data processing velocities are picked every 1km or 0.5km. a test was carried out to study the effect of the lateral velocity pick spacing required to properly flatten events at longer offsets. The evaluation of the test w3as carried out by loading all the CMP gathers along the line on a workstation as a 3D so that the flatness on pre-stack could be studied. The analysis showed that for 2nd order NMO 0.5km spacing is adequate to properly interpolate and flatten events at all CMP gathers along the line. However it was shown that for more advanced processing, such as the 4th order anisotropic three terms non hyperbolic velocity corrections, a more dense lateral velocity picking would be advantageous in terms of flattening of reflections. This presentation show how important long offset processing is and especially the importance of velocity picking

  13. Dermatological diseases in patients with chronic kidney disease.

    Science.gov (United States)

    Gagnon1, Amy L; Desai, Tejas

    2013-04-01

    There are a variety of dermatological diseases that are more commonly seen in patients with chronic kidney disease (CKD) and renal transplants than the general population. Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science has been searched. Some cutaneous diseases are clearly unique to this population. Of them, Lindsay's Nails, xerosis cutis, dryness of the skin, nephrogenic systemic fibrosis and acquired perforating dermatosis have been described in chronic kidney disease patients. The most common malignancy found in all transplant recipients is non-melanoma skin cancer. It is important for patients and physicians to recognize the manifestations of skin disease in patients suffering from chronic kidney disease to mitigate the morbidity associated with these conditions.

  14. Experimental Investigation of the Influence of Confining Stress on Hard Rock Fragmentation Using a Conical Pick

    Science.gov (United States)

    Li, Xibing; Wang, Shaofeng; Wang, Shanyong

    2018-01-01

    High geostress is a prominent condition in deep excavations and affects the cuttability of deep hard rock. This study aims to determine the influence of confining stress on hard rock fragmentation as applied by a conical pick. Using a true triaxial test apparatus, static and coupled static and dynamic loadings from pick forces were applied to end faces of cubic rock specimens to break them under biaxial, uniaxial and stress-free confining stress conditions. The cuttability indices (peak pick force, insertion depth and disturbance duration), failure patterns and fragment sizes were measured and compared to estimate the effects of confining stress. The results show that the rock cuttabilities decreased in order from rock breakages under stress-free conditions to uniaxial confining stress and then to biaxial confining stress. Under biaxial confining stress, only flake-shaped fragments were stripped from the rock surfaces under the requirements of large pick forces or disturbance durations. As the level of uniaxial confining stress increased, the peak pick force and the insertion depth initially increased and then decreased, and the failure patterns varied from splitting to partial splitting and then to rock bursts with decreasing average fragment sizes. Rock bursts will occur under elastic compression via ultra-high uniaxial confining stresses. There are two critical uniaxial confining stress levels, namely stress values at which peak pick forces begin to decrease and improve rock cuttability, and those at which rock bursts initially occur and cutting safety decreases. In particular, hard rock is easiest to split safely and efficiently under stress-free conditions. Moreover, coupled static preloading and dynamic disturbance can increase the efficiency of rock fragmentation with increasing preloading levels and disturbance amplitudes. The concluding remarks confirm hard rock cuttability using conical pick, which can improve the applicability of mechanical excavation in

  15. Pick-N-Pull Auto Dismantlers, Kansas City, LLC Inc.

    Science.gov (United States)

    The EPA is providing notice of a proposed Administrative Penalty Assessment against Pick-N-Pull Auto Dismantlers, Kansas City, LLC, a subsidiary of Schnitzer Steel Industries, Inc., for alleged violations at its facilities at 8012 East Truman Rd., Kansas C

  16. "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

    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. 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. 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 implementation of the clubs, but MACs

  17. 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.

  18. 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.

  19. DeepPicker: A deep learning approach for fully automated particle picking in cryo-EM.

    Science.gov (United States)

    Wang, Feng; Gong, Huichao; Liu, Gaochao; Li, Meijing; Yan, Chuangye; Xia, Tian; Li, Xueming; Zeng, Jianyang

    2016-09-01

    Particle picking is a time-consuming step in single-particle analysis and often requires significant interventions from users, which has become a bottleneck for future automated electron cryo-microscopy (cryo-EM). Here we report a deep learning framework, called DeepPicker, to address this problem and fill the current gaps toward a fully automated cryo-EM pipeline. DeepPicker employs a novel cross-molecule training strategy to capture common features of particles from previously-analyzed micrographs, and thus does not require any human intervention during particle picking. Tests on the recently-published cryo-EM data of three complexes have demonstrated that our deep learning based scheme can successfully accomplish the human-level particle picking process and identify a sufficient number of particles that are comparable to those picked manually by human experts. These results indicate that DeepPicker can provide a practically useful tool to significantly reduce the time and manual effort spent in single-particle analysis and thus greatly facilitate high-resolution cryo-EM structure determination. DeepPicker is released as an open-source program, which can be downloaded from https://github.com/nejyeah/DeepPicker-python. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Dispatched and Scube Mediate the Efficient Secretion of the Cholesterol-Modified Hedgehog Ligand

    Directory of Open Access Journals (Sweden)

    Hanna Tukachinsky

    2012-08-01

    Full Text Available The Hedgehog (Hh signaling pathway plays critical roles in metazoan development and in cancer. How the Hh ligand is secreted and spreads to distant cells is unclear, given its covalent modification with a hydrophobic cholesterol molecule, which makes it stick to membranes. We demonstrate that Hh ligand secretion from vertebrate cells is accomplished via two distinct and synergistic cholesterol-dependent binding events, mediated by two proteins that are essential for vertebrate Hh signaling: the membrane protein Dispatched (Disp and a member of the Scube family of secreted proteins. Cholesterol modification is sufficient for a heterologous protein to interact with Scube and to be secreted in a Scube-dependent manner. Disp and Scube recognize different structural aspects of cholesterol similarly to how Niemann-Pick disease proteins 1 and 2 interact with cholesterol, suggesting a hand-off mechanism for transferring Hh from Disp to Scube. Thus, Disp and Scube cooperate to dramatically enhance the secretion and solubility of the cholesterol-modified Hh ligand.

  1. Late endosomal cholesterol accumulation leads to impaired intra-endosomal trafficking.

    Directory of Open Access Journals (Sweden)

    Komla Sobo

    Full Text Available BACKGROUND: Pathological accumulation of cholesterol in late endosomes is observed in lysosomal storage diseases such as Niemann-Pick type C. We here analyzed the effects of cholesterol accumulation in NPC cells, or as phenocopied by the drug U18666A, on late endosomes membrane organization and dynamics. METHODOLOGY/PRINCIPAL FINDINGS: Cholesterol accumulation did not lead to an increase in the raft to non-raft membrane ratio as anticipated. Strikingly, we observed a 2-3 fold increase in the size of the compartment. Most importantly, properties and dynamics of late endosomal intralumenal vesicles were altered as revealed by reduced late endosomal vacuolation induced by the mutant pore-forming toxin ASSP, reduced intoxication by the anthrax lethal toxin and inhibition of infection by the Vesicular Stomatitis Virus. CONCLUSIONS/SIGNIFICANCE: These results suggest that back fusion of intralumenal vesicles with the limiting membrane of late endosomes is dramatically perturbed upon cholesterol accumulation.

  2. Expression patterns of sterol transporters NPC1 and NPC2 in the cnidarian-dinoflagellate symbiosis.

    Science.gov (United States)

    Dani, Vincent; Priouzeau, Fabrice; Mertz, Marjolijn; Mondin, Magali; Pagnotta, Sophie; Lacas-Gervais, Sandra; Davy, Simon K; Sabourault, Cécile

    2017-10-01

    The symbiotic interaction between cnidarians (e.g., corals and sea anemones) and photosynthetic dinoflagellates of the genus Symbiodinium is triggered by both host-symbiont recognition processes and metabolic exchange between the 2 partners. The molecular communication is crucial for homeostatic regulation of the symbiosis, both under normal conditions and during stresses that further lead to symbiosis collapse. It is therefore important to identify and fully characterise the key players of this intimate interaction at the symbiotic interface. In this study, we determined the cellular and subcellular localization and expression of the sterol-trafficking Niemann-Pick type C proteins (NPC1 and NPC2) in the symbiotic sea anemones Anemonia viridis and Aiptasia sp. We first established that NPC1 is localised within vesicles in host tissues and to the symbiosome membranes in several anthozoan species. We demonstrated that the canonical NPC2-a protein is mainly expressed in the epidermis, whereas the NPC2-d protein is closely associated with symbiosome membranes. Furthermore, we showed that the expression of the NPC2-d protein is correlated with symbiont presence in healthy symbiotic specimens. As npc2-d is a cnidarian-specific duplicated gene, we hypothesised that it probably arose from a subfunctionalisation process that might result in a gain of function and symbiosis adaptation in anthozoans. Niemann-Pick type C proteins may be key players in a functional symbiosis and be useful tools to study host-symbiont interactions in the anthozoan-dinoflagellate association. © 2017 John Wiley & Sons Ltd.

  3. An assessment of the waterside corrosion and hydrogen pick-up in the zircaloy-2 pressure tubes of PHWR

    International Nuclear Information System (INIS)

    Sah, D.N.

    1992-01-01

    In view of the deleterious effect of hydriding on the operating life of zircaloy-2 pressure tubes in PHWRs there is an urgent need for the assessment of the status of the pressure tubes with respect to corrosion and hydrogen pick-up in the operating PHWRs. A model has been developed for analysing the waterside corrosion and hydrogen pick-up in the zircaloy-2 pressure tubes under reactor operating conditions. This model predicts the axial profiles of oxide layer thickness and hydrogen pick-up in the pressure tubes as a function of the operating time of the reactor. The prediction of hydrogen pick-up by the model in the F-10 pressure tube of RAPS-I have been found to be in good agreement with the measured value of hydrogen content. This report gives a brief description of the model and its predictions on the present status of hydrogen pick-up in the pressure tubes of lead reactor RAPS-II. (author). 6 refs., 5 figs., 2 tabs

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

    Directory of Open Access Journals (Sweden)

    H. J. Fahr

    2007-01-01

    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.

  5. 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.

  6. PICK1 deficiency impairs secretory vesicle biogenesis and leads to growth retardation and decreased glucose tolerance

    DEFF Research Database (Denmark)

    Holst, Birgitte; Madsen, Kenneth L; Jansen, Anna M

    2013-01-01

    by electron microscopy showing prominent reduction in secretory vesicle number. Evidence was also obtained for impaired insulin secretion associated with decreased glucose tolerance. PICK1 localized in cells to immature secretory vesicles, and the PICK1 BAR domain was shown by live imaging to associate...

  7. disease patient

    Directory of Open Access Journals (Sweden)

    Setareh Mamishi

    2016-09-01

    Full Text Available Background and Purpose: Chronic granulomatous disease (CGD is an inherited disorder of the nicotinamide adenine dinucleotide phosphate (NADPH oxidase complex. This disorder results in recurrent life-threatening bacterial and fungal infections. Aspergillus species are the most common fungal infections in these patients. Case Report: Herein, we present a case of fungal infection in a girl with CGD. We confirmed aspergillosis through the positive microscopic and macroscopic examinations, as well as radiology results. Invasive aspergillosis in this patient with pneumonia, lung abscess, and osteomyelitis of the ribs was not initially treated with amphotericin B (Am B and recombinant interferon-gamma. Conclusion: Among infectious diseases, fungal infections, in particular aspergillosis, remain a serious problem in CGD patients. Considering poor clinical response and deficient immune system, rapid diagnosis of fungal infection and optimizing the treatment of these patients are recommended.

  8. CONEDEP: COnvolutional Neural network based Earthquake DEtection and Phase Picking

    Science.gov (United States)

    Zhou, Y.; Huang, Y.; Yue, H.; Zhou, S.; An, S.; Yun, N.

    2017-12-01

    We developed an automatic local earthquake detection and phase picking algorithm based on Fully Convolutional Neural network (FCN). The FCN algorithm detects and segments certain features (phases) in 3 component seismograms to realize efficient picking. We use STA/LTA algorithm and template matching algorithm to construct the training set from seismograms recorded 1 month before and after the Wenchuan earthquake. Precise P and S phases are identified and labeled to construct the training set. Noise data are produced by combining back-ground noise and artificial synthetic noise to form the equivalent scale of noise set as the signal set. Training is performed on GPUs to achieve efficient convergence. Our algorithm has significantly improved performance in terms of the detection rate and precision in comparison with STA/LTA and template matching algorithms.

  9. Investigation into the potential for dust and gas explosions in underground coal mines with reference to pick tip geometry

    International Nuclear Information System (INIS)

    Dawood, Albert D.

    2011-01-01

    In underground coal mines, methane gas, if present in sufficient concentration, may be ignited by sparks from hot spots on the picks of coal cutting machines striking hard bands of rock. During the coal cutting, wear-flat areas develop on the trailing side of the tips of picks. As pick wear progresses, the generation of frictional heat and coal dust increases and the development of hot spots at the cutting tips may lead to an explosion of methane gas. Field experience and research work over the last few years have facilitated excellent cutting performance for certain picks through the optimisation of the cutting parameters. Such performance improvements show great promise in preventing the incidence of gas or dust explosions occurring at the coal face area. This study sets out some of the fundamentals of pick geometry and cutting parameters and the methods which have been employed to achieve improvements in reducing the hazards of gas or dust explosions. It is based on the comparative trial results of two types of picks with different designs and on a range of available research information on the subject. My investigation looked at the fundamentals of pick geometry and cutting parameters and the current suppression techniques in place to control the dust and gas explosions on the coal operating face.

  10. Functional Assessment and Behavioral Treatment of Skin Picking in a Teenage Girl With Prader-Willi Syndrome

    NARCIS (Netherlands)

    Radstaake, M.; Didden, H.C.M.; Bolio, M.M.L.; Lang, R.B.; Lancioni, G.E.; Curfs, L.M.G.

    2011-01-01

    Skin picking is common in individuals with Prader-Willi Syndrome (PWS) but few treatment studies exist. This study reports the successful functional behavioral assessment (FBA) and treatment of skin picking in a 16-year-old female with PWS. A treatment package based on FBA results consisted of

  11. A Robust Formant Extraction Algorithm Combining Spectral Peak Picking and Root Polishing

    Directory of Open Access Journals (Sweden)

    Seo Kwang-deok

    2006-01-01

    Full Text Available We propose a robust formant extraction algorithm that combines the spectral peak picking, formants location examining for peak merger checking, and the root extraction methods. The spectral peak picking method is employed to locate the formant candidates, and the root extraction is used for solving the peak merger problem. The location and the distance between the extracted formants are also utilized to efficiently find out suspected peak mergers. The proposed algorithm does not require much computation, and is shown to be superior to previous formant extraction algorithms through extensive tests using TIMIT speech database.

  12. Pick-Up Ion Instabilities at Planetary Magnetospheres

    Science.gov (United States)

    Strangeway, Robert J.; Sharber, James (Technical Monitor)

    2001-01-01

    This effort involved the analysis of low frequency waves as observed by the Galileo spacecraft near the Galilean moon, Io. Io is a significant source of material, especially SO2, and various products of dissociation, and further these atoms and molecules are readily ionized. The initial velocity of the ions is essentially that of the neutral species, i.e., the Keplerian velocity. The plasma, on the other hand is co-rotating, and there is a differential flow of the order 57 km/s between the plasma and the neutral particles. Thus pick-up ion instabilities are Rely to occur within the Jovian magnetosphere. Indeed, magnetometer observations from the Galileo spacecraft clearly show ion cyclotron waves that have been identified with a large variety of plasma species, such as O+, S++ (which has the same gyro-frequency as O+), S+, and SO2+. Typically, however, the dominant frequency is near the SO2+ gyro-frequency. The research effort was originally planned to be a team effort between Robert J. Strangeway as the Principal Investigator, and Debbie Huddleston, who was an Assistant Research Geophysicist at UCLA. Unfortunately, Dr. Huddleston took a position within Industry. The effort was therefore descoped, and Dr. Strangeway instead pursued a collaboration with Dr. Xochitl Blanco-Cano, of the Instituto de Geofisica, Universidad Nacional Autonoma de Mexico. This has proved to be a productive collaboration, with several papers and publications arising out of the effort. The magnetic field oscillations near lo generally fall into two types: ion cyclotron waves, with frequencies near an ion gyro-frequency, and lower frequency mirror-mode waves. The ion cyclotron waves are mainly transverse, and frequently propagate along the ambient magnetic field. The mirror-mode waves are compressional waves, and they have essentially zero frequency in the plasma rest frame. One of the purposes of our investigation is to understand what controls the types of wave modes that occur, since both

  13. An intelligent identification algorithm for the monoclonal picking instrument

    Science.gov (United States)

    Yan, Hua; Zhang, Rongfu; Yuan, Xujun; Wang, Qun

    2017-11-01

    The traditional colony selection is mainly operated by manual mode, which takes on low efficiency and strong subjectivity. Therefore, it is important to develop an automatic monoclonal-picking instrument. The critical stage of the automatic monoclonal-picking and intelligent optimal selection is intelligent identification algorithm. An auto-screening algorithm based on Support Vector Machine (SVM) is proposed in this paper, which uses the supervised learning method, which combined with the colony morphological characteristics to classify the colony accurately. Furthermore, through the basic morphological features of the colony, system can figure out a series of morphological parameters step by step. Through the establishment of maximal margin classifier, and based on the analysis of the growth trend of the colony, the selection of the monoclonal colony was carried out. The experimental results showed that the auto-screening algorithm could screen out the regular colony from the other, which meets the requirement of various parameters.

  14. Relationship between concussion history and neurocognitive test performance in National Football League draft picks.

    Science.gov (United States)

    Solomon, Gary S; Kuhn, Andrew

    2014-04-01

    There are limited empirical data available regarding the relationship between concussion history and neurocognitive functioning in active National Football League (NFL) players in general and NFL draft picks in particular. Potential NFL draft picks undergo 2 neurocognitive tests at the National Invitational Camp (Scouting Combine) every year: the Wonderlic and, since 2011, the Immediate Post-concussion Assessment and Cognitive Testing (ImPACT). After conclusion of the combine and before the draft, NFL teams invite potential draft picks to their headquarters for individual visits where further assessment may occur. To examine the relationship between concussion history and neurocognitive performance (ImPACT and Wonderlic) in a sample of elite NFL draft picks. Cohort study; Level of evidence, 3. Over 7 years, 226 potential draft picks were invited to visit a specific NFL team's headquarters after the combine. The athletes were divided into 3 groups based on self-reported concussion history: no prior concussions, 1 prior concussion, and 2 or more prior concussions. Neurocognitive measures of interest included Wonderlic scores (provided by the NFL team) and ImPACT composite scores (administered either at the combine or during a visit to the team headquarters). The relationship between concussion history and neurocognitive scores was assessed, as were the relationships among the 2 neurocognitive tests. Concussion history had no relationship to neurocognitive performance on either the Wonderlic or ImPACT. Concussion history did not affect performance on either neurocognitive test, suggesting that for this cohort, a history of concussion may not have adverse effects on neurocognitive functioning as measured by these 2 tests. This study reveals no correlation between concussion history and neurocognitive test scores (ImPACT, Wonderlic) in soon-to-be active NFL athletes.

  15. Wavefront picking for 3D tomography and full-waveform inversion

    KAUST Repository

    AlTheyab, Abdullah; Schuster, Gerard T.

    2016-01-01

    We have developed an efficient approach for picking firstbreak wavefronts on coarsely sampled time slices of 3D shot gathers. Our objective was to compute a smooth initial velocity model for multiscale full-waveform inversion (FWI). Using

  16. Study on store-space assignment based on logistic AGV in e-commerce goods to person picking pattern

    Science.gov (United States)

    Xu, Lijuan; Zhu, Jie

    2017-10-01

    This paper studied on the store-space assignment based on logistic AGV in E-commerce goods to person picking pattern, and established the store-space assignment model based on the lowest picking cost, and design for store-space assignment algorithm after the cluster analysis based on similarity coefficient. And then through the example analysis, compared the picking cost between store-space assignment algorithm this paper design and according to item number and storage according to ABC classification allocation, and verified the effectiveness of the design of the store-space assignment algorithm.

  17. Public participation: Picking the players

    International Nuclear Information System (INIS)

    McNeill, L.; Jernigan, G.

    1995-01-01

    When citizens become involved in the public policy decision-making process, who picks the players? Are there any criteria for determining which members of the public should sit at the table? These are questions frequently asked by new participants and observers of the public involvement process. In the interest of trust and credibility, the process must be one of self-selection. Any exclusion on the part of the sponsoring organization would probably be interpreted by the public and the press as manipulative self-interest. Clearly, at times there are irrational people attending public meetings or submitting written comments. But if an organization begins excluding participants, the risk increases that the process will be perceived as a travesty

  18. High-lying neutron hole strengths observed in pick-up reactions

    International Nuclear Information System (INIS)

    Gales, S.

    1980-01-01

    Neutron-hole states in orbits well below the Fermi surface have been observed in a number of medium-heavy nuclei from A=90 to 209 using one nucleon pick-up reactions. The excitation energies, angular distributions of such broad and enhanced structures will be discussed. The fragmentation of the neutron-hole strengths as well as the spreading of such simple mode of excitations into more complex states are compared to recent calculations within the quasiparticle-phonon or the single particle-vibration coupling nuclear models. We report on recent measurements of J for inner-hole states in 89 Zr and 115 Sn 119 Sn using the analyzing power of the (p,d) and (d,t) reactions. Large enhancement of cross-sections are observed at high excitation energy in the study of the (p,t) reactions on Zr, Cd, Sn, Te and Sm isotopes. The systematic features of such high-lying excitation are related to the ones observed in one neutron pick-up experiments. The origin of such concentration of two neutron-hole strengths in Cd and Sn isotopes will be discussed. Preliminary results obtained in the study of the (α, 6 He) reaction at 218 MeV incident energy on 90 Zr, 118 Sn and 208 Pb targets are presented and compared to the (p,t) results. Finally the properties of hole-analog states populated in neutron pick-up reactions (from 90 Zr to 208 Pb) will be presented

  19. Podocyte Pathology and Nephropathy

    Directory of Open Access Journals (Sweden)

    Sandra eMerscher

    2014-07-01

    Full Text Available Sphingolipids are components of the lipid rafts in plasma membranes, which are important for proper function of podocytes, a key element of the glomerular filtration barrier. Research revealed an essential role of sphingolipids and sphingolipid metabolites in glomerular disorders of genetic and non-genetic origin. The discovery that glucocerebrosides accumulate in Gaucher disease in glomerular cells and are associated with clinical proteinuria initiated intensive research into the function of other sphingolipids in glomerular disorders. The accumulation of sphingolipids in other genetic diseases including Tay-Sachs, Sandhoff, Fabry, hereditary inclusion body myopathy 2, Niemann-Pick and nephrotic syndrome of the Finnish type and its implications with respect to glomerular pathology will be discussed. Similarily, sphingolipid accumulation occurs in glomerular diseases of non-genetic origin including diabetic kidney disease (DKD, HIV-associated nephropathy, focal segmental glomerulosclerosis (FSGS and lupus nephritis. Sphingomyelin metabolites, such as ceramide, sphingosine and sphingosine-1-phosphate have also gained tremendous interest. We recently described that sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b is expressed in podocytes where it modulates acid sphingomyelinase (ASMase activity and acts as a master modulator of danger signaling. Decreased SMPDL3b expression in post-reperfusion kidney biopsies from transplant recipients with idiopathic FSGS correlates with the recurrence of proteinuria in patients and in experimental models of xenotransplantation. Increased SMPDL3b expression is associated with DKD. The consequences of differential SMPDL3b expression in podocytes in these diseases with respect to their pathogenesis will be discussed. Finally, the role of sphingolipids in the formation of lipid rafts in podocytes and their contribution to the maintenance of a functional slit diaphragm in the glomerulus will be discussed.

  20. Pick- and waveform-based techniques for real-time detection of induced seismicity

    Science.gov (United States)

    Grigoli, Francesco; Scarabello, Luca; Böse, Maren; Weber, Bernd; Wiemer, Stefan; Clinton, John F.

    2018-05-01

    The monitoring of induced seismicity is a common operation in many industrial activities, such as conventional and non-conventional hydrocarbon production or mining and geothermal energy exploitation, to cite a few. During such operations, we generally collect very large and strongly noise-contaminated data sets that require robust and automated analysis procedures. Induced seismicity data sets are often characterized by sequences of multiple events with short interevent times or overlapping events; in these cases, pick-based location methods may struggle to correctly assign picks to phases and events, and errors can lead to missed detections and/or reduced location resolution and incorrect magnitudes, which can have significant consequences if real-time seismicity information are used for risk assessment frameworks. To overcome these issues, different waveform-based methods for the detection and location of microseismicity have been proposed. The main advantages of waveform-based methods is that they appear to perform better and can simultaneously detect and locate seismic events providing high-quality locations in a single step, while the main disadvantage is that they are computationally expensive. Although these methods have been applied to different induced seismicity data sets, an extensive comparison with sophisticated pick-based detection methods is still missing. In this work, we introduce our improved waveform-based detector and we compare its performance with two pick-based detectors implemented within the SeiscomP3 software suite. We test the performance of these three approaches with both synthetic and real data sets related to the induced seismicity sequence at the deep geothermal project in the vicinity of the city of St. Gallen, Switzerland.

  1. Specific Profile of Tau Isoforms in Argyrophylic Grain Disease

    Directory of Open Access Journals (Sweden)

    Alberto Rábano

    2013-01-01

    Full Text Available Argyrophylic grain disease (AGD is a neurodegenerative condition that has been classified among the sporadic tauopathies. Entities in this group present intracellular aggregates of hyperphosphorylated tau, giving rise to characteristic neuronal and glial inclusions. In different tauopathies, the proportion of several tau isoforms present in the aggregates shows specific patterns. AGD has been tentatively classified in the 4R group (predominance of 4R tau isoforms together with progressive supranuclear palsy and corticobasal degeneration. Pick's disease is included in the 3R group (predominance of 3R isoforms, whereas tau pathology of Alzheimer's disease represents and intermediate group (3 or 4 repeats [3R plus 4R, respectively] isoforms. In this work, we have analyzed tau present in aggregates isolated from brain samples of patients with argyrophylic grain disease. Our results indicate that the main tau isoform present in aggregates obtained from patients with AGD is a hyperphosphorylated isoform containing exons 2 and 10 but lacking exon 3.

  2. Application Value of Slider-Crank Mechanism in Pick-and-Place Operation of Delta Robot

    Directory of Open Access Journals (Sweden)

    Zhe QIN

    2018-01-01

    Full Text Available By absorbing the advantages of the rotary-driven Delta robot and linear-driven Delta robot, a Delta robot for pick-and-place operation that forms a crank-slider at the drive joint is designed.To take the most common gate shaped curve in Cartesian space as the motion trail of robotic pick-and-place operation, according to the kinematics inverse solution theory of Delta robot, this thesis mainly solves the output angular velocity of robot-driven joint. Establishing the static transfer mathematical model and solving the forced condition of driving joint. The simulation analysis show that after the upper slider-crank mechanism is connected to the driving joint, the angular velocity of the driving joint changes suddenly, which caused a rigid impact on the robot in the picking and releasing operation, though the force of the driving joint can be made smaller.

  3. Wear Assessment of Conical Pick used in Coal Cutting Operation

    Czech Academy of Sciences Publication Activity Database

    Dewangan, S.; Chattopadhyaya, S.; Hloch, Sergej

    -, 11/2014 (2014), s. 1-6 ISSN 0723-2632 Institutional support: RVO:68145535 Keywords : conical pick * wear * SEM * EDX Subject RIV: JQ - Machines ; Tools Impact factor: 2.420, year: 2014 http://link.springer.com/article/10.1007/s00603-014-0680-z

  4. Proposal of an efficient operation method about order processing sequence and allocating goods to racks in the automatic picking system; Jido picking system ni okeru shohin no tanawaritsuke to chumon shori junjo no koritsuka un`yo hoshiki no teian

    Energy Technology Data Exchange (ETDEWEB)

    Ono, T.; Kagami, A.; Kosaka, M. [Hitachi Ltd., Tokyo (Japan)

    1997-07-05

    The material distribution center is a facility to store the goods from a factory and to prepare to ship the goods in response to order from retail store. Recently, with multiplication of consumption market, multi-variety and less-amount of the goods, multi-frequency of delivery and time saving form order to delivery are required. As picking work to prepare the stored goods for each customer requires specially many man-hours out of the works in this center, time saving of working becomes an important problem. In this paper, for an object of the automatic picking system constructed by plural equipments and to execute picking of small goods for each order, the following two operation methods were proposed: (1) To define shelf sharing of the goods so that the picking requirement numbers for each picking hand may be uniform as well as possible in response to order distribution for each goods, and (2) to define treating sequence of order so as not to generate large difference in order treating times among each treating hand on operation in parallel. These operation methods were confirmed their total treating time saving by some experiments using actual ordered data. 7 refs., 8 figs., 6 tabs.

  5. Prevalence of coeliac disease in Italian patients affected by Addison's disease.

    Science.gov (United States)

    Biagi, Federico; Campanella, Jonia; Soriani, Alessandra; Vailati, Alberto; Corazza, Gino R

    2006-03-01

    It is well known that coeliac disease is associated with autoimmune endocrine diseases, such as autoimmune thyroid disease and insulin-dependent diabetes mellitus. Recently, coeliac disease has been shown in approximately 10% of patients with autoimmune Addison's disease. Addison's disease is the most common cause of primary adrenocortical insufficiency and it shares several clinical features with coeliac disease. Although hyperpigmentation and hypotension are the most specific signs, gastrointestinal symptoms are common and can be the first complaints of the patients. The aim of our study was to investigate the prevalence of coeliac disease in Italian patients with Addison's disease. Seventeen consecutive patients affected by Addison's disease (14 F, mean age 53.9 years, range 26-79 years) were enrolled in the study. Eleven of them were affected by Addison's disease associated with autoimmune thyroid disease and/or insulin-dependent diabetes mellitus; the other 6 patients were suffering from isolated Addison's disease. Diagnosis had been performed at the age of 40.5 years (range 23-55). Steroid treatment had already been started in 16 of the patients. Endomysial antibodies were tested in all of them and a duodenal biopsy was taken in those found to be positive for antiendomysial antibody (EMA). One out of 17 patients was found to be EMA positive. Duodenal biopsy confirmed the diagnosis of coeliac disease by showing subtotal villous atrophy. Although we studied only a small sample, our preliminary results confirmed that Addison's disease is associated with coeliac disease, being present in 5.9% of patients with Addison's disease. Since the symptoms can be similar and treatment of Addison's disease can mask coeliac disease, this association should always be actively investigated.

  6. 77 FR 40385 - Withdrawal of Regulatory Guide 7.3; Procedures for Picking Up and Receiving Packages of...

    Science.gov (United States)

    2012-07-09

    ... Picking Up and Receiving Packages of Radioactive Material AGENCY: Nuclear Regulatory Commission. ACTION.... Nuclear Regulatory Commission (NRC or Commission) is withdrawing RG 7.3, ``Procedures for Picking Up and... Public Document Room (PDR) reference staff at 1-800-397-4209, or 301-415-4737, or by email at PDR...

  7. Coronary artery disease in patients with cerebrovascular disease: a prospective study

    International Nuclear Information System (INIS)

    Rokey, R.; Rolak, L.A.; Harati, Y.; Kutka, N.; Verani, M.S.

    1984-01-01

    Coronary artery disease is the cause of death in most patients who have transient ischemic attacks or stroke. Evaluation for this condition is not routinely performed in such patients, and no prospective studies have been reported. We prospectively examined 50 consecutive patients with transient ischemic attacks or mild stroke to determine the prevalence and importance of coronary artery disease. All patients were examined by a cardiologist and underwent both exercise thallium-201 scintigraphy and exercise radionuclide ventriculography. Sixteen patients were suspected to have coronary artery disease on the basis of clinical evaluation. In 15 of these the was confirmed by the nuclear scans. The remaining 34 patients had no clinical evidence of heart disease, yet 14 had abnormal cardiac scans. Twenty of 22 patients with abnormal scans who underwent cardiac catheterization had significant coronary artery disease or a cardiomyopathy. The discovery of heart disease altered clinical management in 13 patients. Overall, 29 of 50 patients had significant coronary artery disease, compared with a 7% prevalence of the condition in other patients of similar age at the same institution

  8. 77 FR 36017 - Regulatory Guide 7.3, Procedures for Picking Up and Receiving Packages of Radioactive Material

    Science.gov (United States)

    2012-06-15

    ... NUCLEAR REGULATORY COMMISSION [NRC-2012-0139] Regulatory Guide 7.3, Procedures for Picking Up and... Guide (RG) 7.3, ``Procedures for Picking Up and Receiving Packages of Radioactive Material.'' The guide..., please contact the NRC's Public Document Room (PDR) reference staff at 1-800-397-4209, or 301-415-4737...

  9. UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells

    Science.gov (United States)

    2018-03-15

    Adrenoleukodystrophy; Batten Disease; Mucopolysaccharidosis II; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Neimann Pick Disease; Pelizaeus-Merzbacher Disease; Sandhoff Disease; Tay-Sachs Disease; Brain Diseases, Metabolic, Inborn; Alpha-Mannosidosis; Sanfilippo Mucopolysaccharidoses

  10. [Inpatients days in patients with respiratory diseases and periodontal disease].

    Science.gov (United States)

    Fernández-Plata, Rosario; Olmedo-Torres, Daniel; Martínez-Briseño, David; González-Cruz, Herminia; Casa-Medina, Guillermo; García-Sancho, Cecilia

    2017-01-01

    Periodontal disease is a chronic inflammatory gingival process that has been associated with the severity of respiratory diseases. In Mexico a prevalence of 78% was found in population with social security and > 60 years old. The aim of this study is to establish the association between periodontal disease and respiratory diseases according to the inpatient days. A cross-sectional study was conducted from January to December 2011. We included hospitalized patients, ≥ 18 years of age, without sedation or intubated. A dentist classified patients into two groups according to the severity of the periodontal disease: mild-to-moderate and severe. We estimated medians of inpatient days by disease and severity. Negative binomial models were adjusted to estimate incidence rate ratios and predicted inpatient days. 3,059 patients were enrolled. The median of observed and predicted inpatient days was higher in the group of severe periodontal disease (p disease, tuberculosis, and influenza had the highest incidence rates ratios of periodontal disease (p periodontal disease is positively -associated with inpatient days of patients with respiratory diseases.

  11. How consumers pick a hotel strategic segmentation and target marketing

    CERN Document Server

    Winston, William

    2013-01-01

    Venture through the pages of How Consumers Pick a Hotel to learn the steps of selecting a target and using consumer behavior applications to segment the market to reach your target. Much as a consumer goes through the process of selecting a satisfying hotel, you can choose to use the information provided to make your hospitality career relaxing and satisfying. When you finish this fantastic reading journey, you'll be prepared to offer services that meet the public's demands, and you'll possess the prerequisite knowledge and skills for developing your own strategic approach to a target market. As the many methods of segmentation are discussed in detail, you will also learn effective strategies for communicating with multiple segments. Ideal as a supplementary text for marketing and hospitality marketing courses, How Consumers Pick a Hotel provides a concise overview of consumer behavior and intertwines marketing theory with sound ways in which to implement the theory. This will both orient you and give you a s...

  12. Celiac Disease in Patients with Cystic Fibrosis-Related Bone Disease

    Directory of Open Access Journals (Sweden)

    Melissa S. Putman

    2017-01-01

    Full Text Available Both cystic fibrosis (CF and celiac disease can cause low bone mineral density (BMD and fractures. Celiac disease may occur at a higher frequency in patients with CF than the general population, and symptoms of these conditions may overlap. We report on two patients presenting with CF-related bone disease in the past year who were subsequently found to have concurrent celiac disease. Because adherence to a gluten-free diet may improve BMD in patients with celiac disease, this could have important implications for treatment. Clinicians should consider screening for celiac disease in patients with CF who have low BMD, worsening BMD in the absence of other risk factors, and/or difficult to treat vitamin D deficiency.

  13. The distribution of cerebral muscarinic acetylcholine receptors in vivo in patients with dementia. A controlled study with 123IQNB and single photon emission computed tomography

    International Nuclear Information System (INIS)

    Weinberger, D.R.; Gibson, R.; Coppola, R.; Jones, D.W.; Molchan, S.; Sunderland, T.; Berman, K.F.; Reba, R.C.

    1991-01-01

    A high-affinity muscarinic receptor antagonist, 123IQNB (3-quinuclidinyl-4-iodobenzilate labeled with iodine 123), was used with single photon emission computed tomography to image muscarinic acetylcholine receptors in 14 patients with dementia and in 11 healthy controls. High-resolution single photon emission computed tomographic scanning was performed 21 hours after the intravenous administration of approximately 5 mCi of IQNB. In normal subjects, the images of retained ligand showed a consistent regional pattern that correlated with postmortem studies of the relative distribution of muscarinic receptors in the normal human brain, having high radioactivity counts in the basal ganglia, occipital cortex, and insular cortex, low counts in the thalamus, and virtually no counts in the cerebellum. Eight of 12 patients with a clinical diagnosis of Alzheimer's disease had obvious focal cortical defects in either frontal or posterior temporal cortex. Both patients with a clinical diagnosis of Pick's disease had obvious frontal and anterior temporal defects. A region of interest statistical analysis of relative regional activity revealed a significant reduction bilaterally in the posterior temporal cortex of the patients with Alzheimer's disease compared with controls. This study demonstrates the practicability of acetylcholine receptor imaging with 123IQNB and single photon emission computed tomography. The data suggest that focal abnormalities in muscarinic binding in vivo may characterize some patients with Alzheimer's disease and Pick's disease, but further studies are needed to address questions about partial volume artifacts and receptor quantification

  14. Prevalence of Disability in Patients With Musculoskeletal Pain and Rheumatic Diseases in a Population From Cuenca, Ecuador.

    Science.gov (United States)

    Guevara-Pacheco, Sergio Vicente; Feican-Alvarado, Astrid; Delgado-Pauta, Jorge; Lliguisaca-Segarra, Angelita; Pelaez-Ballestas, Ingris

    2017-09-01

    The aim of this study was to determine the prevalence of disability in patients with musculoskeletal pain and rheumatic diseases in Cuenca, Ecuador. We performed a cross-sectional analytical study with randomized sampling in 4877 subjects, from urban and rural areas. COPCORD (Community Oriented Program for Control of Rheumatic Diseases)-validated questionnaire was administered house-to-house to identify subjects with nontraumatic musculoskeletal pain and rheumatic diseases. The subjects were assessed by rheumatologists for diagnostic accuracy, and the Health Assessment Questionnaire Disability Index was administered to assess functional capacity. A logistic regression analysis was conducted to determine the association of rheumatic diseases with functional disability. Functional disability was found in 221 subjects (73.1% women), with mean age 62 (SD, 18.2) years, residing in rural areas (201 [66.5%]), with education of 6.9 (SD, 5.3) years, and of low income (77 [47.2%]). The value of HAQ-DI was a mean of 0.2 (0-2.9). The real prevalence of physical disability was 9.5%. Moderate and severe disability predominated in activities such as kneeling (4.9% and 3.3%), squatting (4.8% and 2.7%), and leaning to pick up objects (3.7% and 0.9%), respectively. Rheumatic diseases associated with physical disabilities were knee osteoarthritis (95 [31.4%]) and hand osteoarthritis (69 [22.8%]), mechanical low-back pain (43 [14.2%]), fibromyalgia (27 [9.5%]), and rheumatoid arthritis (11 [3.6%]; P Rheumatic diseases associated with disability were hand and knee osteoarthritis, back pain, fibromyalgia, and rheumatoid arthritis.

  15. MgB2 magnetometer with directly coupled pick-up loop

    NARCIS (Netherlands)

    Portesi, C.; Mijatovic, D.; Veldhuis, Dick; Brinkman, Alexander; Monticone, E.; Gonnelli, R.S.

    2006-01-01

    magnetometer with a directly coupled pick-up loop. We used an all in situ technique for fabricating magnesium diboride films, which consists of the co-evaporation of B and Mg by means of an e-gun and a resistive heater respectively. Consequently, we realized the superconducting device, which

  16. Celiac disease and other autoimmune diseases in patients with collagenous colitis.

    Science.gov (United States)

    Vigren, Lina; Tysk, Curt; Ström, Magnus; Kilander, Anders F; Hjortswang, Henrik; Bohr, Johan; Benoni, Cecilia; Larson, Lasse; Sjöberg, Klas

    2013-08-01

    Collagenous colitis (CC) is associated with autoimmune disorders. The aim of the present study was to investigate the relationship between CC and autoimmune disorders in a Swedish multicenter study. Patients with CC answered questionnaires about demographic data and disease activity. The patient's files were scrutinized for information about autoimmune diseases. A total number of 116 CC patients were included; 92 women, 24 men, median age 62 years (IQR 55-73). In total, 30.2% had one or more autoimmune disorder. Most common were celiac disease (CeD; 12.9%) and autoimmune thyroid disease (ATD, 10.3%), but they also had Sjögren's syndrome (3.4%), diabetes mellitus (1.7%) and conditions in skin and joints (6.0%). Patients with associated autoimmune disease had more often nocturnal stools. The majority of the patients with associated CeD or ATD got these diagnoses before the colitis diagnosis. Autoimmune disorders occurred in one-third of these patients, especially CeD. In classic inflammatory bowel disease (IBD), liver disease is described in contrast to CC where no cases occurred. Instead, CeD was prevalent, a condition not reported in classic IBD. Patients with an associated autoimmune disease had more symptoms. Patients with CC and CeD had an earlier onset of their colitis. The majority of the patients with both CC and CeD were smokers. Associated autoimmune disease should be contemplated in the follow-up of these patients.

  17. An Amphipathic Helix Directs Cellular Membrane Curvature Sensing and Function of the BAR Domain Protein PICK1.

    Science.gov (United States)

    Herlo, Rasmus; Lund, Viktor K; Lycas, Matthew D; Jansen, Anna M; Khelashvili, George; Andersen, Rita C; Bhatia, Vikram; Pedersen, Thomas S; Albornoz, Pedro B C; Johner, Niklaus; Ammendrup-Johnsen, Ina; Christensen, Nikolaj R; Erlendsson, Simon; Stoklund, Mikkel; Larsen, Jannik B; Weinstein, Harel; Kjærulff, Ole; Stamou, Dimitrios; Gether, Ulrik; Madsen, Kenneth L

    2018-05-15

    BAR domains are dimeric protein modules that sense, induce, and stabilize lipid membrane curvature. Here, we show that membrane curvature sensing (MCS) directs cellular localization and function of the BAR domain protein PICK1. In PICK1, and the homologous proteins ICA69 and arfaptin2, we identify an amphipathic helix N-terminal to the BAR domain that mediates MCS. Mutational disruption of the helix in PICK1 impaired MCS without affecting membrane binding per se. In insulin-producing INS-1E cells, super-resolution microscopy revealed that disruption of the helix selectively compromised PICK1 density on insulin granules of high curvature during their maturation. This was accompanied by reduced hormone storage in the INS-1E cells. In Drosophila, disruption of the helix compromised growth regulation. By demonstrating size-dependent binding on insulin granules, our finding highlights the function of MCS for BAR domain proteins in a biological context distinct from their function, e.g., at the plasma membrane during endocytosis. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  18. Automatic picking of direct P, S seismic phases and fault zone head waves

    Science.gov (United States)

    Ross, Z. E.; Ben-Zion, Y.

    2014-10-01

    We develop a set of algorithms for automatic detection and picking of direct P and S waves, as well as fault zone head waves (FZHW), generated by earthquakes on faults that separate different lithologies and recorded by local seismic networks. The S-wave picks are performed using polarization analysis and related filters to remove P-wave energy from the seismograms, and utilize STA/LTA and kurtosis detectors in tandem to lock on the phase arrival. The early portions of P waveforms are processed with STA/LTA, kurtosis and skewness detectors for possible first-arriving FZHW. Identification and picking of direct P and FZHW is performed by a multistage algorithm that accounts for basic characteristics (motion polarities, time difference, sharpness and amplitudes) of the two phases. The algorithm is shown to perform well on synthetic seismograms produced by a model with a velocity contrast across the fault, and observed data generated by earthquakes along the Parkfield section of the San Andreas fault and the Hayward fault. The developed techniques can be used for systematic processing of large seismic waveform data sets recorded near major faults.

  19. Interactive Micromanipulation of Picking and Placement of Nonconductive Microsphere in Scanning Electron Microscope

    Directory of Open Access Journals (Sweden)

    Ning Cao

    2017-08-01

    Full Text Available In this paper, classified theoretical models, consisting of contact with and placement of microsphere and picking operations, are simplified and established to depict the interactive behaviors of external and internal forces in pushing manipulations, respectively. Sliding and/or rolling cases, resulting in the acceleration of micromanipulations, are discussed in detail. Effective contact detection is achieved by combining alterations of light-shadow and relative movement displacement between the tip-sphere. Picking operations are investigated by typical interactive positions and different end tilt angles. Placements are realized by adjusting the proper end tilt angles. These were separately conducted to explore the interactive operations of nonconductive glass microspheres in a scanning electron microscope. The experimental results demonstrate that the proposed contact detection method can efficiently protect the end-tip from damage, regardless of operator skills in initial positioning operations. E-beam irradiation onto different interactive positions with end tilt angles can be utilized to pick up microspheres without bending the end-tip. In addition, the results of releasing deviations away from the pre-setting point were utilized to verify the effectiveness of the placement tilt angles.

  20. (p, α) reactions: knock-on(out) or pick-up

    International Nuclear Information System (INIS)

    Gadioli, E.

    1983-01-01

    Nothwithstanding the great lot of data collected starting from the beginning of fifties, it cannot be said that a good degree of knowledge about the (p, α) reaction mechanism has been reached. Experimental data are usually interpreted or on the basis of a pure pick-up or knock-on(out) mechanism, though many results suggest the importance of both mechanism

  1. Order picking in carousel systems under the nearest item heuristic

    NARCIS (Netherlands)

    Litvak, Nelli; Zijm, Willem H.M.; Adan, I.J.B.F.; Wessels, J.

    2001-01-01

    A carousel is a computer-controlled warehousing system, which is widely used to store small- and medium-sized goods. One of the most important performance characteristics of such systems is the pick time of an order, which mostly depends on the travel time of the carousel. In this article, we

  2. Order picking in carousel systems under the nearest item heuristic

    NARCIS (Netherlands)

    Litvak, Nelli; Adan, I.J.B.F.; Wessels, J.; Zijm, Willem H.M.

    2000-01-01

    A carousel is a computer controlled warehousing system, which is widely used to store small and medium sized goods. One of the most important performance characteristics of such systems is the pick time of an order, which mostly depends on the travel time of the carousel. In this paper we consider

  3. Order picking in carousel systems under the nearest item heuristic

    NARCIS (Netherlands)

    Litvak, Nelli; Adan, I.J.B.F.; Wessels, J.B.; Zijm, Willem H.M.

    2001-01-01

    A carousel is a computer-controlled warehousing system, which is widely used to store small- and medium-sized goods+ One of the most important performance character- istics of such systems is the pick time of an order, which mostly depends on the travel time of the carousel+ In this article, we

  4. 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.

  5. Peripheral vascular disease in patients with coronary artery disease

    International Nuclear Information System (INIS)

    Bashir, E. A.; Aslam, N.

    2001-01-01

    Objective: The prevalence of peripheral vascular disease (PVD) in patients with coronary artery disease (CAD) has been investigated in many different ways. It depends on the diagnostic methods used and definition of atherosclerotic manifestations in the different vascular beds. This study was carried out to determine the prevalence of PVD in the lower limbs in group of patients with CAD. Design: This is a prospective observational study. Place and duration of study: The study was conducted at Combined Military Hospital/Armed Forces institute of Cardiology, Rawalpindi, over a period of one year (January 1998 to January 1999). Subjects and methods: A total number of 200 patient (171 male and 29 females) aged 55-77 years with CAD. Diagnosed by coronary angiography were included in the study. In all patients blood pressure was recorded in both arms by sphygmomanometer and ankle systolic pressure by Doppler ultrasound. Ankle branchial index was calculated. Demographic data were obtained from the patient's hospital files. Results: The prevalence of PVD was 22.5% in patients with CAD in agreement with the results of most previous investigation. There was tendency towards increasing prevalence of PVD with more advanced CAD. Thirty patients (27%) showed evidence of triple vessel disease as compared to 13 patient (18%) with double vessel and 2 patients (1%) with single vessel disease. Conclusion: A non-invasive investigation of peripheral arterial circulation should be included early in the clinical consideration of patients with chest pain or similar symptoms suggesting coronary artery disease. Ankle systolic pressure appears to be simple and cheap technique for evaluation of results. (author)

  6. Ac-loss measurement of coated conductors: The influence of the pick-up coil position

    International Nuclear Information System (INIS)

    Schmidt, Curt

    2008-01-01

    The ac-loss measurement by the magnetization method requires calibration for obtaining absolute values. A convenient way of calibration is the calorimetric measurement which yields, within the measuring accuracy, absolute loss values. In the magnetization measurement the hysteresis loop of sample magnetization which determines the losses is measured via the integration of magnetic flux penetrating a pick-up coil. The ratio of flux integral to magnetization integral and hence the calibration factor is however, for a given pick-up coil geometry, not exactly a constant, but depends on the magnetization current pattern within the sample. Especially for thin tapes in perpendicular external field this effect has to be taken into consideration in order to avoid miss measurements. The relation between measured flux and sample magnetization was calculated for special cases of magnetization current distribution in the sample as a function of the pick-up coil position. Furthermore calibration factors were measured as a function of the ac-field amplitude and the result compared with available theoretical models. A good agreement was found between experiment and theory

  7. Picking of foreign television formats by Czech televisions

    OpenAIRE

    Šopovová, Andrea

    2010-01-01

    This paper is concerned with one of the impacts of media globalisation and it is a picking of foreign television formats. It analyzes the structure of television programs offered by Czech television broadcasters and its change from 2005 when TV Nova and TV Prima changed their owners to international ones. After the introduction of media globalisation, the paper describes the television formats and then it includes a list of licensed television programs and a comparison of chosen programs with...

  8. The relationship between the cerebral blood flow, oxygen consumption and glucose metabolism in primary degenerative dementia

    Energy Technology Data Exchange (ETDEWEB)

    Kuwabara, Yasuo; Ichiya, Yuichi; Ichimiya, Atsushi; Sasaki, Masayuki; Akashi, Yuko; Yoshida, Tsuyoshi; Fukumura, Toshimitsu; Masada, Kouji [Kyushu Univ., Fukuoka (Japan). Faculty of Medicine

    1995-03-01

    The CBF, CMRO{sub 2} and CMRGlu were measured in patients with primary degenerative dementia including 5 patients with dementia of Alzheimer`s type and 4 patients with Pick`s disease, and then the correlation between the cerebral blood flow and energy metabolism was evaluated. The control subjects consisted of 5 age-matched normal volunteers. The CBF, CMRO{sub 2} and CMRGlu decreased in the bilateral frontal, temporal and parietal regions in the patients with Alzheimer`s dementia, while they decreased in the bilateral frontal and temporal regions in the patients with Pick`s disease. Both the CBF and CMRO{sub 2} were closely correlated with each other. However, the CMRGlu was more severely impaired than the CBF or CMRO{sub 2} in both pathological conditions. These results suggested that CMRGlu began to decrease before the reduction of the aerobic metabolism and thus measuring the CMRGlu is considered to be the most sensitive method for detecting abnormal regions in primary degenerative dementia. (author).

  9. 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

    The scaffolding protein PICK1 (protein interacting with C kinase 1) contains an N-terminal PSD-95/Discs large/ZO-1 (PDZ) domain and a central lipid-binding Bin/amphiphysin/Rvs (BAR) domain. PICK1 is thought to regulate trafficking of its PDZ binding partners but different and even opposing...... functions have been suggested. Here, we apply ELISA-based assays and confocal microscopy in HEK293 cells with inducible PICK1 expression to assess in an isolated system the ability of PICK1 to regulate trafficking of natural and engineered PDZ binding partners. The dopamine transporter (DAT), which...

  10. Cherry Picking Robot Vision Recognition System Based on OpenCV

    Directory of Open Access Journals (Sweden)

    Zhang Qi Rong

    2016-01-01

    Full Text Available Through OpenCV function, the cherry in a natural environment image after image preprocessing, color recognition, threshold segmentation, morphological filtering, edge detection, circle Hough transform, you can draw the cherry’s center and circular contour, to carry out the purpose of the machine picking. The system is simple and effective.

  11. Brushes and picks used on nails during the surgical scrub to reduce bacteria: a randomised trial.

    Science.gov (United States)

    Tanner, J; Khan, D; Walsh, S; Chernova, J; Lamont, S; Laurent, T

    2009-03-01

    Though brushes are no longer used on the hands and forearms during the surgical scrub, they are still widely used on the nails. The aim of this study was to determine whether nail picks and nail brushes are effective in providing additional decontamination during a surgical hand scrub. A total of 164 operating department staff were randomised to undertake one of the following three surgical hand-scrub protocols: chlorhexidine only; chlorhexidine and a nail pick; or chlorhexidine and a nail brush. Bacterial hand sampling was conducted before and 1h after scrubbing using a modified version of the glove juice method. No statistically significant differences in bacterial numbers were found between any two of the three intervention groups. Nail brushes and nail picks used during surgical hand scrubs do not decrease bacterial numbers and are unnecessary.

  12. Executive functioning and risk-taking behavior in Parkinson's disease patients with impulse control disorders.

    Science.gov (United States)

    Pineau, Fanny; Roze, Emmanuel; Lacomblez, Lucette; Bonnet, Anne-Marie; Vidailhet, Marie; Czernecki, Virginie; Corvol, Jean-Christophe

    2016-06-01

    Impulse control disorders (ICD) are common in Parkinson's disease (PD) and are associated with dopaminergic medication. The purpose of this study was to investigate executive function and risk-taking behavior in PD patients with ICD. 17 PD patients with ICD (ICD-PD) were compared to 20 PD patients without ICD (CTRL-PD) using neuropsychological and experimental tasks. Executive functions were assessed using standard executive testing (Conner's Performance Test, Modified Wisconsin Card Sorting Test, Trail Making Test and phonological verbal fluency). Subjects were also submitted to an experimental gambling task consisted of three decks of money cards: neutral deck (equal opportunity for gains as losses), winning deck (small amount of money with a positive balance) and loser deck (high amount of money with a negative balance), evaluating risk-taking behavior (number of cards picked in each deck) and valuation of the reward (subjective appreciation of the value of each deck). There was no significant difference in executive functioning between groups. Both groups selected more cards in the losing deck (high amount of money) as compared to the neutral deck (Mann-Whitney test, ICD-PD, p = 0.02; CTRL-PD, p = 0.003) and to the winning deck (Mann-Whitney test, ICD-PD p = 0.0001; CTRL-PD p = 0.003), suggesting an increased risk-taking behavior. Interestingly, we found that ICD-PD patients estimated the value of decks differently from CTRL-PD patients, taking into account mainly the positive reinforced value of the decks (Mann-Whitney test, p = 0.04). This study showed that executive pattern and risk-taking behavior are similar between ICD-PD and CTRL-PD patients. However, ICD-PD patients showed a specific deficit of the subjective estimation of the reward. Links between this deficit and metacognitive skills are discussed.

  13. The ATLAS beam pick-up based timing system

    International Nuclear Information System (INIS)

    Ohm, C.; Pauly, T.

    2010-01-01

    The ATLAS BPTX stations are composed of electrostatic button pick-up detectors, located 175 m away along the beam pipe on both sides of ATLAS. The pick-ups are installed as a part of the LHC beam instrumentation and used by ATLAS for timing purposes. The usage of the BPTX signals in ATLAS is twofold: they are used both in the trigger system and for LHC beam monitoring. The BPTX signals are discriminated with a constant-fraction discriminator to provide a Level-1 trigger when a bunch passes through ATLAS. Furthermore, the BPTX detectors are used by a stand-alone monitoring system for the LHC bunches and timing signals. The BPTX monitoring system measures the phase between collisions and clock with a precision better than 100 ps in order to guarantee a stable phase relationship for optimal signal sampling in the sub-detector front-end electronics. In addition to monitoring this phase, the properties of the individual bunches are measured and the structure of the beams is determined. On September 10, 2008, the first LHC beams reached the ATLAS experiment. During this period with beam, the ATLAS BPTX system was used extensively to time in the read-out of the sub-detectors. In this paper, we present the performance of the BPTX system and its measurements of the first LHC beams.

  14. Hodgkin's disease: Analysis of 75 patients

    International Nuclear Information System (INIS)

    Akram, M.; Cheema, M. H.; Sana, S.; Aziz, Z.

    2001-01-01

    Objective: To evaluate patients suffering from Hodgkin's disease to identify its epidemiological characteristics, modalities of treatment and features of survival. Place and Duration of Study: The study was conducted between July 1997 to June 1999 at the Oncology Department of Jinnah Hospital, Lahore. Subjects and Methods: A total 75 patient with Hodgkin's disease underwent Cotswold staging classification, complete hematological, renal and hepatic profile, LDH and uric acid. Chest radiograph abdominal and pelvic ultrasonography and CT scan/MRI bone marrow biopsies. All the patients received combination chemotherapy. Patients with bulky disease received field radiation. Results: Median age was eight ( 18 years). Male to female ratio was 3.5:1, advanced disease accounted for 68%, mixed cellularity was documented in 61% of patients. Eighty-two percent of patients belonged to lower socioeconomic strata. Forty-six patients (65.4%) achieved complete remission (CR) Major toxicities were hematological with febrile neutropenia in 14.6% patients. OS of patients achieving CR with good socioeconomic status was superior compared to patients with lower socioeconomic status (p<0.02). Treatment delays were due to economic constraints, illiteracy, malnutrition and co-morbid conditions. Conclusion: Advanced disease, mixed cellularity and male predominance was common. Socioeconomic status had a significant impact on the presentation of the disease. Poor tolerance to chemotherapy and enhanced toxicities are especially seen in the low socioeconomic group. (author)

  15. 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...

  16. Green Grape Detection and Picking-Point Calculation in a Night-Time Natural Environment Using a Charge-Coupled Device (CCD Vision Sensor with Artificial Illumination

    Directory of Open Access Journals (Sweden)

    Juntao Xiong

    2018-03-01

    Full Text Available Night-time fruit-picking technology is important to picking robots. This paper proposes a method of night-time detection and picking-point positioning for green grape-picking robots to solve the difficult problem of green grape detection and picking in night-time conditions with artificial lighting systems. Taking a representative green grape named Centennial Seedless as the research object, daytime and night-time grape images were captured by a custom-designed visual system. Detection was conducted employing the following steps: (1 The RGB (red, green and blue. Color model was determined for night-time green grape detection through analysis of color features of grape images under daytime natural light and night-time artificial lighting. The R component of the RGB color model was rotated and the image resolution was compressed; (2 The improved Chan–Vese (C–V level set model and morphological processing method were used to remove the background of the image, leaving out the grape fruit; (3 Based on the character of grape vertical suspension, combining the principle of the minimum circumscribed rectangle of fruit and the Hough straight line detection method, straight-line fitting for the fruit stem was conducted and the picking point was calculated using the stem with an angle of fitting line and vertical line less than 15°. The visual detection experiment results showed that the accuracy of grape fruit detection was 91.67% and the average running time of the proposed algorithm was 0.46 s. The picking-point calculation experiment results showed that the highest accuracy for the picking-point calculation was 92.5%, while the lowest was 80%. The results demonstrate that the proposed method of night-time green grape detection and picking-point calculation can provide technical support to the grape-picking robots.

  17. Prevalence and overlap of Disease Management Program diseases in older hospitalized patients

    DEFF Research Database (Denmark)

    Juul-Larsen, Helle Gybel; Petersen, Janne; Sivertsen, Ditte Maria

    2017-01-01

    Many countries, like Denmark, have tailored Disease Management Programs (DMPs) based on patients having single chronic diseases [defined institutionally as "program diseases" (PDs)], which can complicate treatment for those with multiple chronic diseases. The aims of this study were (a) to assess...... the prevalence and overlap among acutely hospitalized older medical patients of PDs defined by the DMPs, and (b) to examine transitions between different departments during hospitalization and mortality and readmission within two time intervals among patients with the different PDs. We conducted a registry study...... of 4649 acutely hospitalized medical patients ≥65 years admitted to Copenhagen University Hospital, Hvidovre, Denmark, in 2012, and divided patients into six PD groups (type 2 diabetes, chronic obstructive pulmonary disease, cardiovascular disease, musculoskeletal disease, dementia and cancer), each...

  18. Dispatched and scube mediate the efficient secretion of the cholesterol-modified hedgehog ligand.

    Science.gov (United States)

    Tukachinsky, Hanna; Kuzmickas, Ryan P; Jao, Cindy Y; Liu, Jing; Salic, Adrian

    2012-08-30

    The Hedgehog (Hh) signaling pathway plays critical roles in metazoan development and in cancer. How the Hh ligand is secreted and spreads to distant cells is unclear, given its covalent modification with a hydrophobic cholesterol molecule, which makes it stick to membranes. We demonstrate that Hh ligand secretion from vertebrate cells is accomplished via two distinct and synergistic cholesterol-dependent binding events, mediated by two proteins that are essential for vertebrate Hh signaling: the membrane protein Dispatched (Disp) and a member of the Scube family of secreted proteins. Cholesterol modification is sufficient for a heterologous protein to interact with Scube and to be secreted in a Scube-dependent manner. Disp and Scube recognize different structural aspects of cholesterol similarly to how Niemann-Pick disease proteins 1 and 2 interact with cholesterol, suggesting a hand-off mechanism for transferring Hh from Disp to Scube. Thus, Disp and Scube cooperate to dramatically enhance the secretion and solubility of the cholesterol-modified Hh ligand. Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Comparative analysis of acid sphingomyelinase distribution in the CNS of rats and mice following intracerebroventricular delivery.

    Directory of Open Access Journals (Sweden)

    Christopher M Treleaven

    Full Text Available Niemann-Pick A (NPA disease is a lysosomal storage disorder (LSD caused by a deficiency in acid sphingomyelinase (ASM activity. Previously, we reported that biochemical and functional abnormalities observed in ASM knockout (ASMKO mice could be partially alleviated by intracerebroventricular (ICV infusion of hASM. We now show that this route of delivery also results in widespread enzyme distribution throughout the rat brain and spinal cord. However, enzyme diffusion into CNS parenchyma did not occur in a linear dose-dependent fashion. Moreover, although the levels of hASM detected in the rat CNS were determined to be within the range shown to be therapeutic in ASMKO mice, the absolute amounts represented less than 1% of the total dose administered. Finally, our results also showed that similar levels of enzyme distribution are achieved across rodent species when the dose is normalized to CNS weight as opposed to whole body weight. Collectively, these data suggest that the efficacy observed following ICV delivery of hASM in ASMKO mice could be scaled to CNS of the rat.

  20. Skin picking disorder with co-occurring body dysmorphic disorder

    DEFF Research Database (Denmark)

    Grant, Jon E; Redden, Sarah A; Leppink, Eric W

    2015-01-01

    There is clinical overlap between skin picking disorder (SPD) and body dysmorphic disorder (BDD), but little research has examined clinical and cognitive correlates of the two disorders when they co-occur. Of 55 participants with SPD recruited for a neurocognitive study and two pharmacological st...... unique clinical and cognitive aspects of SPD may be more pronounced. Future work should explore possible subgroups in SPD and whether these predict different treatment outcomes....

  1. Nanorobotic Manipulation Setup for Pick-and-Place Handling and non-destructive Characterization of Carbon Nanotubes

    DEFF Research Database (Denmark)

    Eicchorn, V.; Carlson, Kenneth; Andersen, Karin Nordström

    2007-01-01

    . The pick-and-place task is carried out by using an electrothermal actuated microgripper, designed for controlled manipulation of nanotubes. The nanotube is picked up from an array of multiwalled carbon nanotubes (MWCNTs) and transferred to the tip of an atomic force microscope (AFM) probe in order...... to assemble a high-aspect ratio AFM supertip. Another application of the nanorobotic setup considered in this paper is the nondestructive mechanical characterization of CNTs. A piezoresistive AFM probe is used to bend MWCNTs, while the bending force is measured, in order to estimate the Young's modulus...

  2. Sodium Pick-Up Ion Observations in the Solar Wind Upstream of Mercury

    Science.gov (United States)

    Jasinski, J. M.; Raines, J. M.; Slavin, J. A.; Regoli, L. R.; Murphy, N.

    2018-05-01

    We present the first observations of sodium pick-up ions upstream of Mercury’s magnetosphere. From these observations we infer properties of Mercury’s sodium exosphere and implications for the solar wind interaction with Mercury’s magnetosphere.

  3. Seasonal variation of Martian pick-up ions: Evidence of breathing exosphere

    Science.gov (United States)

    Yamauchi, M.; Hara, T.; Lundin, R.; Dubinin, E.; Fedorov, A.; Sauvaud, J.-A.; Frahm, R. A.; Ramstad, R.; Futaana, Y.; Holmstrom, M.; Barabash, S.

    2015-12-01

    The Mars Express (MEX) Ion Mass Analyser (IMA) found that the detection rate of the ring-like distribution of protons in the solar wind outside of the bow shock to be quite different between Mars orbital summer (around perihelion) and orbital winter (around aphelion) for four Martian years, while the north-south asymmetry is much smaller than the perihelion-aphelion difference. Further analyses using eight years of MEX/IMA solar wind data between 2005 and 2012 has revealed that the detection frequency of the pick-up ions originating from newly ionized exospheric hydrogen with certain flux strongly correlates with the Sun-Mars distance, which changes approximately every two years. Variation due to the solar cycle phase is not distinguishable partly because this effect is masked by the seasonal variation under the MEX capability of plasma measurements. This finding indicates that the variation in solar UV has a major effect on the formation of the pick-up ions, but this is not the only controlling factor.

  4. Testbeam Studies on Pick-Up in Sensors with Embedded Pitch Adapters

    CERN Document Server

    Rehnisch, Laura; The ATLAS collaboration

    2018-01-01

    Embedded pitch adapters are an alternative solution to external pitch adapters widely used to facilitate the wire-bonding step when connecting silicon strip sensors and readout electronics of different pitch. The pad-pitch adaption can be moved into the sensor fabrication step by implementing a second layer of metal tracks, connected by vias to the primary metal layer of sensor strips. Such a solution, however, might bear the risk of performance losses introduced by various phenomena. One of these effects, the undesired capacitive coupling between the silicon bulk and this second metal layer (pick-up) has been investigated in photon testbeam measurements. For a worst-case embedded pitch adapter design, expected to be maximally susceptible to pick-up, a qualitative analysis has visualized the effect as a function of the location on the second metal layer structure. It was further found that the unwanted effect decreases towards expected values for operating thresholds of the binary readout used. Suggestions fo...

  5. Automatic first-arrival picking based on extended super-virtual interferometry with quality control procedure

    Science.gov (United States)

    An, Shengpei; Hu, Tianyue; Liu, Yimou; Peng, Gengxin; Liang, Xianghao

    2017-12-01

    Static correction is a crucial step of seismic data processing for onshore play, which frequently has a complex near-surface condition. The effectiveness of the static correction depends on an accurate determination of first-arrival traveltimes. However, it is difficult to accurately auto-pick the first arrivals for data with low signal-to-noise ratios (SNR), especially for those measured in the area of the complex near-surface. The technique of the super-virtual interferometry (SVI) has the potential to enhance the SNR of first arrivals. In this paper, we develop the extended SVI with (1) the application of the reverse correlation to improve the capability of SNR enhancement at near-offset, and (2) the usage of the multi-domain method to partially overcome the limitation of current method, given insufficient available source-receiver combinations. Compared to the standard SVI, the SNR enhancement of the extended SVI can be up to 40%. In addition, we propose a quality control procedure, which is based on the statistical characteristics of multichannel recordings of first arrivals. It can auto-correct the mispicks, which might be spurious events generated by the SVI. This procedure is very robust, highly automatic and it can accommodate large data in batches. Finally, we develop one automatic first-arrival picking method to combine the extended SVI and the quality control procedure. Both the synthetic and the field data examples demonstrate that the proposed method is able to accurately auto-pick first arrivals in seismic traces with low SNR. The quality of the stacked seismic sections obtained from this method is much better than those obtained from an auto-picking method, which is commonly employed by the commercial software.

  6. Intracellular Cholesterol Trafficking and Impact in Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Fabian Arenas

    2017-11-01

    Full Text Available Cholesterol is a critical component of membrane bilayers where it plays key structural and functional roles by regulating the activity of diverse signaling platforms and pathways. Particularly enriched in brain, cholesterol homeostasis in this organ is singular with respect to other tissues and exhibits a heterogeneous regulation in distinct brain cell populations. Due to the key role of cholesterol in brain physiology and function, alterations in cholesterol homeostasis and levels have been linked to brain diseases and neurodegeneration. In the case of Alzheimer disease (AD, however, this association remains unclear with evidence indicating that either increased or decreased total brain cholesterol levels contribute to this major neurodegenerative disease. Here, rather than analyzing the role of total cholesterol levels in neurodegeneration, we focus on the contribution of intracellular cholesterol pools, particularly in endolysosomes and mitochondria through its trafficking via specialized membrane domains delineated by the contacts between endoplasmic reticulum and mitochondria, in the onset of prevalent neurodegenerative diseases such as AD, Parkinson disease, and Huntington disease as well as in lysosomal disorders like Niemann-Pick type C disease. We dissect molecular events associated with intracellular cholesterol accumulation, especially in mitochondria, an event that results in impaired mitochondrial antioxidant defense and function. A better understanding of the mechanisms involved in the distribution of cholesterol in intracellular compartments may shed light on the role of cholesterol homeostasis disruption in neurodegeneration and may pave the way for specific intervention opportunities.

  7. Rheumatic Disease Autoantibodies in Patients with Autoimmune Thyroid Diseases.

    Science.gov (United States)

    Nisihara, Renato; Pigosso, Yasmine; Prado, Nathalia; Utiyama, Shirley R R; Carvalho, Gisah; Skare, Thelma

    2018-06-04

    Patients with autoimmune thyroid diseases (ATD) such as Graves' disease (GD) and Hashimoto thyroiditis (HT) may have non-organ specific autoantibodies such as ANA (antinuclear antibodies) and RF (rheumatoid factor). To study the prevalence of rheumatic autoantibodies in a group of ATD patients without known rheumatic diseases and to evaluate its association with the patients' epidemiological and treatment profile. To follow positive non-organ specific autoantibody-positive ATD individuals to investigate whether they will develop a rheumatic disorder. A sample of 154 ATD patients (70 HT and 84 GD; mean age 45.3 ± 14.2) had determination of ANA by immunofluorescence, using hep-2 cells as substrate, extractable nuclear antigen (ENA) profile by ELISA kits and RF by latex agglutination. Epidemiological and treatment profile were obtained through chart review. These patients were followed for the mean period of five years, between 2010 to 2015. Positive ANA was found in 17.5% (27/154) of the patients: anti-Ro/SS-A in 4/154 (2.5%); anti-RNP in 4/154 (2.5%) and anti-La/SS-B in 3/154 (1.9%). None had anti-Sm antibodies. RF was detected in 12/154 (7.7%) of ATD patients and was more common in older individuals (p = 0.007). There was a positive association between the presence of RF and ANA (p = 0.03; OR = 3.89; 95% CI = 1.1-13.3). None of the patients with positive autoantibodies developed clinical rheumatic diseases during the period of observation. We found rheumatic autoantibodies in 17.5% of ATD patients without rheumatic diseases. None of them were associated with the appearance of clinical rheumatic disorder during the period of five years. ©2018The Author(s). Published by S. Karger AG, Basel.

  8. Moyamoya Disease – a Vasculopahty and an Uncommon Cause of Recurrent Cerebrovascular Accidents

    Directory of Open Access Journals (Sweden)

    Yasmin S Hamirani

    2008-09-01

    Full Text Available

    Moyamoya disease is a very rare chronic cerebrovascular disease of unknown etiology characterized by recurrent ischemic or hemorrhagic strokes. Initially diagnosed in Japan and named after finding puff of smoke like collateral blood vessels around the occluded blood vessels of circle of Willis. With increase awareness this disease is now diagnosed more often. Medical and surgical treatment have been used to treat the disease, with surgical treatment been mostly experimental. Special attention should be given to the surgical treatment which has shown to have an edge over the medical treatment in some clinical trials especially in young patients with recurrent strokes to prevent progressive cognitive decline and to improve their quality of life. In our patient, who is a young man, the diagnosis was picked up late and when surgical evaluation was performed, it was considered to be fruitless with findings of nonviable brain tissue on MRI imaging.

  9. 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 a...... lipid binding and/or polymerization capacity. We propose that PICK1 is phosphorylated at Ser77 by PKCα preferentially when bound to membrane vesicles and that this phosphorylation in turn modulates its cellular distribution....

  10. Determining The Optimal Order Picking Batch Size In Single Aisle Warehouses

    NARCIS (Netherlands)

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

    2002-01-01

    textabstractThis work aims at investigating the influence of picking batch size to average time in system of orders in a one-aisle warehouse under the assumption that order arrivals follow a Poisson process and items are uniformly distributed over the aisle's length. We model this problem as an

  11. Analysis of action of device with spring pins for picking up of retted flax straw

    Directory of Open Access Journals (Sweden)

    V. G. Chernikov

    2016-01-01

    Full Text Available Weather conditions in flax cultivation areas during harvesting time can be characterized with high rainfalls, relative humidity and, in some areas, extremely low temperature. Clogging of fields with stones, grass germination through flax swaths, often an absence of homogeneity on length and thickness of straw in swaths require working out new devices for straw lifting. Existing devices for picking up do not provide a high-quality lifting of flax swaths and have a low coefficient of reliability of the process. Researches and experimental-design works were carried out to create a constructive-technological scheme of the picking up device of cylindrical type with spring-loaded rigid pins. The mathematical model of the device operation when a pin touching an obstacle. The condition of balance of the mechanism under which the pin of a cilinder will operate technological process of picking up of retted flax straw without action of the safety device (spring was described. The offered method of calculation of operation of this device was introduced in a common flax swath lifter-turners

  12. Pick-up Lines”: A Fun Way to Facilitate Learning Microbiological Concepts

    Directory of Open Access Journals (Sweden)

    Thomas Edison E. dela Cruz

    2014-05-01

    Full Text Available Learning microbiology can be made fun by writing funny lines related to microbiology. Students were tasked to create their own pick-up lines and explain these based on their understanding of the basic concepts in microbiology.

  13. Understanding Human Hand Gestures for Learning Robot Pick-and-Place Tasks

    Directory of Open Access Journals (Sweden)

    Hsien-I Lin

    2015-05-01

    Full Text Available Programming robots by human demonstration is an intuitive approach, especially by gestures. Because robot pick-and-place tasks are widely used in industrial factories, this paper proposes a framework to learn robot pick-and-place tasks by understanding human hand gestures. The proposed framework is composed of the module of gesture recognition and the module of robot behaviour control. For the module of gesture recognition, transport empty (TE, transport loaded (TL, grasp (G, and release (RL from Gilbreth's therbligs are the hand gestures to be recognized. A convolution neural network (CNN is adopted to recognize these gestures from a camera image. To achieve the robust performance, the skin model by a Gaussian mixture model (GMM is used to filter out non-skin colours of an image, and the calibration of position and orientation is applied to obtain the neutral hand pose before the training and testing of the CNN. For the module of robot behaviour control, the corresponding robot motion primitives to TE, TL, G, and RL, respectively, are implemented in the robot. To manage the primitives in the robot system, a behaviour-based programming platform based on the Extensible Agent Behavior Specification Language (XABSL is adopted. Because the XABSL provides the flexibility and re-usability of the robot primitives, the hand motion sequence from the module of gesture recognition can be easily used in the XABSL programming platform to implement the robot pick-and-place tasks. The experimental evaluation of seven subjects performing seven hand gestures showed that the average recognition rate was 95.96%. Moreover, by the XABSL programming platform, the experiment showed the cube-stacking task was easily programmed by human demonstration.

  14. Wireless Monitoring for Patients with Cardiovascular Diseases and Parkinson's Disease.

    Science.gov (United States)

    Kefaliakos, Antonios; Pliakos, Ioannis; Charalampidou, Martha; Diomidous, Marianna

    2016-01-01

    The use of applications for mobile devices and wireless sensors is common for the sector of telemedicine. Recently various studies and systems were developed in order to help patients suffering from severe diseases such as cardiovascular diseases and Parkinson's disease. They present a challenge for the sector because such systems demand the flow of accurate data in real time and the use of specialized sensors. In this review will be presented some very interesting applications developed for patients with cardiovascular diseases and Parkinson's disease.

  15. 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.

  16. Host-Primed Ebola Virus GP Exposes a Hydrophobic NPC1 Receptor-Binding Pocket, Revealing a Target for Broadly Neutralizing Antibodies.

    Science.gov (United States)

    Bornholdt, Zachary A; Ndungo, Esther; Fusco, Marnie L; Bale, Shridhar; Flyak, Andrew I; Crowe, James E; Chandran, Kartik; Saphire, Erica Ollmann

    2016-02-23

    The filovirus surface glycoprotein (GP) mediates viral entry into host cells. Following viral internalization into endosomes, GP is cleaved by host cysteine proteases to expose a receptor-binding site (RBS) that is otherwise hidden from immune surveillance. Here, we present the crystal structure of proteolytically cleaved Ebola virus GP to a resolution of 3.3 Å. We use this structure in conjunction with functional analysis of a large panel of pseudotyped viruses bearing mutant GP proteins to map the Ebola virus GP endosomal RBS at molecular resolution. Our studies indicate that binding of GP to its endosomal receptor Niemann-Pick C1 occurs in two distinct stages: the initial electrostatic interactions are followed by specific interactions with a hydrophobic trough that is exposed on the endosomally cleaved GP1 subunit. Finally, we demonstrate that monoclonal antibodies targeting the filovirus RBS neutralize all known filovirus GPs, making this conserved pocket a promising target for the development of panfilovirus therapeutics. Ebola virus uses its glycoprotein (GP) to enter new host cells. During entry, GP must be cleaved by human enzymes in order for receptor binding to occur. Here, we provide the crystal structure of the cleaved form of Ebola virus GP. We demonstrate that cleavage exposes a site at the top of GP and that this site binds the critical domain C of the receptor, termed Niemann-Pick C1 (NPC1). We perform mutagenesis to find parts of the site essential for binding NPC1 and map distinct roles for an upper, charged crest and lower, hydrophobic trough in cleaved GP. We find that this 3-dimensional site is conserved across the filovirus family and that antibody directed against this site is able to bind cleaved GP from every filovirus tested and neutralize viruses bearing those GPs. Copyright © 2016 Bornholdt et al.

  17. Adult Congenital Heart Disease Patients Experience Similar Symptoms of Disease Activity.

    Science.gov (United States)

    Cedars, Ari M; Stefanescu Schmidt, Ada; Broberg, Craig; Zaidi, Ali; Opotowsky, Alexander; Grewal, Jasmine; Kay, Joseph; Bhatt, Ami B; Novak, Eric; Spertus, John

    2016-03-01

    There is a lack of objective data on the symptoms characterizing disease activity among adults with congenital heart disease (ACHD). The purpose of this study was to elicit the most important symptoms from patients across the spectrum of ACHD and to examine whether reported symptoms were similar across the spectrum of ACHD as a foundation for creating a patient-reported outcome measure(s). We constructed a 39-item survey using input from physicians specializing in ACHD to assess the symptoms patients associate with disease activity. Patients (n=124) prospectively completed this survey, and the results were analyzed based on underlying anatomy and disease complexity. A confirmatory cohort of patients (n=40) was then recruited prospectively to confirm the validity of the initial data. When grouped based on underlying anatomy, significant differences in disease-related symptom rankings were found for only 6 of 39 symptoms. Six symptoms were identified which were of particular significance to patients, regardless of underlying anatomy. Patients with anatomy of great complexity experienced greater overall symptom severity than those with anatomy of low or moderate complexity, attributable exclusively to higher ranking of 5 symptoms. The second patient cohort had symptom experiences similar to those of the initial cohort, differing in only 5 of 39 symptoms. This study identified 6 symptoms relevant to patients across the spectrum of ACHD and remarkable homogeneity of patient experience, suggesting that a single disease-specific patient-reported outcome can be created for quality and outcome assessments. © 2016 American Heart Association, Inc.

  18. An automated framework for NMR resonance assignment through simultaneous slice picking and spin system forming

    KAUST Repository

    Abbas, Ahmed

    2014-04-19

    Despite significant advances in automated nuclear magnetic resonance-based protein structure determination, the high numbers of false positives and false negatives among the peaks selected by fully automated methods remain a problem. These false positives and negatives impair the performance of resonance assignment methods. One of the main reasons for this problem is that the computational research community often considers peak picking and resonance assignment to be two separate problems, whereas spectroscopists use expert knowledge to pick peaks and assign their resonances at the same time. We propose a novel framework that simultaneously conducts slice picking and spin system forming, an essential step in resonance assignment. Our framework then employs a genetic algorithm, directed by both connectivity information and amino acid typing information from the spin systems, to assign the spin systems to residues. The inputs to our framework can be as few as two commonly used spectra, i.e., CBCA(CO)NH and HNCACB. Different from the existing peak picking and resonance assignment methods that treat peaks as the units, our method is based on \\'slices\\', which are one-dimensional vectors in three-dimensional spectra that correspond to certain (N, H) values. Experimental results on both benchmark simulated data sets and four real protein data sets demonstrate that our method significantly outperforms the state-of-the-art methods while using a less number of spectra than those methods. Our method is freely available at http://sfb.kaust.edu.sa/Pages/Software.aspx. © 2014 Springer Science+Business Media.

  19. [Hypothyroidism in patients with heart disease].

    Science.gov (United States)

    Jiskra, Jan

    Hypothyroidism is frequently found in patients with heart disease. It is a risk factor for atherosclerosis and ischemic heart disease and has a direct negative effect on both the left and right ventricular functions (hypothyroidism-induced cardiomyopathy). The confirmed manifest hypothyroidism is always a reason for replacement therapy with levothyroxine; regarding patients with heart disease, we always begin treatment with a small dose and increase it gradually. The treatment of subclinical hypothyroidism in patients with heart disease is disputable and its benefits probably depend on age. At a higher age, the therapy-related risks often outweigh its benefits, so we make do with the target levels of the thyroid stimulating hormone being within the upper band of the normal range, or even slightly above it, rather than overdosing the patient. To summarize in a simplified way, the treatment of subclinical hypothyroidism in patients with heart disease is the most effective in younger individuals, mainly those aged below 65, while at a higher age > 80 years the risk usually outweighs the benefit.Key words: cardiovascular risk - hypothyroidism - ischemic heart disease - left ventricular dysfunction - right ventricular dysfunction - subclinical hypothyroidism - thyroid peroxidase antibodies.

  20. The Quality of Rambak Cracker from Rabbit Skin (Water Content and Swelling Power using The Different Technique of Fur Picking

    Directory of Open Access Journals (Sweden)

    Dedes Amertaningtyas

    2014-11-01

    Full Text Available This objective of this researchwas to compare the different technique of fur picking (liming and boiling inthe quality rambak cracker from rabbit skin on water content and swelling power.Materials of this research were 20 drying rabbit skin 5 – 6 months old. The tTest was using to compare the different technique of fur picking. Theindependent variables of this research were water content and swelling power onrambak cracker from rabbit skin. The result showed that the different techniqueof fur picking had highly significant effect (P<0.01 on water content and  expanding rate. The best result was limingtechnique of fur picking. It had the following properties: Water content of 1.5922% and expending rate of 855.3798 %. The conclusion showed that the use limingof 4% produced high quality of rambak cracker from rabbit skin or anotheranimal skin (cow, buffalo, chicken or fish. Keywords: rambak cracker, rabbit skin, water content,expanding rate

  1. Perbandingan Algoritma Simulated Annealing dan Harmony Search dalam Penerapan Picking Order Sequence

    Directory of Open Access Journals (Sweden)

    Tanti Octavia

    2017-12-01

    Full Text Available Implementation of mobile rack warehouse is commonly used in manufacturing industry because it can minimize the warehouse area used. Applying picking orders in taking of Stock Keeping Unit (SKU on mobile rack warehouses could give fast loading order. This research aims to find out which algorithm is better in applying picking order sequence in mobile rack warehouse. The algorithm used is Simualted Annealing (SA and Harmony Search (HS algorithm. Both of these algorithms will be compared in terms of the gap with the shortest path method.The result shows that the HS algorithm produces a better solution than the SA algorithm with lower CPU time, but the convergence rate of HS is lower than that of SA.HS was able to produce a better solution than the shortest path method of 9 cases, while SA only 8 cases from 15 cases.

  2. Pick up screens for x-ray image intensifier tubes employing evaporated activated scintillator layer

    International Nuclear Information System (INIS)

    Spicer, W.E.

    1976-01-01

    The present invention relates in general to methods for making pick-up screens for x-ray image intensifier tubes and, more particularly, to an improved method wherein the x-ray fluorescent phosphor screen element is formed by evaporation of an alkali metal halide material in vacuum and condensing the evaporated material on an x-ray transparent portion of the x-ray intensifier tube, whereby a curved x-ray image pick-up screen is formed which has improved quantum efficiency and resolution. Such improved x-ray image intensifier tubes are especially useful for, but not limited in use to x-ray systems and for intensifying gamma ray images obtained in applications of nuclear medicine. 7 claims, 5 drawing figures

  3. A comparative study on fluorescent cholesterol analogs as versatile cellular reporters

    DEFF Research Database (Denmark)

    Sezgin, Erdinc; Betul Can, Fatma; Schneider, Falk

    2016-01-01

    Cholesterol is a crucial component of cellular membranes, but knowledge of its intracellular dynamics is scarce. Thus, it is of utmost interest to develop tools for visualization of cholesterol organization and dynamics in cells and tissues. For this purpose, many studies make use of fluorescently...... for their performance in cellular assays: 1) plasma membrane incorporation, specifically the preference for more ordered membrane environments in phase separated giant unilamellar vesicles (GUVs) and giant plasma membrane vesicles (GPMVs); 2) cellular trafficking, specifically subcellular localization in Niemann-Pick C...... in the intracellular trafficking assay. However, none showed positive performance in all assays. Our results constitute a concise guide for the careful use of fluorescent cholesterol analogs in visualizing cellular cholesterol dynamics....

  4. Mortality in patients with pituitary disease.

    LENUS (Irish Health Repository)

    Sherlock, Mark

    2010-06-01

    Pituitary disease is associated with increased mortality predominantly due to vascular disease. Control of cortisol secretion and GH hypersecretion (and cardiovascular risk factor reduction) is key in the reduction of mortality in patients with Cushing\\'s disease and acromegaly, retrospectively. For patients with acromegaly, the role of IGF-I is less clear-cut. Confounding pituitary hormone deficiencies such as gonadotropins and particularly ACTH deficiency (with higher doses of hydrocortisone replacement) may have a detrimental effect on outcome in patients with pituitary disease. Pituitary radiotherapy is a further factor that has been associated with increased mortality (particularly cerebrovascular). Although standardized mortality ratios in pituitary disease are falling due to improved treatment, mortality for many conditions are still elevated above that of the general population, and therefore further measures are needed. Craniopharyngioma patients have a particularly increased risk of mortality as a result of the tumor itself and treatment to control tumor growth; this is a key area for future research in order to optimize the outcome for these patients.

  5. Prevalence of mucocutaneous findings in Celiac disease patients

    Directory of Open Access Journals (Sweden)

    Derya Yayla

    2015-12-01

    Full Text Available Background and Design: Celiac disease is an immune-mediated enteropathy which develops as a result of exposure to gluten in food products in individuals with a genetic predisposition. Gastrointestinal and extra-gastrointestinal clinical findings can be seen in these patients. An increased frequence of autoimmune diseases has been reported in patients with celiac disease. Some dermatological diseases, such as dermatitis herpetiformis, vitiligo, psoriasis, alopecia areata and recurrent aphthous stomatitis have been reported to be more common among patients with celiac disease. However, there are no controlled studies on this subject. The aim of this study was to identify the mucocutaneous symptoms seen in celiac patients and to compare these findings with a control group. Materials and Methods: Forty-nine celiac patients and 54 age-and sex-matched healthy volunteers were included in the study. In the patient group, celiac disease history, height and weight parameters, the medications of the patients, compliance to a gluten-free diet, concomitant skin disorders and additional illnesses were questioned; height and weight parameters, diagnosed illnesses, and medications were questioned in the control group. Dermatological analyses were performed in all participants. Results: Mucocutaneous findings were found to be present in 38 patients (77.6% in the celiac patient group and in 31 (57.4% individuals in the control group. The presence of mucocutaneous findings in celiac patients was significantly more common than in the control group. While immune-mediated mucocutaneous diseases were detected in 8 celiac patients (16.3%, none of the individuals in the control group had immune-mediated mucocutaneous diseases and a statistically significant difference was found between the two groups. Conclusion: In celiac patients, the frequency of immune-mediated mucocutaneous diseases and all mucocutaneous diseases were found to be increased. Therefore, we suggest

  6. Comparing "pick and place" task in spatial Augmented Reality versus non-immersive Virtual Reality for rehabilitation setting.

    Science.gov (United States)

    Khademi, Maryam; Hondori, Hossein Mousavi; Dodakian, Lucy; Cramer, Steve; Lopes, Cristina V

    2013-01-01

    Introducing computer games to the rehabilitation market led to development of numerous Virtual Reality (VR) training applications. Although VR has provided tremendous benefit to the patients and caregivers, it has inherent limitations, some of which might be solved by replacing it with Augmented Reality (AR). The task of pick-and-place, which is part of many activities of daily living (ADL's), is one of the major affected functions stroke patients mainly expect to recover. We developed an exercise consisting of moving an object between various points, following a flash light that indicates the next target. The results show superior performance of subjects in spatial AR versus non-immersive VR setting. This could be due to the extraneous hand-eye coordination which exists in VR whereas it is eliminated in spatial AR.

  7. N-isopropyl I-123 p-iodoamphetamine (IMP) brain SPECT in Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Momose, Toshimitsu; Nishikawa, Junichi; Kosaka, Noboru; Ohtake, Tohru; Watanabe, Toshiaki; Yoshikawa, Kohki; Iio, Masahiro [Tokyo Univ. (Japan). Faculty of Medicine

    1989-09-01

    Eighteen patients with Alzheimer's disease (AD), 5 patients with Pick disease (PD), 6 patients with other types of degenerative dementia (O) and 12 age-matched normal control subjects (N) were studied using N-isopropyl p-(I-123)iodoamphetamine (I-123 IMP) with SPECT. Regional to cerebellar activity (R/CE) ratio and frontal to parietal (F/R) activity ratio were evaluated in each case. I-123 IMP-SPECT revealed focal abnormality in all cases in AD, PD, O group, while XCT and/or MRI were normal or showed cerebral atrophy without focal abnormal density or intensity. In AD group, R/CE ratio in all the regions except for bilateral Rolandic area and left primary visual cortex were significantly lower (p<0.05 or p<0.01) than that in N group, and F/P ratio were significantly higher (p<0.01) than that in P and O group. In conclusion, I-123 IMP-SPECT is useful to detect focal perfusion abnormality in dementia and may be of value in differentiating Alzheimer's disease from dementia of non-Alzheimer type. (author).

  8. N-isopropyl I-123 p-iodoamphetamine (IMP) brain SPECT in Alzheimer's disease

    International Nuclear Information System (INIS)

    Momose, Toshimitsu; Nishikawa, Junichi; Kosaka, Noboru; Ohtake, Tohru; Watanabe, Toshiaki; Yoshikawa, Kohki; Iio, Masahiro

    1989-01-01

    Eighteen patients with Alzheimer's disease (AD), 5 patients with Pick disease (PD), 6 patients with other types of degenerative dementia (O) and 12 age-matched normal control subjects (N) were studied using N-isopropyl p-[I-123]iodoamphetamine (I-123 IMP) with SPECT. Regional to cerebellar activity (R/CE) ratio and frontal to parietal (F/R) activity ratio were evaluated in each case. I-123 IMP-SPECT revealed focal abnormality in all cases in AD, PD, O group, while XCT and/or MRI were normal or showed cerebral atrophy without focal abnormal density or intensity. In AD group, R/CE ratio in all the regions except for bilateral Rolandic area and left primary visual cortex were significantly lower (p<0.05 or p<0.01) than that in N group, and F/P ratio were significantly higher (p<0.01) than that in P and O group. In conclusion, I-123 IMP-SPECT is useful to detect focal perfusion abnormality in dementia and may be of value in differentiating Alzheimer's disease from dementia of non-Alzheimer type. (author)

  9. Analysis of the Impact of Storage Parameters and the Size of Orders on the Choice of the Method for Routing Order Picking

    Directory of Open Access Journals (Sweden)

    Grzegorz Tarczyński

    2012-01-01

    Full Text Available The paper presents an analysis of the impact of the number of picking aisles, slots in a rack, the size of pick lists, and the routing method on the performance of the order picking process. In the analysis, the forklift truck's maneuvers such as turns back and turns aside, omitted by some scientists, are considered. Although only random storage assignment is examined in this paper, the possible congestion effect is considered. Experiments were performed by the use of simulations. (original abstract

  10. Laparoscopic ovum pick-up in spotted paca ( Cuniculus pacas )

    OpenAIRE

    Barros,F.F.P.C.; Teixeira,P.P.M.; Uscategui,R.A.R.; Coutinho,L.N.; Brito,M.B.S.; Kawanami,A.E.; Almeida,V.T.; Mariano,R.S.G.; Nociti,R.P.; Machado,M.R.F.; Vicente,W.R.R.

    2016-01-01

    ABSTRACT The aim of this work is study the laparoscopic ovum pick-up (LapOPU) technique in spotted paca, describing surgery details, complications and oocyte recovery rate. Nine healthy adult non-pregnant captive females were used, in a total of 39 procedures. When the surgical plane of anaesthesia was achieved, the females were positioned at 20º Trendelenburg. Three 6mm trocars were placed on right and left inguinal and hypogastric regions. Abdomen was inflated with CO2 and the intra-abdomin...

  11. The pick-up mechanism in composite particle emission processes

    International Nuclear Information System (INIS)

    Zhang Jingshang; Yan Shiwei; Wang Cuilan

    1992-01-01

    The pick-up mechanism has been included in the exciton model for the light composite particle emissions. Based on the cluster phase space integration method the formation probabilities of α,d,t, 3 He are obtained. The calculation results of (n,t) cross sections indicate that this theoretical method can reproduce the experimental data nicely. For triton emissions in pre-equilibrium reaction processes, the semi-direct reactions are the dominant terms which are just omitted in the previous model calculation

  12. 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....

  13. 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)

  14. ISCHEMIC HEART DISEASE IN PATIENTS OF CHRONIC KIDNEY DISEASE ON MAINTENANCE HEMODIALYSIS

    OpenAIRE

    Dr. Aijaz Ahmed, Dr. Muhammad Nadeem Ahsan, Dr. Pooran Mal*, Dr. Hamid Nawaz Ali Memon, Dr. Samreen and Dr. Sajjad Ali

    2017-01-01

    Objective: To determine the frequency of ischemic heart disease in patients of chronic kidney disease on maintenance hemodialysis Patients and Methods: A total of 160 patients with diagnosis of CKD in department of Nephrology, Liaquat National Hospital Karachi were recruited in this six months cross sectional study. Demographic information was recorded. Then patients were underwent ECG. Reports were assessed and ischemic heart disease was labeled while all the data was collected using the pro...

  15. Preliminary Specifications for the PS Pick-ups Amplifier to be used in the Transverse Damping System

    CERN Document Server

    Belleman, J; CERN. Geneva. AB Department

    2003-01-01

    The pick-up amplification stage to be used for the CODD in the PS is presently under redesign. It appears that the constraints for the circuit are very similar to those of the transverse feedback project. The AB/BDI group and in particular its PI section has kindly agreed to fulfil the RF group constraints so as to obtain a common design with a common control interface. The reliability aspect is not treated here. Nevertheless radiation has been considered. At the locations foreseen for the pick-ups (SS 2, 94, 98), the annual dose measured on the vacuum chamber (ref: CERN-TIS-2002-06-TE) is about 1000 Gray per year. This value is to be compared to the 100 Gy considered as the critical dose for electronic circuits. The radiation problem has been solved for the CODD pick-ups using distance and shield (active circuits 2 meters below the floor composed of concrete slabs). The same lay out will be applied for the dampers with the drawback of the capacitive plates being loaded with a low impedance -5 meters long- ca...

  16. Efficient data analysis and travel time picking methods for crosshole GPR experiments

    DEFF Research Database (Denmark)

    Keskinen, Johanna; Moreau, Julien; Nielsen, Lars

    2013-01-01

    to the source position, and the vertical axis to the travel time. Using OpendTect (dGB Earth Sciences), this data cube is then displayed and inspected in a 3D environment, which allows for effective and efficient data analysis. Quality control and data editing of the individual transmitter gathers can be rapidly......-attribute analyses. We believe that this approach to 3D representation and analysis of GPR crosshole data greatly improves consistency in travel time picking and reduces the time needed for the picking process. Moreover, the approach is well suited for generation of high quality input data for tomographic inversion...... methods. Future time-lapse GPR studies of different types of chalk aim at characterizing the flow characteristics of these economically important lithologies. In the framework of the current study, we have collected new crosshole GPR data from a site located in a former quarry in Eastern Denmark, where...

  17. Two adolescent patients with coexistent Graves' disease and Moyamoya disease in Korea.

    Science.gov (United States)

    Cheon, Chong Kun; Kim, Su Yung; Yoo, Jae-Ho

    2014-06-01

    Moyamoya disease is a cerebrovascular condition that results in the narrowing of the vessels of the circle of Willis and collateral vessel formation at the base of the brain. Although relationships between Graves' disease and cerebrovascular accidents in Moyamoya disease are obscure, the coexistence of the two diseases is noteworthy. Moyamoya disease has been rarely reported in adolescent patients with thyrotoxicosis. Recently, we encountered two adolescent Korean patients with Moyamoya disease associated with Graves' disease who presented with episodic right-sided hemiparesis and syncope. These two girls who had Graves' disease had no history of other diseases or head trauma. A thyroid function test revealed a euthyroid state and a high thyroid-stimulating hormone (TSH) receptor antibody titer at that time. The patients were diagnosed with Moyamoya disease based on brain magnetic resonance angiography and cerebral four-vessel angiography. The patients underwent cranial revascularization by encephalo-duroarterio-synangiosis as soon as a diagnosis was made, which resulted in successful symptom resolution. They fared well and had no additional neurological symptoms as of their last follow-up visits. Here, we report these two cases of confirmed Moyamoya disease complicated by Graves' disease with a review of the literature, and discuss the possible association between the two diseases. To our knowledge, this is the first report in South Korea on Moyamoya disease associated with Graves' disease in adolescents with a euthyroid.

  18. Cometary pick-up ions observed near Giacobini-Zinner

    Science.gov (United States)

    Gloeckler, G.; Hovestadt, D.; Ipavich, F. M.; Scholer, M.; Klecker, B.

    1986-01-01

    The number and energy density of cometary water-group ions observed near Comet Giacobini-Zinner are derived using the rest-frame distribution functions. The data reveal that density profiles of inbound and outbound passes and their shape correlate with pick-up ion production model predictions. The lose rate and production rate of water-group cometary molecules calculated from predicted and measured density profiles are 2 x 10 to the -6th/sec and 2.6 x 10 to the 28th/sec respectively. The shapes of the distribution functions are examined to study the solar wind/cometary ions interaction process.

  19. Easily configured real-time CPOE Pick Off Tool supporting focused clinical research and quality improvement.

    Science.gov (United States)

    Rosenbaum, Benjamin P; Silkin, Nikolay; Miller, Randolph A

    2014-01-01

    Real-time alerting systems typically warn providers about abnormal laboratory results or medication interactions. For more complex tasks, institutions create site-wide 'data warehouses' to support quality audits and longitudinal research. Sophisticated systems like i2b2 or Stanford's STRIDE utilize data warehouses to identify cohorts for research and quality monitoring. However, substantial resources are required to install and maintain such systems. For more modest goals, an organization desiring merely to identify patients with 'isolation' orders, or to determine patients' eligibility for clinical trials, may adopt a simpler, limited approach based on processing the output of one clinical system, and not a data warehouse. We describe a limited, order-entry-based, real-time 'pick off' tool, utilizing public domain software (PHP, MySQL). Through a web interface the tool assists users in constructing complex order-related queries and auto-generates corresponding database queries that can be executed at recurring intervals. We describe successful application of the tool for research and quality monitoring.

  20. Radiotherapy in patients with connective tissue diseases.

    Science.gov (United States)

    Giaj-Levra, Niccolò; Sciascia, Savino; Fiorentino, Alba; Fersino, Sergio; Mazzola, Rosario; Ricchetti, Francesco; Roccatello, Dario; Alongi, Filippo

    2016-03-01

    The decision to offer radiotherapy in patients with connective tissue diseases continues to be challenging. Radiotherapy might trigger the onset of connective tissue diseases by increasing the expression of self-antigens, diminishing regulatory T-cell activity, and activating effectors of innate immunity (dendritic cells) through Toll-like receptor-dependent mechanisms, all of which could potentially lead to breaks of immune tolerance. This potential risk has raised some debate among radiation oncologists about whether patients with connective tissue diseases can tolerate radiation as well as people without connective tissue diseases. Because the number of patients with cancer and connective tissue diseases needing radiotherapy will probably increase due to improvements in medical treatment and longer life expectancy, the issue of interactions between radiotherapy and connective tissue diseases needs to be clearer. In this Review, we discuss available data and evidence for patients with connective tissue diseases treated with radiotherapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Lubricant Film Breakdown and Material Pick-Up in Sheet Forming of Advanced High Strength Steels and Stainless Steels when Using Environmental Friendly Lubricants

    DEFF Research Database (Denmark)

    Ceron, Ermanno; Olsson, M.; Bay, Niels

    2014-01-01

    chemically with the tool and workpiece material forming thin films, which adhere strongly to the surfaces and reduce the tendency to metal-metal contact and material pick-up. Production tests of new, environmentally benign tribo-systems are, however, costly and laboratory tests are preferred as a preliminary...... the tribological performance, i.e. tendency to material pick-up and galling, of the evaluated tribo-systems. Moreover the SEM analysis shows that different workpiece materials result in different types of material pick-up....

  2. Misdiagnosis of Addison's disease in a patient with end-stage renal disease.

    Science.gov (United States)

    Kocyigit, Ismail; Unal, Aydin; Tanriverdi, Fatih; Hayri Sipahioglu, Murat; Tokgoz, Bulent; Oymak, Oktay; Utas, Cengiz

    2011-01-01

    Addison's disease is a rare disorder in patients with end-stage renal disease (ESRD). In patients, the diagnosis of Addison's disease is difficult in clinical practice because most of the clinical findings of this disease are similar to those of the renal failure. We present a 51-year-old male patient, who underwent hemodialysis therapy for 8 years, diagnosed with Addison's disease after having myalgia, skin hyperpigmentation, weight loss, sweating, and nausea for the past few weeks. The physical examination was completely normal except for muscle weakness, hyperpigmentation on labial mucosa and skin in a patient. The laboratory tests revealed anemia and hypoglycemia. Serum cortisol, adrenocorticotropic hormone (ACTH) levels, and ACTH stimulation test results were consistent with Addison's disease. Adrenal computerized tomography revealed bilateral atrophic glands. Additionally, it was found that elevated serum thyroid stimulating hormone levels and antithyroid peroxidase antibody titer were positive. Our purpose is to emphasize that physicians should be alert to the potential for additional different conditions particularly in terms of adrenal failure in patients with ESRD.

  3. 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.

  4. Direct-acting antiviral agents against hepatitis C virus and lipid metabolism.

    Science.gov (United States)

    Kanda, Tatsuo; Moriyama, Mitsuhiko

    2017-08-21

    Hepatitis C virus (HCV) infection induces steatosis and is accompanied by multiple metabolic alterations including hyperuricemia, reversible hypocholesterolemia and insulin resistance. Total cholesterol, low-density lipoprotein-cholesterol and triglyceride levels are increased by peginterferon and ribavirin combination therapy when a sustained virologic response (SVR) is achieved in patients with HCV. Steatosis is significantly more common in patients with HCV genotype 3 but interferon-free regimens are not always effective for treating HCV genotype 3 infections. HCV infection increases fatty acid synthase levels, resulting in the accumulation of fatty acids in hepatocytes. Of note, low-density lipoprotein receptor, scavenger receptor class B type I and Niemann-Pick C1-like 1 proteins are candidate receptors that may be involved in HCV. They are also required for the uptake of cholesterol from the external environment of hepatocytes. Among HCV-infected patients with or without human immunodeficiency virus infection, changes in serum lipid profiles are observed during interferon-free treatment and after the achievement of an SVR. It is evident that HCV affects cholesterol metabolism during interferon-free regimens. Although higher SVR rates were achieved with interferon-free treatment of HCV, special attention must also be paid to unexpected adverse events based on host metabolic changes including hyperlipidemia.

  5. Congenital heart disease screening: which referral factors are most important

    International Nuclear Information System (INIS)

    Fayyaz, A.; Ahmed, W.

    2013-01-01

    To identify the referral factors for fetal echocardiography which are associated with congenital cardiac defects in the fetus. Study Design: Cross-sectional descriptive study. Place and Duration of Study: Radiology Department, CMH, Rawalpindi, from January 2007 to November 2010. Methodology: All patients referred for fetal echocardiography with one or more risk factors for the development of congenital heart disease, and those patients with incidental discovery of congenital heart disease on antenatal ultrasound were evaluated. Patients with no risk factors who were found to have normal fetal echocardiography were excluded from the study. Univariate logistic regression analysis was carried out for each variable. The variables with statistical significance of less than 0.05 were subjected to multivariate logistic regression. Fetal echocardiographic diagnosis was taken as the dependent variable and all other variables were the independent variables. Results: Two hundred and sixty four patients were evaluated by fetal echocardiography for congenital heart disease. The statistically significant factor was detection of congenital heart disease on routine ultrasound examination. Conclusion: A routine obstetric scan should include evaluation of the heart with four-chamber and base-of-heart views to exclude cardiac anomalies. A cardiac anomaly picked up on routine ultrasound scan is the most important indication for referral for fetal echocardiography. Fetal arrhythmias and echogenic focus in the left ventricle do not have a significant association with structural cardiac malformation. (author)

  6. [Serum glycosaminoglycans in Graves' disease patients].

    Science.gov (United States)

    Winsz-Szczotka, Katarzyna B; Olczyk, Krystyna Z; Koźma, Ewa M; Komosińska-Vassev, Katarzyna B; Wisowski, Grzegorz R; Marcisz, Czesław

    2006-01-01

    The aim of the study was to determine the blood serum sulfated glycosaminoglycans (GAGs) and hyaluronic acid (HA) concentration of Graves' disease patients before treatment and after attainment of the euthyroid state. The study was carried out on the blood serum obtained from 17 patients with newly recognised Graves' disease and from the same patients after attainment of the euthyroid state. Graves' patients had not any clinical symptoms neither of ophthalmopathy nor pretibial myxedema. GAGs were isolated from the blood serum by the multistage extraction and purification using papaine hydrolysis, alkali elimination, as well as cetylpyridium chloride binding. Total amount of GAGs was quantified by the hexuronic acids assay. HA content in obtained GAGs sample was evaluated by the ELISA method. Increased serum concentration of sulfated GAGs in non-treated Graves' disease patients was found. Similarly, serum HA level in untreated patients was significantly elevated. The attainment of euthyroid state was accompanied by the decreased serum sulfated GAGs level and by normalization of serum HA concentration. In conclusion, the results obtained demonstrate that the alterations of GAGs metabolism connected with Graves' disease can lead to systemic changes of the extracellular matrix properties.

  7. Colorectal cancer in patients with inflammatory bowel disease

    DEFF Research Database (Denmark)

    Andersen, Vibeke; Halfvarson, Jonas; Vogel, Ulla Birgitte

    2012-01-01

    The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), may be complicated by colorectal cancer (CRC). In a recent population-based cohort study of 47 347 Danish patients with IBD by Tine Jess and colleagues 268 patients with UC and 70 patients with CD developed C...... preventive strategies in order to avoid CRC in IBD patients. The achieved knowledge may also be relevant for other inflammation-associated cancers.......The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), may be complicated by colorectal cancer (CRC). In a recent population-based cohort study of 47 347 Danish patients with IBD by Tine Jess and colleagues 268 patients with UC and 70 patients with CD developed CRC...... during 30 years of observation. The overall risk of CRC among patients with UC and CD was comparable with that of the general population. However, patients diagnosed with UC during childhood or as adolescents, patients with long duration of disease and those with concomitant primary sclerosing...

  8. Congenital genetic inborn errors of metabolism presenting as an adult or persisting into adulthood: neuroimaging in the more common or recognizable disorders.

    Science.gov (United States)

    Krishna, Shri H; McKinney, Alexander M; Lucato, Leandro T

    2014-04-01

    Numerous congenital-genetic inborn errors of metabolism (CIEMs) have been identified and characterized in detail within recent decades, with promising therapeutic options. Neuroimaging is becoming increasingly utilized in earlier stages of CIEMs, and even in asymptomatic relatives of patients with a CIEM, so as to monitor disease progress and treatment response. This review attempts to summarize in a concise fashion the neuroimaging findings of various CIEMs that may present in adulthood, as well as those that may persist into adulthood, whether because of beneficial therapy or a delay in diagnosis. Notably, some of these disorders have neuroimaging findings that differ from their classic infantile or early childhood forms, whereas others are identical to their early pediatric forms. The focus of this review is their appearance on routine magnetic resonance imaging sequences, with some basic attention to the findings of such CIEMs on specialized neuroimaging, based on recent or preliminary research. The general classes of disorders covered in this complex review are: peroxisomal disorders (adrenoleukodystrophy), lysosomal storage disorders (including metachromatic leukodystrophy, Krabbe or globoid cell leukodystrophy, Fabry, Niemann-Pick, GM1, GM2, Gaucher, mucopolysaccharidoses, and Salla diseases), mitochondrial disorders (including mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes, myoclonic epilepsy with ragged red fibers, Leigh disease, and Kearns-Sayre syndrome), urea cycle disorders, several organic acidemias (including phenylketonuria, maple syrup urine disease, 3-hydroxy-3-methylglutaryl colyase deficiency, glutaric acidurias, methylmalonic academia, proprionic academia, 3-methylglucatonic aciduria, and 2-hydroxyglutaric acidurias), cytoskeletal or transporter molecule defects (including Alexander or fibrinoid leukodystrophy, proteolipid protein-1 defect or Pelizaeus Merzbacher, Wilson, and Huntington diseases), and several

  9. An order batching algorithm for wave picking in a parallel-aisle warehouse

    NARCIS (Netherlands)

    Gademann, A.J.R.M.; Berg, van den J.P.; Hoff, van der H.H.

    2001-01-01

    In this paper we address the problem of batching orders in a parallel-aisle warehouse, with the objective to minimize the maximum lead time of any of the batches. This is a typical objective for a wave picking operation. Many heuristics have been suggested to solve order batching problems. We

  10. Pick-a-mood; development and application of a pictorial mood-reporting instrument

    NARCIS (Netherlands)

    Desmet, P.M.A.; Vastenburg, M.H.; Van Bel, D.; Romero Herrera, N.A.

    2012-01-01

    This paper presents ‘Pick-A-Mood’ (PAM), a cartoon-based pictorial instrument for reporting and expressing moods. The use of cartoon characters enables people to unambiguously and visually express or report their mood in a rich and easy-to-use way. PAM consists of three characters that each express

  11. [Thyroid cancer in patients with Grave's Disease].

    Science.gov (United States)

    Mssrouri, R; Benamr, S; Essadel, A; Mdaghri, J; Mohammadine, El H; Lahlou, M-K; Taghy, A; Belmahi, A; Chad, B

    2008-01-01

    To evaluate the incidence of thyroid carcinoma in patients operated on for Graves' disease, to identify criteria which may predict malignancy, and to develop a practical approach to determine the extensiveness of thyroidectomy. Retrospective study of all patients who underwent thyroidectomy for Graves' disease between 1995 and 2005. 547 patients underwent subtotal thyroidectomy for Graves' disease during this period. Post-operative pathology examination revealed six cases of thyroid cancer (1.1%). All six cases had differentiated thyroid carcinoma (papillary carcinoma in 3 cases, follicular carcinoma in 2 cases and papillo-follicular carcinoma in 1 case). The indication for initial thyroidectomy was a palpable thyroid nodule in 3 cases (50%), failure of medical treatment for Grave's disease in 2 cases (33%), and signs of goiter compression in 1 case (17%). Five patients underwent re-operative total thyroidectomy. This study shows that while malignancy in Grave's disease is uncommon, the presence of thyroid nodule(s) in patients with Grave's disease may be considered as an indication for radical surgery. The most adequate radical surgery in this situation is to perform a total thyroidectomy.

  12. Lumbar Spine Surgery in Patients with Parkinson Disease.

    Science.gov (United States)

    Schroeder, Joshua E; Hughes, Alexander; Sama, Andrew; Weinstein, Joseph; Kaplan, Leon; Cammisa, Frank P; Girardi, Federico P

    2015-10-21

    Parkinson disease is the second most common neurodegenerative condition. The literature on patients with Parkinson disease and spine surgery is limited, but increased complications have been reported. All patients with Parkinson disease undergoing lumbar spine surgery between 2002 and 2012 were identified. Patients' charts, radiographs, and outcome questionnaires were reviewed. Parkinson disease severity was assessed with use of the modified Hoehn and Yahr staging scale. Complications and subsequent surgeries were analyzed. Risk for reoperation was assessed. Ninety-six patients underwent lumbar spine surgery. The mean patient age was 63.0 years. The mean follow-up duration was 30.1 months. The Parkinson disease severity stage was Parkinson disease severity stage of ≥3 (p Parkinson disease is good, with improvement of spine-related pain. A larger prospective study is warranted. Copyright © 2015 by The Journal of Bone and Joint Surgery, Incorporated.

  13. Frequency of undiagnosed chronic obstructive pulmonary disease in patients with coronary artery disease

    International Nuclear Information System (INIS)

    Ullah, R.; Ghaffar, T.; Khan, I.; Muhammad, R.; Salman, S.

    2017-01-01

    Chronic obstructive airway disease (COPD) is considered as risk factor for coronary artery disease (CAD) along with other risk factors. This study was conducted to determine the frequency of undiagnosed chronic obstructive pulmonary disease in patients with coronary artery disease. Methods: This cross-sectional study was conducted in the Pulmonology and Cardiology wards/OPD's of Khyber Teaching Hospital Peshawar. Patients more than 35 years of age, diagnosed with CAD of either gender were included. Patients already diagnosed with COPD, recent myocardial infarction (within 7 days), left ventricular impairment, pneumothorax, bronchiectasis, comatose patient, asthmatic and those with chest trauma were excluded. All the patients underwent spirometry examination before and after administration of salbutamol (5 mg for 5 minutes) via nebulizer. FEV1/FVC less than 70% confirmed the presence of COPD. Results: Out of 151 patients, 57 (37.7%) were found to have COPD. Among them, 39 (68.42%) were male and 18 (31.57%) were female. Among male patients with COPD, 82.05% (n=32) were smokers and 17.94% (n=7) were nonsmokers while in females with COPD no one was smoker. Conclusion: COPD is an under-diagnosed progressive disease in patients with high risk patients with coronary artery disease. (author)

  14. Lysosomal storage diseases: current diagnostic and therapeutic options

    International Nuclear Information System (INIS)

    Malinova, V.; Honzik, T.

    2013-01-01

    Lysosomal storage diseases are rare genetic diseases caused by insufficient activity of some of the lysosomal enzymes and/or transport proteins. Initial symptoms may appear any time from the neonatal period to late adulthood; early forms tend to have a severe course with rapid progression and unfavorable prognosis. There is multisystem involvement with continuous progression of symptoms and involvement of metabolically active organs or tissues – the bone marrow, liver, bones, skeletal muscles, myocardium, or CNS. The diagnosis is definitively confirmed by demonstration of reduced activity of the particular enzyme and by mutation analysis. Some of the storage diseases can be effectively treated by intravenous administration of recombinant enzymes or by limiting the amount of the substrate stored. In a small number of lysosomal storage diseases, bone marrow transplantation is successful. Multidisciplinary collaboration, including genetic counselling and prenatal diagnosis in patient families, is required. The first part of the paper deals with general characteristics of lysosomal storage diseases and the most common diseases that are currently treatable in the Czech Republic (Gaucher’s disease, Pompe disease, Fabry disease, Niemann–Pick disease, cholesterol ester storage disease). The second part of the paper deals with mucopolysaccharidase, another group of rare lysosomal storage diseases. (author)

  15. High-performance integrated pick-up circuit for SPAD arrays in time-correlated single photon counting

    Science.gov (United States)

    Acconcia, Giulia; Cominelli, Alessandro; Peronio, Pietro; Rech, Ivan; Ghioni, Massimo

    2017-05-01

    The analysis of optical signals by means of Single Photon Avalanche Diodes (SPADs) has been subject to a widespread interest in recent years. The development of multichannel high-performance Time Correlated Single Photon Counting (TCSPC) acquisition systems has undergone a fast trend. Concerning the detector performance, best in class results have been obtained resorting to custom technologies leading also to a strong dependence of the detector timing jitter from the threshold used to determine the onset of the photogenerated current flow. In this scenario, the avalanche current pick-up circuit plays a key role in determining the timing performance of the TCSPC acquisition system, especially with a large array of SPAD detectors because of electrical crosstalk issues. We developed a new current pick-up circuit based on a transimpedance amplifier structure able to extract the timing information from a 50-μm-diameter custom technology SPAD with a state-of-art timing jitter as low as 32ps and suitable to be exploited with SPAD arrays. In this paper we discuss the key features of this structure and we present a new version of the pick-up circuit that also provides quenching capabilities in order to minimize the number of interconnections required, an aspect that becomes more and more crucial in densely integrated systems.

  16. Diagnosis and treatment of invasive fungal diseases in patients with severe liver diseases

    Directory of Open Access Journals (Sweden)

    ZANG Hong

    2016-09-01

    Full Text Available Invasive fungal diseases (IFDs are an important factor affecting the prognosis of patients with severe liver diseases, and their early diagnosis remains a challenge for clinicians. The four most commonly seen IFDs are candidiasis, aspergillosis, cryptococcosis, and pneumocystis pneumonia. We should pay attention to the risk of developing IFDs in patients with severe liver diseases during clinical management. Particularly, early diagnosis and proper treatment of IFDs are important in high-risk patients. These are vital to improving the prognosis of patients with severe liver diseases.

  17. Automated Trajectory Planner of Industrial Robot for Pick-and-Place Task

    Directory of Open Access Journals (Sweden)

    S. Saravana Perumaal

    2013-02-01

    Full Text Available Industrial robots, due to their great speed, precision and cost-effectiveness in repetitive tasks, now tend to be used in place of human workers in automated manufacturing systems. In particular, they perform the pick-and-place operation, a non-value-added activity which at the same time cannot be eliminated. Hence, minimum time is an important consideration for economic reasons in the trajectory planning system of the manipulator. The trajectory should also be smooth to handle parts precisely in applications such as semiconductor manufacturing, processing and handling of chemicals and medicines, and fluid and aerosol deposition. In this paper, an automated trajectory planner is proposed to determine a smooth, minimum-time and collision-free trajectory for the pick-and-place operations of a 6-DOF robotic manipulator in the presence of an obstacle. Subsequently, it also proposes an algorithm for the jerk-bounded Synchronized Trigonometric S-curve Trajectory (STST and the ‘forbidden-sphere’ technique to avoid the obstacle. The proposed planner is demonstrated with suitable examples and comparisons. The experiments show that the proposed planner is capable of providing a smoother trajectory than the cubic spline based trajectory.

  18. Acid sphingomyelinase (aSMase) deficiency leads to abnormal microglia behavior and disturbed retinal function

    Energy Technology Data Exchange (ETDEWEB)

    Dannhausen, Katharina; Karlstetter, Marcus; Caramoy, Albert [Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne (Germany); Volz, Cornelia; Jägle, Herbert [Department of Ophthalmology, University Hospital Regensburg, Regensburg (Germany); Liebisch, Gerhard [Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg (Germany); Utermöhlen, Olaf [Institute for Medical Microbiology, Immunology and Hygiene and Center for Molecular Medicine Cologne, University of Cologne, Cologne (Germany); Langmann, Thomas, E-mail: thomas.langmann@uk-koeln.de [Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne (Germany)

    2015-08-21

    Mutations in the acid sphingomyelinase (aSMase) coding gene sphingomyelin phosphodiesterase 1 (SMPD1) cause Niemann-Pick disease (NPD) type A and B. Sphingomyelin storage in cells of the mononuclear phagocyte system cause hepatosplenomegaly and severe neurodegeneration in the brain of NPD patients. However, the effects of aSMase deficiency on retinal structure and microglial behavior have not been addressed in detail yet. Here, we demonstrate that retinas of aSMase{sup −/−} mice did not display overt neuronal degeneration but showed significantly reduced scotopic and photopic responses in electroretinography. In vivo fundus imaging of aSMase{sup −/−} mice showed many hyperreflective spots and staining for the retinal microglia marker Iba1 revealed massive proliferation of retinal microglia that had significantly enlarged somata. Nile red staining detected prominent phospholipid inclusions in microglia and lipid analysis showed significantly increased sphingomyelin levels in retinas of aSMase{sup −/−} mice. In conclusion, the aSMase-deficient mouse is the first example in which microglial lipid inclusions are directly related to a loss of retinal function. - Highlights: • aSMase-deficient mice show impaired retinal function and reactive microgliosis. • aSMase-deficient microglia express pro-inflammatory transcripts. • aSMase-deficient microglia proliferate and have increased cell body size. • In vivo imaging shows hyperreflective spots in the fundus of aSMase-deficient mice. • aSMase-deficient microglia accumulate sphingolipid-rich intracellular deposits.

  19. Structural and functional analysis of the ASM p.Ala359Asp mutant that causes acid sphingomyelinase deficiency.

    Science.gov (United States)

    Acuña, Mariana; Castro-Fernández, Víctor; Latorre, Mauricio; Castro, Juan; Schuchman, Edward H; Guixé, Victoria; González, Mauricio; Zanlungo, Silvana

    2016-10-21

    Niemann-Pick disease (NPD) type A and B are recessive hereditary disorders caused by deficiency in acid sphingomyelinase (ASM). The p.Ala359Asp mutation has been described in several patients but its functional and structural effects in the protein are unknown. In order to characterize this mutation, we modeled the three-dimensional ASM structure using the recent available crystal of the mammalian ASM as a template. We found that the p.Ala359Asp mutation is localized in the hydrophobic core and far from the sphingomyelin binding site. However, energy function calculations using statistical potentials indicate that the mutation causes a decrease in ASM stability. Therefore, we investigated the functional effect of the p.Ala359Asp mutation in ASM expression, secretion, localization and activity in human fibroblasts. We found a 3.8% residual ASM activity compared to the wild-type enzyme, without changes in the other parameters evaluated. These results support the hypothesis that the p.Ala359Asp mutation causes structural alterations in the hydrophobic environment where ASM is located, decreasing its enzymatic activity. A similar effect was observed in other previously described NPDB mutations located outside the active site of the enzyme. This work shows the first full size ASM mutant model describe at date, providing a complete analysis of the structural and functional effects of the p.Ala359Asp mutation over the stability and activity of the enzyme. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Psychotropic medication use among patients with celiac disease.

    Science.gov (United States)

    Zylberberg, Haley M; Ludvigsson, Jonas F; Green, Peter H R; Lebwohl, Benjamin

    2018-03-27

    Celiac disease is a multi-system disorder with manifestations that may result in psychiatric disorders. We assessed the prevalence of medication use to treat psychiatric disorders in celiac disease patients. We conducted a cross-sectional study of patients undergoing esophagogastroduodenoscopy over 9-years at a celiac disease referral center. We compared the prevalence of psychotropic medication use among celiac disease patients (n = 1293) to a control group (n = 1401) with abdominal pain or reflux. Among all patients the mean age was 48.4 years, most were female (69.5%), and 22.7% used any psychotropic medication. There was no difference between overall psychotropic medication use among celiac disease patients and controls (23.9% vs 21.8%, OR 1.16; 95% CI 0.96-1.39, p = 0.12). However, those with celiac disease were more likely to use antidepressants on univariate (16.4% vs 13.4%, p = 0.03) and multivariate analysis (OR 1.28; 95% CI 1.03-1.59; p = 0.03). Use of psychotropic medications was not associated with disease duration or mode of presentation of celiac disease. Celiac disease patients use psychotropic medications at similar rates as those with other gastrointestinal diseases, though subgroup analysis suggests they may use more antidepressants. Future studies should investigate whether celiac disease is associated with mood disorders that are not treated with medications.

  1. Gallstones in Patients with Chronic Liver Diseases

    Directory of Open Access Journals (Sweden)

    Xu Li

    2017-01-01

    Full Text Available With prevalence of 10–20% in adults in developed countries, gallstone disease (GSD is one of the most prevalent and costly gastrointestinal tract disorders in the world. In addition to gallstone disease, chronic liver disease (CLD is also an important global public health problem. The reported frequency of gallstone in chronic liver disease tends to be higher. The prevalence of gallstone disease might be related to age, gender, etiology, and severity of liver disease in patients with chronic liver disease. In this review, the aim was to identify the epidemiology, mechanisms, and treatment strategies of gallstone disease in chronic liver disease patients.

  2. EFFICACY OF CITALOPRAM IN TREATMENT OF PATHOLOGICAL SKIN PICKING, A RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED TRIAL

    Directory of Open Access Journals (Sweden)

    M Arbabi

    2008-11-01

    Full Text Available "nVarious studies suggest that selective serotonin reuptake inhibitors (SSRIs may be useful in treating pathological skin picking (PSP. This study sought to assess effectiveness of citalopram in comparison with placebo in treating PSP. Forty five individuals with PSP were recruited in a four-week, randomized clinical trial of citalopram (20 mg/day in comparison with placebo. Study measures assessing skin picking severity, mental health status, obsessive compulsive disorder and quality of life were given at baseline, weeks 2 and 4. PSP severity, general health status, obsession-compulsion severity and quality of life level were similar between two groups at baseline (P > 0.05. Treatment analyses revealed significant improvements in quality of life, general health status and obsession-compulsion severity in citalopram group compared to placebo group (P < 0.05. Mean PSP severity reduction in citalopram group was more than placebo group but this difference was not significant. Citalopram can improve general health status and quality of life in individuals with PSP but its effect on skin picking behavior doesn't differ significantly with placebo. Other trials with longer time are needed to determine the exact efficacy of citalopram on PSP

  3. Simulation model of a single-server order picking workstation using aggregate process times

    NARCIS (Netherlands)

    Andriansyah, R.; Etman, L.F.P.; Rooda, J.E.; Biles, W.E.; Saltelli, A.; Dini, C.

    2009-01-01

    In this paper we propose a simulation modeling approach based on aggregate process times for the performance analysis of order picking workstations in automated warehouses with first-in-first-out processing of orders. The aggregate process time distribution is calculated from tote arrival and

  4. The relationship between different information sources and disease-related patient knowledge and anxiety in patients with inflammatory bowel disease.

    Science.gov (United States)

    Selinger, C P; Carbery, I; Warren, V; Rehman, A F; Williams, C J; Mumtaz, S; Bholah, H; Sood, R; Gracie, D J; Hamlin, P J; Ford, A C

    2017-01-01

    Patient education forms a cornerstone of management of inflammatory bowel disease (IBD). The Internet has opened new avenues for information gathering. To determine the relationship between different information sources and patient knowledge and anxiety in patients with IBD. The use of information sources in patients with IBD was examined via questionnaire. Anxiety was assessed with the hospital anxiety and depression scale and disease-related patient knowledge with the Crohn's and colitis knowledge score questionnaires. Associations between these outcomes and demographics, disease-related factors, and use of different information sources were analysed using linear regression analysis. Of 307 patients (165 Crohn's disease, 142 ulcerative colitis) 60.6% were female. Participants used the hospital IBD team (82.3%), official leaflets (59.5%), and official websites (53.5%) most frequently in contrast to alternative health websites (9%). University education (P sex (P = 0.004), clinically active disease (P sources are associated with better knowledge or worse anxiety levels. Face-to-face education and written information materials remain the first line of patient education. Patients should be guided towards official information websites and warned about the association between the use of alternative health websites or random links and anxiety. © 2016 John Wiley & Sons Ltd.

  5. Chronic kidney disease in congenital heart disease patients: a narrative review of evidence.

    Science.gov (United States)

    Morgan, Catherine; Al-Aklabi, Mohammed; Garcia Guerra, Gonzalo

    2015-01-01

    Patients with congenital heart disease have a number of risk factors for the development of chronic kidney disease (CKD). It is well known that CKD has a large negative impact on health outcomes. It is important therefore to consider that patients with congenital heart disease represent a population in whom long-term primary and secondary prevention strategies to reduce CKD occurrence and progression could be instituted and significantly change outcomes. There are currently no clear guidelines for clinicians in terms of renal assessment in the long-term follow up of patients with congenital heart disease. Consolidation of knowledge is critical for generating such guidelines, and hence is the purpose of this view. This review will summarize current knowledge related to CKD in patients with congenital heart disease, to highlight important work that has been done to date and set the stage for further investigation, development of prevention strategies, and re-evaluation of appropriate renal follow-up in patients with congenital heart disease. The literature search was conducted using PubMed and Google Scholar. Current epidemiological evidence suggests that CKD occurs in patients with congenital heart disease at a higher frequency than the general population and is detectable early in follow-up (i.e. during childhood). Best evidence suggests that approximately 30 to 50 % of adult patients with congenital heart disease have significantly impaired renal function. The risk of CKD is higher with cyanotic congenital heart disease but it is also present with non-cyanotic congenital heart disease. Although significant knowledge gaps exist, the sum of the data suggests that patients with congenital heart disease should be followed from an early age for the development of CKD. There is an opportunity to mitigate CKD progression and negative renal outcomes by instituting interventions such as stringent blood pressure control and reduction of proteinuria. There is a need to

  6. Perancangan dan Proses Pembuatan Inner Door Panel Mobil Pick Up Multiguna

    Directory of Open Access Journals (Sweden)

    Bambang Prayogi

    2014-09-01

    Full Text Available Sejak tahun 2012 Jurusan Teknik Mesin bekerja sama dengan PT. INKA mengembangkan mobil murah multigna. Mobil pick up tersebut diberi nama GEA. Pengembangan dilakukan pada body, chasis dan engine. Sebagai bagian dari body, pintu mobil juga akan dikembangkan. Pada tahun 2013, penelitian terhadap posisi handle pengatur kaca jendela atau window regulator mobil pick up GEA telah dilakukan. Evaluasi tersebut mengharuskan adanya perubahan desain dari inner door panel. Suatu rancangan pengembangan desain inner door panel perlu dilakukan agar inner door panel dapat diproduksi secara massal. Langkah-langkah penelitian yang dilakukan meliputi penyusunan list of requirement untuk pengembangan konsep, analisa getaran dan tegangan yang terjadi pada panel dengan bantuan software CATIA. Selanjutnya perancangan proses pembuatan dan perancangan punch and dies-nya dilakukan. Dari analisa getaran yang dilakukan, dapat diketahui inner door panel memiliki frekuensi natural sebesar 166,94 Hz (10.016,4 rpm artinya panel aman dan tidak terpengaruh oleh getaran dari mesin mobil. Tegangan yang terjadi pada inner door panel akibat gaya pembebanan pada handle pintu bagian dalam adalah 2,9159 x 107 Pa (2,97 Kg/mm2 sehingga lebih kecil dari tegangan ijin materialnya 13,94 Kg/mm2 dan rancangan masih berada dalam kategori aman. Untuk membuat inner door panel dilakukan 3 macam proses pembentukan yaitu trimming, embossing dan piercing. Total gaya pembentukan masing-masing proses sebagai berikut: Gaya pembentukan proses trimming = 48.96 ton, proses embossing = 26.89 ton dan proses piercing = 41.66 ton. Window regulator yang disarankan untuk digunakan pada mobil pick up multiguna ini adalah scissor type window regulator dengan tenaga penggerak manual. Pada perancangan punch and dies, tegangan kompresi masing-masing proses dihitung dan hasilnya adalah sebagai berikut: Tegangan kompresi proses trimming 0.11 Kg/mm2, tegangan kompresi proses embossing 0.28 Kg/mm2, tegangan kompresi

  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. Procedural learning changes in patients with Wilson's disease

    Institute of Scientific and Technical Information of China (English)

    Yumei Jiang; Xiang Shen; Xiaoping Wang; Wenjie Li

    2011-01-01

    In the present study, we compared explicit memory performance, using the Wechsler Memory Scale, and implicit memory performance, using the Nissen software version of the serial reaction time task, in patients with Wilson's disease to normal controls. The Wilson's disease patients exhibited deficits in explicit memory tasks, such as figure recall and understanding memory. Moreover, the Wilson's disease patients exhibited deficits in implicit memory tasks, including significantly prolonged response times. These findings indicate that Wilson's disease patients have explicit and implicit partial memory impairments.

  9. 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.

  10. Dental profile of patients with Gaucher disease

    Science.gov (United States)

    Fischman, Stuart L; Elstein, Deborah; Sgan-Cohen, Harold; Mann, Jonathan; Zimran, Ari

    2003-01-01

    Background This study was conducted to determine whether patients with Gaucher disease had significant dental pathology because of abnormal bone structure, pancytopenia, and coagulation abnormalities. Methods Each patient received a complete oral and periodontal examination in addition to a routine hematological evaluation. Results Gaucher patients had significantly fewer carious lesions than otherwise healthy carriers. Despite prevalence of anemia, there was no increase in gingival disease; despite the high incidence of thrombocytopenia, gingival bleeding was not noted; and despite radiological evidence of bone involvement, there was no greater incidence loss of teeth or clinical tooth mobility. Conclusions These data represent the first survey of the oral health of a large cohort of patients with Gaucher disease. It is a pilot study of a unique population and the results of the investigation are indications for further research. Based on our findings, we recommend regular oral examinations with appropriate dental treatment for patients with Gaucher disease as for other individuals. Consultation between the dentist and physician, preferably one with experience with Gaucher disease, should be considered when surgical procedures are planned. PMID:12875661

  11. Empowering Patients with Chronic Diseases

    DEFF Research Database (Denmark)

    Bestek, Mate; Meglič, Matic; Kurent, Blaž

    2012-01-01

    Background: Chronic diseases require most of the resources in todays healthcare systems. Healthcare systems, as such, are thus not sustainable in the long term. Solutions to this problem are needed and a lot of research is focused on finding new approaches to more sustainable healthcare systems...... himself to become empowered. The patient needs to see data about his health in order to start thinking about new decisions in life that can lead to change in his behaviour. Objective: We have approached the problem of empowering patients with chronic diseases from a biological, psychological, sociological....... We want to develop extensible technology to support even more new interventions for different chronic diseases. We want the technology to enable semantic interoperability with other systems. Methods: We have collaborated with doctors in order to model the care plans for different chronic diseases...

  12. Evaluation of strip-line pick-up system for the SPS wideband transverse feedback system

    CERN Document Server

    Kotzian, G; Steinhagen, R J; Valuch, D; Wehrle, U

    2017-01-01

    The proposed SPS Wideband Transverse Feedback sys- tem requires a wide-band pick-up system to be able to de- tect intra-bunch motion within the SPS proton bunches, captured and accelerated in a 200 MHz bucket. We present the electro-magnetic design of transverse beam position pick-up options optimised for installation in the SPS and evaluate their performance reach with respect to direct time domain sampling of the intra-bunch motion. The analy- sis also discusses the achieved subsystem responses of the associated cabling with new low dispersion smooth wall coaxial cables, wide-band generation of intensity and posi- tion signals by means of 180 degree RF hybrids as well as passive techniques to electronically suppress the beam off- set signal, needed to optimise the dynamic range and posi- tion resolution of the planned digital intra-bunch feedback system.

  13. Comparison of magnetic and electrostatic Schottky pick-up in the CERN AD

    CERN Document Server

    Federmann, S

    2013-01-01

    The present note is intended to exploit the possibility of using a dedicated electrostatic beam pick-up for Schottky diagnostics in the future ELENA ring. A test setup is described allowing the evaluation of its performance compared to the extra low-noise beam current transformer used successfully in the AD. The results of this experiment are summarized and discussed.

  14. Role of CT in patients with prostatic disease

    International Nuclear Information System (INIS)

    Yoshizako, Takeshi; Sugimura, Kazuro; Kaji, Yasushi; Moriyama, Masahiro; Ishida, Tetsuya

    1994-01-01

    The purpose of this study was to evaluate the role of CT in patients with and without prostatic disease. CT and MR findings were reviewed in 25 patients without known prostatic disease, 11 patients with benign prostatic hyperplasia and 11 patients with prostatic cancer. Differential attenuation allowed for distinction of the peripheral zone and inner gland of the prostate by CT in 72% of normal patients. The distinction rate of prostatic zonal anatomy by CT decreased to 30% in the diseased group. When zonal anatomy of the prostate is not visualized on pelvic enhanced CT, the presence of prostatic disease might be considered. (author)

  15. Clinically Unsuspected Prion Disease Among Patients With Dementia Diagnoses in an Alzheimer's Disease Database.

    Science.gov (United States)

    Maddox, Ryan A; Blase, J L; Mercaldo, N D; Harvey, A R; Schonberger, L B; Kukull, W A; Belay, E D

    2015-12-01

    Brain tissue analysis is necessary to confirm prion diseases. Clinically unsuspected cases may be identified through neuropathologic testing. National Alzheimer's Coordinating Center (NACC) Minimum and Neuropathologic Data Set for 1984 to 2005 were reviewed. Eligible patients had dementia, underwent autopsy, had available neuropathologic data, belonged to a currently funded Alzheimer's Disease Center (ADC), and were coded as having an Alzheimer's disease clinical diagnosis or a nonprion disease etiology. For the eligible patients with neuropathology indicating prion disease, further clinical information, collected from the reporting ADC, determined whether prion disease was considered before autopsy. Of 6000 eligible patients in the NACC database, 7 (0.12%) were clinically unsuspected but autopsy-confirmed prion disease cases. The proportion of patients with dementia with clinically unrecognized but autopsy-confirmed prion disease was small. Besides confirming clinically suspected cases, neuropathology is useful to identify unsuspected clinically atypical cases of prion disease. © The Author(s) 2015.

  16. Celiac disease in patients with Williams-Beuren syndrome.

    Science.gov (United States)

    Mıhçı, Ercan; Nur, Banu Güzel; Berker-Karaüzüm, Sibel; Yılmaz, Aygen; Artan, Reha

    2015-01-01

    Celiac disease is an autoimmune, gastrointestinal disorder characterized by intolerance to the dietary grain protein gluten. An increased prevalence of celiac disease has been reported in Down syndrome and Turner syndrome, but there has been only few previous reports with respect to the association of celiac disease in Williams-Beuren syndrome. The aim of this study was to evaluate the frequency of celiac disease in our 24 Williams-Beuren syndrome patients. Gastrointestinal problems and celiac disease symptoms of patients were noted. All patients were analyzed by the titer of tissue transglutaminases IgA and IgG. HLA genotyping and intestinal biopsy was performed to the patients with positive serology. We also performed gluten free diet in the presence of compatible symptoms, serology, HLA genotyping and intestinal biopsy. In our study, two patients had positive tTG antibodies, but only one had positive biopsy finding for celiac disease. The frequency of celiac disease in patients with Williams-Beuren syndrome was estimated as 1/24 (4.1%). Though the number of participants in this study was limited, the results show that the frequency of celiac disease is higher in Williams-Beuren syndrome compared to the general population. We suggest that a high suspicion and testing for celiac disease should be recommended at certain intervals in all cases with Williams-Beuren syndrome to detect the cause of growth retardation and gastrointestinal problems.

  17. The spectrum of bone disease in Jordanian hemodialysis patients

    International Nuclear Information System (INIS)

    Younes, Nidal A.; Al-Mansour, M.; Sroujieh, Ahmad S.; Wahbeh, A.; Ailabouni, W.; Hamzah, Y.; Mahafzah, W.

    2006-01-01

    To evaluate the spectrum of mineral abnormalities and bone disease (BD) in hemodialysis patients at Jordan University Hospital (JUH), Amman, Jordan. A cross-sectional study was conducted among 63 patients (38 males and 25 females), mean age 44.19 years (range 17-76 years), with chronic kidney disease (CKD) on regular hemodialysis at JUH between November 2004 and April 2005. All patients have undergone complete blood count, chemistry profile, alkaline phosphatase, serum albumin, intact parathyroid hormone (iPTH) and plain x-rays. Bone disorders were identified in 45 patients on x-rays (70%). Osteopenia was found in 43 patients (68.3%), subperiosteal resorption in 24 patients (38.3%) and metastatic calcification in 22 patients (35%). Hypocalcemia was found in 28.6% and hypercalcemia in 7.9%. All patients were taking calcium carbonate, and 55.5% of patients were on vitamin D supplements. The calcium levels in 63.5% and the phosphorus levels in 50.8% of patients were within the recommended guidelines of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI). Serum i-PTH level was above 300 pg/ml high turnover bone disease in 24.6% of patients, 21.3% had iPTH of 150-300 pg/ml target, and 44.3% had i-PTH levels below 100 pg/mL suggesting a dynamic bone disease. Patients with severe bone disease had a statistically significant higher iPTH levels (p<0.005). Bone disease and mineral abnormalities are common in hemodialysis patients at JUH. Earlier detection of bone disease and better overall management strategy may reduce the frequency and severity of bone disease in CKD patients in Jordan. (author)

  18. Pick-N-Pull Auto Dismantlers, Kansas City, LLC Inc. - Clean Water Act Public Notice

    Science.gov (United States)

    The EPA is providing notice of a proposed Administrative Penalty Assessment against Pick-N-Pull Auto Dismantlers, Kansas City, LLC, a subsidiary of Schnitzer Steel Industries, Inc., for alleged violations at its facilities at 8012 East Truman Rd., Kansas C

  19. Screening Fabry's disease in chronic kidney disease patients not on dialysis: a multicenter study.

    Science.gov (United States)

    Yeniçerioğlu, Yavuz; Akdam, Hakan; Dursun, Belda; Alp, Alper; Sağlam Eyiler, Funda; Akın, Davut; Gün, Yelda; Hüddam, Bülent; Batmazoğlu, Mehmet; Gibyeli Genek, Dilek; Pirinççi, Serhat; Ersoy, İsmail Rıfkı; Üzüm, Atilla; Soypaçacı, Zeki; Tanrısev, Mehmet; Çolak, Hülya; Demiral Sezer, Sibel; Bozkurt, Gökay; Akyıldız, Utku Oğan; Akyüz Ünsal, Ayşe İpek; Ünübol, Mustafa; Uslu, Meltem; Eryılmaz, Ufuk; Günel, Ceren; Meteoğlu, İbrahim; Yavaşoğlu, İrfan; Ünsal, Alparslan; Akar, Harun; Okyay, Pınar

    2017-11-01

    Fabry's disease is an X-linked inherited, rare, progressive, lysosomal storage disorder, affecting multiple organs due to the deficient activity of α-galactosidase A (α-Gal A) enzyme. The prevalence has been reported to be 0.15-1% in hemodialysis patients; however, the information on the prevalence in chronic kidney disease not on dialysis is lacking. This study aimed to determine the prevalence of Fabry's disease in chronic kidney disease. The patients older than 18 years, enclosing KDIGO 2012 chronic kidney disease definitions, not on dialysis, were enrolled. Dried blood spots on Guthrie papers were used to analyze α-Gal A enzyme and genetic analysis was performed in individuals with enzyme activity ≤1.2 μmol/L/h. A total of 1453 chronic kidney disease patients not on dialysis from seven clinics in Turkey were screened. The mean age of the study population was 59.3 ± 15.9 years. 45.6% of patients were female. The creatinine clearance of 77.3% of patients was below 60 mL/min/1.73 m 2 , 8.4% had proteinuria, and 2.5% had isolated microscopic hematuria. The mean value of patients' α-Gal A enzyme was detected as 2.93 ± 1.92 μmol/L/h. 152 patients had low levels of α-Gal A enzyme activity (≤1.2 μmol/L/h). In mutation analysis, A143T and D313Y variants were disclosed in three male patients. The prevalence of Fabry's disease in chronic kidney disease not on dialysis was found to be 0.2% (0.4% in male, 0.0% in female). Fabry's disease should be considered in the differential diagnosis of chronic kidney disease with unknown etiology even in the absence of symptoms and signs suggestive of Fabry's disease.

  20. Automatic traveltime picking using local time-frequency maps

    KAUST Repository

    Saragiotis, Christos

    2011-01-01

    The arrival times of distinct and sufficiently concentrated signals can be computed using Fourier transforms. In real seis- mograms, however, signals are far from distinct. We use local time-frequency maps of the seismograms and its frequency derivatives to obtain frequency-dependent (instantaneous) traveltimes. A smooth division is utilized to control the resolution of the instantaneous traveltimes to allow for a trade-off between resolution and stability. We average these traveltimes over the frequency band which is data-dependent. The resulting traveltime attribute is used to isolate different signals in seismic traces. We demonstrate the effectiveness of this automatic method for picking arrivals by applying it on synthetic and real data. © 2011 Society of Exploration Geophysicists.

  1. 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...... encompassing bilateral dorsal striatum (maximal in right caudate), bilateral anterior cingulate and right medial frontal regions. These abnormalities were, for the most part, outside the dorsal planning network typically activated by executive planning tasks. Conclusions: Abnormalities of neural regions...... 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....

  2. Binding of canonical Wnt ligands to their receptor complexes occurs in ordered plasma membrane environments.

    Science.gov (United States)

    Sezgin, Erdinc; Azbazdar, Yagmur; Ng, Xue W; Teh, Cathleen; Simons, Kai; Weidinger, Gilbert; Wohland, Thorsten; Eggeling, Christian; Ozhan, Gunes

    2017-08-01

    While the cytosolic events of Wnt/β-catenin signaling (canonical Wnt signaling) pathway have been widely studied, only little is known about the molecular mechanisms involved in Wnt binding to its receptors at the plasma membrane. Here, we reveal the influence of the immediate plasma membrane environment on the canonical Wnt-receptor interaction. While the receptors are distributed both in ordered and disordered environments, Wnt binding to its receptors selectively occurs in more ordered membrane environments which appear to cointernalize with the Wnt-receptor complex. Moreover, Wnt/β-catenin signaling is significantly reduced when the membrane order is disturbed by specific inhibitors of certain lipids that prefer to localize at the ordered environments. Similarly, a reduction in Wnt signaling activity is observed in Niemann-Pick Type C disease cells where trafficking of ordered membrane lipid components to the plasma membrane is genetically impaired. We thus conclude that ordered plasma membrane environments are essential for binding of canonical Wnts to their receptor complexes and downstream signaling activity. © 2017 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

  3. Prevalence of celiac disease among first-degree relatives of Indian celiac disease patients.

    Science.gov (United States)

    Mishra, Asha; Prakash, Shyam; Kaur, Gurvinder; Sreenivas, Vishnubhatla; Ahuja, Vineet; Gupta, Siddhartha Datta; Makharia, Govind K

    2016-03-01

    Celiac disease, once thought to be uncommon in Asia, is now recognized in Asian nations as well. We investigated the prevalence of celiac disease in first-degree relatives of celiac disease patients followed in our centre. First-degree relatives were screened prospectively for celiac disease using questionnaire-based interview and anti-tissue transglutaminase antibody. Serology positive first-degree relatives underwent duodenal biopsies. Diagnosis of celiac disease was made based on positive serology and villous abnormality Marsh grade 2 or higher. Human leucocyte antigen DQ2/-DQ8 was also assessed in 127 first-degree relatives. 434 first-degree relatives of 176 celiac disease patients were prospectively recruited; 282 were symptomatic (64.9%), 58 were positive for serology (13.3%). Seroprevalence was higher in female than in males (19% vs 8.5%; p=0.001) and highest in siblings (16.9%) than parents (13.6%) and children (5.9%) of celiac patients (p=0.055); 87.4% first-degree relatives were human leucocyte antigen-DQ2/-DQ8 positive. Overall prevalence of celiac disease was 10.9% amongst first-degree relatives. The prevalence of celiac disease in first-degree relatives of celiac disease patients was 10.9% in our cohort, and 87% had human leucocyte antigen-DQ2 or -DQ8 haplotype. All first-degree relatives of celiac disease patients should be screen for celiac disease even if asymptomatic or with atypical manifestations. Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  4. The assessment of muscle strain with surface electromyograms during simulated mushroom picking

    DEFF Research Database (Denmark)

    Ohashi, Jun-Ya; Blangsted, Anne Katrine; Kofoed Nielsen, Pernille B.

    2008-01-01

    Muscle strain was assessed with surface EMG during simulated mushroom picking. Nine female subjects performed five periods of work (W1-W5). The duration of each period was about 20 min. W1, W2 and W3 were separated by a short break of several minutes. W3, W4 and W5 were separated by a rest period...

  5. Analysis of cognitive function and regional cerebral blood flow in Parkinson's disease by 123I-IMP SPECT

    International Nuclear Information System (INIS)

    Kato, Takayuki; Morohoshi, Toshio; Hasegawa, Yukihiro; Fukui, Toshiya; Kawamura, Mitsuru; Sugita, Koujiro

    2000-01-01

    Several studies have found that the uptake of a radioisotope is reduced in the frontal or parietooccipital lobe on SPECT scans of patients with Parkinson's disease accompanied by cognitive impairment. The present study investigated the relationship between the results of SPECT imaging and those of cognitive function tests in patients with Parkinson's disease accompanied by cognitive impairment. Thirty patients with Parkinson's disease served as subjects, including 9 men and 21 women with an average of 66.1 years. Patients underwent 123 I-IMP SPECT and various cognitive function tests (Japanese alphabet pick-up test, Stroop test, Hasegawa's dementia screening scale, Raven color matrix, and course cube-combination test). Next, three neurologists with no knowledge of the patient's clinical symptoms were asked to analyze the reduced uptake on SPECT scans as follows: frontal lobe, parietooccipital lobe, frontal and parietooccipital lobes, diffused reduction, and no reduced uptake. The results of SPECT imaging and each cognitive function test were compared. Reduced uptake in the frontal and parietooccipital lobes and diffused reduction correlated with decreases in cognitive function. Cognitive impairment is not notable when cortical blood flow is partially reduced, but is notable when cortical blood flow is widely reduced. (author)

  6. Small bowel ultrasound in patients with celiac disease

    Energy Technology Data Exchange (ETDEWEB)

    Bartusek, D. [Department of Radiology, Masaryk University hospital Brno (Czech Republic)], E-mail: dbartusek@fnbrno.cz; Valek, V. [Department of Radiology, Masaryk University hospital Brno (Czech Republic)], E-mail: v.valek@fnbrno.cz; Husty, J. [Department of Radiology, Masaryk University hospital Brno (Czech Republic)], E-mail: jhusty@fnbrno.cz; Uteseny, J. [Department of Pediatric Internal Medicine, Masaryk University hospital Brno (Czech Republic)], E-mail: juteseny@fnbrno.cz

    2007-08-15

    Objective: Celiac disease (CD) is a common, lifelong disease with small bowel malabsorption based on genetically conditioned gluten intolerance. The clinical manifestation could be very heterogeneous. The proof of celiac disease is now based mainly on clinical and laboratory (antibodies and enterobiopsy) signs, which are in some cases problematic and inconvenient. Materials and methods: In our study we have examined 250 patients with suspection or with proven celiac disease and we evaluated specific ultrasound small bowel changes in this group. In the next step, we chose 59 patients with laboratory proved celiac disease and we statistically compared ultrasound, other laboratory and clinical findings in different forms and stages of the disease. Results: Specific small bowel pathologies in patients with celiac disease (like changes of intestinal villi in different parts of small bowel, abnormal peristalsis and mesenterial lymphadenopathy) can be well visualized by ultrasound and in combination with clinical and laboratory signs ultrasound examination could have an important role in screening, determination of diagnosis and monitoring of patients with different forms of celiac disease.

  7. Small bowel ultrasound in patients with celiac disease

    International Nuclear Information System (INIS)

    Bartusek, D.; Valek, V.; Husty, J.; Uteseny, J.

    2007-01-01

    Objective: Celiac disease (CD) is a common, lifelong disease with small bowel malabsorption based on genetically conditioned gluten intolerance. The clinical manifestation could be very heterogeneous. The proof of celiac disease is now based mainly on clinical and laboratory (antibodies and enterobiopsy) signs, which are in some cases problematic and inconvenient. Materials and methods: In our study we have examined 250 patients with suspection or with proven celiac disease and we evaluated specific ultrasound small bowel changes in this group. In the next step, we chose 59 patients with laboratory proved celiac disease and we statistically compared ultrasound, other laboratory and clinical findings in different forms and stages of the disease. Results: Specific small bowel pathologies in patients with celiac disease (like changes of intestinal villi in different parts of small bowel, abnormal peristalsis and mesenterial lymphadenopathy) can be well visualized by ultrasound and in combination with clinical and laboratory signs ultrasound examination could have an important role in screening, determination of diagnosis and monitoring of patients with different forms of celiac disease

  8. Embodied intersubjective engagement in mother-infant tactile communication: a cross-cultural study of Japanese and Scottish mother-infant behaviors during infant pick-up.

    Science.gov (United States)

    Negayama, Koichi; Delafield-Butt, Jonathan T; Momose, Keiko; Ishijima, Konomi; Kawahara, Noriko; Lux, Erin J; Murphy, Andrew; Kaliarntas, Konstantinos

    2015-01-01

    This study examines the early development of cultural differences in a simple, embodied, and intersubjective engagement between mothers putting down, picking up, and carrying their infants between Japan and Scotland. Eleven Japanese and ten Scottish mothers with their 6- and then 9-month-old infants participated. Video and motion analyses were employed to measure motor patterns of the mothers' approach to their infants, as well as their infants' collaborative responses during put-down, pick-up, and carry phases. Japanese and Scottish mothers approached their infants with different styles and their infants responded differently to the short duration of separation during the trial. A greeting-like behavior of the arms and hands was prevalent in the Scottish mothers' approach, but not in the Japanese mothers' approach. Japanese mothers typically kneeled before making the final reach to pick-up their children, giving a closer, apparently gentler final approach of the torso than Scottish mothers, who bent at the waist with larger movements of the torso. Measures of the gap closure between the mothers' hands to their infants' heads revealed variably longer duration and distance gap closures with greater velocity by the Scottish mothers than by the Japanese mothers. Further, the sequence of Japanese mothers' body actions on approach, contact, pick-up, and hold was more coordinated at 6 months than at 9 months. Scottish mothers were generally more variable on approach. Measures of infant participation and expressivity indicate more active participation in the negotiation during the separation and pick-up phases by Scottish infants. Thus, this paper demonstrates a culturally different onset of development of joint attention in pick-up. These differences reflect cultures of everyday interaction.

  9. Embodied intersubjective engagement in mother–infant tactile communication: a cross-cultural study of Japanese and Scottish mother–infant behaviors during infant pick-up

    Science.gov (United States)

    Negayama, Koichi; Delafield-Butt, Jonathan T.; Momose, Keiko; Ishijima, Konomi; Kawahara, Noriko; Lux, Erin J.; Murphy, Andrew; Kaliarntas, Konstantinos

    2015-01-01

    This study examines the early development of cultural differences in a simple, embodied, and intersubjective engagement between mothers putting down, picking up, and carrying their infants between Japan and Scotland. Eleven Japanese and ten Scottish mothers with their 6- and then 9-month-old infants participated. Video and motion analyses were employed to measure motor patterns of the mothers’ approach to their infants, as well as their infants’ collaborative responses during put-down, pick-up, and carry phases. Japanese and Scottish mothers approached their infants with different styles and their infants responded differently to the short duration of separation during the trial. A greeting-like behavior of the arms and hands was prevalent in the Scottish mothers’ approach, but not in the Japanese mothers’ approach. Japanese mothers typically kneeled before making the final reach to pick-up their children, giving a closer, apparently gentler final approach of the torso than Scottish mothers, who bent at the waist with larger movements of the torso. Measures of the gap closure between the mothers’ hands to their infants’ heads revealed variably longer duration and distance gap closures with greater velocity by the Scottish mothers than by the Japanese mothers. Further, the sequence of Japanese mothers’ body actions on approach, contact, pick-up, and hold was more coordinated at 6 months than at 9 months. Scottish mothers were generally more variable on approach. Measures of infant participation and expressivity indicate more active participation in the negotiation during the separation and pick-up phases by Scottish infants. Thus, this paper demonstrates a culturally different onset of development of joint attention in pick-up. These differences reflect cultures of everyday interaction. PMID:25774139

  10. Parametric Optimal Design of a Parallel Schönflies-Motion Robot under Pick-And-Place Trajectory Constraints

    DEFF Research Database (Denmark)

    Wu, Guanglei; Bai, Shaoping; Hjørnet, Preben

    2015-01-01

    This paper deals with the parametric optimum design of a parallel Schoenflies-motion robot, named "Ragnar", designed for fast and flexible pick-and-place applications. The robot architecture admits a rectangular workspace, which can utilize the shop-floor space efficiently. In this work......, the parametric models of the transmission quality, elasto-statics and dynamics are established. By taking into consideration of design requirements and pick-and-place trajectory, a comprehensive multi-objective optimization problem is formulated to optimize both kinematic and dynamic performances. The Pareto......-front is obtained, which provides optimal solutions to the robot design. Robot prototyping work based on the optimal results is described....

  11. Trichotillomania (hair pulling disorder), skin picking disorder, and stereotypic movement disorder: toward DSM-V.

    Science.gov (United States)

    Stein, Dan J; Grant, Jon E; Franklin, Martin E; Keuthen, Nancy; Lochner, Christine; Singer, Harvey S; Woods, Douglas W

    2010-06-01

    In DSM-IV-TR, trichotillomania (TTM) is classified as an impulse control disorder (not classified elsewhere), skin picking lacks its own diagnostic category (but might be diagnosed as an impulse control disorder not otherwise specified), and stereotypic movement disorder is classified as a disorder usually first diagnosed in infancy, childhood, or adolescence. ICD-10 classifies TTM as a habit and impulse disorder, and includes stereotyped movement disorders in a section on other behavioral and emotional disorders with onset usually occurring in childhood and adolescence. This article provides a focused review of nosological issues relevant to DSM-V, given recent empirical findings. This review presents a number of options and preliminary recommendations to be considered for DSM-V: (1) Although TTM fits optimally into a category of body-focused repetitive behavioral disorders, in a nosology comprised of relatively few major categories it fits best within a category of motoric obsessive-compulsive spectrum disorders, (2) available evidence does not support continuing to include (current) diagnostic criteria B and C for TTM in DSM-V, (3) the text for TTM should be updated to describe subtypes and forms of hair pulling, (4) there are persuasive reasons for referring to TTM as "hair pulling disorder (trichotillomania)," (5) diagnostic criteria for skin picking disorder should be included in DSM-V or in DSM-Vs Appendix of Criteria Sets Provided for Further Study, and (6) the diagnostic criteria for stereotypic movement disorder should be clarified and simplified, bringing them in line with those for hair pulling and skin picking disorder. (c) 2010 Wiley-Liss, Inc.

  12. Patients with inflammatory bowel disease have increased risk of autoimmune and inflammatory diseases

    DEFF Research Database (Denmark)

    Halling, Morten L; Kjeldsen, Jens; Knudsen, Torben

    2017-01-01

    were significantly increased (P celiac disease, type 1 diabetes (T1D), sarcoidosis, asthma, iridocyclitis, psoriasis, pyoderma gangrenosum, rheumatoid arthritis, and ankylosing spondylitis. Restricted to UC (P ...AIM: To investigate whether immune mediated diseases (IMD) are more frequent in patients with inflammatory bowel disease (IBD). METHODS: In this population based registry study, a total of 47325 patients with IBD were alive and registered in the Danish National Patient Registry on December 16, 2013....... Controls were randomly selected from the Danish Civil Registration System (CRS) and matched for sex, age, and municipality. We used ICD 10 codes to identify the diagnoses of the included patients. The IBD population was divided into three subgroups: Ulcerative colitis (UC), Crohn's disease (CD) and Both...

  13. Flow time prediction for a single-server order picking workstation using aggregate process times

    NARCIS (Netherlands)

    Andriansyah, R.; Etman, L.F.P.; Rooda, J.E.

    2010-01-01

    In this paper we propose a simulation modeling approach based on aggregate process times for the performance analysis of order picking workstations in automated warehouses. The aggregate process time distribution is calculated from tote arrival and departure times. We refer to the aggregate process

  14. Oral Anticoagulation in Patients With Liver Disease.

    Science.gov (United States)

    Qamar, Arman; Vaduganathan, Muthiah; Greenberger, Norton J; Giugliano, Robert P

    2018-05-15

    Patients with liver disease are at increased risks of both thrombotic and bleeding complications. Many have atrial fibrillation (AF) or venous thromboembolism (VTE) necessitating oral anticoagulant agents (OACs). Recent evidence has contradicted the assumption that patients with liver disease are "auto-anticoagulated" and thus protected from thrombotic events. Warfarin and non-vitamin K-antagonist OACs have been shown to reduce thrombotic events safely in patients with either AF or VTE. However, patients with liver disease have largely been excluded from trials of OACs. Because all currently approved OACs undergo metabolism in the liver, hepatic dysfunction may cause increased bleeding. Thus, the optimal anticoagulation strategy for patients with AF or VTE who have liver disease remains unclear. This review discusses pharmacokinetic and clinical studies evaluating the efficacy and safety of OACs in patients with liver disease and provides a practical, clinically oriented approach to the management of OAC therapy in this population. Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  15. An automated framework for NMR resonance assignment through simultaneous slice picking and spin system forming

    KAUST Repository

    Abbas, Ahmed; Guo, Xianrong; Jing, Bingyi; Gao, Xin

    2014-01-01

    positives and negatives impair the performance of resonance assignment methods. One of the main reasons for this problem is that the computational research community often considers peak picking and resonance assignment to be two separate problems, whereas

  16. Color Discrimination in Patients with Gaucher Disease and Parkinson Disease.

    Science.gov (United States)

    Simon-Tov, Shlomi; Dinur, Tama; Giladi, Nir; Bar-Shira, Anat; Zelis, Mayaan; Zimran, Ari; Elstein, Deborah

    2015-01-01

    Poor color discrimination among patients with Parkinson disease (PD) has long been recognized. It has been shown that carrying one or two mutations in the β-glucocerebrosidase gene (GBA) for the autosomal disease Gaucher disease (GD), as based initially on clinical evidence, is a genetic risk factor for early-onset PD. The purpose of this study was to assess color discrimination in patients with one or two GBA mutations relative to healthy controls to ascertain whether this function is affected when persons with GD or even one GBA mutation develop PD. The Farnsworth-Munsell 100 hue test (FMHT) was evaluated among patients with GD+PD compared to patients with GD only, obligate GBA carriers with and without PD, patients with PD only, and healthy controls. FMHT outcome include computer-generated TES (Total Error Score) and values recommended by Vingrys & King-Smith. Six groups of 10 persons were tested. Significant differences were seen for male GD+PD and for age in PD. The highest mean TES was in the PD only group, the lowest in the GD only group. There was a significant difference because of PD in groups with GD and GBA carriers. GD+PD means were between GD only and PD only mean scores. These findings confirm that PD impacts color discrimination, more in males with GD+PD but nonetheless, GD+PD patients (but not GBA carriers) had better scores than PD only patients.

  17. What Skills and Tactics Are Needed to Play Adult Pick-Up Basketball Games?

    Science.gov (United States)

    Wang, Jianyu; Liu, Wenhao; Moffit, Jeffrey

    2010-01-01

    The purpose of this study was to examine skill levels and performance patterns of regular players of pick-up basketball games. By a survey, 65 participants were identified as regular players and participated in the study. An observational instrument used to analyze game performance of the participants was developed and both content and construct…

  18. Medications Used for Cognitive Enhancement in Patients With Schizophrenia, Bipolar Disorder, Alzheimer's Disease, and Parkinson's Disease.

    Science.gov (United States)

    Hsu, Wen-Yu; Lane, Hsien-Yuan; Lin, Chieh-Hsin

    2018-01-01

    Cognitive impairment, which frequently occurs in patients with schizophrenia, bipolar disorder, Alzheimer's disease, and Parkinson's disease, has a significant impact on the daily lives of both patients and their family. Furthermore, since the medications used for cognitive enhancement have limited efficacy, the issue of cognitive enhancement still remains a clinically unsolved challenge. We reviewed the clinical studies (published between 2007 and 2017) that focused on the efficacy of medications used for enhancing cognition in patients with schizophrenia, bipolar disorder, Alzheimer's disease, and Parkinson's disease. Acetylcholinesterase inhibitors and memantine are the standard treatments for Alzheimer's disease and Parkinson's disease. Some studies have reported selective cognitive improvement in patients with schizophrenia following galantamine treatment. Newer antipsychotics, including paliperidone, lurasidone, aripiprazole, ziprasidone, and BL-1020, have also been reported to exert cognitive benefits in patients with schizophrenia. Dopaminergic medications were found to improve language function in patients with Parkinson's disease. However, no beneficial effects on cognitive function were observed with dopamine agonists in patients with schizophrenia. The efficacies of nicotine and its receptor modulators in cognitive improvement remain controversial, with the majority of studies showing that varenicline significantly improved the cognitive function in schizophrenic patients. Several studies have reported that N -methyl-d-aspartate glutamate receptor (NMDAR) enhancers improved the cognitive function in patients with chronic schizophrenia. NMDAR enhancers might also have cognitive benefits in patients with Alzheimer's disease or Parkinson's disease. Raloxifene, a selective estrogen receptor modulator, has also been demonstrated to have beneficial effects on attention, processing speed, and memory in female patients with schizophrenia. Clinical trials with

  19. Frontotemporal Dementia (Pick's Disease)

    Science.gov (United States)

    ... changes in food preferences; agitation or, conversely, blunted emotions; neglect of personal hygiene; repetitive or compulsive behavior, and decreased energy and motivation. The second type primarily features symptoms of language ...

  20. Whole body organization during a symmetric bimanual pick up task in overweight and obese children.

    Science.gov (United States)

    Hung, Ya-Ching; Mangiafreno, Melissa; Gill, Simone V

    2017-02-01

    Information on the effects of obesity on the biomechanics of whole body movement control in children is limited. The purpose of the current study is to test the hypothesis that during a simple pick up task, overweight and obese children will organize their whole body movements differently than those in normal weight children. Twelve children who were overweight or obese (5-13 years old) and twelve age matched normal weight children participated in the study. Children picked up an empty box to waist height at a self-selected pace while kinematic and kinetic data were recorded and analyzed using a VICON system and two AMTI force plates. The overweight and obese group showed less knee flexion in both legs, more spine flexion, and less excursion in the height of their center of mass (all Psoverweight and obese group had more anterior movement in their center of mass (Poverweight and obese group had greater anterior excursion with faster average anterior moving speed and spent a longer time with the center of pressure reached forward (all Psoverweight and obese children organize their whole body movement during a simple pick up task differently with higher and more forward center of mass, quickly shifting their center of pressure anteriorly, and with a longer period of time with the center of pressure remaining forward. Their movement strategy may put them in a less stable condition and thus make them prone to losing balance. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. 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.

  2. Somatostatin receptor scintigraphy in patients with cat-scratch disease

    International Nuclear Information System (INIS)

    Krause, R.; Schnedl, W.J.; Hoier, S.; Piswanger-Soelkner, C.; Lipp, R.W.; Daxboeck, F.; Reisinger, E.C.

    2006-01-01

    Aim: somatostatin receptor scintigraphy images various neoplastic, granulomatous, and auto-immun diseases. Cat-scratch disease in an infectious granulomatous disease usually affecting the lymphnodes. It is not known whether cat-scratch disease provides positive somatostatin receptor scintigrams. Patients, methods: twelve patients with lymphadenitis and suspected cat-scratch disease were investigated by immunofluorescence antibody testing and somatostatin receptor scintigraphy. Suppurated lymphnodes were extracted or drained and Bartonella henselae specific PCR was then performed. Results: eleven of 12 patients showed IgG antibodies against B. henselea. SRS showed positive scintigraphic results in 6 of 11 patients with CSD. B. henselae DNA was detected in tissue of lymphnodes from 4 of 5 patients with lymphnode extraction or lymphnode drainage. SRS demonstrated positive scintigrams in all patients with a positive PCR. In one patient with suspected CSD SRS was negative as well as antibody testing. Conclusion: somatostatin receptor scintigraphy correlated with positive Bartonella henselae specific PCR tests and positive Bartonella henselae specific antibody tests in patients with CSD. (orig.)

  3. Somatostatin receptor scintigraphy in patients with cat-scratch disease

    Energy Technology Data Exchange (ETDEWEB)

    Krause, R.; Schnedl, W.J.; Hoier, S. [Div. of Infectious Diseases, Dept. of Internal Medicine, Univ. Graz (Austria); Piswanger-Soelkner, C.; Lipp, R.W. [Div. of Nuclear Medicine, Dept. of Internal Medicine, Univ. Graz (Austria); Daxboeck, F. [Clinical Inst. for Hygiene and Medical Microbiology, Div. of Hospital Hygiene, Univ. of Vienna (Austria); Reisinger, E.C. [Div. of Infectious Diseases and Tropical Medicine, Dept. of Internal Medicine, Univ. Rostock (Germany)

    2006-07-01

    Aim: somatostatin receptor scintigraphy images various neoplastic, granulomatous, and auto-immun diseases. Cat-scratch disease in an infectious granulomatous disease usually affecting the lymphnodes. It is not known whether cat-scratch disease provides positive somatostatin receptor scintigrams. Patients, methods: twelve patients with lymphadenitis and suspected cat-scratch disease were investigated by immunofluorescence antibody testing and somatostatin receptor scintigraphy. Suppurated lymphnodes were extracted or drained and Bartonella henselae specific PCR was then performed. Results: eleven of 12 patients showed IgG antibodies against B. henselea. SRS showed positive scintigraphic results in 6 of 11 patients with CSD. B. henselae DNA was detected in tissue of lymphnodes from 4 of 5 patients with lymphnode extraction or lymphnode drainage. SRS demonstrated positive scintigrams in all patients with a positive PCR. In one patient with suspected CSD SRS was negative as well as antibody testing. Conclusion: somatostatin receptor scintigraphy correlated with positive Bartonella henselae specific PCR tests and positive Bartonella henselae specific antibody tests in patients with CSD. (orig.)

  4. Thrombophilic Risk Factors in Patients With Inflammatory Bowel Disease.

    Science.gov (United States)

    Yazici, Ayten; Senturk, Omer; Aygun, Cem; Celebi, Altay; Caglayan, Cigdem; Hulagu, Sadettin

    2010-06-01

    Inflammatory bowel disease (IBD) patients have an increased risk for thromboembolism. The aim of this study was to assess the presence of thrombophilic risk factors in IBD patients and to assess the associations of these factors with disease activity. Forty-eight patients with IBD (24 ulcerative colitis, 24 Crohn's disease) and 40 matched healthy control individuals were enrolled. In addition to routine biochemical analysis, fasting blood samples were studied for prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, protein-C, protein-S, antithrombin III, factor VII, factor VIII, D-dimer, vitamin B 12 , folic acid and homocysteine. Levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fibrinogen, D-dimer and the number of platelets were significantly higher in patients with IBD. When compared to control group, in patients with Crohn's disease serum homocystein levels were significantly higher (p = 0.025) while serum folic acid levels were significantly lower (p homocystein and the number of platelets were found to be significantly higher in Crohn's disease patients who were in active period of the disease. Thrombophilic defects are multifactorial and might be frequently seen in IBD patients. They might contribute to thrombotic complications of this disease.

  5. A Port-Hamiltonian Approach to Visual Servo Control of a Pick and Place System

    NARCIS (Netherlands)

    Dirksz, Daniel A.; Scherpen, Jacquelien M. A.; Steinbuch, Maarten

    In this paper, we take a port-Hamiltonian approach to address the problem of image-based visual servo control of a pick and place system. Through a coordinate transformation and a passive interconnection between mechanical system and camera dynamics we realize a closed-loop system that is

  6. Helping Patients Cope with Inflammatory Bowel Disease.

    Science.gov (United States)

    1984-01-01

    these strategies can be effective as long as the strategy leads to 1) containment of guilt, fear, anxiety, and grief, 2) generation of hope , 3...patients with a sense of hope and a feeling that the disease can be coped with. The most difficult aspect of living with inflammatory bowel disease is...Recovery (mastectomy patients) and the Ostomy Association. They consist of people with Inflammatory Bowel Disease. Members support one another by sharing

  7. [Disease management for chronic heart failure patient].

    Science.gov (United States)

    Bläuer, Cornelia; Pfister, Otmar; Bächtold, Christa; Junker, Therese; Spirig, Rebecca

    2011-02-01

    Patients with chronic heart failure (HF) are limited in their quality of life, have a poor prognosis and face frequent hospitalisations. Patient self-management was shown to improve quality of life, reduce rehospitalisations and costs in patients with chronic HF. Comprehensive disease management programmes are critical to foster patient self-management. The chronic care model developed by the WHO serves as the basis of such programmes. In order to develop self-management skills a needs orientated training concept is mandatory, as patients need both knowledge of the illness and the ability to use the information to make appropriate decisions according to their individual situation. Switzerland has no established system for the care of patients with chronic diseases in particular those with HF. For this reason a group of Swiss experts for HF designed a model for disease management for HF patients in Switzerland. Since 2009 the Swiss Heart Foundation offers an education programme based on this model. The aim of this programme is to offer education and support for practitioners, patients and families. An initial pilot evaluation of the program showed mixed acceptance by practitioners, whereas patient assessed the program as supportive and in line with their requirements.

  8. Collision free pick up and movement of large objects

    International Nuclear Information System (INIS)

    Drotning, W.D.; McKee, G.R.

    1998-01-01

    An automated system is described for the sensor-based precision docking and manipulation of large objects. Past work in the remote handling of large nuclear waste containers is extensible to the problems associated with the handling of large objects such as coils of flat steel in industry. Computer vision and ultrasonic proximity sensing as described here are used to control the precision docking of large objects, and swing damped motion control of overhead cranes is used to control the position of the pick up device and suspended payload during movement. Real-time sensor processing and model-based control are used to accurately position payloads

  9. Heart disease in patients with pulmonary embolism.

    Science.gov (United States)

    Pesavento, Raffaele; Piovella, Chiara; Prandoni, Paolo

    2010-09-01

    Several heart diseases are promoters of left-side cardiac thrombosis and could lead to arterial embolism. The same mechanism may be responsible for right-side cardiac thrombosis and therefore be a direct source of pulmonary embolism. Yasuoka et al. showed a higher incidence of perfusion defects in lung scan in patients with spontaneous echocontrast in the right atrium than in those without it (40% and 7% respectively; P=0.006). We recently assessed the prevalence of heart diseases in 11.236 consecutive patients older than 60 years discharged from Venetian hospitals with a diagnosis of pulmonary embolism. We observed a higher prevalence of all-cause heart diseases (odds ratio 1.26; 95% confidence interval, 1.13-1.40) in patients with a diagnosis of pulmonary embolism alone (secondary or unprovoked) compared with those discharged with a diagnosis of pulmonary embolism associated with deep vein thrombosis, generating the hypothesis that some specific heart diseases in older patients could themselves be a possible source of pulmonary emboli. Further prospective studies are required to confirm these findings, which have the potential to open new horizons for the interpretation and management of venous thromboembolic disease.

  10. Celiac Disease Autoimmunity in Patients with Autoimmune Diabetes and Thyroid Disease among Chinese Population.

    Directory of Open Access Journals (Sweden)

    Zhiyuan Zhao

    Full Text Available The prevalence of celiac disease autoimmunity or tissue transglutaminase autoantibodies (TGA amongst patients with type 1 diabetes (T1D and autoimmune thyroid disease (AITD in the Chinese population remains unknown. This study examined the rate of celiac disease autoimmunity amongst patients with T1D and AITD in the Chinese population. The study included 178 patients with type 1 diabetes and 119 with AITD where 36 had both T1D and AITD, classified as autoimmune polyglandular syndrome type 3 variant (APS3v. The study also included 145 patients with type 2 diabetes (T2D, 97 patients with non-autoimmune thyroid disease (NAITD, and 102 healthy controls. Serum islet autoantibodies, thyroid autoantibodies and TGA were measured by radioimmunoassay. TGA positivity was found in 22% of patients with either type 1 diabetes or AITD, much higher than that in patients with T2D (3.4%; p< 0.0001 or NAITD (3.1%; P < 0.0001 or healthy controls (1%; p<0.0001. The patients with APS3v having both T1D and AITD were 36% positive for TGA, significantly higher than patients with T1D alone (p = 0.040 or with AITD alone (p = 0.017. T1D and AITD were found to have a 20% and 30% frequency of overlap respectively at diagnosis. In conclusion, TGA positivity was high in the Chinese population having existing T1D and/or AITD, and even higher when both diseases were present. Routine TGA screening in patients with T1D or AITD will be important to early identify celiac disease autoimmunity for better clinical care of patients.

  11. Hibernia field construction pace picks up speed

    International Nuclear Information System (INIS)

    Anon.

    1992-01-01

    This paper reports that the pace of construction is increasing for the $5.2 billion (Canadian) Hibernia oil field development project off Newfoundland with a new partner close to signing on. Texaco, Inc. is reported ready to pick up a 25% interest in the project within a month. Construction activity for offshore systems was cut 50% last February when Gulf Canada Resources Inc. The it planned to withdraw from its 25% interest in Hibernia. Since then, remaining interest owners Mobil Oil Canada Ltd., Chevron Canada Resources Ltd., and Petro-Canada have been seeking new partners. The effort has focused on Texaco with Canadian Energy Minister Jake Epp playing a role in talks. Hibernia's construction work force has risen to 850 from a low of 600. A spokesman for Hibernia Management and Development Co., project manager, the a steady increase in the work force is planned

  12. Perianal disease, small bowel disease, smoking, prior steroid or early azathioprine/biological therapy are predictors of disease behavior change in patients with Crohn's disease.

    Science.gov (United States)

    Lakatos, Peter Laszlo; Czegledi, Zsofia; Szamosi, Tamas; Banai, Janos; David, Gyula; Zsigmond, Ferenc; Pandur, Tunde; Erdelyi, Zsuzsanna; Gemela, Orsolya; Papp, Janos; Lakatos, Laszlo

    2009-07-28

    To assess the combined effect of disease phenotype, smoking and medical therapy [steroid, azathioprine (AZA), AZA/biological therapy] on the probability of disease behavior change in a Caucasian cohort of patients with Crohn's disease (CD). Three hundred and forty well-characterized, unrelated, consecutive CD patients were analyzed (M/F: 155/185, duration: 9.4 +/- 7.5 years) with a complete clinical follow-up. Medical records including disease phenotype according to the Montreal classification, extraintestinal manifestations, use of medications and surgical events were analyzed retrospectively. Patients were interviewed on their smoking habits at the time of diagnosis and during the regular follow-up visits. A change in disease behavior was observed in 30.8% of patients with an initially non-stricturing, non-penetrating disease behavior after a mean disease duration of 9.0 +/- 7.2 years. In a logistic regression analysis corrected for disease duration, perianal disease, smoking, steroid use, early AZA or AZA/biological therapy use were independent predictors of disease behavior change. In a subsequent Kaplan-Meier survival analysis and a proportional Cox regression analysis, disease location (P = 0.001), presence of perianal disease (P < 0.001), prior steroid use (P = 0.006), early AZA (P = 0.005) or AZA/biological therapy (P = 0.002), or smoking (P = 0.032) were independent predictors of disease behavior change. Our data suggest that perianal disease, small bowel disease, smoking, prior steroid use, early AZA or AZA/biological therapy are all predictors of disease behavior change in CD patients.

  13. Novel combined management approaches to patients with diabetes, chronic kidney disease and cardiovascular disease.

    Science.gov (United States)

    Spaak, J

    2017-03-01

    Most patients we care for today suffer from more than one chronic disease, and multimorbidity is a rapidly growing challenge. Concomitant cardiovascular disease, renal dysfunction and diabetes represent a large proportion of all patients in cardiology, nephrology and diabetology. These entities commonly overlap due to their negative effects on vascular function and an accelerated atherosclerosis progression. At the same time, a progressive subspecialisation has caused the cardiologist to treat 'only' the heart, nephrologists 'only' the kidneys and endocrinologists' 'only' diabetes. Studies and guidelines follow the same pattern. This often requires patients to visit specialists for each field, with a risk of both under-diagnosis and under-treatment. From the patient's perspective, there is a great need for coordination and facilitation of the care, not only to reduce disease progression but also to improve quality of life. Person-centred integrated clinics for patients with cardiovascular disease, renal dysfunction and diabetes are a promising approach for complex chronic disease management.

  14. A port-Hamiltonian approach to visual servo control of a pick and place system

    NARCIS (Netherlands)

    Dirksz, Daniel A.; Scherpen, Jacquelien M.A.

    2012-01-01

    In this paper we take a port-Hamiltonian approach to address the problem of image-based visual servo control of a pick and place system. We realize a closed-loop system, including the nonlinear camera dynamics, which is port-Hamiltonian. Although the closed-loop system is nonlinear, the resulting

  15. Patient and Disease Characteristics Associated with Activation for Self-Management in Patients with Diabetes, Chronic Obstructive Pulmonary Disease, Chronic Heart Failure and Chronic Renal Disease: A Cross-Sectional Survey Study

    Science.gov (United States)

    Bos-Touwen, Irene; Schuurmans, Marieke; Monninkhof, Evelyn M.; Korpershoek, Yvonne; Spruit-Bentvelzen, Lotte; Ertugrul-van der Graaf, Inge; de Wit, Niek; Trappenburg, Jaap

    2015-01-01

    A substantial proportion of chronic disease patients do not respond to self-management interventions, which suggests that one size interventions do not fit all, demanding more tailored interventions. To compose more individualized strategies, we aim to increase our understanding of characteristics associated with patient activation for self-management and to evaluate whether these are disease-transcending. A cross-sectional survey study was conducted in primary and secondary care in patients with type-2 Diabetes Mellitus (DM-II), Chronic Obstructive Pulmonary Disease (COPD), Chronic Heart Failure (CHF) and Chronic Renal Disease (CRD). Using multiple linear regression analysis, we analyzed associations between self-management activation (13-item Patient Activation Measure; PAM-13) and a wide range of socio-demographic, clinical, and psychosocial determinants. Furthermore, we assessed whether the associations between the determinants and the PAM were disease-transcending by testing whether disease was an effect modifier. In addition, we identified determinants associated with low activation for self-management using logistic regression analysis. We included 1154 patients (53% response rate); 422 DM-II patients, 290 COPD patients, 223 HF patients and 219 CRD patients. Mean age was 69.6±10.9. Multiple linear regression analysis revealed 9 explanatory determinants of activation for self-management: age, BMI, educational level, financial distress, physical health status, depression, illness perception, social support and underlying disease, explaining a variance of 16.3%. All associations, except for social support, were disease transcending. This study explored factors associated with varying levels of activation for self-management. These results are a first step in supporting clinicians and researchers to identify subpopulations of chronic disease patients less likely to be engaged in self-management. Increased scientific efforts are needed to explain the greater

  16. Patient and disease characteristics associated with activation for self-management in patients with diabetes, chronic obstructive pulmonary disease, chronic heart failure and chronic renal disease: a cross-sectional survey study.

    Science.gov (United States)

    Bos-Touwen, Irene; Schuurmans, Marieke; Monninkhof, Evelyn M; Korpershoek, Yvonne; Spruit-Bentvelzen, Lotte; Ertugrul-van der Graaf, Inge; de Wit, Niek; Trappenburg, Jaap

    2015-01-01

    A substantial proportion of chronic disease patients do not respond to self-management interventions, which suggests that one size interventions do not fit all, demanding more tailored interventions. To compose more individualized strategies, we aim to increase our understanding of characteristics associated with patient activation for self-management and to evaluate whether these are disease-transcending. A cross-sectional survey study was conducted in primary and secondary care in patients with type-2 Diabetes Mellitus (DM-II), Chronic Obstructive Pulmonary Disease (COPD), Chronic Heart Failure (CHF) and Chronic Renal Disease (CRD). Using multiple linear regression analysis, we analyzed associations between self-management activation (13-item Patient Activation Measure; PAM-13) and a wide range of socio-demographic, clinical, and psychosocial determinants. Furthermore, we assessed whether the associations between the determinants and the PAM were disease-transcending by testing whether disease was an effect modifier. In addition, we identified determinants associated with low activation for self-management using logistic regression analysis. We included 1154 patients (53% response rate); 422 DM-II patients, 290 COPD patients, 223 HF patients and 219 CRD patients. Mean age was 69.6±10.9. Multiple linear regression analysis revealed 9 explanatory determinants of activation for self-management: age, BMI, educational level, financial distress, physical health status, depression, illness perception, social support and underlying disease, explaining a variance of 16.3%. All associations, except for social support, were disease transcending. This study explored factors associated with varying levels of activation for self-management. These results are a first step in supporting clinicians and researchers to identify subpopulations of chronic disease patients less likely to be engaged in self-management. Increased scientific efforts are needed to explain the greater

  17. Patient and disease characteristics associated with activation for self-management in patients with diabetes, chronic obstructive pulmonary disease, chronic heart failure and chronic renal disease: a cross-sectional survey study.

    Directory of Open Access Journals (Sweden)

    Irene Bos-Touwen

    Full Text Available A substantial proportion of chronic disease patients do not respond to self-management interventions, which suggests that one size interventions do not fit all, demanding more tailored interventions. To compose more individualized strategies, we aim to increase our understanding of characteristics associated with patient activation for self-management and to evaluate whether these are disease-transcending. A cross-sectional survey study was conducted in primary and secondary care in patients with type-2 Diabetes Mellitus (DM-II, Chronic Obstructive Pulmonary Disease (COPD, Chronic Heart Failure (CHF and Chronic Renal Disease (CRD. Using multiple linear regression analysis, we analyzed associations between self-management activation (13-item Patient Activation Measure; PAM-13 and a wide range of socio-demographic, clinical, and psychosocial determinants. Furthermore, we assessed whether the associations between the determinants and the PAM were disease-transcending by testing whether disease was an effect modifier. In addition, we identified determinants associated with low activation for self-management using logistic regression analysis. We included 1154 patients (53% response rate; 422 DM-II patients, 290 COPD patients, 223 HF patients and 219 CRD patients. Mean age was 69.6±10.9. Multiple linear regression analysis revealed 9 explanatory determinants of activation for self-management: age, BMI, educational level, financial distress, physical health status, depression, illness perception, social support and underlying disease, explaining a variance of 16.3%. All associations, except for social support, were disease transcending. This study explored factors associated with varying levels of activation for self-management. These results are a first step in supporting clinicians and researchers to identify subpopulations of chronic disease patients less likely to be engaged in self-management. Increased scientific efforts are needed to explain

  18. [Anesthesia for patients with neurological diseases].

    Science.gov (United States)

    Kimura, Masafumi; Saito, Shigeru

    2010-09-01

    Several surgical treatments can be employed for the patients with neurological disorders, such as multiple sclerosis, Guillain-Barré syndrome, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer disease and spinal cord injury. It is possible that anesthesia related complications are induced in these neurologically complicated patients in the perioperative period. Respiratory dysfunction and autonomic nervous system dysfunction are most common in this population. Respiratory muscle weakness and bulbar palsy may cause aspiration pneumonia. Sometimes, postoperative ventilatory support is mandatory in these patients. Autonomic nervous system dysfunction may cause hypotension secondary to postural changes, blood loss, or positive airway pressure. Some therapeutic agents prescribed for neurological symptoms have drug interaction with anesthetic agents. Patients with motor neuron disease should be considered to be vulnerable to hyperkalemia in response to a depolarizing muscle relaxant. Although perioperative treatment guideline for most neurologic disorders has not been reported to lessen perioperative morbidity, knowledge of the clinical features and the interaction of common anesthetics with the drug therapy is important in planning intraoperative and postoperative management.

  19. Interaction of AnxA6 with isolated and artificial lipid microdomains; importance of lipid composition and calcium content.

    Science.gov (United States)

    Domon, Magdalena M; Besson, Françoise; Tylki-Szymanska, Anna; Bandorowicz-Pikula, Joanna; Pikula, Slawomir

    2013-04-05

    Niemann-Pick type C (NPC) disease is a lipid storage disorder characterized by accumulation of lipids in the late endosome/lysosome (LE/LY) compartment. In our previous report we isolated membranes of the LE/LY compartment from NPC L1 skin fibroblasts with a mutation in the NPC1 gene and found that they were characterized by low fluidity which likely contributed to the impaired function of membrane proteins involved in storage and turnover of cholesterol. In this report we isolated lipid microdomains (DRMs) from membranes of various cellular compartments and observed an increased amount of DRMs in the LE/LY compartment of NPC L1 cells in comparison to control cells, with no change in the DRM content in the plasma membrane. In addition, in the NPC cells, the majority of the cholesterol-interacting protein, AnxA6, which participates in the transport and distribution of cholesterol, translocated to DRMs upon a rise in Ca(2+) concentration. The mechanism of this translocation was further studied in vitro using Langmuir monolayers. We found that Ca(2+) is the main factor which regulates the interaction of AnxA6 with monolayers composed of neutral lipids, such as DPPC and sphingomyelin, and may also determine AnxA6 localization in cholesterol and sphingomyelin enriched microdomains, thus contributing to the etiology of the NPC disease.

  20. Sensitivity to lysosome-dependent cell death is directly regulated by lysosomal cholesterol content.

    Directory of Open Access Journals (Sweden)

    Hanna Appelqvist

    Full Text Available Alterations in lipid homeostasis are implicated in several neurodegenerative diseases, although the mechanisms responsible are poorly understood. We evaluated the impact of cholesterol accumulation, induced by U18666A, quinacrine or mutations in the cholesterol transporting Niemann-Pick disease type C1 (NPC1 protein, on lysosomal stability and sensitivity to lysosome-mediated cell death. We found that neurons with lysosomal cholesterol accumulation were protected from oxidative stress-induced apoptosis. In addition, human fibroblasts with cholesterol-loaded lysosomes showed higher lysosomal membrane stability than controls. Previous studies have shown that cholesterol accumulation is accompanied by the storage of lipids such as sphingomyelin, glycosphingolipids and sphingosine and an up regulation of lysosomal associated membrane protein-2 (LAMP-2, which may also influence lysosomal stability. However, in this study the use of myriocin and LAMP deficient fibroblasts excluded these factors as responsible for the rescuing effect and instead suggested that primarily lysosomal cholesterol content determineD the cellular sensitivity to toxic insults. Further strengthening this concept, depletion of cholesterol using methyl-β-cyclodextrin or 25-hydroxycholesterol decreased the stability of lysosomes and cells became more prone to undergo apoptosis. In conclusion, cholesterol content regulated lysosomal membrane permeabilization and thereby influenced cell death sensitivity. Our data suggests that lysosomal cholesterol modulation might be used as a therapeutic strategy for conditions associated with accelerated or repressed apoptosis.

  1. Reestructuración del layout de la zona de picking en una bodega industrial

    Directory of Open Access Journals (Sweden)

    Martín Darío Arango Serna

    2010-12-01

    Full Text Available Este artículo tiene como objetivo presentar una propuesta orientada al mejoramiento de los procesos de distribución y Picking en la bodega de una empresa del sector industrial. Este presenta, inicialmente el marco teórico y la problemática, finaliza con la presentación del caso empresarial objeto de estudio. Las actividades relacionadas con el almacenamiento de materiales son de las que más interfieren en los costos logísticos totales en una empresa o cadena de suministro. Una de las actividades primordiales para intentar reducir los costos operativos es la optimización de los espacios requeridos en el almacenamiento. La finalidad del estudio radica principalmente en la disminución de los tiempos de preparación de pedido para lograr una mejora en el servicio y en la reducción del área destinada al almacenamiento para mitigar los costos de operación. / The main objective of this paper is to present a proposal aimed at improving the distribution and picking processes in a warehouse of an industrial company. Initially, it outlines the theory and problem to be solved, and concludes with a description of a case study. Warehousing activities affect the total logistics costs of a company or supply chain most; thus, optimizing the required spaces for warehousing is one of the most important activities when attempting to reduce operative costs in a company. The purpose of this study is to reduce the time required for picking activities and, therefore, obtain an improvement in the service and a reduction of the area used in the warehouse, which leads to cost reductions.

  2. Prognosis of patients with rheumatic diseases admitted to intensive care.

    Science.gov (United States)

    Beil, M; Sviri, S; de la Guardia, V; Stav, I; Ben-Chetrit, E; van Heerden, P V

    2017-01-01

    Variable mortality rates have been reported for patients with rheumatic diseases admitted to an intensive care unit (ICU). Due to the absence of appropriate control groups in previous studies, it is not known whether the presence of a rheumatic disease constitutes a risk factor. Moreover, the accuracy of the Acute Physiology and Chronic Health Evaluation II (APACHE II) score for predicting outcome in this group of patients has been questioned. The primary goal of this study was to compare outcome of patients with rheumatic diseases admitted to a medical ICU to those of controls. The records of all patients admitted between 1 April 2003 and 30 June 2014 (n=4020) were screened for the presence of a rheumatic disease during admission (n=138). The diagnosis of a rheumatic disease was by standard criteria for these conditions. An age- and gender-matched control group of patients without a rheumatic disease was extracted from the patient population in the database during the same period (n=831). Mortality in ICU, in hospital and after 180 days did not differ significantly between patients with and without rheumatic diseases. There was no difference in the performance of the APACHE II score for predicting outcome in patients with rheumatic diseases and controls. This score, as well as a requirement for the use of inotropes or vasopressors, accurately predicted hospital mortality in the group of patients with rheumatic diseases. In conclusion, patients with a rheumatic condition admitted to intensive care do not do significantly worse than patients without such a disease.

  3. Epiretinal membrane removal in patients with Stargardt disease

    Directory of Open Access Journals (Sweden)

    Muna Bhende

    2015-01-01

    Full Text Available Epiretinal membranes (ERMs in Stargardt disease have been known to undergo spontaneous separation in children. Results of surgical intervention in adult patients with Stargardt disease have rarely been reported. A retrospective review of results of surgical intervention for ERM causing visual impairment in two adult patients of Stargardt disease was carried out. Both patients developed ERM in one eye during their follow-up period with the resultant drop in their preexisting visual acuity. Postsurgery, restoration of foveal contour with some improvement in visual acuity was observed in both patients. No adverse effect of surgery was noted.

  4. Effect of frequency of clinic visits and medication pick-up on antiretroviral treatment outcomes: a systematic literature review and meta-analysis.

    Science.gov (United States)

    Mutasa-Apollo, Tsitsi; Ford, Nathan; Wiens, Matthew; Socias, Maria Eugenia; Negussie, Eyerusalem; Wu, Ping; Popoff, Evan; Park, Jay; Mills, Edward J; Kanters, Steve

    2017-07-21

    Expanding and sustaining antiretroviral therapy (ART) coverage may require simplified HIV service delivery strategies that concomitantly reduce the burden of care on the health system and patients while ensuring optimal outcomes. We conducted a systematic review to assess the impact of reduced frequency of clinic visits and drug dispensing on patient outcomes. As part of the development process of the World Health Organization antiretroviral (ARV) guidelines, we systematically searched medical literature databases for publications up to 30 August 2016. Information was extracted on trial characteristics, patient characteristics and the following outcomes: mortality, morbidity, treatment adherence, retention, patient and provider acceptability, cost and patients exiting the programme. When feasible, conventional pairwise meta-analyses were conducted. Results and discussion Of 6443 identified citations, 21 papers, pertaining to 16 studies, were included in this review, with 11 studies contributing to analyses. Although analyses were feasible, they were limited by the sparse evidence base, despite the importance of the research area, and relatively low quality. Comparative analyses of eight studies reporting on frequency of clinic visits showed that less frequent clinic visits led to higher odds of being retained in care (odds ratio [OR]: 1.90; 95% CI: 1.21-2.99). No differences were found with respect to viral failure, morbidity or mortality; however, most estimates were favourable to reduced clinic visits. Reduced frequency of ARVs pick-ups showed a trend towards better retention (OR: 1.93; 95% CI: 0.62-6.04). Strategies using community support tended to have better outcomes; however, their implementation varied, particularly by location. External validity may be questionable. Our systematic review suggests that reduction of clinical visits (and likely ARVs pick-ups) may improve clinical outcomes, and that they are a viable option to relieve health systems and reduce

  5. Exact Solutions to the Symmetric and Asymmetric Vehicle Routing Problem with Simultaneous Delivery and Pick-Up

    Directory of Open Access Journals (Sweden)

    Julia Rieck

    2013-05-01

    Full Text Available In reverse logistics networks, products (e.g., bottles or containers have to be transported from a depot to customer locations and, after use, from customer locations back to the depot. In order to operate economically beneficial, companies prefer a simultaneous delivery and pick-up service. The resulting Vehicle Routing Problem with Simultaneous Delivery and Pick-up (VRPSDP is an operational problem, which has to be solved daily by many companies. We present two mixed-integer linear model formulations for the VRPSDP, namely a vehicle-flow and a commodity-flow model. In order to strengthen the models, domain-reducing preprocessing techniques, and effective cutting planes are outlined. Symmetric benchmark instances known from the literature as well as new asymmetric instances derived from real-world problems are solved to optimality using CPLEX 12.1.

  6. Suicide and patients with neurologic diseases. Methodologic problems

    DEFF Research Database (Denmark)

    Stenager, E N; Stenager, Egon

    1992-01-01

    OBJECTIVE: The suicide risk in patients with many neurologic diseases has been reported to be greater than that in the general population. Studies on the subject are, however, often encumbered with methodologic problems. We appraised these problems and, based on an evaluation, reappraised knowledge...... of the suicide risk in patients with specific neurologic diseases. DATA SOURCE: Using the computerized database MEDLINE, we identified all published reports with the key words suicide, attempted suicide, and neurologic diseases. STUDY SELECTION: We assessed and reviewed studies concerning the most common...... of the studies, the methods used gave rise to uncertainty about the conclusion presented. CONCLUSION: An increased suicide risk was found in patients suffering from multiple sclerosis and spinal cord lesions as well as in selected groups of patients with epilepsy. In other neurologic diseases, the suicide risk...

  7. The Prevalence of Fabry Disease in Patients with Chronic Kidney Disease in Turkey: The TURKFAB Study

    Directory of Open Access Journals (Sweden)

    Kultigin Turkmen

    2016-12-01

    Full Text Available Background/Aims: Fabry disease is a treatable cause of chronic kidney disease (CKD characterized by a genetic deficiency of α-galactosidase A. European Renal Best Practice (ERBP recommends screening for Fabry disease in CKD patients. However, this is based on expert opinion and there are no reports of the prevalence of Fabry disease in stage 1-5 CKD. Hence, we investigated the prevalence of Fabry disease in CKD patients not receiving renal replacement therapy. Methods: This prospective study assessed α-galactosidase activity in dried blood spots in 313 stage 1-5 CKD patients, 167 males, between ages of 18-70 years whose etiology of CKD was unknown and were not receiving renal replacement therapy. The diagnosis was confirmed by GLA gene mutation analysis. Results: Three (all males of 313 CKD patients (0.95% were diagnosed of Fabry disease, for a prevalence in males of 1.80%. Family screening identified 8 aditional Fabry patients with CKD. Of a total of 11 Fabry patients, 7 were male and started enzyme replacement therapy and 4 were female. The most frequent manifestations in male patients were fatigue (100%, tinnitus, vertigo, acroparesthesia, hypohidrosis, cornea verticillata and angiokeratoma (all 85%, heat intolerance (71%, and abdominal pain (57%. The most frequent manifestations in female patients were fatigue and cornea verticillata (50%, and tinnitus, vertigo and angiokeratoma (25%. Three patients had severe episodic abdominal pain attacks and proteinuria, and were misdiagnosed as familial Mediterranean fever. Conclusions: The prevalence of Fabry disease in selected CKD patients is in the range found among renal replacement therapy patients, but the disease is diagnosed at an earlier, treatable stage. These data support the ERBP recommendation to screen for Fabry disease in patients with CKD of unknown origin.

  8. Learning disabilities in Darier's disease patients.

    Science.gov (United States)

    Dodiuk-Gad, R; Lerner, M; Breznitz, Z; Cohen-Barak, E; Ziv, M; Shani-Adir, A; Amichai, B; Zlotogorski, A; Shalev, S; Rozenman, D

    2014-03-01

    Neuropsychiatric features and intellectual difficulties have been reported in studies of Darier's disease. Learning disabilities have never been reported or evaluated systematically in these patients. To assess the prevalence of learning disabilities in 76 patients with Darier's disease, and cognitive functioning in 19 of them. The data were collected by two methods: a questionnaire, as part of a larger study on the clinical characteristics of 76 patients; and neuropsychological measures for the assessment of learning disabilities in 19 of them. Thirty-one of the 76 patients reported learning disabilities (41%) and 56 (74%) reported a family history of learning disabilities. Significant differences were found between the 19 patients evaluated on cognitive tasks and a control group of 42 skilled learners on subtraction and multiplication tasks. Six (32%) of the 19 were identified as having reading difficulties and five (26%) exhibited low performance on the Concentration Performance Test. All patients had general cognitive ability in the average range. Findings suggest an association between Darier's disease and learning disabilities, a heretofore unreported association, pointing to the need to obtain personal and family history of such disabilities in order to refer cases of clinical concern for further study. © 2013 The Authors Journal of the European Academy of Dermatology and Venereology © 2013 European Academy of Dermatology and Venereology.

  9. Fibromyalgia in patients with other rheumatic diseases: prevalence and relationship with disease activity.

    Science.gov (United States)

    Haliloglu, Sema; Carlioglu, Ayse; Akdeniz, Derya; Karaaslan, Yasar; Kosar, Ali

    2014-09-01

    Fibromyalgia (FM) is a syndrome characterized by chronic widespread pain and the presence of specific tender points. The prevalence of FM has been estimated at 2-7 % of the general global population. The presence of FM in several rheumatic diseases with a structural pathology has been reported as 11-30 %. The objectives of this study were to determine the prevalence of FM and to evaluate the possible relationship between FM existence and disease activity among rheumatic diseases. The study group included 835 patients--197 rheumatoid arthritis (RA), 67 systemic lupus erythematosus (SLE), 119 ankylosing spondylitis (AS), 238 osteoarthritis (OA), 14 familial Mediterranean fever (FMF), 53 Behçet's disease (BD), 71 gout, 25 Sjögren's syndrome (SS), 20 vasculitis, 29 polymyalgia rheumatica (PMR), and two polymyositis (PM)--with or without FM. Recorded information included age, gender, laboratory parameters, presence of fatigue, and disease activity indexes. The prevalence of FM in patients with rheumatologic diseases was found to be 6.6 % for RA, 13.4 % for SLE, 12.6 % for AS, 10.1 % for OA, 5.7 % for BD, 7.1 % for FMF, 12 % for SS, 25 % for vasculitis, 1.4 % for gout, and 6.9 % for PMR. One out of two patients with PM was diagnosed with FM. Some rheumatologic cases (AS, OA) with FM were observed mostly in female patients (p = 0.000). Also, there were significant correlations between disease activity indexes and Fibromyalgia Impact Questionnaire scores for most rheumatologic patients (RA, AS, OA, and BD) (p diseases, and its recognition is important for the optimal management of these diseases. Increased pain, physical limitations, and fatigue may be interpreted as increased activity of these diseases, and a common treatment option is the prescription of higher doses of biologic agents or corticosteroids. Considerations of the FM component in the management of rheumatologic diseases increase the likelihood of the success of the treatment.

  10. Nonmotor symptoms in patients suffering from motor neuron diseases

    Directory of Open Access Journals (Sweden)

    Rene Günther

    2016-07-01

    Full Text Available Background: The recently postulated disease spreading hypothesis has gained much attention, especially for Parkinson’s disease (PD. The various nonmotor symptoms (NMS in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND is primarily known as a group of diseases with a selective loss of motor function. Recent evidence, however, suggests disease spreading into nonmotor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND.Methods: We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric and sleep complaints (NMSQuest which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls.Results: In total, MND patients reported significantly higher NMS scores (median: 7 points in comparison to controls (median: 4 points. Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression.Conclusions: NMS in MND patients seemed to increase with disease progression which would fit with the recently postulated disease spreading hypothesis. The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND.

  11. Software for dosimetry hypothyroid patients treated with I131 pick up and using probe gamma camera

    International Nuclear Information System (INIS)

    Jimenez Felstrom, D.; Luis simon, J.; Reyes Garcia, R.; Derecho Torres, P.; Herrador Cordoba, M.

    2015-01-01

    In this communication the process recently implemented in our hospital for pre and post treatment of patients treated with I-131 in benign diseases of the thyroid gland internal dosimetry is described. We have developed a proprietary software that facilitates the process of dosimetry. Through scans Planar or pictures Spect be determines the mass of the gland thyroid. In function of the mass, is calculated by Monte Carlo the media power absorbed by disintegration of the I-131 in said gland endocrine. (Author)

  12. Peak picking multidimensional NMR spectra with the contour geometry based algorithm CYPICK

    International Nuclear Information System (INIS)

    Würz, Julia M.; Güntert, Peter

    2017-01-01

    The automated identification of signals in multidimensional NMR spectra is a challenging task, complicated by signal overlap, noise, and spectral artifacts, for which no universally accepted method is available. Here, we present a new peak picking algorithm, CYPICK, that follows, as far as possible, the manual approach taken by a spectroscopist who analyzes peak patterns in contour plots of the spectrum, but is fully automated. Human visual inspection is replaced by the evaluation of geometric criteria applied to contour lines, such as local extremality, approximate circularity (after appropriate scaling of the spectrum axes), and convexity. The performance of CYPICK was evaluated for a variety of spectra from different proteins by systematic comparison with peak lists obtained by other, manual or automated, peak picking methods, as well as by analyzing the results of automated chemical shift assignment and structure calculation based on input peak lists from CYPICK. The results show that CYPICK yielded peak lists that compare in most cases favorably to those obtained by other automated peak pickers with respect to the criteria of finding a maximal number of real signals, a minimal number of artifact peaks, and maximal correctness of the chemical shift assignments and the three-dimensional structure obtained by fully automated assignment and structure calculation.

  13. Peak picking multidimensional NMR spectra with the contour geometry based algorithm CYPICK

    Energy Technology Data Exchange (ETDEWEB)

    Würz, Julia M.; Güntert, Peter, E-mail: guentert@em.uni-frankfurt.de [Goethe University Frankfurt am Main, Institute of Biophysical Chemistry, Center for Biomolecular Magnetic Resonance (Germany)

    2017-01-15

    The automated identification of signals in multidimensional NMR spectra is a challenging task, complicated by signal overlap, noise, and spectral artifacts, for which no universally accepted method is available. Here, we present a new peak picking algorithm, CYPICK, that follows, as far as possible, the manual approach taken by a spectroscopist who analyzes peak patterns in contour plots of the spectrum, but is fully automated. Human visual inspection is replaced by the evaluation of geometric criteria applied to contour lines, such as local extremality, approximate circularity (after appropriate scaling of the spectrum axes), and convexity. The performance of CYPICK was evaluated for a variety of spectra from different proteins by systematic comparison with peak lists obtained by other, manual or automated, peak picking methods, as well as by analyzing the results of automated chemical shift assignment and structure calculation based on input peak lists from CYPICK. The results show that CYPICK yielded peak lists that compare in most cases favorably to those obtained by other automated peak pickers with respect to the criteria of finding a maximal number of real signals, a minimal number of artifact peaks, and maximal correctness of the chemical shift assignments and the three-dimensional structure obtained by fully automated assignment and structure calculation.

  14. Prevalence of celiac disease in siblings of Iranian patients with celiac disease.

    Science.gov (United States)

    Chomeili, Bashir; Aminzadeh, Majid; Hardani, Amir Kamal; Fathizadeh, Payam; Chomeili, Pooya; Azaran, Azarakhsh

    2011-01-01

    Celiac disease, one of the best-known autoimmune human leukocyte antigen-dependent disorders, has a relatively increased prevalence in first-degree relatives. To determine the prevalence of celiac disease in siblings of patients with confirmed celiac disease. Siblings of confirmed celiac disease patients in our center were identified and enrolled in this study. Their serum immunoglobulin A and tissue transglutaminase antibody-enzyme-linked immunosorbent assay (anti-tissue transglutaminase, immunoglobulin A, and immunoglobulin G) were measured and multiple endoscopic duodenal biopsy specimens were obtained with parental consensus. Celiac disease was confirmed by observation of characteristic histological changes. A total of 49 children (male, 29; female, 20; age, 2-16 years) with confirmed celiac disease in a pediatric gastroenterology ward were studied from 1999 to 2006. We found 30 siblings (female, 16) all shared in both parents. The only measurement available was for immunoglobulin A tissue transglutaminase antibody. A duodenal biopsy was performed in all 30 siblings. Clinical findings such as abdominal pain, fatigue, growth retardation and diarrhea were found in 53.3% of the completely studied siblings, and positive serology without histological changes was identified in four cases. Both serology and biopsy (confirmed new cases) were positive in 2 of the 30 siblings. High prevalence of celiac disease among siblings of patients with confirmed celiac disease necessitates serologic screening (and confirmatory biopsy if indicated) in families having celiac disease. It is advantageous to diagnose the disease as soon as possible because early diagnosis and diet intervention may prevent serious complications such as growth retardation, short stature, chronic diarrhea, and malignancy.

  15. Enhanced thyroid iodine metabolism in patients with triiodothyronine-predominant Graves' disease

    International Nuclear Information System (INIS)

    Takamatsu, J.; Hosoya, T.; Naito, N.

    1988-01-01

    Some patients with hyperthyroid Graves' disease have increased serum T3 and normal or even low serum T4 levels during treatment with antithyroid drugs. These patients with elevated serum T3 to T4 ratios rarely have a remission of their hyperthyroidism. The aim of this study was to investigate thyroid iodine metabolism in such patients, whom we termed T3-predominant Graves' disease. Mean thyroid radioactive iodine uptake was 51.0 +/- 18.1% ( +/- SD) at 3 h, and it decreased to 38.9 +/- 20.1% at 24 h in 31 patients with T3-predominant Graves' disease during treatment. It was 20.0 +/- 11.4% at 3 h and increased to 31.9 +/- 16.0% at 24 h in 17 other patients with hyperthyroid Graves' disease who had normal serum T3 and T4 levels and a normal serum T3 to T4 ratio during treatment (control Graves' disease). The activity of serum TSH receptor antibodies was significantly higher in the patients with T3-predominant Graves' disease than in control Graves' disease patients. From in vitro studies of thyroid tissue obtained at surgery, both thyroglobulin content and iodine content in thyroglobulin were significantly lower in patients with T3-predominant Graves' disease than in the control Graves' disease patients. Thyroid peroxidase (TPO) activity determined by a guaiacol assay was 0.411 +/- 0.212 g.u./mg protein in the T3-predominant Graves' disease patients, significantly higher than that in the control Graves' disease patients. Serum TPO autoantibody levels determined by immunoprecipitation also were greater in T3-predominant Graves' disease patients than in control Graves' disease patients. Binding of this antibody to TPO slightly inhibited the enzyme activity of TPO, but this effect of the antibody was similar in the two groups of patients

  16. Using electronic patient records to discover disease correlations and stratify patient cohorts.

    Directory of Open Access Journals (Sweden)

    Francisco S Roque

    2011-08-01

    Full Text Available Electronic patient records remain a rather unexplored, but potentially rich data source for discovering correlations between diseases. We describe a general approach for gathering phenotypic descriptions of patients from medical records in a systematic and non-cohort dependent manner. By extracting phenotype information from the free-text in such records we demonstrate that we can extend the information contained in the structured record data, and use it for producing fine-grained patient stratification and disease co-occurrence statistics. The approach uses a dictionary based on the International Classification of Disease ontology and is therefore in principle language independent. As a use case we show how records from a Danish psychiatric hospital lead to the identification of disease correlations, which subsequently can be mapped to systems biology frameworks.

  17. Multiple Cationic Amphiphiles Induce a Niemann-Pick C Phenotype and Inhibit Ebola Virus Entry and Infection

    Science.gov (United States)

    2013-02-18

    Volume 8 | Issue 2 | e56265 mL. After disrupting the membranes with 20 mM methionine methyl -ester for 1 hr at RT, ,150 mg of disrupted NPC1- enriched...PLoS Biol 9: e1000598. 42. Simmons G, Rennekamp AJ, Chai N, Vandenberghe LH, Riley JL, et al. (2003) Folate receptor alpha and caveolae are not required

  18. Kleptomania in Patients with Neuro-Behçet's Disease

    OpenAIRE

    Shugaiv, Erkingül; Kıyat-Atamer, Aslı; Tüzün, Erdem; Kürtüncü, Murat; Baral-Kulaksızoğlu, Işın; Akman Demir, Gülşen

    2013-01-01

    Objective This study was conducted to characterize the prevalence and clinical features of kleptomania, an impulse control disorder, in patients with Behçet's disease involving the central nervous system. Subjects and Methods Medical records of 350 patients with neuro-Behçet's disease were evaluated, and clinical and neuropsychological features of patients with kleptomania were noted. Results Of the 350 neuro-Behçet's disease patients 6 (1.7%) had presented with symptoms that fulfilled the cr...