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Chun Xu, Sabine Krabbe, Jan Gründemann, Paolo Botta, Jonathan P Fadok, Fumitaka Osakada, Dieter Saur, Benjamin F Grewe, Mark J Schnitzer, Edward M Callaway, Andreas Lüthi
Memories about sensory experiences are tightly linked to the context in which they were formed. Memory contextualization is fundamental for the selection of appropriate behavioral reactions needed for survival, yet the underlying neuronal circuits are poorly understood. By combining trans-synaptic viral tracing and optogenetic manipulation, we found that the ventral hippocampus (vHC) and the amygdala, two key brain structures encoding context and emotional experiences, interact via multiple parallel pathways...
October 18, 2016: Cell
Scott W Krabbe, Vincent S Chan, Thaddeus S Franczyk, Shashank Shekhar, José G Napolitano, Carmina A Presto, Justin A Simanis
A Cu-catalyzed synthesis of amides from alcohols and secondary amines using the oxygen in air as the terminal oxidant has been developed. The methodology is operationally simple requiring no high pressure equipment or potentially explosive O2 balloons. The commercially available, non-precious metal catalyst, Cu(phen)Cl2, in conjunction with di-tert-butyl hydrazine dicarboxylate and an inorganic base provides a variety of benzamides in moderate to excellent yields. The pKa of amine conjugate acid and electronics of alcohol were shown to impact the selection of base for optimal reactivity...
October 14, 2016: Journal of Organic Chemistry
Ethan D Goddard-Borger, Christina Tysoe, Stephen G Withers
Globoid cell leukodystrophy (GCL), or Krabbe disease, is a lysosomal storage disorder characterized by a deficiency in galactosylceramidase (GALC), which hydrolyses galactosylceramide and galactosylsphingosine (psychosine). Early detection of GCL in newborns is essential for timely therapeutic intervention and could be achieved by testing infant blood samples with isotopically labeled lysosmal enzyme substrates and mass spectrometry. While isotopically labeled psychosine would be a useful tool for the early diagnosis of GCL, its synthesis is lengthy and expensive...
September 22, 2016: Carbohydrate Research
Laura-Maria Krabbe, Solomon L Woldu, Shahrokh F Shariat, Yair Lotan
The high recurrence rates associated with non-muscle invasive bladder cancer requires close surveillance with cystoscopy, an invasive and expensive procedure with risk of missing cancer. Finding an accurate urinary biomarker that can detect recurrent disease would represent a significant advancement in management. Areas covered: This review summarizes the commercially-available urinary biomarkers including cytology, UroVysion, BTA, NMP22, uCyt+, and CxBladder assays. Additionally, we review recent investigational urinary biomarkers that hold promise in bladder cancer surveillance...
October 4, 2016: Expert Review of Molecular Diagnostics
S Krabbe, R Bolce, C H Brahe, U M Døhn, B J Ejbjerg, M L Hetland, E H Sasso, D Chernoff, M S Hansen, L S Knudsen, A Hansen, O R Madsen, M Hasselquist, J Møller, M Østergaard
OBJECTIVES: To investigate the multi-biomarker disease activity (MBDA) score by comparison with imaging findings in an investigator-initiated rheumatoid arthritis (RA) trial (HURRAH trial, NCT00696059). METHOD: Fifty-two patients with established RA initiated adalimumab treatment and had magnetic resonance imaging (MRI), ultrasonography (US), computed tomography (CT), and radiography performed at weeks 0, 26, and 52. Serum samples were analysed using MBDA score assays and associations between clinical measures, MBDA score, and imaging findings were investigated...
September 28, 2016: Scandinavian Journal of Rheumatology
Ayumi Yoshimura, Tetsuya Kibe, Kaori Irahara, Norio Sakai, Kenji Yokochi
A case of late-infantile Krabbe disease in a patient who presented with developmental regression and spastic quadriplegia in late infancy is reported. Brain magnetic resonance imaging (MRI) at 11 months of age showed predominant corticospinal tract involvement, which usually appears in adult Krabbe disease. Galactocerebrosidase activity in lymphocytes and skin fibroblasts was very low. Genetic testing revealed compound heterozygous mutations of the galactocerebrosidase (GALC) gene, c.635_646 delinsCTC and c...
2016: Japanese Clinical Medicine
Allison Bradbury, David Peterson, Charles Vite, Steven Chen, N Matthew Ellinwood, James Provenzale
PURPOSE: The goal of this study was to compare the diffusion tensor imaging (DTI) metrics from an end-stage canine Krabbe brain evaluated by MR imaging ex vivo to those of a normal dog brain. We hypothesized that the white matter of the canine Krabbe brain would show decreased fractional anisotropy (FA) values and increased apparent diffusion coefficient (ADC) and radial diffusivity (RD) values. METHODS: An 11-week-old Krabbe dog was euthanized after disease progression...
September 27, 2016: Neuroradiology Journal
Laura-Maria Krabbe, Okyaz Eminaga, Shahrokh F Shariat, Ryan C Hutchinson, Yair Lotan, Arthur I Sagalowsky, Jay D Raman, Christopher G Wood, Alon Z Weizer, Marco Roscigno, Francesco Montorsi, Christian Bolenz, Giacomo Novara, Eiji Kikuchi, Harun Fajkovic, Leonid M Rapoport, Peter V Glybochko, Richard Zigeuner, Mesut Remzi, Karim Bensalah, Wassim Kassouf, Vitaly Margulis
PURPOSE: To develop a prognostic nomogram after extirpative for patients with high-grade UTUC. MATERIALS AND METHODS: Clinical data were available for 2,926 patients diagnosed with high-grade UTUC who underwent extirpative surgery. Cox proportional hazard regression models identified independent prognosticators of relapse in the development cohort (n=838). A backward step-down selection process was applied to achieve the most informative nomogram with the least number of variables...
September 23, 2016: Journal of Urology
Subha Karumuthil-Melethil, Steven J Gray
Globoid cell leukodystrophy (GLD, or Krabbe's disease) is a severe inherited neurodegenerative disease caused by the lack of a lysosomal enzyme, GALC. The disease has been characterized in humans as well as three naturally occurring animal models, murine, canine, and nonhuman primate. Multiple treatment strategies have been explored for GLD, including enzyme replacement therapy, small-molecule pharmacological approaches, gene therapy, and bone marrow transplant. No single therapeutic approach has proved to be entirely effective, and the reason for this is not well understood...
November 2016: Journal of Neuroscience Research
Gregory B Potter, Magdalena A Petryniak
Neuroinflammation, activation of innate immune components of the nervous system followed by an adaptive immune response, is observed in most leukodystrophies and coincides with white matter pathology, disease progression, and morbidity. Despite this, there is a major gap in our knowledge of the contribution of the immune system to disease phenotype. Inflammation in Krabbe's disease has been considered a secondary effect, resulting from cell-autonomous oligodendroglial cell death or myelin loss resulting from psychosine accumulation...
November 2016: Journal of Neuroscience Research
Giuseppe Scesa, Ana Lis Moyano, Ernesto R Bongarzone, Maria I Givogri
The discovery that most cells produce extracellular vesicles (EVs) and release them in the extracellular milieu has spurred the idea that these membranous cargoes spread pathogenic mechanisms. In the brain, EVs may have multifold and important physiological functions, from deregulating synaptic activity to promoting demyelination to changes in microglial activity. The finding that small EVs (exosomes) contain α-synuclein and β-amyloid, among other pathogenic proteins, is an example of this notion, underscoring their potential role in the brains of patients with Parkinson's and Alzheimer's diseases...
November 2016: Journal of Neuroscience Research
Michael S Marshall, Ernesto R Bongarzone
New insights into the pathophysiological mechanisms behind late-onset neurodegenerative diseases have come from unexpected sources in recent years. Specifically, the group of inherited metabolic disorders known as lysosomal storage diseases that most commonly affect infants has been found to have surprising similarities with adult neurodegenerative disorders. Most notable has been the identification of Gaucher's disease as a comorbidity for Parkinson's disease. Prompted by the recent identification of neuronal aggregates of α-synuclein in another lysosomal storage disease, Krabbe's disease, we propose the idea that a similar connection exists between adult synucleinopathies and Krabbe's...
November 2016: Journal of Neuroscience Research
Giovanna Pannuzzo, Adriana Carol Eleonora Graziano, Martina Pannuzzo, Marcelo Fabricio Masman, Rosanna Avola, Venera Cardile
Krabbe's disease is a neurodegenerative disorder caused by deficiency of galactocerebrosidase activity that affects the myelin sheath of the nervous system, involving dysfunctional metabolism of sphingolipids. It has no cure. Because substrate inhibition therapy has been shown to be effective in some human lysosomal storage diseases, we hypothesize that a substrate inhibition therapeutic approach might be appropriate to allow correction of the imbalance between formation and breakdown of glycosphingolipids and to prevent pathological storage of psychosine...
November 2016: Journal of Neuroscience Research
Alessandra Ricca, Angela Gritti
Globoid cell leukodystrophy (GLD), or Krabbe's disease, is a lysosomal storage disorder resulting from deficiency of the lysosomal hydrolase galactosylceramidase. The infantile forms are characterized by a unique relentless and aggressive progression with a wide range of neurological symptoms and complications. Here we review and discuss the basic concepts and the novel mechanisms identified as key contributors to the peculiar GLD pathology, highlighting their therapeutic implications. Then, we evaluate evidence from extensive experimental studies on GLD animal models that have highlighted fundamental requirements to obtain substantial therapeutic benefit, including early and timely intervention, high levels of enzymatic reconstitution, and global targeting of affected tissues...
November 2016: Journal of Neuroscience Research
Glyn Dawson
Enzyme replacement therapy and substrate reduction therapy have proved useful in reversing many pathological consequences of many nonneural lysosomal storage diseases but have not yet reversed pathology or influenced disease outcome in Krabbe's disease (KD). This Review discusses the relative merits of stem cell therapy, molecular chaperone therapy, gene therapy, substrate reduction therapy, enzyme replacement therapy, and combination therapy. Given the limitations of these approaches, this Review introduces the idea of using tiny, 6-nm, intensely fluorescent quantum dots (QDs) to deliver a cell-penetrating peptide and 6 histidine residue-tagged β-D-galactocerebrosidase across the blood-brain barrier...
November 2016: Journal of Neuroscience Research
Rosanna Avola, Adriana Carol Eleonora Graziano, Giovanna Pannuzzo, Elisa Alvares, Venera Cardile
This Review describes some in vitro approaches used to investigate the mechanisms involved in Krabbe's disease, with particular regard to the cellular systems employed to study processes of inflammation, apoptosis, and angiogenesis. The aim was to update the knowledge on the results obtained from in vitro models of this neurodegenerative disorder and provide stimuli for future research. For a long time, the nonavailability of established neural cells has limited the understanding of neuropathogenic mechanisms in Krabbe's leukodystrophy...
November 2016: Journal of Neuroscience Research
Alice Luddi, Laura Crifasi, Angela Capaldo, Paola Piomboni, Elvira Costantino-Ceccarini
Krabbe's disease (KD) is a degenerative lysosomal storage disease resulting from deficiency of β-galactocerebrosidase activity. Over 100 mutations are known to cause the disease, and these usually occur in compound heterozygote patterns. In affected patients, nonsense mutations leading to a nonfunctional enzyme are often found associated with other mutations. The twitcher mouse is a naturally occurring model of KD, containing in β-galactocerebrosidase a premature stop codon, W339X. Recent studies have shown that selected compounds may induce the ribosomal bypass of premature stop codons without affecting the normal termination codons...
November 2016: Journal of Neuroscience Research
Scott A Sands, Steven M LeVine
Krabbe's disease (KD) is a lysosomal storage disorder in which galactosylceramide, a major glycosphingolipid of myelin, and psychosine (galactose-sphingosine) cannot be adequately metabolized because of a deficiency in galactosylceramidase. Substrate reduction therapy (SRT) has been tested in preclinical studies. The premise of SRT is to reduce the synthesis of substrates that are not adequately digested so that the substrate burden is lowered, resulting in less accumulation of unmetabolized material. SRT is used for Gaucher's disease, in which inhibitors of the terminal biosynthetic step are used...
November 2016: Journal of Neuroscience Research
Dae Song Jang, Wenjuan Ye, Tian Guimei, Melani Solomon, Noel Southall, Xin Hu, Juan Marugan, Marc Ferrer, Gustavo H B Maegawa
Krabbe's disease, also known as globoid cell leukodystrophy (GLD), is a lysosomal storage disease caused by the deficiency of the lysosomal enzyme β-galactocerebrosidase (GALC), resulting in severe neurological manifestations related to demyelination secondary to elevated galactosylsphingosine (psychosine) with its subsequent cytotoxicity. The only available treatment is hematopoietic stem cell transplantation, which delays disease onset but does not prevent long-term neurological manifestations. This article describes the identification of small molecules that enhance mutant GALC activity, identified by quantitative cell-based high-throughput screening (qHTS)...
November 2016: Journal of Neuroscience Research
Adriana Carol Eleonora Graziano, Giovanna Pannuzzo, Rosanna Avola, Venera Cardile
Krabbe's disease (KD) is an autosomal recessive, neurodegenerative disorder. It is classified among the lysosomal storage diseases (LSDs). It was first described in , but the genetic defect for the galactocerebrosidase (GALC) gene was not discovered until the beginning of the 1970s, 20 years before the GALC cloning. Recently, in 2011, the crystal structures of the GALC enzyme and the GALC-product complex were obtained. For this, compared with other LSDs, the research on possible therapeutic interventions is much more recent...
November 2016: Journal of Neuroscience Research
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