Classification and Differential Diagnosis of Wilson's Disease
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Supplemental Information to Mammadova-Bach Et Al., “Laminin Α1 Orchestrates VEGFA Functions in the Ecosystem of Colorectal Carcinogenesis”
Supplemental information to Mammadova-Bach et al., “Laminin α1 orchestrates VEGFA functions in the ecosystem of colorectal carcinogenesis” Supplemental material and methods Cloning of the villin-LMα1 vector The plasmid pBS-villin-promoter containing the 3.5 Kb of the murine villin promoter, the first non coding exon, 5.5 kb of the first intron and 15 nucleotides of the second villin exon, was generated by S. Robine (Institut Curie, Paris, France). The EcoRI site in the multi cloning site was destroyed by fill in ligation with T4 polymerase according to the manufacturer`s instructions (New England Biolabs, Ozyme, Saint Quentin en Yvelines, France). Site directed mutagenesis (GeneEditor in vitro Site-Directed Mutagenesis system, Promega, Charbonnières-les-Bains, France) was then used to introduce a BsiWI site before the start codon of the villin coding sequence using the 5’ phosphorylated primer: 5’CCTTCTCCTCTAGGCTCGCGTACGATGACGTCGGACTTGCGG3’. A double strand annealed oligonucleotide, 5’GGCCGGACGCGTGAATTCGTCGACGC3’ and 5’GGCCGCGTCGACGAATTCACGC GTCC3’ containing restriction site for MluI, EcoRI and SalI were inserted in the NotI site (present in the multi cloning site), generating the plasmid pBS-villin-promoter-MES. The SV40 polyA region of the pEGFP plasmid (Clontech, Ozyme, Saint Quentin Yvelines, France) was amplified by PCR using primers 5’GGCGCCTCTAGATCATAATCAGCCATA3’ and 5’GGCGCCCTTAAGATACATTGATGAGTT3’ before subcloning into the pGEMTeasy vector (Promega, Charbonnières-les-Bains, France). After EcoRI digestion, the SV40 polyA fragment was purified with the NucleoSpin Extract II kit (Machery-Nagel, Hoerdt, France) and then subcloned into the EcoRI site of the plasmid pBS-villin-promoter-MES. Site directed mutagenesis was used to introduce a BsiWI site (5’ phosphorylated AGCGCAGGGAGCGGCGGCCGTACGATGCGCGGCAGCGGCACG3’) before the initiation codon and a MluI site (5’ phosphorylated 1 CCCGGGCCTGAGCCCTAAACGCGTGCCAGCCTCTGCCCTTGG3’) after the stop codon in the full length cDNA coding for the mouse LMα1 in the pCIS vector (kindly provided by P. -
Iron Dysregulation in Movement Disorders
Neurobiology of Disease 46 (2012) 1–18 Contents lists available at SciVerse ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi Review Iron dysregulation in movement disorders Petr Dusek a,c, Joseph Jankovic a,⁎, Weidong Le b a Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA b Parkinson's Disease Research Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA c Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic article info abstract Article history: Iron is an essential element necessary for energy production, DNA and neurotransmitter synthesis, myelination Received 9 November 2011 and phospholipid metabolism. Neurodegeneration with brain iron accumulation (NBIA) involves several genetic Revised 22 December 2011 disorders, two of which, aceruloplasminemia and neuroferritinopathy, are caused by mutations in genes directly Accepted 31 December 2011 involved in iron metabolic pathway, and others, such as pantothenate-kinase 2, phospholipase-A2 and fatty acid Available online 12 January 2012 2-hydroxylase associated neurodegeneration, are caused by mutations in genes coding for proteins involved in phospholipid metabolism. Phospholipids are major constituents of myelin and iron accumulation has been linked Keywords: Iron to myelin derangements. Another group of NBIAs is caused by mutations in lysosomal enzymes or transporters Neurodegeneration such as ATP13A2, mucolipin-1 and possibly also β-galactosidase and α-fucosidase. Increased cellular iron uptake Dystonia in these diseases may be caused by impaired recycling of iron which normally involves lysosomes. -
Zebrafish Models of Neurology Biochimica Et Biophysica Acta
Biochimica et Biophysica Acta 1812 (2011) 333–334 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbadis Editorial Preface: Zebrafish Models of Neurology☆ Forming hypotheses about the Molecular Basis of Neurological benefitted primarily from biochemistry/ biophysics of protein Disease has traditionally been based on human genetics, biochemistry aggregation, cell culture work and mouse models; These paradigms and molecular biology, whereas testing these hypotheses requires us are challenging to implement in a fashion that tells us how disease in to turn to cell culture and animal models. Zebrafish have emerged as a one portion of the CNS spreads to another. Zebrafish are positioned tractable platform to complement and bridge these paradigms in brilliantly to fill this gap, not only because of its efficiency as a genetic many diseases, allowing integration of human genetics and cell and neuroscience model, but because zebrafish have a long history as biology within the in vivo setting. Perhaps it is in Neurology and a platform for assessing non-cell-autonomous effects of protein Neurodegeneration, however, where zebrafish have special promise perturbations in the in vivo setting. Thus it is common for zebrafish to make contributions. Four special advantages of zebrafish to biologists to ask if changing gene abundance or character in one group Neurology are worth highlighting here: efficient in vivo tests for of neurons is able to affect the fate and function of neighboring cells. genetic interactions, conserved cellular architecture of the CNS, the Creative and ambitious deployment of this ability will complement ability to create genetically mosaic animals, and tractable behaviour established tools to promise a deep understanding of how disease and electrophysiology to assess experimental interventions. -
Friedreich Ataxia Mouse Models with Progressive Cerebellar and Sensory Ataxia Reveal Autophagic Neurodegeneration in Dorsal Root Ganglia
The Journal of Neuroscience, February 25, 2004 • 24(8):1987–1995 • 1987 Neurobiology of Disease Friedreich Ataxia Mouse Models with Progressive Cerebellar and Sensory Ataxia Reveal Autophagic Neurodegeneration in Dorsal Root Ganglia Delphine Simon,1 Herve´ Seznec,1 Anne Gansmuller,1 Nade`ge Carelle,1 Philipp Weber,1 Daniel Metzger,1 Pierre Rustin,2 Michel Koenig,1 and He´le`ne Puccio1 1Institut de Ge´ne´tique et de Biologie Mole´culaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Sante´ et de la Recherche Me´dicale (INSERM)/Universite´ Louis Pasteur, 67404 Illkirch cedex, CU de Strasbourg, France, and 2Unite´ de Recherches sur les Handicaps Ge´ne´tiques de l’Enfant, INSERM U393, Hoˆpital Necker-Enfants Malades, 75015 Paris, France Friedreich ataxia (FRDA), the most common recessive ataxia, is characterized by degeneration of the large sensory neurons of the spinal cord and cardiomyopathy. It is caused by severely reduced levels of frataxin, a mitochondrial protein involved in iron–sulfur cluster (ISC) biosynthesis. Through a spatiotemporally controlled conditional gene-targeting approach, we have generated two mouse models for FRDA that specifically develop progressive mixed cerebellar and sensory ataxia, the most prominent neurological features of FRDA. Histological studies showed both spinal cord and dorsal root ganglia (DRG) anomalies with absence of motor neuropathy, a hallmark of the human disease. In addition, one line revealed a cerebellar granule cell loss, whereas both lines had Purkinje cell arborization defects. These lines represent the first FRDA models with a slowly progressive neurological degeneration. We identified an autophagic process as the causative pathological mechanism in the DRG, leading to removal of mitochondrial debris and apparition of lipofuscin deposits. -
Sodium Pumps Mediate Activity-Dependent Changes in Mammalian Motor Networks
906 • The Journal of Neuroscience, January 25, 2017 • 37(4):906–921 Systems/Circuits Sodium Pumps Mediate Activity-Dependent Changes in Mammalian Motor Networks X Laurence D. Picton, XFilipe Nascimento, XMatthew J. Broadhead, XKeith T. Sillar, and XGareth B. Miles School of Psychology and Neuroscience, University of St Andrews, St Andrews KY16 9JP, United Kingdom Ubiquitously expressed sodium pumps are best known for maintaining the ionic gradients and resting membrane potential required for generating action potentials. However, activity- and state-dependent changes in pump activity can also influence neuronal firing and regulate rhythmic network output. Here we demonstrate that changes in sodium pump activity regulate locomotor networks in the spinal cord of neonatal mice. The sodium pump inhibitor, ouabain, increased the frequency and decreased the amplitude of drug-induced locomotor bursting, effects that were dependent on the presence of the neuromodulator dopamine. Conversely, activating the pump with the sodium ionophore monensin decreased burst frequency. When more “natural” locomotor output was evoked using dorsal-root stimulation, ouabain increased burst frequency and extended locomotor episode duration, whereas monensin slowed and shortened episodes. Decreasing the time between dorsal-root stimulation, and therefore interepisode interval, also shortened and slowed activity, suggesting that pump activity encodes information about past network output and contributes to feedforward control of subsequent locomotor bouts. Using whole-cell patch-clamp recordings from spinal motoneurons and interneurons, we describe a long-duration (ϳ60 s), activity-dependent, TTX- and ouabain-sensitive, hyperpolarization (ϳ5 mV), which is mediated by spike-dependent increases in pump activity. The duration of this dynamic pump potential is enhanced by dopamine. -
Assembling the Mitochondrial ATP Synthase Jiyao Songa, Nikolaus Pfannera,B,1, and Thomas Beckera,B
COMMENTARY COMMENTARY Assembling the mitochondrial ATP synthase Jiyao Songa, Nikolaus Pfannera,b,1, and Thomas Beckera,b Mitochondria are known as the powerhouses of the of the ATP synthase (5–7). A recent high-resolution cell. The F1Fo-ATP synthase of the mitochondrial inner cryoelectron microscopic structure of the dimeric Fo membrane produces the bulk of cellular ATP. The re- region of yeast ATP synthase revealed that the subunits spiratory chain complexes pump protons across the Atp6 and i/j form the contact sites between two ATP inner membrane into the intermembrane space and synthase monomers, supported by interaction between thereby generate a proton-motive force that drives subunits e and k (8). In mitochondria, rows of ATP syn- the ATP synthase. In a fascinating molecular mecha- thase dimers localize to the rims of the cristae mem- nism, the ATP synthase couples the synthesis of ATP branes, which are invaginations of the inner membrane. to the transport of protons into the matrix (1–3). For- The ATP synthase dimers bend the inner membrane mation of the ATP synthase depends on the associa- and are crucial for forming the typical cristae shape (9, tion of 17 different structural subunits of dual genetic 10). The supernumerary subunits e and g, together with origin. Whereas a number of assembly factors and the N-terminal portion of the peripheral stalk subunit b, steps have been identified in the model organism affect the curvature of the inner membrane (8, 9, 11). baker’s yeast, little has been known about the assem- Thus, the ATP synthase not only synthesizes ATP but bly of the human ATP synthase. -
Difference Between Atpase and ATP Synthase Key Difference
Difference Between ATPase and ATP Synthase www.differencebetween.com Key Difference - ATPase vs ATP Synthase Adenosine triphosphate (ATP) is a complex organic molecule that participates in the biological reactions. It is known as “molecular unit of currency” of intracellular energy transfer. It is found in almost all forms of life. In the metabolism, ATP is either consumed or generated. When ATP is consumed, energy is released by converting into ADP (adenosine diphosphate) and AMP (adenosine monophosphate) respectively. The enzyme which catalyzes the following reaction is known as ATPase. ATP → ADP + Pi + Energy is released In other metabolic reactions which incorporate external energy, ATP is generated from ADP and AMP. The enzyme which catalyzes the below-mentioned reaction is called an ATP Synthase. ADP + Pi → ATP + Energy is consumed So, the key difference between ATPase and ATP Synthase is, ATPase is the enzyme that breaks down ATP molecules while the ATP Synthase involves in ATP production. What is ATPase? The ATPase or adenylpyrophosphatase (ATP hydrolase) is the enzyme which decomposes ATP molecules into ADP and Pi (free phosphate ion.) This decomposition reaction releases energy which is used by other chemical reactions in the cell. ATPases are the class of membrane-bound enzymes. They consist of a different class of members that possess unique functions such as Na+/K+-ATPase, Proton-ATPase, V-ATPase, Hydrogen Potassium–ATPase, F-ATPase, and Calcium-ATPase. These enzymes are integral transmembrane proteins. The transmembrane ATPases move solutes across the biological membrane against their concentration gradient typically by consuming the ATP molecules. So, the main functions of the ATPase enzyme family members are moving cell metabolites across the biological membrane and exporting toxins, waste and the solutes that can hinder the normal cell function. -
Syllabus METAL ION EXCESS TOXICITY
Syllabus Metalionexcesstoxicity-Feexcesstoxicity-Africansiderosis,hemosiderosis, hemochromatosis(bronzediabetes)anddetoxification.Cuexcesstoxicity:Wilson’sdisease andtreatment. Heavymetaliontoxicity:Hg,Pb,Cd,Astoxiceffects–mechanismoftoxiceffects.Heavy metaltoxicitytreatment-chelationtherapy:chelatingagentsforHg,Pb,Cd,Astoxicity. Metalcomplexesasdrugs:cis-plainasanticanceragent:mechanismofactionandside effects;goldcomplexesasantiarthriticdrugs-chrysotherapy.Metalcomplexesindiagnosis- Gdcomplexesinmagneticresonanceimaging(MRI). METALIONEXCESSTOXICITY Ironexcesstoxicity ü ItisduetoaccidentalintakeofFeSO4tabletscausingerosionofthegastrointestinal tract. ü Hemochomatosisisageneticdisorder,depositionofironoccursinvitalorganslike liver,spleen,pancreas,skinetc.Itleadstobronzepigmentationontheskiniscalled bronzediabetes. ü Siderosis(depositionofFeOdustinthelungs)isassociatedwithexcessofiron. ü AfricansiderosisisanironoverloaddisorderfirstobservedamongpeopleofSouthern AfricaandCentralAfrica.Dietaryironoverloadistheconsumptionoflargeamount ofhome-brewedbeerwithhighamountofironcontentinit. Detoxification : Siderophore desferrioxamine is a chelating antidote used for Fe removal Coppertoxicity Copper is a principal component of several metalloproteins and some naturally occurring pigments.Ahealthyadultpossessescopperbetween200to300mgandthehighestamountis concentratedin the locus of brain. Wilson’sdiseaseand Menkes’ kinky hair syndromeare associatedwithageneticdisorderinthemetabolismofcopper. Wilson’sdisease ü In Wilson'sdisease,the copper-content -
ATP Synthase K+- and H+-Flux Drive ATP Synthesis and Enable Mitochondrial K+-Uniporter Function
bioRxiv preprint doi: https://doi.org/10.1101/355776; this version posted April 22, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. ATP synthase K+- and H+-flux drive ATP synthesis and enable mitochondrial K+-uniporter function Magdalena Juhaszova,1,9 Evgeny Kobrinsky,1,9 Dmitry B. Zorov,1,5,9 H. Bradley Nuss,1† Yael Yaniv,1‡ Kenneth W. Fishbein,2 Rafael de Cabo,3 Lluis Montoliu,6 Sandra B. Gabelli,4,7,8 Miguel A. Aon,1 Sonia Cortassa,1 and Steven J. Sollott1,* 1Laboratories of Cardiovascular Science and 2Clinical Investigation, and 3Translational Gerontology Branch, National Institute on Aging, NIH, and 4Dept. Medicine, 7Dept. Oncology, 8Dept. Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, USA 5A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia 6Centro Nacional de Biotecnología, CSIC, Madrid, Spain Present address: †Center for Scientific Review, NIH, Bethesda, MD, USA ‡Biomedical Engineering Faculty, Technion-IIT, Haifa, Israel 9 Co-first author * Correspondence: [email protected] Running title: ATP synthase K+- and H+-flux drive ATP synthesis Lead Contact: Steven J. Sollott, M.D. Chief, Cardioprotection Section Laboratory of Cardiovascular Science Biomedical Research Center, Suite 100 National Institute on Aging, NIH 251 Bayview Blvd Baltimore, MD 21224-2816 USA TEL: 410-558-8657 FAX: 410-558-8150 bioRxiv preprint doi: https://doi.org/10.1101/355776; this version posted April 22, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. -
Chelation Therapy
Corporate Medical Policy Chelation Therapy File Name: chelation_therapy Origination: 12/1995 Last CAP Review: 2/2021 Next CAP Review: 2/2022 Last Review: 2/2021 Description of Procedure or Service Chelation therapy is an established treatment for the removal of metal toxins by converting them to a chemically inert form that can be excreted in the urine. Chelation therapy comprises intravenous or oral administration of chelating agents that remove metal ions such as lead, aluminum, mercury, arsenic, zinc, iron, copper, and calcium from the body. Specific chelating agents are used for particular heavy metal toxicities. For example, desferroxamine (not Food and Drug Administration [FDA] approved) is used for patients with iron toxicity, and calcium-ethylenediaminetetraacetic acid (EDTA) is used for patients with lead poisoning. Note that disodium-EDTA is not recommended for acute lead poisoning due to the increased risk of death from hypocalcemia. Another class of chelating agents, called metal protein attenuating compounds (MPACs), is under investigation for the treatment of Alzheimer’s disease, which is associated with the disequilibrium of cerebral metals. Unlike traditional systemic chelators that bind and remove metals from tissues systemically, MPACs have subtle effects on metal homeostasis and abnormal metal interactions. In animal models of Alzheimer’s disease, they promote the solubilization and clearance of β-amyloid protein by binding to its metal-ion complex and also inhibit redox reactions that generate neurotoxic free radicals. MPACs therefore interrupt two putative pathogenic processes of Alzheimer’s disease. However, no MPACs have received FDA approval for treating Alzheimer’s disease. Chelation therapy has also been investigated as a treatment for other indications including atherosclerosis and autism spectrum disorder. -
Nr 1. Each Patient Suffering from Acute Coronary Syndrome Must Be Treated With
SED - 3 - VERSION I February 2009 Nr 1. Each patient suffering from acute coronary syndrome must be treated with: A. Acetylsalicylic acid (ASA). B. ASA or clopidogrel. C. ASA and clopidogrel. D. depending on the type of myocardial infarction – ASA and clopidogrel or ASA only. E. depending on the mode of treatment (invasive vs noninvasive) – ASA and clopidogrel or ASA only. Nr 2. A patient in the class IV of Killip-Kimball classification has: A. pulmonary oedema. B. cardiogenic shock. C. blood retention (haemostasis) below the level of inferior angles of scapulae. D. no signs of heart insufficiency. E. chronic heart insufficiency, previously at least in NYHA class III. Nr 3. Schőnlein-Henoch purpura is a vasculitis that: A. is characterized by nephritic syndrome with cANCA antibodies. B. may present as rapidly progressive glomerulonephritis. C. is often accompanied by granulomas in the lungs. D. is typically treated by a surgical excision of granuloma. E. is typically treated by nephrectomy of the kidney with granulomas. Nr 4. Which of the below given drugs can cause hyperkalemia? 1) angiotensin converting enzyme inhibitors. 2) loop diuretics. 3) aldosterone antagonist. 4) thiazide. 5) indapamide. The correct answer is: A. 1,3. B. 1,2,3. C. 1,3,4. D. 1,3,5. E. all of the above. Nr 5. Which of the below is an absolute contraindication to thrombolytic therapy in acute myocardial infarction: A. age above 75. B. suspected dissecting aortic aneurysm. C. past cerebral stroke 2 years ago. D. high blood pressure >175/110 mmHg. E. invasive cardiology unit available on duty, which can be reached within 90 minutes. -
Movement Disorders in the Elderly
MOVEMENT DISORDERS IN THE ELDERLY Eugene C. Lai, M.D., Ph.D. Michael E. DeBakey VA Medical Center Baylor College of Medicine Houston, Texas MOVEMENT DISORDERS Neurologic dysfunctions in which there is either a paucity of voluntary and automatic movements (HYPOKINESIA) or an excess of movement (HYPERKINESIA) or uncontrolled movements (DYSKINESIA) typically unassociated with weakness or spasticity HYPOKINESIAS • Parkinson‟s disease • Secondary Parkinsonism • Parkinson‟s plus syndromes HYPERKINESIAS • Akathisia • Hemifacial spasm • Athetosis • Myoclonus • Ballism • Restless leg syndrome • Chorea • Tics • Dystonia • Tremor COMMON MOVEMENT DISORDERS IN THE ELDERLY • Parkinsonism • Tremor • Gait disorder • Restless leg syndrome • Drug-induced syndrome PARKINSONISM • Parkinson‟s disease • Secondary parkinsonism • Drug-induced parkinsonism • Vascular parkinsonism • Parkinson‟s plus syndromes • Multiple system atrophy • Progressive supranuclear palsy PARKINSON’S DISEASE PARKINSON’S DISEASE Classical Clinical Features • Resting Tremor • Cogwheel Rigidity • Bradykinesia • Postural Instability PARKINSON’S DISEASE Associated Clinical Features • Micrographia • Hypophonia • Hypomimia • Shuffling gait / festination • Drooling • Dysphagia NON-MOTOR COMPLICATIONS IN PARKINSON’S DISEASE • Sleep disturbances • Autonomic dysfunctions • Sensory phenomena • Neuropsychiatric manifestations • Cognitive impairment PARKINSON’S DISEASE General Considerations • The second most common progressive neurodegenerative disorder • The most common neurodegenerative movement