DOCSLIB.ORG

Potential of Anaplerotic Triheptanoin for the Treatment Of

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Potential of Anaplerotic Triheptanoin for the Treatment Of POTENTIAL OF ANAPLEROTIC TRIHEPTANOIN FOR THE TREATMENT OF LONG-CHAIN FATTY ACID OXIDATION DISORDERS by LEI GU Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation Advisor: Dr. Henri Brunengraber Department of Nutrition School of Medicine CASE WESTERN RESERVE UNIVERSITY May, 2010 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of ______________________________________________________LEI GU candidate for the ________________________________degreeDoctor of Philosophy *. (signed)_______________________________________________Edith Lerner, PhD (chair of the committee) ________________________________________________Henri Brunengraber, MD, PhD ________________________________________________Janos Kerner, PhD ________________________________________________Colleen M. Croniger, PhD ________________________________________________Michelle A. Puchowicz, PhD ________________________________________________ (date) _______________________Nov 30, 2009 *We also certify that written approval has been obtained for any proprietary material contained therein. Table of Contents Table of Contents ........................................................................................... iii List of Tables ................................................................................................... ix List of Figures .................................................................................................. x Acknowledgements ....................................................................................... xii List of Abbreviations .................................................................................... xiii Abstract ......................................................................................................... xvi 1. LIPOLYSIS .................................................................................................... 1 1.1 Introduction of Lipolysis ............................................................................... 1 1.2 Introduction of Hormone-Sensitive Lipase .................................................. 3 1.3 Regulation of Adipocyte Lipolysis ................................................................ 4 1.4 Lipolysis under Stress ................................................................................. 8 1.5 Measurement of Lipolysis............................................................................ 9 2. FATTY ACID OXIDATION ........................................................................... 10 2.1 Introduction of Fatty Acid Oxidation Pathway ........................................... 10 2.1.1 Cellular Uptake of Fatty Acids ......................................................... 10 iii 2.1.2 Activation of Fatty Acids .................................................................. 12 2.1.3 Carnitine Palmitoyltransferase System ........................................... 14 2.1.4 Mitochondrial β-oxidation Spiral ...................................................... 16 2.1.5 Fatty Acid α- and ω-oxidation .......................................................... 18 2.2 Regulation of Fatty Acid Oxidation ............................................................ 19 2.2.1 Regulation of Carnitine Palmitoyltransferase I by Malonyl-CoA ..... 19 2.2.2 Redox Regulation ............................................................................ 21 2.2.3 Feedback Regulation of Fatty Acid Oxidation ................................. 22 2.2.4 Regulation of Fatty Acid Oxidation by CoA ..................................... 23 2.3 Ketone Body Synthesis ............................................................................. 24 2.3.1 C4-ketogenesis ................................................................................ 24 2.3.2 C5-ketogenesis ................................................................................ 26 2.3.3 HMG-CoA synthase ......................................................................... 26 2.3.4 Interrelations between C4- and C5-ketogenesis .............................. 31 2.4 Ketone Body Utilization ............................................................................. 32 2.4.1 Ketolysis Pathway ........................................................................... 32 2.4.2 Utilization of Ketone Bodies in Brain ............................................... 32 2.4.3 Utilization of Ketone Bodies in Heart ............................................... 34 2.4.4 Utilization of Ketone Bodies in Kidney ............................................ 35 3. FATTY ACID OXIDATION DISORDERS .................................................... 36 3.1 Introduction of Fatty Acid Oxidation Disorders (FOD) ............................... 36 iv 3.1.1 Disorders of Plasma Membrane Functions ..................................... 36 3.1.2 Disorders of the Carnitine Palmitoyltransferase System ................. 37 3.1.3 Long-chain Fatty Acid Oxidation Disorders ..................................... 38 3.1.4 Disorders of Medium-chain Fatty Acid Oxidation ............................ 39 3.1.5 Disorders of Short-chain Fatty Acid Oxidation ................................ 40 3.2 Pathogenesis of Fatty Acid Oxidation Disorders ....................................... 41 3.3 Diagnosis of Fatty Acid Oxidation Disorders ............................................. 42 3.4 Treatment of Fatty Acid Oxidation Disorders ............................................ 43 3.4.1 Carnitine Supplementation .............................................................. 43 3.4.2 Decreased Dietary Fat intake .......................................................... 44 3.4.3 Increased Dietary Carbohydrate ..................................................... 44 3.4.4 Minimizing Fat Mobilization ............................................................. 45 3.4.5 Infusion of Glucose and Insulin as Acute Treatment ...................... 45 3.4.6 Medium-chain Triglycerides (MCT) ................................................. 46 3.4.7 Other Strategies .............................................................................. 47 3.5 Triheptanoin as the Treatment for Long-chain Fatty Acid Oxidation Disorders ......................................................................................................... 47 3.5.1 Introduction of Triheptanoin ............................................................. 47 3.5.2 Metabolism of Triheptanoin ............................................................. 49 3.5.3 Triheptanoin versus Trioctanoin ...................................................... 51 3.5.4 Previous Studies of Triheptanoin .................................................... 54 v 4. ANAPLEROSIS ........................................................................................... 55 4.1 Introduction of Anaplerosis ........................................................................ 55 4.2 Anaplerotic Substrates .............................................................................. 58 4.2.1 Pyruvate ........................................................................................... 58 4.2.2 Glutamate/Glutamine ....................................................................... 59 4.2.3 Precursors of Propionyl-CoA ........................................................... 60 4.3 Measurement of Anaplerosis ..................................................................... 63 5. GLYCERONEOGENESIS ........................................................................... 66 5.1 Introduction of Glyceroneogenesis ............................................................ 66 5.2 Regulation of Glyceroneogenesis ............................................................. 69 5.3 Measurement of Glyceroneogenesis ........................................................ 69 5.4 Problems in Measuring Glyceroneogenesis in vivo .................................. 72 6. STATEMENT OF PURPOSES .................................................................... 74 7. HYPOTHESES ............................................................................................ 75 8. EXPERIMENTAL PROCEDURES .............................................................. 76 8.1 Animals ...................................................................................................... 76 8.2 Protocol ..................................................................................................... 77 8.3 Tracer Studies ........................................................................................... 81 vi 8.4 Rationale for Selection of Infusion Groups ............................................... 81 8.5 Assay of Glucose and Glycerol in the Plasma .......................................... 82 8.6 Assay of Heptanoate, C4-ketone Bodies, C5-ketone Bodies, and Oleate in the Plasma ....................................................................................................... 84 8.7 Assay of Short-chain and Medium-chain Acyl-CoAs in the Liver .............. 85 8.8 Calculations ............................................................................................... 87 8.9 Statistics .................................................................................................... 88 9. RESULTS .................................................................................................... 89 9.1 Plasma Heptanoate Concentrations ........................................................
Load more

Recommended publications
  • 01 Excipients Prelims 1..9
    Triolein 757 and tablets). Included in the Canadian List of Acceptable Non- 3 Steurnagel CR. Latex emulsions for controlled drug delivery. McGinity medicinal Ingredients. JW, ed. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms. New York: Marcel Dekker, 1989; 1–61. 4 Gutierrez-Rocca JC, McGinity JW. Influence of aging on the physical– 17 Related Substances mechanical properties of acrylic resin films cast from aqueous Acetyltributyl citrate; acetyltriethyl citrate; tributyl citrate. dispersions and organic solutions. Drug Dev Ind Pharm 1993; 19(3): 315–332. 5 Liu J, Williams R. Properties of heat-humidity cured cellulose acetate 18 Comments phthalate free films. Eur J Pharm Sci 2002; 17(1–2): 31–41. 6 Lewis RJ, ed. Sax’s Dangerous Properties of Industrial Materials, 11th A specification for triethyl citrate is contained in the Food (7) edn. New York: Wiley, 2004; 3546. Chemicals Codex (FCC). 7 Food Chemicals Codex, 6th edn. Bethesda, MD: United States The EINECS number for triethyl citrate is 201-070-7. The Pharmacopeia, 2008; 988. PubChem Compound ID (CID) for triethyl citrate is 6506. 20 General References 19 Specific References Vertellus Specialties Inc. Technical data sheet: Citroflex 2, 2007. 1 Gutierrez-Rocca JC, McGinity JW. Influence of water soluble and insoluble plasticizers on the physical and mechanical properties of 21 Author acrylic resin copolymers. Int J Pharm 1994; 103: 293–301. J Teckoe. 2 Lehmann K. Chemistry and application properties of polymethacrylate coating systems. McGinity JW, ed. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms. New York: Marcel Dekker, 1989; 153– 22 Date of Revision 245. 24 February 2009. Triolein 1 Nonproprietary Names 6 Functional Category None adopted.
    [Show full text]
  • The Role of Alpha Oxidation in Lipid Metabolism, 2017
    THE ROLE OF ALPHA OXIDATION IN LIPID METABOLISM Benjamin John Jenkins Darwin College Medical Research Council – Human Nutrition Research Department of Biochemistry University of Cambridge This dissertation is submitted for the degree of Doctor of Philosophy July 2018 DECLARATION This dissertation is the result of my own work and includes nothing, which is the outcome of work done in collaboration except as declared in the preface and specified in the text. It is not substantially the same as any that I have submitted, or, is being concurrently submitted for a degree or diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. I further state that no substantial part of my dissertation has already been submitted, or, is being concurrently submitted for any such degree, diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. In accordance with the University of Cambridge guidelines, this thesis does not exceed 60,000 words. Signed: ______________________________________________________________ Date: _______________________________________________________________ Benjamin John Jenkins BSc. MSc. Darwin College, Silver Street, Cambridge, CB3 9EU by i 2014 Word Template Template Friedman Friedman & Morgan Morgan & ii The Role of Alpha Oxidation in Lipid Metabolism, 2017 ABSTRACT Recent findings have shown an inverse association between the circulating levels of pentadecanoic acid (C15:0) and heptadecanoic acid (C17:0) with the risk of pathological development in type 2 diabetes, cardio vascular disease and neurological disorders. From previously published research, it has been said that both these odd chain fatty acids are biomarkers of their dietary intake and are significantly correlated to dietary ruminant fat intake.
    [Show full text]
  • Citric Acid Cycle
    CHEM464 / Medh, J.D. The Citric Acid Cycle Citric Acid Cycle: Central Role in Catabolism • Stage II of catabolism involves the conversion of carbohydrates, fats and aminoacids into acetylCoA • In aerobic organisms, citric acid cycle makes up the final stage of catabolism when acetyl CoA is completely oxidized to CO2. • Also called Krebs cycle or tricarboxylic acid (TCA) cycle. • It is a central integrative pathway that harvests chemical energy from biological fuel in the form of electrons in NADH and FADH2 (oxidation is loss of electrons). • NADH and FADH2 transfer electrons via the electron transport chain to final electron acceptor, O2, to form H2O. Entry of Pyruvate into the TCA cycle • Pyruvate is formed in the cytosol as a product of glycolysis • For entry into the TCA cycle, it has to be converted to Acetyl CoA. • Oxidation of pyruvate to acetyl CoA is catalyzed by the pyruvate dehydrogenase complex in the mitochondria • Mitochondria consist of inner and outer membranes and the matrix • Enzymes of the PDH complex and the TCA cycle (except succinate dehydrogenase) are in the matrix • Pyruvate translocase is an antiporter present in the inner mitochondrial membrane that allows entry of a molecule of pyruvate in exchange for a hydroxide ion. 1 CHEM464 / Medh, J.D. The Citric Acid Cycle The Pyruvate Dehydrogenase (PDH) complex • The PDH complex consists of 3 enzymes. They are: pyruvate dehydrogenase (E1), Dihydrolipoyl transacetylase (E2) and dihydrolipoyl dehydrogenase (E3). • It has 5 cofactors: CoASH, NAD+, lipoamide, TPP and FAD. CoASH and NAD+ participate stoichiometrically in the reaction, the other 3 cofactors have catalytic functions.
    [Show full text]
  • Intravenous Treatment with a Long-Chain Omega-3 Lipid Emulsion Provides Neuroprotection in a Murine Model of Ischemic Stroke – a Pilot Study
    RESEARCH ARTICLE Intravenous Treatment with a Long-Chain Omega-3 Lipid Emulsion Provides Neuroprotection in a Murine Model of Ischemic Stroke ± A Pilot Study Dirk Berressem1*, Konrad Koch1, Nicole Franke1, Jochen Klein1, Gunter P. Eckert1,2 1 Goethe-University of Frankfurt, Department of Pharmacology, Germany, 2 Justus-Liebig-University Giessen, Institute of Nutritional Sciences, Germany * [email protected] a11111 Abstract Single long-chain omega-3 fatty acids (e.g. docosahexaenoic acid (DHA) or eicosapentae- noic acid (EPA)) are known for their neuroprotective properties associated with ischemic stroke. This pilot study aimed to test the effectiveness of an acute treatment with a long- OPEN ACCESS chain omega-3 lipid emulsion (Omegaven 10%®, OGV) that contains fish oil (DHA 18 mg/ Citation: Berressem D, Koch K, Franke N, Klein J, Eckert GP (2016) Intravenous Treatment with a ml; EPA 21 mg/ml) and α-tocopherol (0.2 mg/ml) in a transient middle cerebral artery occlu- Long-Chain Omega-3 Lipid Emulsion Provides sion (MCAO) model of ischemic stroke in mice. For this purpose, female CD-1 mice were Neuroprotection in a Murine Model of Ischemic anesthetized and subjected to 90 minutes of MCAO. To reflect a clinically relevant situation Stroke ± A Pilot Study. PLoS ONE 11(11): for an acute treatment, either after induction of stroke or after reperfusion, a single dose of e0167329. doi:10.1371/journal.pone.0167329 OGV was injected intravenously into the tail vein (5 ml/kg b.w.). A neurological severity Editor: Muzamil Ahmad, Indian Institute of score was used to assess motor function and neurological outcome.
    [Show full text]
  • Triheptanoin for Glucose Transporter Type I Deficiency (G1D) Modulation of Human Ictogenesis, Cerebral Metabolic Rate, and Cognitive Indices by a Food Supplement
    Research Original Investigation Triheptanoin for Glucose Transporter Type I Deficiency (G1D) Modulation of Human Ictogenesis, Cerebral Metabolic Rate, and Cognitive Indices by a Food Supplement Juan M. Pascual, MD, PhD; Peiying Liu, PhD; Deng Mao, BS; Dorothy I. Kelly, MA; Ana Hernandez, MS; Min Sheng, PhD; Levi B. Good, PhD; Qian Ma, MD, PhD; Isaac Marin-Valencia, MD, MS; Xuchen Zhang, MD; Jason Y. Park, MD, PhD; Linda S. Hynan, PhD; Peter Stavinoha, PhD; Charles R. Roe, MD; Hanzhang Lu, PhD Supplemental content at IMPORTANCE Disorders of brain metabolism are multiform in their mechanisms and jamaneurology.com manifestations, many of which remain insufficiently understood and are thus similarly treated. Glucose transporter type I deficiency (G1D) is commonly associated with seizures and with electrographic spike-waves. The G1D syndrome has long been attributed to energy (ie, adenosine triphosphate synthetic) failure such as that consequent to tricarboxylic acid (TCA) cycle intermediate depletion. Indeed, glucose and other substrates generate TCAs via anaplerosis. However, TCAs are preserved in murine G1D, rendering energy-failure inferences premature and suggesting a different hypothesis, also grounded on our work, that consumption of alternate TCA precursors is stimulated and may be detrimental. Second, common ketogenic diets lead to a therapeutically counterintuitive reduction in blood glucose available to the G1D brain and prove ineffective in one-third of patients. OBJECTIVE To identify the most helpful outcomes for treatment evaluation and to uphold (rather than diminish) blood glucose concentration and stimulate the TCA cycle, including anaplerosis, in G1D using the medium-chain, food-grade triglyceride triheptanoin. DESIGN, SETTING, AND PARTICIPANTS Unsponsored, open-label cases series conducted in an academic setting.
    [Show full text]
  • Fatty Acid Oxidation
    FATTY ACID OXIDATION 1 FATTY ACIDS A fatty acid contains a long hydrocarbon chain and a terminal carboxylate group. The hydrocarbon chain may be saturated (with no double bond) or may be unsaturated (containing double bond). Fatty acids can be obtained from- Diet Adipolysis De novo synthesis 2 FUNCTIONS OF FATTY ACIDS Fatty acids have four major physiological roles. 1)Fatty acids are building blocks of phospholipids and glycolipids. 2)Many proteins are modified by the covalent attachment of fatty acids, which target them to membrane locations 3)Fatty acids are fuel molecules. They are stored as triacylglycerols. Fatty acids mobilized from triacylglycerols are oxidized to meet the energy needs of a cell or organism. 4)Fatty acid derivatives serve as hormones and intracellular messengers e.g. steroids, sex hormones and prostaglandins. 3 TRIGLYCERIDES Triglycerides are a highly concentrated stores of energy because they are reduced and anhydrous. The yield from the complete oxidation of fatty acids is about 9 kcal g-1 (38 kJ g-1) Triacylglycerols are nonpolar, and are stored in a nearly anhydrous form, whereas much more polar proteins and carbohydrates are more highly 4 TRIGLYCERIDES V/S GLYCOGEN A gram of nearly anhydrous fat stores more than six times as much energy as a gram of hydrated glycogen, which is likely the reason that triacylglycerols rather than glycogen were selected in evolution as the major energy reservoir. The glycogen and glucose stores provide enough energy to sustain biological function for about 24 hours, whereas the Triacylglycerol stores allow survival for several weeks. 5 PROVISION OF DIETARY FATTY ACIDS Most lipids are ingested in the form of triacylglycerols, that must be degraded to fatty acids for absorption across the intestinal epithelium.
    [Show full text]
  • Eႇects of Alternative Oxidase on Drosophila Under Environmental
    6,1$6$$5, (ႇHFWVRI$OWHUQDWLYH 2[LGDVHRQDrosophila XQGHU(QYLURQPHQWDO6WUHVV 7DPSHUH8QLYHUVLW\'LVVHUWDWLRQV 7DPSHUH8QLYHUVLW\'LVVHUWDWLRQV 6,1$6$$5, (IIHFWVRI$OWHUQDWLYH 2[LGDVHRQDrosophila XQGHU(QYLURQPHQWDO6WUHVV $&$'(0,&',66(57$7,21 7REHSUHVHQWHGZLWKWKHSHUPLVVLRQRI WKH)DFXOW\RI0HGLFLQHDQG+HDOWK7HFKQRORJ\ RI7DPSHUH8QLYHUVLW\ IRUSXEOLFGLVFXVVLRQLQWKHDXGLWRULXP) RIWKH$UYREXLOGLQJ$UYR<OS|QNDWX7DPSHUH RQ2FWREHUDWR¶FORFN $&$'(0,&',66(57$7,21 7DPSHUH8QLYHUVLW\)DFXOW\RI0HGLFLQHDQG+HDOWK7HFKQRORJ\ )LQODQG Responsible 3URIHVVRU+RZDUG7-DFREV supervisor 7DPSHUH8QLYHUVLW\ and Custos )LQODQG Pre-examiners 3URIHVVRU:LOOLDP-%DOODUG 'RFHQW(LMD3LULQHQ 8QLYHUVLW\RI1HZ6RXWK:DOHV 8QLYHUVLW\RI+HOVLQNL $XVWUDOLD )LQODQG Opponent $VVRFLDWH3URIHVVRU9LOOH+LHWDNDQJDV 8QLYHUVLW\RI+HOVLQNL )LQODQG 7KHRULJLQDOLW\RIWKLVWKHVLVKDVEHHQFKHFNHGXVLQJWKH7XUQLWLQ2ULJLQDOLW\&KHFN VHUYLFH &RS\ULJKWDXWKRU &RYHUGHVLJQ5RLKX,QF ,6%1 SULQW ,6%1 SGI ,661 SULQW ,661 SGI KWWSXUQIL851,6%1 3XQD0XVWD2\±<OLRSLVWRSDLQR 7DPSHUH To Pulla iii iv ABSTRACT The mitochondrion is a unique organelle with a central role in energy production and metabolic homeostasis while regulating the life and death of the entire cell. In mitochondrial dysfunction, deficiencies or abnormalities of the mitochondrial oxidative phosphorylation (OXPHOS) system impair cellular energy production. Due to its ability to bypass Complex III and IV of the OXPHOS system and divert electrons from ubiquinol to oxygen, the mitochondrial alternative oxidase (AOX) has drawn attention as a potential
    [Show full text]
  • The Citric Acid Cycle
    Chapter 16 The Citric Acid Cycle: CAC Kreb’s Cycle Tricarboxylic Acid Cycle: TCA The Citric Acid Cycle Key topics: To Know – Also called Tricarboxylic Acid Cycle (TCA) or Krebs Cycle. Three names for the same thing. – Cellular respiration and intermediates for biosynthesis. – Conversion of pyruvate to activated acetate – Reactions of the citric acid cycle – Anaplerotic reactions to regenerate the acceptor – Regulation of the citric acid cycle – Conversion of acetate to carbohydrate precursors in the glyoxylate cycle Discovered CAC in Pigeon Flight Muscle Cellular Respiration • Process in which cells consume O2 and produce CO2 • Provides more energy (ATP) from glucose than Glycolysis • Also captures energy stored in lipids and amino acids • Evolutionary origin: developed about 2.5 billion years ago • Used by animals, plants, and many microorganisms • Occurs in three major stages: - acetyl CoA production (This chapter) - acetyl CoA oxidation (This chapter) - electron transfer and oxidative phosphorylation (Chapter 19) Overall Picture Overall Picture Acetyl-CoA production The area blocked off all occurs in the takes place in the mitochondria. Mitochondrion. So, first pyruvate has to get Acetyl-CoA enters the transported from the CAC. cytoplasm into the mitochondrion. In this Figure, only Glycolysis is in the Cytoplasm. Pyr DH is a Complex Enzyme Pyruvate Dehydrogenase Model TEM Lipoic Acid is linked to a Lys (K) Remember HSCoA ? from Chapter 1 It is down here One Unit of Pyr DH EOC Problem 6: Tests your knowledge of PyrDH. EOC Problem 7: Thiamin deficiency and blood pyruvate. Pyr DH is a Cool Enzyme EOC Problem 5: NAD+ in oxidation and reduction reactions (a through f should be easy).
    [Show full text]
  • Lecture 9: Citric Acid Cycle/Fatty Acid Catabolism
    Metabolism Lecture 9 — CITRIC ACID CYCLE/FATTY ACID CATABOLISM — Restricted for students enrolled in MCB102, UC Berkeley, Spring 2008 ONLY Bryan Krantz: University of California, Berkeley MCB 102, Spring 2008, Metabolism Lecture 9 Reading: Ch. 16 & 17 of Principles of Biochemistry, “The Citric Acid Cycle” & “Fatty Acid Catabolism.” Symmetric Citrate. The left and right half are the same, having mirror image acetyl groups (-CH2COOH). Radio-label Experiment. The Krebs Cycle was tested by 14C radio- labeling experiments. In 1941, 14C-Acetyl-CoA was used with normal oxaloacetate, labeling only the right side of drawing. But none of the label was released as CO2. Always the left carboxyl group is instead released as CO2, i.e., that from oxaloacetate. This was interpreted as proof that citrate is not in the 14 cycle at all the labels would have been scrambled, and half of the CO2 would have been C. Prochiral Citrate. In a two-minute thought experiment, Alexander Ogston in 1948 (Nature, 162: 963) argued that citrate has the potential to be treated as chiral. In chemistry, prochiral molecules can be converted from achiral to chiral in a single step. The trick is an asymmetric enzyme surface (i.e. aconitase) can act on citrate as through it were chiral. As a consequence the left and right acetyl groups are not treated equivalently. “On the contrary, it is possible that an asymmetric enzyme which attacks a symmetrical compound can distinguish between its identical groups.” Metabolism Lecture 9 — CITRIC ACID CYCLE/FATTY ACID CATABOLISM — Restricted for students enrolled in MCB102, UC Berkeley, Spring 2008 ONLY [STEP 4] α-Keto Glutarate Dehydrogenase.
    [Show full text]
  • Renal Mitochondrial Cytopathies
    SAGE-Hindawi Access to Research International Journal of Nephrology Volume 2011, Article ID 609213, 10 pages doi:10.4061/2011/609213 Review Article Renal Mitochondrial Cytopathies Francesco Emma,1 Giovanni Montini,2 Leonardo Salviati,3 and Carlo Dionisi-Vici4 1 Division of Nephrology and Dialysis, Department of Nephrology and Urology, Bambino Gesu` Children’s Hospital and Research Institute, piazza Sant’Onofrio 4, 00165 Rome, Italy 2 Nephrology and Dialysis Unit, Pediatric Department, Azienda Ospedaliera di Bologna, 40138 Bologna, Italy 3 Clinical Genetics Unit, Department of Pediatrics, University of Padova, 35128 Padova, Italy 4 Division of Metabolic Diseases, Department of Pediatric Medicine, Bambino Gesu` Children’s Hospital and Research Institute, 00165 Rome, Italy Correspondence should be addressed to Francesco Emma, [email protected] Received 19 April 2011; Accepted 3 June 2011 Academic Editor: Patrick Niaudet Copyright © 2011 Francesco Emma et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Renal diseases in mitochondrial cytopathies are a group of rare diseases that are characterized by frequent multisystemic involvement and extreme variability of phenotype. Most frequently patients present a tubular defect that is consistent with complete De Toni-Debre-Fanconi´ syndrome in most severe forms. More rarely, patients present with chronic tubulointerstitial nephritis, cystic renal diseases, or primary glomerular involvement. In recent years, two clearly defined entities, namely 3243 A > GtRNALEU mutations and coenzyme Q10 biosynthesis defects, have been described. The latter group is particularly important because it represents the only treatable renal mitochondrial defect.
    [Show full text]
  • 6 Minute Walk Results
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date r i 1 /1 i 22 December 2011 (22.12.2011) » 2U1 1/159634ft Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/23 (2006.01) A61P 3/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (21) International Application Number: CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, PCT/US201 1/040234 DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, JL, IN, IS, JP, KE, KG, KM, KN, KP, 13 June 201 1 (13.06.201 1) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (25) Filing Language: English NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (26) Publication Language: English SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/354,472 14 June 2010 (14.06.2010) US (84) Designated States (unless otherwise indicated, for every 13/159,329 13 June 201 1 (13.06.201 1) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, (71) Applicant (for all designated States except US): BAY¬ ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, LOR RESEARCH INSTITUTE [US/US]; 33 10 Live TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Oak Street, Suite 501, Dallas, TX 75204 (US).
    [Show full text]
  • Chemoprevention in Kidney Cancer by Madhur Nayan
    Chemoprevention in Kidney Cancer by Madhur Nayan A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy in Clinical Epidemiology, Graduate Department of Health Policy, Management, and Evaluation, in the University of Toronto © Copyright by Madhur Nayan, 2017 THESIS ABSTRACT Thesis Title: Chemoprevention in kidney cancer Degree: Doctor of Philosophy (PhD) in Clinical Epidemiology Year of Convocation: 2017 Student: Madhur Nayan Graduate Department: Health Policy, Management and Evaluation University: University of Toronto Background: This thesis is a composition of three studies that explore the role of statins in kidney cancer. Furthermore, I evaluate the potential for different interpretations from the same data depending on the method of classifying medication use. Methods: The first study was a population-based case-control study evaluating the association of statin use with risk of incident kidney cancer. The second study was a systematic review and meta-analysis reviewing the current evidence relating statins with kidney cancer survival outcomes. The final study was a population-based cohort study evaluating the association of statin use with survival. In the observational studies, I used fractional polynomials for the primary analysis to allow for a non-linear relationship between cumulative exposure and the risk of the outcome. I also compared risk estimates obtained by different methods of classifying medication exposure. Results: The population-based case-control study included 10,377 incident cases of kidney cancer and 35,939 matched controls. Increasing cumulative use of statins was not associated with kidney cancer risk. I identified 12 studies for inclusion in the systematic review and meta- analysis and found that statin use was significantly associated with markedly improved cancer- specific and overall survival.
    [Show full text]