Multiple-Choice Questions in Medical Physiology For Postgraduate Medical Entrance Examinations [Revised May 2013] E.S.Prakash, MBBS, MD _____________________________________________________________________________________ Written and Published May 2013 by E.S.Prakash. Copyright © 2013, all rights reserved by E.S.Prakash. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means or stored in a database or retrieval system without prior written permission from the author. This version has not yet been peer reviewed. 150 Pages Please avoid using previous editions of this book. Disclaimer: Science and medicine constantly change and while I have tried to check information presented here with sources known to be reliable, I cannot guarantee that this book is error free. I encourage you to crosscheck information contained herein with other sources. This book is not written to be used to directly guide the care of patients. Therefore, I cannot accept any responsibility for any consequences that may arise from the use of information contained here in the care of patients – E.S.Prakash 1 E.S.Prakash. MCQs in Medical Physiology, May 2013 2 minutes please Think of this book as a tool to help you assess how well you have learnt medical physiology. It was written primarily for use in revision courses for doctors who are preparing for competitive postgraduate (PG) medical entrance examinations in India, but undergraduate medical students and postgraduate physiology students may find this helpful. The intent here is to use multiple-choice questions (MCQ) as a means to help the reader revise some key facts, test understanding of concepts and the ability to apply them, and thereby improve one’s understanding of human physiology and its relevance to clinical medicine. Thus, besides the traditional select the single best response type of MCQ which is the question type used in most entrance exams, I have frequently included questions solely intended for learning and practice and so these may not be equivalent in standard to questions commonly appearing in entrance examinations. Also, the difficulty level of questions vary across entrance exams and I’ve attempted to simulate it here. As MCQs with multiple correct answers enable more material to be revised with fewer questions, I have also frequently used such questions; further, this helps us get into and sustain the important habit of carefully reading all options in a question. Some entrance exams use the select all correct answers (multiple true-false) type of MCQ, so some practice with this type of question is needed. In general, a significant fraction of the questions that I have seen appear on PG entrance examinations test conceptual understanding and meaningful learning. However, some test knowledge of facts that are not of significance to a primary care physician, and while this can be partly rationalized, an undesirable backwash effect of this on students is it tends to encourage rote learning over indepth learning of important concepts. I have focused on the immediate ‘learning needs’ of the target audience, as well as to exemplify the relevance of medical physiology in clinical practice. For the purpose of preparing and revising for PG entrance examinations, I recommend Ganong’s Review of Medical Physiology (abbreviated as WFG in the rest of this book), published by Mc Graw Hill. For more practice questions in physiology, I recommend the following sources: • Self-Study Questions in WFG • National Medical Series for Independent Study. Physiology. Eds. Bullock J, Boyle J, Wang MB. Williams & Wilkins, 2001 (or a newer edition) • Ryan JP and Tuma RF. PreTest – Physiology, 13th ed. Mc Graw Hill. • Questions from previous PG entrance exams, if they are publicly available. Clarifications, Follow-up Notes, Some more practice questions: I’ll post them on my website at http://esprakash.wordpress.com/mcqmedphy/ Images and Schematic Diagrams accompanying this book: You can download them from the above webpage; these figures render better on PowerPoint Slides rather than on a 2-column Word Document. I’ve greatly benefitted from review of this book by students who used it in the past, and I welcome suggestions for improving this book. If you spot an error, please let me know. I dedicate this book to the memory of Dr William F Ganong. E.S.Prakash, MBBS, MD Associate Professor of Physiology Mercer University School of Medicine, Macon, Georgia, USA E-mail: [email protected] Website: http://esprakash.wordpress.com Editor & Publisher, Medical Physiology Online [ISSN 1985-4811] http://www.medicalphysiologyonline.org 2 E.S.Prakash. MCQs in Medical Physiology, May 2013 Table of Contents Topic Page 2 minutes please 2 General Physiology 4 Cell Physiology; Intercellular Communication 11 Physiology of Nerve and Muscle 14 Central Nervous System 24 Endocrinology and Reproduction 39 Gastrointestinal Physiology 48 Circulating Body Fluids 52 Cardiovascular Physiology 56 Pulmonary Physiology 68 Renal and Acid-Base Physiology 82 Critical Care Physiology 93 Self-Scorers 1 – General Physiology 98 2 – Physiology of Nerve and Muscle 99 3 – Central Nervous System 101 4 – Endocrinology and Reproduction 104 5 – Gastrointestinal Physiology 108 6 – Cardiovascular Physiology 110 7 – Pulmonary Physiology 112 8 – Renal and Acid-Base Physiology 114 Blast from the Past 116 More Questions for Self-Study 131 3 E.S.Prakash. MCQs in Medical Physiology, May 2013 1. General Physiology 7. In a healthy adult weighing 70 kg, plasma volume was estimated to be 3000 ml. His In each of the following questions, select the hematocrit was 40%. His blood volume would be single best response unless instructed otherwise. about: A. 5000 ml 1. ECF volume is determined by: B. 5200 ml A. plasma [Na] C. 5400 ml B. plasma protein concentration D. 5600 ml C. the amount of sodium in the ECF 8. The water content of lean body mass is: 2. The chief determinant of plasma osmolality is A. 30 ml/100 g A. plasma [Na] B. 50 ml/100 g B. plasma [glucose] C. 70 ml/100 g C. blood [urea] D. highly variable D. plasma [albumin] 9. The following values are obtained on a sample 3. The volume of distribution of intravenously of plasma from a child that has clinical evidence administered sucrose in a healthy 70-kg man is of dehydration. about: A. 3.5 liters Plasma [Na] = 135 mmol/L B. 10.5 liters Plasma [glucose] = 400 mg/dL C. 14 liters Blood urea nitrogen = 100 mg/dL. D. 28 liters The osmolality of plasma is expected to be close 4. Which of the following markers administered to: intravenously distributes exclusively in A. 290 mOsm/kg H2O intracellular fluid? B. 310 mOsm/ kg H2O A. Evans blue dye C. 330 mOsm/kg H2O B. Heavy water D. 350 mOsm/kg H2O C. Sucrose D. None of the above 10. What percentage of osmolality of plasma in a healthy, well hydrated individual is attributable to 5. Which compartment does the term “sucrose sodium and its accompanying anions? space” refer to? A. 30 % A. Extracellular fluid (ECF) B. 50 % B. Interstitial fluid (ISF) C. 70 % C. Intracellular fluid (ICF) D. 90 % D. Plasma 11. Which of the following contributes least to the 6. 100 mg of sucrose is injected intravenously into osmolality of plasma? an adult male weighing 70 kg. The plasma A. Glucose concentration of sucrose after mixing is 0.01 B. Proteins mg/ml. If 5 mg of sucrose has been metabolized C. Sodium during this period, the ECF volume in this D. Urea individual is approximately: A. 6 liters 12. In the steady state, the value of which of the B. 9.5 liters following variables is the same in ICF and ECF? C. 14 liters A. pH D. 17.5 liters B. osmolality C. concentration of proteins 4 E.S.Prakash. MCQs in Medical Physiology, May 2013 D. number of osmoles 19. Which of the following exerts the greatest osmotic effect on a mole-mole basis? 13. The body fluid compartment that contains A. Dextran more osmotically active particles (in relation to B. Hydroxyethyl starch other fluid compartments in the same individual) C. Albumin is: D. Fibrinogen A. intracellular fluid B. plasma 20. Connexins do not allow the passage of: C. interstitial fluid A. polypeptides B. Na ions 14. Normal red blood cells from a healthy C. Ca ions individual were placed in each of the following D. inositol trisphosphate solutions and observations made after 1 hour. E. amino acids Cells would have most likely have lysed in red blood cells placed in: 21. Of the following substances, the lipid bilayer A. 0.3% NaCl per se (i.e., without proteins) is most permeable B. 0.9% NaCl to: C. 1.2% NaCl A. sodium ions B. urea 15. Which of the following solutions is C. glucose hypertonic? D. water A. 0.9 % NaCl B. 5% dextrose 22. The rate of diffusion of a substance across the C. 20% mannitol cell membrane is inversely proportional to: D. Distilled water A. concentration gradient for the substance B. diffusion coefficient 16. Two liters of 0.9% NaCl is administered to a C. surface area available for diffusion 12-year old boy with moderate isotonic D. thickness of the membrane dehydration. What is the expected change in ICF volume after NaCl administration? 23. Which one of the following is an example of A. No change passive transport? B. Increase by 0.5 liter A. Calcium efflux by calcium pump C. Increase by 2 liters B. Na-Ca exchanger D. Decrease by 0.5 liter C. Potassium efflux through potassium leak E. Decrease by 2 liters channels D. Calcium sequestration in sarcoplasmic 17. ICF volume decreases when dehydration is: reticulum A. isotonic B. hypertonic 24. Most of the ATP generated in nerve cells is C. hypotonic utilized to energize the: A. Na-Ca exchanger 18. If the intent is to replenish total body water in B. H-ATPase in the cell membrane a dehydrated individual which one of the C. Na-K ATPase following should be administered intravenously? D. synthesis of proteins A. 0.9% NaCl B. 5% dextrose solution 25. Which of the following is incorrectly C. Albumin matched? D. 10% glucose solution A. Na-K ATPase: antiport E. Distilled water B. H-ATPase: uniport C. SGLT: symport 5 E.S.Prakash. MCQs in Medical Physiology, May 2013 D. Ca-ATPase: biport Thus, urea concentration of 60 mg/dL corresponds to a [BUN] of 28 mg/dL. 26. The core body temperature of an experimental animal is raised from 98ºF to 106ºF by passive heating. Eventually, it dropped back to 99ºF. Normally, plasma osmolality is chiefly due to Na What is the gain of the temperature regulation and its accompanying anions Cl and HCO . 3 system in this instance? Normally, serum osmolality ranges from 280–295 A. Zero mOsm/Kg H O. 2 B. One C. -7 4-6. Intravenously administered sucrose D. Infinity distributes throughout ECF (plasma + interstitial fluid). ECF volume in a 70-kg healthy adult is 27. Which of the following is not true about about 14 L (20% of body weight). The volume of negative feedback control systems? interstitial fluid is about 10.5 L (75% of ECF A. Output is one of the inputs to the system volume) and plasma volume is about 3.5L (25% B. It is based on a ‘set-point’ for the controlled of ECF volume). Heavy water distributes variable. throughout body water. Sucrose, inulin and C. The system corrects “errors” mannitol distribute exclusively in the ECF. Evans D. The ‘set point’ of the system cannot be blue dye stays in the plasma. changed by inputs other than the controlled variable Typical values in a healthy adult male weighing 70 kg are as given below: Answers: General Physiology Compartment Volume Marker 1C 2A 3C 4D 5A Total body water 42 L D O 2 6B 7A 8C 9C 10D ICF 28 L - 11B 12B 13A 14A 15C ECF 14 L Sucrose 16A 17B 18B 19C 20A Interstitial fluid 10.5 L - 21D 22D 23C 24C 25D Plasma 3.5 L Evans blue 26C 27D Indicator-dilution principle: Answer Explanations: Volume of distribution of the indicator equals the 1. Children and adults have the same amount injected (A) divided by the concentration concentration of sodium in plasma. Yet their ECF (C) in plasma (of the indicator) after mixing. volumes are greatly different. Thus, ECF volume is proportional to the amount of sodium in ECF. In the above example, First, sucrose distributes throughout ECF. 2. The concentration of sodium in ECF is Amount of sucrose injected = 100 mg quantitatively the most important determinant of Amount metabolized = 5 mg plasma osmolality. Amount remaining in ECF = 95 mg Concentration after mixing = 0.01 mg/ml Plasma osmolality (mosm/Kg H O) = Volume of distribution of sucrose 2 2 [Na+] + [glucose] / 20 + [BUN] ×18/50 = 95 mg / 0.01 mg/ml = 9500 ml = 9.5 L (mmol/L) (mg/dL) (mg/dL) 7. Blood volume Blood urea and urea nitrogen: = plasma volume × [100 / (100–Hct)] The formula of urea is NH CONH 2 2 Molar mass of urea is 60 g; each molecule of urea 8. Body mass = fat mass + lean body mass. has 2 nitrogen atoms. The water content of lean body mass (fat-free The mass of nitrogen in urea is 2 × 14 = 28 g mass) is relatively constant and is about 70 ml/100 g. For example, in an individual weighing 70 kg 6 E.S.Prakash. MCQs in Medical Physiology, May 2013 and whose total body water is measured to be 42 Osmotic pressure is the pressure that would be L (= 42 kg), lean body mass = 42 / 0.7 = 60 kg, required to stop water flux (osmosis) across a and fat mass is 10 kg. Fat is relatively anhydrous. semi permeable membrane. Body fat % = 10/70 × 100 = 14%. Body fat percentage is greater in women compared to men. Osmotic pressure P = CRT (Van’t Hoff equation), where, 12. ICF is much more acidic than ECF. For C = concentration of osmoles example, in muscle cells the pH is about 6.8. The R = a constant steady state osmolality (i.e., concentration of T = temperature in Kelvin osmotically active particles) of all body fluid compartments must be the same. The fact that, in In the steady state, the osmolality of all body a healthy adult, ICF volume is twice as large as fluids is identical; that is, osmotic pressure across ECF volume should indicate that the absolute the plasma membranes of cells in the steady state number of osmoles is much greater in the ICF. is zero and there would be no net water flux (osmosis) across the cell membrane. 13-16. What is osmosis? Osmosis is the movement of water across a Osmolality is a colligative property that depends semipermeable membrane permeable to water but upon the number of solute particles, and not the not to solutes, from a solution with lesser size of the particles. To illustrate, the contribution concentration of osmoles to a solution with a of 1 Na ion and 1 albumin molecule toward greater concentration of osmoles. This continues osmolality of plasma is the same. Since the molar until osmotic equilibrium (i.e., the osmolality of concentration of proteins in plasma is very low either compartment is equal) is attained. (60 g/L) compared to that of Na (140 mM) and Cl (100 mM), one can understand why plasma What is an osmole? proteins contribute very little to the osmolality of An osmole (effective osmole) is an osmotically plasma compared to Na and its accompanying active particle potentially capable of causing ions. osmosis. Examples include sodium ion, chloride ion, protein anions, and phosphate ion. A solute to Colloid osmotic pressure of plasma: While which the cell membrane is not as freely proteins are present in plasma at a concentration permeable as it is to water will function as an of 60-80 g/L, they are not normally present in effective osmole. For example, in comparison to significant concentrations in the interstitium. water, the cell membrane is relatively Thus, the osmotic pressure of plasma proteins impermeable to sodium and chloride ions, (called colloid osmotic pressure or oncotic mannitol. The amount of ions crossing the cell pressure) is much greater than the osmotic membrane through channels and transporters is pressure of proteins in the interstitium. This much smaller relative to osmotically driven water oncotic pressure gradient across the capillary fluxes. restrains fluid filtration and favors reabsorption of fluid into the capillary. What is an ineffective osmole? If the cell membrane is permeable to a solute (for Hemolysis begins when normocytes are placed in example, urea), the substance will move across 0.5% NaCl and is complete in 0.3% NaCl. In the membrane until its concentration is exactly the contrast, when RBCs are placed in hypertonic same on both sides of the membrane. In such an saline, they lose water and diminish in size. instance, osmosis (net movement of water) does not occur. However, note that urea does indeed Why is 0.9% NaCl called an isotonic solution? function as an effective osmole in the renal 0.9% (precisely 0.85%) NaCl has the same medullary interstitium. osmolality as normal human plasma (about 290 mOsm/kg H O, please see the calculation below); 2 further, when it is infused into a normal human 7 E.S.Prakash. MCQs in Medical Physiology, May 2013 (i.e., one with an ECF osmolality of 290 mOsm/kg H O), it does not cause any change in Is 5% dextrose isotonic or hypotonic? 2 the steady state volume of red blood cells or other Molar mass of dextrose (D-glucose, C H O ) is 6 12 6 cells; i.e. because it does not change the steady 180 g state osmolality of normal human plasma, it is an 5% solution contains 50 grams of dextrose per isotonic solution. liter of the solution 50g = 50/180 mol = 0.277 mol = 277 mmol = 277 Calculate the osmolality of 0.85% NaCl. mOsm/L ~ 270–280 mOsm/kg H O 2 0.85% NaCl contains 0.85 g of NaCl per deciliter of the solution. As 5% dextrose has approximately the same = 8.5 g/ L of the solution osmolality as normal human plasma, it is an Molar mass of NaCl = 58.5 g isosmotic solution. However, when dextrose is 1 mol of NaCl = 58.5 g infused, it is metabolized and the net effect (over a 8.5 g = 8.5/58.5 mol = 0.145 mol = 145 mmol/L period of time, especially when large volumes are Each Na is accompanied by 1 chloride ion infused) is that of adding water to plasma. This Therefore, total concentration of osmoles “excess” water can enter cells. Thus, 5% dextrose (osmotically active particles) = 2 × 145 = 290 is of value in replenishing ICF volume in mOsm/L intracellular dehydration. Also, note 5% dextrose is hypotonic because it dilutes plasma in the 16-17. ECF volume changes steady state. When the terms dehydration and overhydration are used without further qualification, they are In well hydrated individuals, the hypo-osmolality typically used to refer to ECF volume contraction that occurs when hypotonic dextrose solutions are and ECF volume expansion respectively. The infused is sensed by osmoreceptors and secretion term dehydration can be used to refer to a of antidiuretic hormone is promptly inhibited to reduction in total body water as well. However, excrete ‘excess’ water. hypovolemia and dehydration are not synonymous. Hypovolemia specifically refers to a To summarize, tonicity of a solution refers to the reduction in blood volume. Blood volume is more effect of an administered solution on the steady critically regulated than ECF volume. state osmolality of normal human plasma. Classification of dehydration*: 19. Starling’s law of filtration Type Example of a cause Isosmotic Blood loss Starling described forces that affect fluid flux Hyperosmotic ADH deficiency across capillaries. Hypoosmotic Adrenocortical insufficiency *Overhydration is classified likewise. Fluid movement = Kf [(Pc + πi) – (Pi + πc)], Changes in ICF volume in various types of where, dehydration: Kf = capillary filtration coefficient Type ECF ICF Pc = hydrostatic pressure in the capillaries volume volume Pi = hydrostatic pressure in the interstitium Isosmotic Decreases No change πc = capillary colloid osmotic pressure Hyperosmotic Decreases Decreases Hypoosmotic Decreases Increases πi = colloid osmotic pressure in the interstitium 18. The key phrase here is ‘body water’ which Normally, Pc is the principal force favoring includes ICF as well as ECF. In the steady state, filtration. The osmotic pressure of plasma is hypertonic dehydration is associated with a normally about 25 mm Hg higher relative to the reduction in ECF as well as ICF volume. So osmotic pressure of interstitium because ‘plasma’ therapy must be aimed at replenishing total body proteins (colloids) are limited to plasma; proteins water, not merely ECF volume. 8 E.S.Prakash. MCQs in Medical Physiology, May 2013 in plasma restrain fluid filtration into the understanding but there is some risk of teleologic interstitium. fallacies. Albumin is quantitatively the most important Take temperature regulation as an example. The contributor to the colloid osmotic pressure of ‘controller’ is the hypothalamus. The fact that a plasma. 1 g of albumin in 100 ml of plasma exerts rise in body temperature leads to a fall in an osmotic effect of 6 mm Hg; the same temperature back toward 98.6ºF suggests that concentration of globulins will exert a pressure of temperature is the controlled variable, and this only about 1.5 mm Hg. operates as a negative feedback control system. This means that there must be a ‘sensor’ for 22. Fick’s law of diffusion: temperature. The hypothalamus is in fact able to Diffusion rate (J) = DA dc/dx sense core body temperature. D: Diffusion coefficient A: Area available for diffusion When there is an infection, often the release of dc: concentration gradient cytokines as part of the immunologic response act dx: thickness of membrane on the brain to raise the ‘set-point’ of the temperature regulation system to a higher level so The diffusion coefficient is affected by factors that a higher than normal body temperature is such as temperature, and the permeability of the maintained and results in fever. The control membrane to the molecule/ion in question. system is then said to be ‘reset’ to a higher Permeability of a membrane to an ion/molecule is operating level. However, once the infection and in turn affected by the number of ion channels or the immune response resolve and the transporter molecules available to transport the concentration of cytokines and prostaglandins that species in question. reset the temperature set point upward resolve, the set point returns to 98.6ºF indicating that resetting 23. Ion flux through ion channels is a passive of a control system is not necessarily permanent. process; i.e. it occurs down a concentration gradient and requires no input of free energy. *************************************** Supplement: Classification of mechanism of 24. A large fraction of ATP (nearly 70%) transport across cell membranes: synthesized in neurons is used to energize the Na- K ATPase and maintain ion gradients across the Mechanism Examples Simple diffusion Diffusion of oxygen, nerve cell membrane. carbon dioxide, anesthetic gases, nitric oxide through 25. Ca-ATPase is a uniport because it transports lipid layer one species. It is a primary active transport Facilitated diffusion Glucose entry into cells process as it uses ATP as the source of energy. through GLUT 1-5; passage of ions through ion channels* 26. Gain = correction / error; in this example, the Primary active Na-K ATPase, H-K correction is 7 degrees i.e. from 106ºF down to 99 transport ATPase, Ca-ATPase, H- ºF, and the error (deviation from the original value ATPase of 98ºF) is 1ºF. The gain of a negative feedback Secondary active Na-glucose cotransporter control system is negative. If the error is zero, transport (SGLT), Na-amino acid cotransport, Na-H gain is infinite. Guyton and colleagues suggested exchanger, Na-Ca that the renal ‘pressure-natriuresis’ mechanism for exchanger controlling body fluid volumes has infinite gain. Simple diffusion, by definition, is diffusion 27. As far as biological systems are concerned, the occurring through the lipid bilayer. Facilitated application of control system theory is a means to diffusion occurs through protein molecules in the cell membrane (ion channels or transport 9 E.S.Prakash. MCQs in Medical Physiology, May 2013 proteins). Some authors consider ion flux through ion channels also as an instance of “simple Name Definition Example diffusion” – this distinction is a matter of taste. Uniport 1 species Ca-ATPase, transported GLUT* Symport 2 species Na-glucose By definition, a primary active transport (also cotransport) transported cotransport, process is driven by hydrolysis of ATP. in the Na-K-2Cl same cotransport Notes about the Na-K ATPase: direction • It is a primary active transport process Antiport (also 2 species Na-K • The pump is present in the cell membrane countertransport) transported ATPase, in opposite Na-H • It is ubiquitous i.e., present in all cells directions exchanger, • It pumps 3 Na out of the cell and 2 K ions in. Cl-HCO 3 Thus it makes the inside of the cell negative exchanger. with respect to exterior; i.e. it contributes to a *GLUT – glucose transporter small extent (about 4 mV) to the genesis of RMP. Carrier mediated transport – this term refers to • It plays an important role in maintaining cell transport processes in which the transport species physically attaches to a carrier molecule, and is volume. If the pump is inhibited as can happen carried by it. Carrier mediated transport processes when ATP is limiting or pharmacologically can be active or passive. Na-K ATPase (an active (with digoxin) intracellular Na increases also transport process) and glucose transport via increasing the size of cells. • Digoxin, a cardiac glycoside inhibits this GLUT (a passive transport process) are both examples of carrier-mediated transport. pump. Inhibition of the pump leads to an increase in cytosolic Ca and this augments the Different authors use the word transport in this force of contraction of cardiac muscle cells. • About 70% of the ATP generated in nerve context differently. Some do not use the word transport to refer to ion movement through ion cells is used to energize the Na-K ATPase. channels; for them transport entails physical attachment of the transported species to the A secondary active transport process utilizes an transporter molecule. ion gradient as a source of energy rather than ATP. The Na-Glucose cotransporter (SGLT) Other modes of transport: Exocytosis, utilizes the energy of the Na gradient (Na battery) endocytosis, transcytosis (vesicular transport). to drive the uphill transport of glucose from ECF Exocytosis is triggered by a rise in intracellular to ICF. Note that the species that is actively calcium. Proteins injected into the circulation transported by SGLT is glucose. The Na-amino often have been endocytosed into vesicles by acid symporter is similar. The term ‘secondary’ endothelial cells to be exocytosed as vesicles into refers to the fact that the energy source (the the interstitium. This process called transcytosis sodium ion gradient), which drives this process, or vesicular transport requires an input of free depends upon normal operation of a primary energy. active transport process – the Na-K pump that ************************************* generates a Na ion gradient. If the Na-K pump fails due to lack of ATP or any other reason, then, the Na gradient will be gradually reduced and all secondary active transport processes powered by the Na gradient will also be affected. Nomenclature of transporters based on the direction of movement and the number of species of transported. Note: this is not a classification of mechanism of transport. 10 E.S.Prakash. MCQs in Medical Physiology, May 2013