First Aid 2013 Step 1 pdf free download - First Aid for the USMLE Step 1 2013 (First Aid USMLE) - Free Download FA 2013 Pdf Ebook

You can download it from the link below for free:

First-Aid-Usmle-Step-1-2013.pdf

• Advice from students who aced the 2012 exam 
• 1200+ frequently tested facts and mnemonics 
• Hundreds of high-yield color images and diagrams throughout 
• Student ratings of more than 300 review products

Here is a part of the book:

A STUDENT-TO-STUDENT GUIDE ..,.. Advice from students who aced the 2012 exam 􀀁 ..,.. 1200+ frequently tested facts and mnemonics 􀀁 ..,.. Hundreds of high-yield color images and diagrams throughout 􀀁 ..,.. Student ratings of more than 300 review products 􀀁 TAO LE, MD, MHS Associate Clinical Professor of Medicine and Pediatrics Chief, Section of Allergy and Immunology Department of Medicine University of Louisville VIKAS BHUSHAN, MD Diagnostic Radiologist Los Angeles VIVEK T. KULKARNI Yale School of Medicine Class of 2014 MAT THEW M. SOCHAT Warren Alpert Medical School of Brown University Class of 2013 ID Medical New York I Chicago I San Francisco I Lisbon I London I Madrid I Mexico City Milan I New Delhi I San Juan I Seoul I Singapore I Sydney I Toronto The McGraw·Hill Companies , ,. ···􀂁'i i'll First Aid for the® USMLE Step 1 2013: A Student-to-Student Guide Copyright © 2013 by Tao Le and Vikas Bhushan. All rights reserved. Printed in the United States of America. 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 data base or retrieval system, without the prior written permission of the publisher. Previous editions copyright © 1991 through 2012 by Vikas Bhushan and Tao Le. First edition copyright © 1990, 1989 by Vikas Bhushan, Jeffrey Hansen, and Edward Hon. Photo credits for this book begin on page 633 and are considered an extension of this copyright page. First Aid for the® is a registered trademark of The McGraw-Hill Companies, Inc. 1 2 3 4 5 6 7 8 9 0 DOW /DOW 14 13 1 2 ISBN 978-0-07-180232-1 MHID 0-07-180232-0 ISSN 1532-6020 Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. This book was set in Electra LH by Rainbow Graphics. The editors were Catherine A. Johnson and Peter J. Boyle. Project management was provided by Rainbow Graphics. The production supervisor was Jeffrey Herzich. RR Donnelley was printer and binder. This book is printed on acid-free paper. McGraw-Hill books are available at special quantity discounts to use as premiums and sales promotions, or for use in corporate training programs. To contact a representative please e-mail us at bulksales@mcgraw-hill.com. Dedication To the contributors to this and past editions, who took time to share their knowledge, insight, and humor for the benefit of students. Contents Contributing Authors vii How to Contribute XVII Associate Authors viii How to Use This Book xix Faculty Reviewers ix Common USMLE Laboratory Values XXI Preface xi Basic Science Discipline Cross-Reference Special Acknowledgments xii Table for High-Yield Facts xxiii Acknowledgments for Online Contributors xiii First Aid Checklist for the USMLE Step 1 xxiv 􀁥SECTION I G UIDE TO EFFICIE NT E XAM PREPARATIO N 1 Introduction 2 Clinical Vignette Strategies 21 USMLE Step 1-The Basics 2 If You Think You Failed 22 Defining Your Goal 12 If You Failed 22 Timeline for Study 12 Testing Agencies 23 Study Materials 17 References 23 Test-Taking Strategies 19 􀁥SECTION I SUPPLEMENT SPECIAL SIT UATIO NS 25 First Aid for the International Medical Graduate First Aid for the Osteopathic Medical Student 26 36 First Aid for the Podiatric Medical Student First Aid for the Student with a Disability 41 43 􀁥SECTION II HIGH-YIELD GE NERAL PRI NCIPLES 45 How to Use the Database 46 Immunology 191 Behavioral Science 49 Pathology 211 Biochemistry 63 Pharmacology 225 Microbiology 117 v 􀀒SECTION Ill HIGH-YIELD ORGA N SYSTEMS 245 Cardiovascular 249 Psychiatry 457 Endocrine 285 Renal 477 Gastrointestinal 307 Reproductive, 503 Hematology and Oncology 343 Respiratory 543 Musculoskeletal, Skin, and Connective Tissue 377 Rapid Review 565 Neurology 407 􀀒SECTION IV TOP-RATED REVIEW RESO URCES 583 How to Use the Database 584 Microbiology and Immunology 601 IJ Question Banks 586 Pathology 605 Question Books 587 Pharmacology 610 Internet Sites 588 Physiology 614 Comprehensive 589 Commercial Review Courses 619 Anatomy, Embryology, and Neuroscience 591 Publisher Contacts 624 Behavioral Science 595 Abbreviations and Symbols 625 Biochemistry 597 Photo Acknowledgments 633 Cell Biology and Histology 599 Index 641 About the Authors 695 VI Contri buti ng Authors JACOB BARANOSKI Yale School of Medicine Class of 2014 VICKI Z. J. BING Yale School of Medicine Class of 2014 JEFFREY S. FUTTERLEIB Yale School of Medicine Class of 2013 ABHIJEET GUMMADAVELLI Yale School of Medicine Class of 2014 LAUREN HIBLER Yale School of Medicine Class of 2014 JEFFREY HOFMANN Warren Alpert Medical School of Brown University Class of 2016 OLGA LAUR Yale School of Medicine Class of 2014 KELSEY B. LOELIGER Medical Scientist Training Program Yale School of Medicine GORAN MICEVIC Medical Scientist Training Program Yale School of Medicine MAX C. PETERSEN Medical Scientist Training Program Yale School of Medicine ROBERT STRETCH Yale School of Medicine Class of 2014 GARTH STROHBEHN Yale School of Medicine Class of 2014 NICHOLAS THEODOSAKIS Medical Scientist Training Program Yale School of Medicine RICHARD P. USATINE, MD Dermatology Images Contributor Professor, Dermatology and Cutaneous Surgery Professor, Family and Community Medicine University of Texas Health Science Center San Antonio CAROLINE A. WALKER Yale School of Medicine Class of 2014 SAMANTHA X. Y. WANG Yale School of Medicine Class of 2014 WALTER F. WIGGINS, PhD Editor, firstaidteam.com Wake Forest School of Medicine Class of 2014 PETER ZHAO Yale School of Medicine Class of 2014 VI I Associate Authors FADY AKLADIOS Medical University of the Americas Class of 2013 ADITYA BARDIA, MD, MPH Attending Physician, Massachusetts General Hospital Cancer Center Instructor in Medicine, Harvard Medical School MICHELLE M. BRAVO Warren Alpert Medical School of Brown University Class of 2013 RAFAEL A. BUERBA Yale School of Medicine Class of 2014 JONATHAN FU Yale School of Medicine Class of 2013 ALEJANDRO RAFAEL GENER Universidad Central del Caribe Class of 201 5 ASHWANI GORE St. George's University School of Medicine Class of 201 5 JAMES M. GRAY University College Dublin School of Medicine and Medical Science Class of 2014 WILLIAM L. HWANG, MSc Health Sciences & Technology and Biophysics Programs Harvard University/Massachusetts Institute of Technology MD/PhD candidate KATHARINE JOO Warren Alpert Medical School of Brown University Class of 2013 VI I I AMY MORENO Yale School of Medicine Class of 2014 AYESHA NZERIBE Warren Alpert Medical School of Brown University Class of 2013 KEZIA SPENCE Warren Alpert Medical School of Brown University Class of 2013 RANY WOO Yale School of Medicine Class of 2013 ANDREW HANOI WU Boston University School of Medicine Class of 201 5 MICHAEL XIONG Warren Alpert Medical School of Brown University Class of 201 5 PATRICIA ZADNICK Johns Hopkins School of Medicine Class of 2014 CHRISTINE ZENDER-PRINCETON, DO Resident Physician, Lakeland Regional Healthcare Adjunct Professor, Clinical Michigan State University College of Medicine JINYU (JANE) ZHANG Warren Alpert Medical School of Brown University Class of 2014 Faculty Reviewers CHARLES DELA CRUZ, MD Assistant Professor, Department of Pulmonary and Critical Care Medicine Yale School of Medicine EMILY R. ESPOSITO, PhD Assistant Professor Sullivan University College of Pharmacy CONRAD FISCHER, MD Associate Professor of Physiology, Medicine, and Pharmacology Touro College of Medicine, New York City STUART FLYNN, MD Dean, College of Medicine The University of Arizona, Phoenix ANUJ GAGGAR, MD Clinical Fellow Department of Infectious Disease University of San Francisco School of Medicine MATTHEW GARABEDIAN, MD Division of Maternal-Fetal Medicine Department of Obstetrics and Gynecology Santa Clara Valley Medical Center ANTHONY GLASER, MD, PhD Assistant Professor, Department of Family Medicine Medical University of South Carolina RYAN C. W. HALL, MD Assistant Professor, Department of Medical Education University of Central Florida, Orlando Affiliate Assistant Professor, Department of Psychiatry University of South Florida, Tampa RAJESH JARI, MD, MBA Spine, Medicine, and Rehabilitation Therapies-SMART Pain Management Westminster and White Marsh, Maryland KURT JOHNSON , PhD Professor, Department of Anatomy and Regenerative Biology and Department of Obstetrics and Gynecology George Washington University School of Medicine SHANTA KAPADIA, MD Lecturer, Department of Surgery Yale School of Medicine BERTRAM KATZUNG, MD, PhD Professor Emeritus University of California, San Francisco GERALD LEE, MD Assistant Professor, Section of Allergy and Immunology Department of Internal Medicine University of Louisville School of Medicine WARREN LEVINSON, MD, PhD Professor, Department of Microbiology and Immunology University of California, San Francisco N ICHOLAS MAHONEY, MD Assistant Professor, Department of Ophthalmology Wilmer Eye Institute/Johns Hopkins University PETER MARKS, MD, PhD Associate Professor, Department of Internal Medicine Yale School of Medicine PATRICIA J. MElTING, PhD Professor of Physiology & Pharmacology and of Medicine Vice Chancellor and Senior Associate Dean for Student Affairs The University of Toledo College of Medicine and Life Sciences AFSOON MOKTAR, PhD Assistant Professor Sullivan University College of Pharmacy ROBERT NOVAK, MD Chair, Department of Pathology and Laboratory Medicine Akron Children's Hospital DAVID PERRY, PhD Professor, Department of Pharmacology and Physiology George Washington University School of Medicine IX MICHAEL S. RAFII, MD, PhD Director, Memory Disorders Clinic Assistant Professor of Neurosciences University of California San Diego Health System DANIEL J. RUBIN, MD, MSC Assistant Professor of Medicine, Division of Endocrinology Associate Program Director, Endocrinology Fellowship Temple University School of Medicine JOSEPH SCHINDLER, MD Assistant Professor, Department of Neurology and Neurosurgery Clinical Director, Yale New Haven Stroke Program Yale School of Medicine SANJIV SHAH, MD Assistant Professor, Division of Cardiology Department of Medicine Northwestern University X HOWARD STEINMAN, PhD Professor, Department of Biochemistry Assistant Dean of Biomedical Science Education Albert Einstein College of Medicine STEPHEN THUNG, MD Associate Professor, Department of Obstetrics/Gynecology Ohio State University RICHARD P. USATINE, MD Professor, Dermatology and Cutaneous Surgery Professor, Family and Community Medicine University of Texas Health Science Center San Antonio HILARY VERNON, MD Assistant Professor, McKusick-Nathans Institute of Genetic Medicine Johns Hopkins University ADAM WEINSTEIN, MD Assistant Professor, Section of Pediatric Nephrology Department of Pediatrics Geisel School of Medicine at Dartmouth Preface With this edition o f First Aid for the USMLE Step 1, we continue our commitment to provide students with the most useful and up-to-elate preparation guide for the USMLE Step 1 . Th is edition represents a comprehensive revision in many ways and includes: • An updated, full-color design with new color photos, enhanced illustrations, and improved formatting of tabular material and mnemonics integrated throughout the text. • Extensive text and image revisions, clarifications, errata corrections, and new material based on student experience with the 20 1 2 administrations of the USMLE Step 1 . • A revised and updated exam preparation guide for the U SMLE Step 1 with updated data from the NBME and NRMP. Includes student feedback as well as study and test-taking strategies for the current exam format. Thoroughly revised U S M LE advice for international medical graduates and osteopath ic medical students. • More than 1 200 frequently tested facts and useful mnemonics, including hundreds of new or revised entries and tables. An updated guide to recommended U SMLE Step 1 review resources, based on a nationwide survey of randomly selected third-year medical students. Bm1us Step 1 high-yield facts, cases, video lectures, corrections, and updates can be found exclusively on our blog at www.firstaidteam.com. The improvements in this edition would not have been possible without the help of the thousands of medical students, graduates, and faculty members who contributed their feedback, suggestions, and error corrections. We invite students and faculty to continue sharing their thoughts and ideas to help us i mprove First Aid for the USMLE Step 1. ( See How to Contribute, p. xvi i . ) Lou isville Los Angeles New Haven Providence Tao Le Vikas Bhushan Vivek T. Kulkarni Matthew M. Sochat XI Special Acknowledgments This has been a collaborative project from the start. We gratefully acknowledge the thousands o f thoughtful comments, corrections, and advice of the many medical students, international medical graduates, and faculty who have supported the authors in the continuing development of First Aid for the USMLE Step 1. We provide special acknowledgment and thanks to the following students who contributed on many levels: Peter Gayed, Chika Anekwe, Ashleigh Bouchelion, Jack Cossman, Rahul Dalal, Abdelaziz Farhat, Yun Rose Li, E l izabeth Marshall, Sean Martin, and Aj it Rao. For help on the Web, thanks to Jaysson Brooks, Molly Lewis, Sean Martin, Luke M urray, Sarah-Grace Wesley, and Vamsi Kancherla. Thanks to the First Aid Step 1 Express team: Jeffrey Hofmann, Will iam Hwang, Stephen A. Allsop, Karolina Brook, Aaron Feinstein, Adrian I-laimovich, Katie Lee Hwang, Vivek Kulkarni, Mihan Lee, ilay Patel, Max Petersen , Nick Theodosakis, and Rany Woo. For support and encouragement throughout the process, we are grateful to Thao Pham and Jonathan Kirsch , Esq. Thanks to Selina Franklin and Louise Petersen for organizing and supporting the proj ect. Thanks to our publ isher, McGraw-H ill, for the valuable assistance of its staff, including Midge Haramis, Jeffrey Herzich, and John Williams. For enthusiasm, support, and commitment for this ongoing and ever-challenging project, thanks to our editor, Catherine Johnson . For editorial support, enormous thanks to Emma D. Underdown , Linda Bradford, and Linda Davoli . We are also grateful to Tara Price for the interior design of the book and to the medical illustrators, Diana Kryski and Hans euhart, for their great work on the new and updated illustrati ons. Special thanks to Jan Beclnarczuk for a greatly improved index. Many thanks to Dr. Richard Usatine of Usatine Media for his outstanding clermatologic image and editorial contributions. We are also very thankful to Freel Howell and Robert Cannon of Textensor for providing access and support to their Annotate collaborative platform, which will allow us to more efficiently manage contributions from thousands of medical students and graduates. Lastly, tremendous thanks to Rainbow Graphics, especially David Hommel and Tina Castle, for remarkable ongoing editorial and production work under time pressure . XI I Louisville Los Angeles New Haven Providence Tao Le Vikas Bhushan Vivek T. Kulkarni Matthew M. Sochat Acknowl edgments for Onl i ne Contri butors This year we were fortunate t o receive the input of thousands of medical students and graduates who provided new material, clarifications, and potential corrections through our Web site and our new collaborative editing platform. This has been a tremendous help in clarifying difficult concepts, correcting errata from the previous edition, and minimizing new errata during the revision of the current edition. This reflects our long-standing vision of a true student-to-student publication. We have done our best to thank each person individually below, but we recognize that errors and omissions are likely. Therefore, we will post an updated list of acknowledgments at our Web site www.firstaidteam.com under the Errata and Updates tab. We will gladly make corrections if they are brought to our attention. For submitting contributions and corrections, many thanks to Solomon Abay, Hussein Abbas, Ramzi Abboud, Assya Abdallah, Mohamad Abdelfattah, George Abdelmessieh, Salwan Abdullah, Yazan Abou-lsmail, Khalil Abusabha, Stacy Achdjian, Ebele Achebe, James Ackerman, Nivia Acosta, lance Adams, Robert Adams, Carson Adams, Adebanke Adebayo, Jessica Adefusika, Mona Adeli, Mishuka Adhikary, Amina Adil, Brandon Adler, David Adler, Sumit Agarwal, Deepak Agarwal, Manik Aggarwal, Neha Agnihotri, Nupur Agrawal, Cynthia Aguirre, Daniel Ahmad, Michele Ahmadi, Tina Ahmadinejad, Rabia Ahmed, Kamran Ahmed, Mushfique Ahmed, Annie Ahn, Sahir Ahsan, Zahab Ahsan, Jared Aida, Carol Akers, Oyinade Akinyede, Fady Akladios, Danso Ako-Adjei, Ani! Akoon, Erik Akopian, Oluronke Alate, Mahdi Alajaj, Mohammad Alam, Ridwaan Albeiruti, Carlos Albrecht, Anas Albrejawi Alhomsi, Austin Albright, Carmen Alcala, Tiara Aldridge, Samia Aleem, Michail Alevizakos, Sheby Alexander, Eirene Alexandrou, Shad Ali, Mohammad Ali, Huzair Ali, Munni Ali, Mariam Ali, Zahra Alibrahim, Evan Alicuben, Narges Alipanah, Atush Alipuria, Niloo Allahyari, laura Almquist, Raed Alnaji, Brock Alonzo, Omar AI-Qudsi, Zina AI-Sakini, Aileen Alviar, Saif Alzoobaee, Chelsey Amer, Kunal Amin, Alec Amram, Keshav Anand, Kayley Ancy, Carl Andersen, Thomas Anderson, Dallin Anderson, Daniel Anderson, Mark Anderson, David Andrews, Zubair Ansari, Ali Ansary, Chase Ansok, Ahmed Antably, Emeka Anyanwu, Dillon Arando, Chris Arbonies, Saeed Arefanian, Alejandro Arenas, Nkiruka Arinze, Anne Armstrong, Grayson Armstrong, Jonathan Arnold, Mack Arroliga, Praag Arya, Rozana Asfour, Derrick Ashong, Karam Asmaro, Ricardo Au let, Rik Austin, Meghan Auten, liezl Avila, Shiri Avraham, Temitope Awosogba, Gabriel Axelrud, Derek Axibal, Reed Ayabe, Giselle Ayala, Ndang Azang-Njaah, Ali Ahsan Azeem, Eisha Azhar, Corneliu Bacauanu, Becca Bacharach, Warren Backman, Karam Badran, Javier Baez, Kandy Bahadur, Sara Bahraini, Mirza Baig, Ursula Bailey, Erin Bailey, Mayank Bajpai, Joshua Bakhsheshian, Maria Bakkal, Asha Balakrishnan, Jill Balala, Rajinder Balasuriya, Zach Balest, Rebekah Baltz, Gaurav Bansal, Aiyush Bansal, Faustino Banuelos, Daniel Bar, Nicholas Barasch, Mike Barca, Nicolas Barcelo, Ayse Dalsu Baris, Anne Barnard, Morgan Barnell, Kyle Bartlett, Joshua Barzilai, Bruce Bassi, Bennett Battle, Marianne Bauer, Mark Bauernfeind, Harinder K. Bawa, Omkar Baxi, Michael Baxter, Ahmad Najdat Bazarbashi, Joel Beachey, Tyler Beals, Ryan Beck, Jessica Beckerman, Nic Beckmann, Angela Beckon, Sumeer Bedi, Rachel Beekman, Ryan Begley, Jordan Bell, Joseph Benedict, Nontawan Benja-Athonsirikul, Krista Bergman, Justin Berkowitz, Elizabeth Berry, Adam Berry, Marina Bessel, Adam Betz, Anita Bharath, Suraj Bhargav, Vijay Bhat, Ankit Bhatia, Nita Bhatt, Sajjad Akbar Bhatti, Osman Bhatty, Nora Biary, Charlotte Bibbee, Alexander Bick, David Bishop, Rohan Biswas, Rachel Blair, Max Blanter, Jessamyn Blau, Greg Bligard, David Bluhm, Sarah Bly, Raymond Boakye, Satish Babu Bodapati, Joanne Boisvert, Craig Bollig, Romin Bonakdar, Jeffrey Bonenfant, Valentina Bonev, Namrita Boparai, Nicholas Bope, Sanket Borgaonkar, Joshua Borsook, Tarrah Bowen, Anthony Bowen, Grace Boynton, Hemal Brahmbhatt, Mike Bramati, James Brann, Steve Braun, Kathryn Breidenbach, Jennifer Bress, Jamie Brett, Betsy Breuker, Elizabeth Brezinski, Valerie Brice, Bryan Broach, Benjamin Brockbank, Frank Brodie, Karolina Brooks, Aaron Brown, Sareena Brown, Blair Brown, Gabrielle Brown, Ronnie Brown, Christopher Brown, Will Brubaker, Nataly Bruk, Tina Bruno, Jason Brustein, Daniel Bryan, Campbell Bryson, Rob Buchanan, Floyd Buen, Antiem Bui, John Bui, Jaclyn Burch, Ross Burge, Katelyn Burgess, Adrian Burgos, Colin Burke, Stephen Burks, Bradley Burmeister, Sharlena Burnett, lauren Burtz, Cathleen Bury, Aaron Bush, Alex Buss, Steve Butala, Emran Butt, Matt Byun, Armando Cabrera, Melissa Cain, Nora Callinan, Sean Campbell, Andrew Campbell, Melissa Campos, Adam (anion, David Capaldi, lindsay Capron, Jordan Carl, Tyler Carllee, Silva Carlos, Harris Carmichael, Nathan Carpenter, leah Carr, Madeline Carroll, Evan Carstensen, Phil Carullo, Priscilla Carvalho, Alan Casciola, Ryan Casserly, leon Castaneda, Crystal Castaneda, Jonas Castaneda, Brandi Castro, Alexander Cavalea, Garrett Cavanaugh, Thomas Cayce, Alberto Cerra, Esther Cha, Ausim Chaghtai, Gaurab Chakrabarti, Jason Chan, Daniela Chan, Maria Chancay, Anisha Chandiramani, Sidharth Chandra, Mahesh Chandrasekhar, Sunny Chang, Khalid Hamid Changal, David Charles, Mubeen Sultan Cheema, Alice Chen, Thomas Chen, lu Chen, Joanna Chen, Frank Chen, Eric Chen, Andrew Chen, Daniel Cheng, Jacklyn Cheng, Julie Cheng, Esther Cheng, Chris Chesnut, Monica Cheung, Michael Chevinsky, Sharon Chi, Tiffany Chi, Kelly Chien, Jordan Chinai, Cathy Patricia Lee Ching, Anny Ching, Shideh Chinichian, Allen Chiou, Lironn Chitayat, Megan Chock, Michael Choe, Mohammad Rizwan Chaudhary, Ahmad Chaudhry, Ryan Choudhury, Mohsin Chowdhury, laura Christensen, Andrew Christiansen, Amy Chu, Kai Chu, Philip Chu, Jonathan Chun, Jina Chung, XIII Andrew Cichowski, Anthony Cipriano, Dave Ciufo, Andrew Clair, Michael Clark, Summer Clark, Danielle Clark, Emily Clemetson, Michael Cloud, Sarah Codrea, Steven Cogorno, Alex Cohen, Rachel Cohen-Shohet, Elizabeth Collins, Amy Collins, Xavier Colon, Jennifer Colon, Hadassah Consuegra Anderson, Jonathan Copp, Nikhil Cordeiro, Samuel Cordeiro, Elizabeth Cordie, Sarah Cormie, Amarilis Cornejo, Eva Corona, Matthew Cossack, Ryan Cotter, Jennifer Cottral, Molly Cowdrey, Laurel Cox, Katherine Cox, Gordon Crabtree, Paul Craig, Matthew Craig, Crystal Craig, Elizabeth Cramer, Teela Crecelius, Katherine Crifasi, Brian Cripe, Michael Cronin, Nick Crowley, Niall Crowley, Daniel Croymans, Allison Cruse, John Cummins, William Currie, Eileen Curry, Brian Curry, Carl D, Howard Dai, Jessica Dai, David Dai, Thomas Dailey, Pavan Dalal, Mariaana Dalangin, Erika Daley, Keren Dallalzadeh, Thuan Dang, Avace Dani, Gabrielle Daniel, Ameesh Dara, Tyler Darnell, Ryan Daro, Tony Darrington, Alvin Das, Shayna Dattani, Neil Dattani, Shravan Dave, Joshua Davidson, Kerri Davis, Andrew Davis, Chelsea Davis, Michael Davis, Noor Dawood, Solomon Dawson, Andrew Daya, Daniel Dayan, Charles De Jesus, Hector De Jesus, Ivan De Jesus, Nastassia De Souza, Nakyda Dean, Nakydadean Dean, Malcolm Debaun, Cory Deburghgraeve, Johannes Decker, Jennifer Decoste-Lopez, Alison Dedent, Raj Dedhia, Mhair Dekmezian, Henry Del Rosario, Ritchie Mae Delara, Sara Delarosa, Steven Delbello, James Delgadillo, Joseph Delio, Samantha Demar, Dawit Demissie, Kathryn Demitruk, John Demuth, Kara Denby, Vedant Desai, Danielle Desjardins, Danielle Detelich, Andrew Deutsch, Anjan Devaraj, Ryan Devenyi, David Deyoung, Trisha Dickey, Marine Dididze, Christine Dillingham, Bill Diplas, Ebony Dix, Erin Dizon, Teresa Do, Chris Dobson, Taylor Dodgen, Natasha Dolgin, Sarah Donaldson, Patrick Dooling, Amy Dora, Bradleigh Dornfeld, Heather Douthitt, Dr Munaf, Alex Drake, Mariah Dreisinger, Maggie Driscoll, lan Dryden, Xi Du, Milap Dubal, Genia Dubrovsky, Brittany Duchene, Matthew Duda, Sarah Duhon, Mark Dukshtein, Rachelle Duquette, Zachary Dureau, Jonathan Dutt, Alison Dzwonczyk, Micah Eades, John Eager, Anas Easa, Christian Eckmann, Colin Edwards, Jared Ee, Nima Eftekhary, Ashley Egan, Badi Eghterafi, Nick Eglitis, Ehren Ekhause, Lindsay Elbaum, Justen Elbayar, llyas Eli, Tyler Ellington, Alexis Elliott, Alejandra Ellison-Barnes, Sora Ely, Matthew Emerich, Drew Emge, Trine Engebretsen, Christopher English, Chris English, Feras Entabi, Esther Enuanwa, Elizabeth Ernst, Rito Escareno, Michael Esparza, Diego Espinoza, Chris Ethridge, Clay Evans, Brendan Everett, Abieyuwa Eweka, Cyril Eyadiel, Nnenna Ezeilo, Abayomi Fabunmi, Eric Faden, Josh Fage, Laura Fagen, Kerolos Fahmi, Falcon Falcon, Kimberly Faldetta, Lu Fan, Hang Fang, Hongfei Fang, Lawrence Fannon, Joseph Farahany, Abdelaziz Farhat, Bilal Farhat, Amy Farkas, Amanda Farris, Michael Fay, Alicia Febles De Lorow, ldo Feferkorn, Rebecca Fega, Leah Feldman, Robert Feng, Jenny Feng, Yaniv Fenig, Elizabeth Fenstermacher, Agha Hassan Feroze, Abdullah Feroze, Michael Ferro, Michael Fickes, Vikram Fielding-Singh, Tucker Fischbeck, Juliya Fisher, Alex Fisher, Mark Fisher, Erin Fitzgerald, Heidi Fjeldstad, Jason Flamendorf, Kenneth Flax, Mario Flores, Katy Flynn-Meketon, Kelly Fong, Christopher Foote, Jon Forbes, Lisa Fosnot, Andrew Fouche, Nyssa Fox, Loren Fox, Sarah Franjoine, Harris Frank, Miguel Frau, Rob Freeman, Monika Freiser, Appolinia Frey, Yev Freyvert, Martin Fried, Robin Friedman, Jamie Friedmanjamief, Melanie Friess, Jason Frischhertz, Nathan Frogge, Simona Frunza-Stefan, Alicia Fuhrman, Tim Fuller, Tracy Fulton, Brian Fung, August Funk, Nicholas Furlani, Bob Furlong, Michael Gabbard, Alex Gaidarski, James Gallagher, Sylvia Bea Galvan, Nikita Ganatra, Anjalika Gandhi, Niral Gandhi, Niket Gandhi, Abby Gandolfi, Milan Ganger, Akshay Ganju, Jared Gans, lan Gao, Jennifer Gao, Maria Victoria Garcia, Heidy Garcia, Benjamin Garden, Michael Garitty, John Garlich, Michael Gazes, Daniel Gealy, Alison Gegios, Steven Gelb, Scott Gelman, Alejandro Gener, Douglas George, Ramez Ghabour, Marcel Ghanem, Saad Ghazipura, Alexander Ghobadimanesh, Martin Gibbs, David Gill, Harrison Gimbel, Will Gionfriddo, Jacob Gire, Christine Glendon, Steven Glenn, Joshua Glick, Chad Glisch, Catherine Go, Shanette Go, Michelle Go, Nikhil Godbole, Melanie Goebel, Aneesh Goel, George Gold, Andrew Goldman, Whitney Goldsberry, lan Goldstein, Greg Goldstein, Aaron Goldstein, Nicholas Golinvaux, Anurekha Gollapudi, Jane Golub, Charles Gonzales, Lillian Gonzalez, Wilfreda Gonzalez, Javier Gonzalez, Abigail Goodman, Avi Goodman, Ashwani Gore, Shaun Gould, Morgen Govindan, Indira Gowda, Daniel Grabell, Trevor Grace, Cynthia Grady, Jaykumar Grandhi, Rebecca Graves, James Gray, Emily Gray, Christian Greco, Clifton Green, Ari Greenbaum, Steven Greenstein, Alexander Greenstein, Tobin Greensweig, Char Grif, Gabriel Griffin, Ashley Grigsby, Brian Grisez, Nathan Grohmann, Britt Gros, Bridget Gro s, Kelli Gross, Daniel Grosser, Andrea Grosz, Alan Groves, Joanna Grzadziel, Allen Guehl, Arthur Guepe, Jonah Gunalda, Robin Guo, Ling Guo, Jessie Guo, Akash Gupta, Sheena Gupta, Abhishek Gupta, Gita Gupta, Ankur Gupta, Apar Gupta, Kiran Guthikonda, Kai Ha, lnna Hadass, Cathryn Haeffele, Kevin Hageman, Sue Hahn, Moosa Haider, Adrian Haimovich, Angie Hairrell, Mark Hall, Sarah Hall, Charles Hall, Jeremy Hall, Alexander Hallac, Akbar Hamid, Kam Hanamaikai, John Hanks, Jesse Hansen, Stephanie Harbison, Brian Harms, Jessica Harrell, David Harrington, Holly Harris, Frank Harris, Jennifer Harris, Cynthia Hart, Bridget Hartman, Heather Hartman, Becca Hartog, Georgina Hartzell, Zach Harvanek, Connor Hasbrook, Hasnain Hasham, Omar Hashmi, Jordan Haskins, Ammar Hassan, John Hassani, Kai Hata, Mike Hausberger, Andriy Havrylyan, Liz Haworth, Shane Hawthorne, Shakaib Hayat, Lisa Hayman, George Hayward, Sindalisa Hean, Jason Hedge, Elise Heeringa, Jeff Heimiiler, Christine Helou, Krista Hemmesch, Martha Henao, Phi lip Hendley, Whitney Hendrickson, Rachel Henrickson, Eduardo Hernandez, Matthew Hernandez, Miriam Herschman, Anthony Herzog, Matthew Hess, Amber Hetrick, Jarred Hicks, Andrew Higdon, David Hilburn, Derek Hill, Graham Hill, Julia Hiner, Jonathan Hirshberg, Whitney Hitchcock, Yoona Ho, Marjorie Ho, Alan Hoang, Sandra Hobson, Max Hockstein, Evan Hodell, Aaron Hodes, Erika Hoenke, Zach Hoffman, Martin Hofmann, Kaitlin Holdstem, Charles Hong, Michael Hong, Chris Hong, Austin Horrocks, Wendy Hosin, Elika Hoss, Reza Hosseini Ghomi, Pearl Houghteling, Nicholas Hountras, L. Mclean House li, Kara Hoverson, Lee Howard, Ryan Howard, Tifany Hoyne, Ahmed Hozain, Ruth Hsiao, Jenmfer Hsu, Wei-Chun Hsu, Anna Hsu, Annie Hsu, Jen Hsu, Derek Hsu, Peifen Hu, Jessie Hu, Cindy Hu, Charles Hua, Linda Huang, Hanwei Huang, Christopher Huelsman, Brandon Huffman, Myriam Hughes, Hayley Hunt, Nakia Hunter, Jennie Huo, Lara Hurlburt, Irene Hurst, Mustafa Husaini, Adnan Hussain, Hanif Hussaini, Monica Huynh, Daniel Hwang, Michael Hwang, Patrick Hyppolite, Adaora lfeanyi, Kevan lffrig, Atanas lliev, Hasan IMANLI, Peter lp, Neil Issar, Kilali lyalla, Mangala Iyengar, Lee Jablow, Deidrya Jackson, Lishan Jackson, Robert Jackson, Joshua Jackson, Jacoby Jacobsen, Asif Jafferani, Syed Jaffery, Ariba Jahan, Supriya Jam, Amita Jain, Sechin Jain, Christopher Jakubowski, Asha Jamzadeh, Samantha Jamga, Daniel Javaherian, Matthew Jaykel, Tim Jaykel, Isaac Jenabi, Jack Jeng, Kimberly Jenkins, Kim Jenna, Brett Jensen, Jonathan Jerkins, Forrest Jespersen, Krishan Jethwa, Shiel Jhaveri, Lunan Ji, Rui Jiang, Yike Jiang, Ahce Jiang, William Jiang, Ying Jin, Peter Jin, Bennett Johnson, Ben Johnson, Linda Johnson, Wcs Johnson, Stacey Johnson, I real Johnson, Brianna Johnson-Rabbett, Benjamin Jones, Roger Jones, Tyler Jones, Chelsea Jones, Andrew Jones, Nate Jones, Patrick Jorda, Mary Kate Jordan, Lia Jordana, Walter Joseph, Claire Joseph, Rahul Joy, Alexander Juhn, Jenny Jun, Sarah Jung, Michael Jung, Sam K, Nida K, Payal Kadakia, Clhan Kadipasaoglu, Jessica Kafer, Jodi Kagihara, Rachel Kahn, Adam Kahn, Charissa Kahue, Mehboob Kalani, Mowffaq Kalantan, Shana Kalaria, Mariya Kalashnikova, Sudhir Kalaskar, Zach Kalb, Omar Kallas, Kunal Kambli, Caroline Kan, Pridvi Kandagatla, Sean Kandel, Ravinder Kang, David Kang, Sarv Kannapiran, Ro er Kanumuri, Jordan Kapper, Ni a Karamooz, Peter Karempelis, Syed Karim, Justin Karlin, Joshua Karlin, Krupa Karnik, Anthony Kasch, Stephen Kasteler, Kenan Katranji, Igor Katsyv, Leah Katta, Monica Katz, Matthew Katz, Benjamin Kaufman, Anatoly Kazakin, Amir Ka erouninia, Matthew Kelley, Sandra Kellum, Jonathan Ken, Donan XIV Kenleigh, Daniel Kennedy, Kristen Kent, Kyle Kern, Amanda Kern, Rohit Kesarwani, Briana Ketterer, Ryan Key, Andrew Keyser, Phue Khaing, Mazen Khan, Rabnawaz Khan, ldrees Khan, Aimal Khan, Muhammad Zubair Khan, Shadab Khan, Rabeea Khan, Tamer Khashab, Sameer Khatri, Ben Khazan, Ali Khiabani, Akhil Khosla, Gohar Khosravi, Michal Kidacki, Zachariah Kidman, Crystal Kiewert, Daniel Kil, David Kim, Ellen Kim, Grace Kim, Jenna Kim, Jun Kim, Kristin Kim, Christopher Kim, Soo Jeong Kim, Phillip Kim, Ajin Kim, Julie Kim, Samuel Kim, David Kimball, Jonathan King, Eric King, Nikhar Kinger, Kathleen Kirkland, Annah Kirkley, Drew Kiser, Joshua Kiss, Wissam Kiwan, Maximilian Klein, Nicole Klekowski, Kris Klem, Isaiah Kletenik, Dane Klett, Bradley Kliewer, Michelle Knoll, Pin-Vi Ko, Brett Kadish, Kristin Koenig, Aaron Kofman, Lauren Kohan, Pratistha Koirala, Nadeem Kolia, Franchesca Konig Toro, Matthew Koo, Hannah Kooperkamp, Yelena Korotkaya, Jacqueline Korpics, Karthik Kota, Uzma Kothawala, Yann-Fuu Kou, Adam Kowalski, David Kraft, Scott Kramer, Landon Krantz, Sarah Krantz, Brad Krasnick, Carl Kraus, Vijay Krishna, Ross Krista!, Malgorzata Krzyszczak, Paul Kuder, Elizabeth Kuilanoff, Nishat Kulkarni, Robret Kulwin, Keerthana Kumar, Anupam Kumar, Sanjay Kumar, Aashish Kumar, Hanesh Kumar, Preethi Kumar, Hiren Kunadia, Joseph Kundukulam, Edward Kuoy, Daniel Kurbanov, Vadim Kurbatov, Ashleigh M. Kussman, Levon Kuypelyan, Melissa Kwan, Rui Kwan, Janet Kwok, Levon Kyupelyan, Tiffany L, Alison La, Jennifer Ladd, Carlos Lago, Hamed Lahijani, Erica Lai, Isabella Lai, Kuan-Chi Lai, Bryan Lai, Rosalind Lai, Charlene Lai, Chandru Jay Lalwani, Lauren Lambeth, Jon Lamee, Rongpei Lan, Megan Land, Kristen Landry, Maria Lapchenko, Marissa Lapedis, Caroline Larosa, Derek Laskar, Joe Lau, Wincie Lau, Samantha Lavergne, John Le, Jessica Lee, Kacia Lee, Paul Lee, Raymond Lee, Dane Lee, Dianne Lee, Yungah Lee, Jisoo Lee, Christina Lee, Katherine Lee, Joo Yeon Lee, Michelle N Lee, Eunjoo Lee, Anna Lee, Michelle Lee, Jason Lee, Jennifer Lee, Katie Lees, Lucas Lenci, Kyle Leneweaver, Mike Leonard, Scott Lester, Stephanie Leung, Peggy Leung, Celine Leung, Steven Leung, Seth Levin, Matthew Levine, Kate Levy, Vivian Levy, Natashia Lewis, Molly Lewis, Lei Li, Luming Li, Yun Li, Li Li, Angela Li, Kai Li, Carol Li, Bin Li, Qiansheng Liang, Emily Liebling, Sofia Ligard, Caitlin Lim, Simon Lim, Lian Lim, Geoffrey Lim, David Lin, Alex Lin, Tsung Hsien Lin, Jennifer Ling, Matthew Listo, Alison Little, Amy Liu, Kevin Liu, Emberlynn Liu, Lars Logdberg, Kevin Loh, Paula Lomba, David Long, Cesar Lopez Angel, Christopher Lops, Jaime Loso, Kristian Loveridge, Dylan Lovin, Michele Luhm Vigor, Jason Luijasonl, Karen Luk, Chris Lunt, Leo Luo, David Luu, Ying Luu, Catherine Ly, Blair M, E M, Nilam M, Andrea Ma, Stephanie Ma, Ashlee Macdonald, Andrew Macquarrie, Mahesh Madhavan, Jai Madhok, Selena Magalotti, Paula Magee, lsha Mahamud, Michael Mahan, Val Maharaj, Mithu Maheswaranathan, Mithunan Maheswaranathan, Hadi Mahmaljy, Mhd Abdallah Mahrous, Herman Mai, Thi Mai, Leann Mainis, Vivian Mai-Tran, Gary Mak, Lindsay Makara, Vyacheslav Makler, Slava Makler, Mona Malakouti, Veshal Malhotra, William Malins, llir Manaj, Sarah Mancini, Jason Mandell, Morgan Mandigo, Nicole Mangiboyat, Christopher Manieri, Alexandra Mannix, Abdallah Mansour, Soohan Mansuri, David Mao, Marnonette Marallag, Leanna Marderian, Fernando Mariz, Dan Marks, Benjamin Marsh, Kerry Marshall, Daniel Martig, Kent Martin, Pablo Martinez, Luis Martinez, Ryan Martinez, Jaime Martinez, Pablo F. Martinez, Jessica Mason, Sunil Mathew, Gladcy Mathew, Irene Mathieu, Sandy Mazzoni, Jamie Mazzurco, Ositadinma Mbadugha, Ndi Mbride, Tom Mcbride, Alexis Mccabe, Heather Mccain, Marissa Mccay, Brittani Mcclain, James Mcclurg, Jonathan Mcgovern, Sarah Mcguffin, Caitlin Mcintyre, Nicholas Mckenna, Tina Mckenzie, Tyler Mckinnon, Lance Mcleroy, Jake Mcmillin, Colton Mcnichols, Casey Means, Oren Mechanic, James Medley, Britton Mehr, Hirai Mehta, Komal Mehta, Dillon Meier, Chris Meinzen, Maayan Melamed, Joshua Melito, Clay Merritt, Phoebe Mesiha, Andrew Meyers, Okechukwu Mgbemena, Erik Miguel, Amir Mikhchi, Mark Mikhly, Brian Miller, Moshe Miller, Andrew Miller, Tom Miller, Chris Millhouse, Steven Mills, Daniel Miranda, Leonidas Miras, Anne Misiura, Stuart Mitchell, Kevin Mitchell, Todd Miyake, Takudzwa Mkorombindo, Lauren Moak, Sarah Mohajeri, Abdirahman Mohamed, Girish Mohan, Desh Mohan, Chaitra Mohan, Shifa Mohiuddin, Ghulam Rehman Mohyuddin, Jeffrey Mojica, Richard Molena, Domingo Molina, Daniel Mollengarden, Ryan Moore, Lindsay Morgenstern, Marina Morie, Andrew Morris, Elizabeth Morris, Gregory Morris, Aimee Morris, Tyler Morrison, Daniel Mortensen, Chris Morton, Shawn Moshrefi, Natalie Mota, Saba Motakef, Moustafa Moustafa, Murali Mukkamala, Benjamin Mullenbach, Katherine Mun, Marlon Munian, Jacob Murphree, Tim Murphy, Praveen Murthy, Raza Mushtaq, John Muzic, Kledia Myrtolli, Jennifer Mytar, Lucy Na, Elizabeth Nadal, Diana Naderi, Hodad Naderi, Navid Nafissi, Jonathan Nahas, Kiran Naidoo, Neil Naik, Yuree Nam, Hiroya Nambu, Yuree Namyureen, Ashwin Narayana, Dustin Nash, Daniel Nassau, Neelima Navuluri, Shariq Nawab, Giseli Nazmi, Ryan Neeley, Steven Neeley, Anoop Nehra, Steven Nelson, Joseph Nelson, Mithun Neral, Craig Ness, Kevin Nethers, Jordan Newman, Natalie Ngai, Quoc Ngo, Julius Ngu, Bao Nguyen, Mai Trang Nguyen, Jennifer Nguyen, Brian Nguyen, Angeline Nguyen, Nga Nguyen, Vy Nguyen, Andrew Nguyen, Christine Nguyen, Phi Nguyen, Peter Nguyen, Ronald Nguyen, Anthony Nguyen, Hung Nguyen, Sheena Nguyen, Alexandre Nguyen, Dan Nguyen, Janie Nguyen, Tram Nguyen, Ruba Nicola, Carl Nieweld, Lena Ning, Isabella Niu, Conway Niu, Leila Njimoluh, Mark Noble, Tomoki Nomakuchi, Adrian Nugent, Drew Nunziat, Aisulu Nurgozha, Tarik Nurkic, Emmanuel Nwelue, Ada Nwozuzu, Ernestina Nyarko, Kunal Oak, Souzana Obretenova, James O'Dowd, Florence Odufalu, Michael Ofori, Ben Oglivie, Oladoyin Ogunbayo, Kyle Oholendt, Kene Okeke, Michelle Okoronkwo, Bunmi Olaloye, John O'laughlin, Elizabeth Oler, Edgar Olivas, Cara Olsen, Joseph Omlor, Sina Salehi Omran, Neil Onizuka, Abimbola Orisamolu, Christopher Orr, Kenneth Ortiz, Vedran Oruc, Lais Osmani, Erik Ostler, Adetola Otesile, Robert Oubre, Xiaoxi Ouyang, Steve Ovada, Jordan Owens, Kolawole Oyewole, Rudy P, Sigmund Paczkowski, Kevin Padrez, Alyssa Pagliere, Allyson Palmer, Jd Palmer, Brian Palmisano, Jason Pan, Qinshi Pan, Saman Panahipour, Prakash Panchani, Gabrielle Paoletti, Amit Parekh, Ruby Parikh, Sneha Parikh, Sonal Parikh, Jong Park, Anthony Park, Braden Parmer, Christian Parobek, James Parris, Scott Pascal, Vanessa Pascoe, Janaki Paskaradevan, Parimal Patel, Ronak Patel, Suketu Patel, Amy Patel, Satya Patel, Sagar Patel, Shyam Patel, Tariq Patel, Hasita Patel, Parin Patel, Devin Patel, Neal Patel, Hiren Patel, Priya Patel, Maharsh Patel, Kinner Patel, Gaurav Patel, Lance Patel, Tejas Patel, Manisha Patel, Vishal Patel, Krupa Patel, Nilam Patel, Mahesh Patel, Mita Patel, Kershaw Patel, Romy Patel, Janus Patel, Tejas Patil, Rajesh Patnaik, Melissa Patterson, Kelly Paulk, Brit Payton, Justin Peacock, Katherine Pederson, Alia Pekareva, Andrew Pelikan, Andrew Peranteau, Alex Perelman, Enmanuel Perez, Rafael Perez, Mari Perez-Rosendahl, Tiffany Perkins, Liz Perkins, Barry Perlman, Michael Perone, David Perry, Asad Pervez, Max Petersen, Ashley Peterson, Sarah Peterson, Camille Petri, Tracy Pham, Andrew Pham, Tiffany Phanhdone, Douglas Phelan, Adam Phillips, Carson Phillips, Nick Piazza, Michael Pierce, Allison Pierce, Sara Pike, Meredith Plant, Alex Podolsky, Marc Polacca, Quiana Pollock, Kathleen Polonchek, Kristina Pontarelli, Francesco Pontoriero, Adrienne Poon, Nicole Pope, Jeremy Porter, Lesley Portugal, Michael Posch, Emily Pospiech, Thomas Powell, Catherine Powell, Jamila Power, Shrestha Prajib, Tyler Prestwood, Andrea Price, Jason Primus, Emilie Prot, Caroline Protin, Liese Pruitt, Kristina Prus, Alena Prystupa, Ramya Punati, Ashvin Punnyamurthi, David Purger, Anthony Purgianto, Raghuveer Puttagunta, H Q, Zuhab Qamar, Seema Qayum, Hazeeb Qazi, Xiaoming Qi, Ann Qiu, Ming Vi Qiu, Nabila Quadri, Cara Quant, Jose Quesada, Nick Quinn, Thomas Quinn, Sidra Qureshi, Jenn Raab, Amanda Rabideau, Ashwinee Ragam, Preethi Raghu, Vikram Raghu, Christina Ragland, Roxana Rahmanian, Samira Rahmanian, Asirna Raja, Akriti Raju, Charles Ramkishun, Josean Ramos, Jonathan Ramsey, Neerva Rana, Jessica Randell, Ajit Rao, Justin Raper, Ken Rapp, Rita Raturi, Rebecca Raub, Curtis Read, Alan Reagan, David Rebedew, Joshua Reber, Matthew Rebesco, Thomas Reher, XV Daniel Reid, Joshua Reid, Rebecca Reimers, Steven Reinhart, Michael Reinsbach, Brock Reiter, Sonia Replansky, David Retamar, Monica Rettenmier, Joshua Reuss, Wissam Rhayem, Jamie Rhodes, Fady Riad, Andrew Richardson, Aaron Richler, Sabah R'id, John Riester, Catherine Rim, Ryan Rimer, Kathryn Rimmer, Dalianne Rivera, Alicia Rizzo, Kris Roach, Joshua Roark, Michael Robers, Leslie Robin, Michelle Robinette, Monica Roca, Will Roche, Ellis Rochelson, Alejandro Rodriguez, Jesus Rodriguez, Carmen Rodriguez, Javier Rodriguez Kovacs, Jackeline Rodriguez-Smith, Samuel Rogers, Ben Rogers, Eric Rohman, Sarah Rollins, Christine Rollins, Brice Rolston, Vladimir Romannikov, Bobby Rombola, David Roraff, Javier Rosales, Evan Rosenbaum, Matthew Rosenbaum, Elizabeth Rosenberger, Eric Rosenfeld, Jared Ross, Joshua Ross, Lela Ross, Bryan Roth, Ryan Roth, Ben Roth, Kara Rothenberg, Steven Rothenberg, Zach Rottmann, Jonathan Roy, David Roy, David Rubins, Sharmistha Rudra, Chloe Rugut, Eric Rupe, William Rusnak, Meghan Rutgers, Nidia Ryan, Yamaan Saadeh, Janany Sabescumar, Sandeep Sabhlok, Michael Saco, Radha Sadacharan, Ahmed Sadek, Cameron Saffer, Abigail Sage, Atith Saheba, Sachin Sahni, S M Nazmus Sakib, Yusuf Salah, Mohamad Saleh, Ramy Saleh, Dr. Salway, Diana Samberg, Yoni Samocha, Glenn San Agustin, Christopher Sanchez, Juan Sanchez, Evan Sander, Britt Sandier, Kiri Sandier, Kenneth Sands, Jake Sanning, Margarita Santiago, Nishtha Sareen, Joyatee Sarker, Luay Sarsam, Milan Satcher, Alexander Satin, Alexandra Satty, Christopher Schaefer, William Schaffenburg, Jessica Schancupp, Matthew Schear, Sid Schechet, Eli Scher, Kai Schlingmann, Megan Schmidt, Amanda Schmitt, Drew Schmucker, Sam Schroeder, Adam Schwalje, Dan Schwartz, Brandon Schwartz, Kristopher Schwebler, Sarah Scott, Elliot Scott, Eric Seachrist, Derek Seehausen, Nilmaris Segarra, Tracy Seimears, Jackie Selbst, Philip Senger, Gina Sequeira, Nikhil Seth, Sajiv Sethi, Tasneam Shagroni, Raju Shah, Halie Shah, Rusha Shah, Manan Shah, Kinchit Shah, Bijal Shah, Tejal Shah, Ankur Shah, Anna Shah, Arpeet Shah, Vishal Shah, Anand Shah, Archana Shah, Zoheb Shaikh, Berje Shammassian, Angela Shan, Brett Shannon, Ayesha Shariff, Amal Shariff, Anil Sharma, Aarti Sharma, Allison Shatz, Brian Shayota, Mike Shelton, Kartik Shenoy, Rashna Shetty, Johanna Sheu, Eugenia Shevchenko, Sandra Shi, James Shi, Kyle Shibuya, Jessica Shie, Matthew Shiel, Yushane Shih, John Shin, Mackenzie Shindorf, Justine Shum, Thomas Shum, Erik Shwarts, Shan Siddiqi, Ashhad Siddiqui, Eliud Sifonte, Nathan Silvestri, Aaron Sin, Vikal Singh, Shashank Singh, Harmandeep Singh, Amteshwar Singh, Vikram Singh, Melissa Singh, Punit Singh, Arindam Singha, Varsha Sinha, Mark Sittig, Tim Sitton, Stephanie Skala, Ahalya Skandarajah, David Skoglund, Racquel Skold, Ernest Sliwinski, Justin Sloane, Emily Smergel, Nicholas Smith, Amanda Smith, Justin Smith, Kyle Smith, Craig Smith, Kendall Snyder, Kunmi Sobowale, Matthew Sochat, Jae Ho Sohn, Shantanu Solanki, Sanaa Somalya, David Somsen, Raku Son, Daniel Son, Joohyun Song, Yohan Song, Jasen Sood, Sufian Sorathia, Brett Sorge, Juan Sosa, Michael Sotiriou, Mario Soto, Yehuda Julian Spector, Julian Spector, Cory Spicer, Daniel Spiegel, Lauren Spiegel, Adam Spjute, Kathryn Stadeli, Irina Staicu, Michael Stanaek, Anna-Bianca Stashak, Jake Steel, Christopher Steele, Ruth Stefanos, Mike Stengel, Kevin Stephens, Scott Stiles, Blair Stocks, Jon Stoever, IIana Stol, Timothy Stooksberry, Tony Stover, Michelle Stram, Alyssa Stram, Jehu Strange, Marshall Strother, Daphna Stroumsa, Sean Sturm, Maham Subhani, Mark Suguitan, Matthew Sullivan, Farheen Sultana, Lishi Sun, Cliff Sung, Srinivas Sunkara, Matthew Surdel, Tyler Surma, Ryan Sutherland, Alex Swan, Christopher Sweat, Adam Sweeney, Tyler Swiss, Ali Syed, David Symister, Ariana Tabing, Hannah Taft, Shahein Tajmir, James Tak, Brandon Takase, Malia Takeuchi, Selorm Takyi, Afsaneh Talai, Sejal Tamakuwala, Neal Tambe, Tanya Tan, Amit Tandon, Lynda Tang, Mengyao Tang, Frances Tangherlini, Dantera Tangpisuthipongsa, Jackie Tanios, Kathryn Tapper, Karen Tart, Christine Tat, Elias Taxakis, Rachel Taylor, Scott Taylor, Miguel Teixeira, Kara Teruya, Zach Testo, Mazell Tetruashvily, Yana Thaker, Prakash Thapa, William Thieu, Aaron Thomas, Jerry Thomas, Taryn Thomas, Barrett Thomas, Alexandra Thomas, Ashley Thompson, Jason Thompson, Sibo Tian, Wayne Tie, Tom Tielleman, Thomas Tielleman, Connie Tien, Meghan Tierney, Tonia Tiewul, Andrew Timmons, Corey Tingey, Joanne Tisak, Wissam Tobea, Marko Todorovic, Josef Tofte, Thomas Tolbert, Justin Tomal, Jimmy Ton, Corey Tong, Olivia Tong, Gabriel Tonkin, Nevkeet Toor, Thalia Torres, Bela Toth, Jamie Totman, Lauren Towne, Jorge Trabanco, Albert Train, Patrick Tran, Bao Tran, Sunyu Tran, Darrell Tran, Pat Tran, Norris Tran Due, Daniel Treister, Hung Trinh, Adrian Tripp, Chelsea Troiano, Ryan Trowbridge, Kim Truong, Cindy Tsai, Valerie Tsang, Brian Tse, Victor Tseng, Pei-Yuan Tsou, Brian Tu, Alex Turin, Sergey Turin, Stefan Turkula, Alison Ullman, Sphoorti Umarjee, Chelsea Dawn Unruh, Krishna Upadhyaya, Oleg Uryasev, Eric Uzoma, Nataly Vadasz, Kimaya Vaidya, Jason Valadao, Erik Valenti, Kippie Valentine, Carla Valenzuela, Tina Varghese, Ross Varma, Matthew Varner, Bradley Varner, Jacob Varney, Ashley Vaughn, Aria Vazirnia, Christine Velazquez, Laura Veras, Christopher Verdick, Saurabh Verma, Marissa Versalle, Benjamin Vidalis, Albert Vien, Anita Vijapura, Liliana Villa mil-Nunez, David Villanueva, Tomas Villarreal, Howard Vo, Peter Vu, Charles Vu, John Vu, Elizabeth W, Christianne Wa, Cherisse Wad a, Jacob Wagner, Brittany Wagner, John Wainwright, Kevin Walker, Brandon Walker, Sean Wallace, Scott Walter, Joseph Wan, Tony Wang, Bo Wang, Jessica Wang, Jonathan Wang, Vivian Wang, Wendy Wang, Lindsay Warner, James Warren, Joshua Wasmund, Ryan Watson, Dovie Watson, Daniel Watson, Kathleen Weber, Katie Weber, Catherine Wei, Sam Weimer, Frank Weinberg, Candice Weiner, Ken Weinlander, Mark Weinreich, Lindsay Weiss, Claire Welteroth, Nick Wendling, Michael West, Kyle Westerholt, Derek Weyhrauch, Matthew Wheelwright, Natalie White, lan Whiteside, Rachel Whynott, Jenna Wickersham, Shira Wieder, Renee Wierz, Olivia Wilcox, Nicholas Wilkie, Sara Williams, Elbert Williams, Emily Willner, Erika Wilson, Brant Wilson, Rachael Winchester, Daniel Wingo, Lee Winkler, Paul Winograd, Keith Wirth, Lauren Wiznia, Sean Wo, Lindsey Woeste, William Wojtusiak, Amanda Wolf, Tiana Won, Christina Wong, Anthony Wong, Kimberly Wong, Stephanie Wong, Linda Wong, James Wong, Christopher Wood, Jennifer Wootton, Megan Worthley, Xinyu Wu, Sarah Wu, Gregory Wu, Wayland Wu, Susan Wu, Chester Wu, Daniel Wu, Andrew Wu, Andrew Wuenstel, Rachel Wurmser, Kirk Wyatt, Jonathan Xia, Michael Xiong, Willa Xiong, Baogang Xu, Ron Yalon, Tarek Yamany, Xiaofeng Van, Jennifer Van, Debby Yanes, Kimberly Yang, Jonathan Yang, Christine Yang, Jimmy Yao, Gokul Yaratha, Golsa Yazdy, Allen Ye, Brittany Vee, James Yeh, Emily Yeh, John Yeh, Aleksandr Yelenskiy, Amanda Yen, Albert Yen, Johnny Yep, Nury Vim, Kathleen Yip, Michael Yip, Yin Yiu, Stella Yoo, Jane Yoon, Kei Yoshimatsu, Makoto Yoshino, Jae You, Jovante Young, Andrew Young, Michael Youssef, Xin Yu, Connie Yu, Mary Yu, Hana Yu, Cathy Yu, Michael Yuan, Marshall Yuan, Michael Yudelevich, Etana Zack, Muhammad Usman Zafar, Lisansha Zahirsha, Andreina Zambrano, Ferdous Zannat, Helio Zapata, Katherine Zappia, Rolla Zarifa, Debra Zauner, Mariam Zeini, Jennifer Zhan, Jinmeng Zhang, Steven Zhang, Jane Zhang, Yingtao Zhang, Bingnan Zhang, Qian Zhang, Wency Zhao, Shuang Zhao, Betty Zhao, Ludan Zhao, Sherry Zhao, Theresa Zhou, Xun Zhou, Shira Ziegler, Nicole Zimmerman, Mark Zobeck, Ad nan Zubair, and Michael Zumwalt. For submitting book reviews, thanks to Rami Abukamil, Kristen Anderson, Maureen Ayers Looby, Glorilee Balistrieri, Emaad Basith, Matthew Bloom, Pierre Bueser, Elspeth Call, Hector Casiano, Edgie-Mark Co, Loren Colson, Alex Doudt, Clinton Ezekiel, Kendell Felker, Michael Flores, Cynthia Gee, Michael Greff, Lindsay Henderson, Ryan Tyler Hoff, Sebastian Jacobi, Priyanka Jagar, Kunal Kamboj, Harris Khan, Sameer Lakha, Tsung Hsien Lin, Michelle Liu, Lyndon Luk, Neil Majithia, Vanessa Mallol, Shane Mandalia, Gretchen Metzenberg, Naila Mirza, Steven Mong, Yen Nguyen, Fernando Ovalle, Nirav Patel, Jason Pesqueira, Alison Petrie, Hassan Qadir, Yujie Qiao, Faith Quenzer, Monique Roberts, Jasjeet Sekhon, Gabriel Soto, Kazuhiro Takahashi, Richard Tapnio, Jasmine Toor, Trung Tran, Michael Tran, Dana Turker, Sierra Witte, and Betty Zhao. XVI How to Contri bute This version of First Aid for the USMLE Step 1 incorporates hundreds of contributions and changes suggested by faculty and student reviewers. We invite you to participate in this process. We also offe r paid internships in medical education and publishing rangi ng from three months to one year. Please send us your suggestions for: • Study and test-taking strategies for the USMLE Step 1 • New facts, mnemonics, diagrams, and illustrations • High-yield topics that may appear on future Step 1 exams • Personal ratings and comments on review books, online question banks, videos, and courses For each new entry incorporated into the next edition, you will receive up to a $20 Amazon.com gift certificate per entry from the author group, as well as personal acknowledgment in the next edition. Diagrams, tables, partial entries, updates, corrections, and study h ints are also appreciated, and significant contributions will be compensated at the discretion of the authors. Also, let us know about material in this edition that you feel is low yield and should be deleted . The preferred way to submit new entries, clarifications, mnemonics, or potential corrections with a valid, authoritative reference is via our Web site : www.firstaidteam.com This Web site will be continuously updated with val idated errata, new high-yield content, and a new online platform to contribute suggestions, mnemonics, diagrams, clinical images, and potential errata. Alternatively, you can e-mail us at: firstaidteam@yahoo.com. Contributions submitted by June 1 5 , 20 1 3 , receive priority consideration for the 2 0 1 4 edition of First Aid for the USMLE Step 1. We thank you for taking the time to share your experience and apologize in advance that we cannot individually respond to all contributors as we receive hundreds of contributions each year. XVI I 􀀆 N O T E TO C O N T R I B U T O R S All contributions become property of th e authors and are subj ect to editing and reviewing. Please verify all data and spellings carefully. In the event that similar or duplicate entries are received, only the first complete entry received with a valid, authoritative reference will be used. Please follow the style, punctuation, and format of this edition as much as possible. 􀀆 J O I N T H E F I R S T A I D T E A M The First Aid author team i s pleased to offer part-time and full-time paid internships i n medical education and publishing to motivated medical students and physicians. Internships may range from a few months ( e .g. , a summer) up to a full year. Participants will have an opportunity to author, edit, and earn academic credit on a wide variety of projects, including the popular First Aid series. In 20 1 3 , we are actively seeking passionate medical students and graduates with a specific interest in improving our medical illustrations and expanding our database of medical photographic i mages. We welcome people with prior experience and talent in this area. Relevant skills include digital photography, digital asset management, information design, medical illustration, and graphic design . Please email us at firstaidteam@yahoo.com with a CV and summary of your interest or sample work. XVI I I How to Use This Book Medical students who have used previous editions of this guide have given us feedback o n how best to make use of the book. It is recommended that yo u begin using this book as early as possible while learning the basic medical scienc s. You can use Section IV to select first-year course review books and Internet reso urces and the n use thos books for review while taking your medical school classes. Use diffe r nt parts of the book at different stages in your preparation for the USMLE Step l. Before you b gm to study for the U SMLE Step l , we suggest that you read Section I: Guide to EHicient Exam Preparation nd Section IV: To p-Rated Revi ew Resources. If you are an international medical raduate student, an o t opathi medical student, a podiatry student, or a student with a disability, refer to the appropriate Section I s upplem nt for additional advice. Devise a study plan and decide what resources to buy. We 􀐿trongly recommend that y u inv st in the latest edition of at least one or two top-rated review books on each subj ect. First Aid is not a comprehensive review book, and it is not a panacea for i nadequate preparation during the first two years of medical school . Scanning Sections II and III will give you an i nitial idea of the diverse ran e of topics covered on the U SMLE Step 1 . As you study each discipline, use the cor sponding high-yield-fact section in First Aid for the USMLE Step 1 as a means of consolidating the mate ial and tes ting yourself to see if you have mastered wme of the fr qu ntly t s t d items. Actively work withi n the book to integrate important facts i nto your fund of knowledge . Using First Aid for th USMLE Step 1 as a review can serve as both a self-test of your knowledge and a repetJtion of imp rtant fa ts to learn. The Rapid Review section includes h igh-yield topics and vignettes are a bstracted from 1 cent e ams to h lp guicl your preparation. To broad n your learning stratee,ry, yo u can int ate your First Aid study with First Aid Cases for the USMLE St p 1 , First Aid Q6A for the USMLE tep 1, and the USMLE-Rx Qmax Step l test bank. Fi rst Aid Cases and First Aid Q6A are organized to match First Aid for the USMLE Step 1 chapt r for chapt r. After r viewmg a dtsciplin r organ system chapter with i n First Aid, yo u can r view c ses on the same topics and then test your kn ledge in the corresponding chapters of First Aid Cases and Fin;t Aid Q6A and with USMLE-Rx Qma Step 1 . If y u want a d per revi w of the h igh-yield topics, consider adding First Aid for the Basic Sciences: Genera l Prin ipl s nd Organ Systems and the First Aiel Express or Ultimate video courses (vvww. usmle-rx.com) to your study plan. Return to Sections II and III frequ ntly during yo ur preparation and fill yo ur shurt-te ·m memory with remaining high-yi eld fa cts a fe v days before the USMLE Step l. The book can serve as a useful way of retaining key associations and keep ing high-yi eld fa cts fr esh in your memory just prior to the examination . Reviewing the book immediately after the exam is probably the best way to help us improve the next edition. Decide what wa s truly high and low yield and send in your comments, post them on our We b site, or send us a s anned copy of your e tir a nnotated book. Reme m b e r th at you cannot disclose any exam mate rial fr om the lJSMLE. IX Common U SM LE La boratory Va l ues * = Included in the B iochemical Profile ( S MA- 1 2 ) Blood, Plasma, Serum * Alanine aminotransfe rase (A LT, CPT at 30°C ) Amylase, seru m * Aspartate a m i notransferase (AST, GOT at 30°C ) Biliru b i n , serum (adult) Total II D i rect * Calcium, serum (Total) * Cholesterol , serum (Total) * Creatinine, serum (Total) Electrolytes, serum Sodium Chloride * Potassium B icarbonate Gases, arterial blood (room a i r) Poz Pcoz pH * Glucose, serum Growth hormone - arginine sti mulation Osmolality, serum * Phosphatase (alka l i n e ) , serum (p-NPP at 30°C ) * Phosphorus (inorga nic) , serum * Proteins, serum Total (recumbent) Album i n Globul i ns * Urea n itrogen, serum ( B U N ) * Uric a c i d , serum Cerebrospinal Fluid Glucose Reference Range 8-20 U/L 2 5-1 2 5 U/L 8-20 U/L 0 . 1 - l . O mg/d L // 0.0-0 . 3 m g/dL 8 .4- 1 0 . 2 mg/dL 140-200 mg/d L 0.6-1 . 2 mg/dL 1 3 5- 147 mEq/L 9 5 - 1 0 5 m E q /L 3 . 5-5.0 mEq/L 22-28 mEq/L 7 5 - 10 5 mmHg 3 3 -44 mmi-Ig 7. 3 5 -7.45 Fasting: 70-1 1 0 mg/d L 2-h postprand ial : < 1 20 m g/d L Fasting: < 5 ng/m L provocative stimu l i : > 7 ng/m L 27 5-295 mOsm /kg 20-70 U/L 3 . 0-4. 5 mg/d L 6 .0-7. 8 g/dL 3 . 5 - 5 . 5 g/d L 2 . 3-3 . 5 g/dL 7- 1 8 mg/dL 3.0-8 . 2 mg/dL 40-70 mg/d L Sl Reference Intervals 8-20 U/L 2 5 - 1 2 5 U/L 8-20 U/L 2 - 1 7 pmoi!L // 0-5 pmol/L 2 . 1 -2 . 8 m moi!L 3 . 6 -6 . 5 m mol /L 5 3 - 1 0 6 pmoi!L 1 3 5 - 1 47 mmol/L 9 5 - 1 0 5 mmoi !L 3 . 5 -5 . 0 mmoi !L 22-28 m moi !L 1 0 .0-14.0 k Pa 4.4-5 .9 kPa [1--J+] 3 6 -44 nmoi!L 3 . 8 - 6 . 1 m moi!L < 6.6 m moi!L < 5 pg/L > 7 pg/L 2 7 5 -2 9 5 mOsm/kg 20-70 U /L l . 0 - 1 . 5 m mol/L 60-78 g/L 3 5 - 5 5 g/L 23-35 g/L 1 . 2-3 . 0 mmol/L 0 . 1 8 - 0 .48 mmoi!L 2 . 2-3 .9 m mol/L (continues) XXI Hematologic Eryth rocyte count Male : 4.3-5.9 m i l l ion/mm3 4.3-5.9 X 1 01 2/L Female : 3 . 5 - 5 . 5 m i l l ion/mm 3 3 . 5 - 5 . 5 X 1 0 1 2/L Hematocrit Male : 41-5 3 % 0.41-0. 5 3 Female : 36-46% 0 . 3 6 - 0 .46 Hemoglobin, blood Male : 1 3. 5 - 1 7. 5 g/dL 2 .09-2 .7 1 m mol /L Female: 1 2 .0-16.0 g/dL 1 . 86-2 .48 m moi!L Reticulocyte count 0 . 5 - 1 . 5 % of red cells 0 . 0 0 5 - 0 . 0 1 5 Hemoglobin, plasma l -4 mg/dL 0 . 1 6-0.62 J.Imoi!L Leukocyte count and d i fferential Leukocyte count 4500-l l ,OOO/mm3 4. 5 - 1 1 .0 X 1 09/L Segmented neutroph ils 54-62 % 0 . 54-0.62 Band forms 3-5% 0 . 0 3 - 0 . 0 5 Eosi nophils 1-3% 0 . 0 1 - 0 . 0 3 Basophils 0-0.7 5 % 0-0 . 0 0 7 5 Lymphocytes 2 5-3 3 % 0 . 2 5 - 0 . 3 3 Monocytes 3-7% 0.03-0.07 Mean corpuscular hemoglobin 2 5 .4-34.6 pg/cell 0 . 39-0 . 5 4 fmol!cell Mean corpuscular volume 80-100 11m3 80-1 0 0 fL Platelet count 1 50,000-400,000/mm3 1 5 0-400 X 1 09/L Prothrombin time 1 1-1 5 seconds 1 1- 1 5 seconds Activated partial thromboplastin time 2 5-40 seconds 2 5 -40 seconds Sedimentation rate, erythrocyte Male: 0-1 5 m m /h 0-1 5 m m /h (Westergren) Female : 0-20 m m /h 0-20 m m /h Proteins in urine, total < 1 50 mg/24 h < 0. 1 5 g/24 h XXI I Basic Science Discipl ine Cross-Reference Ta ble for H igh-Yield Facts Hema- Cardio- Endocri- Gastro- tology/ lmmu- Musculovascular nology intestinal Oncology no logy skeletal Neurology Behavioral 6 1 -62 Science Embryology 2 5 0-2 5 2 286 308-309 2 5 1 408-4 1 0 Anatomy 2 5 3 286-289 309-3 1 8 344-347 378-386 4 1 1 -442 Biochemistry l ! O 1 1 0- 1 1 1 , 77-79, 1 1 5 86, 1 1 4 Microbiology 1 24, 1 49 20 1 -202 1 44, 1 69, 1 48, 1 62, 1 3 5- 1 37, 1 72, 1 74 1 66- 1 67, 1 47, 1 69, 1 74 1 5 1 - 1 5 2 , 1 67- 1 68 Pathology 26 5-278 2 2 3 , 324-340 2 1 8-224, 200, 387-40 3 4 1 6-4 1 7, 296-304 3 50-366 20 3-208 4 1 9-420, 422-448 Pharmacology 279-284 30 5-306 340-342 367-37 5 209-2 1 0 404-406 449-4 56 Physiology 2 5 3-26 5 289-29 5 3 1 9-3 2 3 347-349 378-386 4 1 1 -442 Repro- Respira- Psychiatry Renal ductive tory 60, 62 59-60 478 504- 5 1 4 479 5 1 4-5 1 7 544-546 82-89 1 69- 1 70 1 3 8- 1 4 1 , 1 3 1 - 1 32, 1 50, 1 56, 1 68, 1 74 1 7 1 , 1 7 3 4 5 9-472 488-498 524- 5 3 7 5 5 3- 5 6 1 472-476 499-502 5 3 8-54 1 562-564 480-488 5 1 8- 5 2 3 546- 5 5 2 XXI I I XXIV First Aid Checklist for the USMLE Step 1 Th is is a n exa m p l e of how you m i ght use the i nformation i n Section I to p repa re fo r the U S M LE Step 1 . Refer to correspond i n g top i cs i n Sectio n I for more deta i ls. Years Prior 0 Select top-rated review books as stu dy guides for fi rst-yea r m e d i ca l school cou rses. 0 Ask for advice from those who h ave recently taken the U S M LE Step 1 . Months Prior 0 Revi ew com p uter test format a n d registration i nformation. 0 Register six m o nths i n a dva nce. Ca refu l ly verify name a n d a d d ress pri nted o n sched u l i n g perm it. C a l l Pro m etric or go o n l i n e f o r test date ASAP. 0 Defi ne goa ls for the U S M LE Step 1 (e.g., comforta bly pass, beat the mean, a ce the test) . 0 Set u p a rea l istic t i m e l i n e for stu dy. Cover less cra m m a bl e su bjects fi rst. Review su bject-by-su bject emphasis a n d c l i n ical vignette format. 0 S i m u l ate the U SM L E Step 1 to p i n point strengths and wea knesses i n knowl edge and test-ta ki n g ski l ls. 0 Eva l u ate and choose study m ethods and materials (e.g., review books, p ractice tests, softwa re) . Weeks Prior 0 S i m u l ate the U S M LE Step 1 a ga i n . Assess how close you a re to you r goa l . 0 P i n p o i n t rema i n i ng wea knesses. Stay hea lthy (exercise, sleep) . 0 Verify i nformation o n a d m issio n ticket (e.g., l ocation, date) . One Week Prior 0 Remember comfo rt measu res (loose cloth ing, earpl ugs, etc.) . 0 Wo rk out test site logistics such as l ocation, tra n sportation, pa rki ng, a n d l u nch. 0 Ca l l Pro m etric a n d confirm yo u r exa m a ppoi ntment. One Day Prior 0 Relax. 0 Lightly revi ew short-term m ateri a l if n ecessa ry. Skim h i gh-yi eld facts. 0 Get a good n ight's sleep. 0 M a ke s u re the name pri nted o n you r photo ID appears EXACTLY the sa m e as the name p ri nted on you r sched u l i n g perm it. Day of Exam 0 Relax. Eat b rea kfast. M i n i m ize bath room b rea ks d u ri n g the exa m by avo i d i n g excessive m o r n i n g caffei n e. 0 Ana lyze a n d m a ke adjustm ents i n test-ta king tech nique. You a re a l l owed to review n otes/study m ateri a l d u ri n g b rea ks o n exa m day. After the Exam D Celebrate, rega rd l ess. D Send feed back to us on o u r Web site at www.firstaidteam.com. S E C T I O N I G u ide to Efficient Exam Prepa ration 􀀧 􀀧 􀀧 􀀧 􀀧 􀀧 􀂓 􀂓 􀀧 􀀧 􀀧 I ntro d u ction U S M LE Ste p 1 -Th e Basics D efi n i ng You r Goal Ti m e l i n e for Stud y Study Materi a l s Test-Ta k i n g Strategies C l i n i ca l Vignette Strategies If You Th i n k You Fa i l e d If You Fa i l ed Testing Agencies References 1 2 2 1 2 1 2 1 7 1 9 2 1 22 22 23 23 2 S E C T I O N I G U I D E T O E F F I C I E N T E X A M P R E PA R AT I O N 􀀒 The test at a glance: 8-hour exam Total of 322 multiple choice items 7 test blocks (60 min/block) 46 test items per block 45 minutes of break time, plus another 15 if you skip the tutorial 􀀆 I N T R O D U C T I O N Relax. Th is section is intended to make your exam preparation easier, not harder. Our goal is to reduce your level of anxiety and help you make the m ost of your efforts by helping you understand more about the United States Medical Licensing Examination, Step 1 ( USMLE Step 1 ). As a medical student, you are no doubt familiar with taking standardized examinations and qui ckly absorbing large amounts of material . When you first confront the U SMLE Step 1 , however, you may find it all too easy to become sidetracked from your goal of studying with maximal effectiveness. Common mistakes that students make when studying for Step 1 include the following: • Not understanding how scoring is performed or what the score means • Starting to study ( including First Aid) too late • Starting to study intensely too early and burning out • Using inefficient or inappropriate study methods • Buying the wrong books or buying more books than you can ever use • Buying only one publ isher's review series for all subj ects • ot using practice examinations to maximum benefit • Not using review books along with your classes • Not analyzing and improving your test-taking strategies • Getting bogged down by reviewing difficult topics excessively • Studying material that is rarely tested on the U SMLE Step 1 • Failing to master certain high-yield subj ects owing to overconfidence • Using First Aid as your sole study resource • Trying to do it all alone In th is section, we offer advice to help you avoid these pitfalls and be more productive in your studies. 􀀆 U S M L E S T E P 1 - T H E B A S I C S The U SMLE Step 1 i s the first o f three examinations that you must pass in order to become a l i c e nsed physician i n the U nited States. The U SMLE is a j oint endeavor of the ational Board of Medical Examiners ( N B M E ) and the Federation o f State Medical Boards ( F S M B ) . The U SM LE serves as the single examination system for U . S . medical students and international medical graduates (IMGs) seeking medical licensure in the United States. The Step 1 exam includes test items drawn from the following content areas: • Anatomy • Behavioral sciences • B iochemistry • M icrobiology and immunology • Pathology G U I D E TO E F F I C I E N T E X A M P R E PA R AT I O N S E C T I O N I 3 Pharmacology Physiology Interdisciplinary topics such as nutrition, genetics, and aging How Is the Computer-Based Test (CBT) Strudured? The C BT Step 1 exam consists of one "optional" tutorial/simulation block and seven "real" question blocks of 46 questions each (see Figure 1 ) for a total of 3 2 2 questions, timed at 60 minutes per block. A short 1 1 -question survey follows the last question block. The computer begins the survey with a prompt to proceed to the next block of questions . Once an examinee finishes a particular question block on the CBT, he or she must click on a screen icon to continue to the next block. Examinees cannot go back and change their answers to questions from any previously completed block. However, changi ng ans wers is allowed within a block of questions as long as time permits - unless the questions are part of a sequential item test set (see p. 4) . What Is the CBT Like? Given the unique environment of the C BT, it's important that you become familiar ahead of time with what your test-day conditions will be l ike. In fact, you can easily add 1 5 minutes to your break time ! This is because the I S-minute tutorial offered on exam day may be skipped if you are al ready familiar with the exam procedures and the testing interface. The 1 5 minutes is then added to your allotted break time of 45 minutes for a total of 1 hour of potential break time. You can download the tutorial from the U SMLE Web site and do it before test day. This tutorial is the exact same interface you will use in the exam; learn it now and you can skip taking it duri ng the exam, giving you 1 5 extra minutes of break time. You can also gain experience with the CBT format by taking the 1 5 0 practice questions available online or by F I G U R E 1 . Schematic of CBT Exam. AM 􀀒 If you know the format you can skip the tutorial and add 15 minutes to your break time! Exam Survey 4 S E CT I O N I G U I D E T O E F F I C I E N T E X A M P R E PA R AT I O N 􀀒 Keyboard shortcuts: A, 8, etc. -letter choices Enter or spacebar-move to next question Esc-exit pop-up Lab and Exhibit windows Alt-T-countdown timers for current session and overall test 􀀒 Heart sounds are tested via media questions. Make sure you know how different heart diseases sound on auscultation. 􀀒 Test illustrations include: Gross photos Histology slides Radiographs Electron micrographs Line drawings signing up for a practice session at a test center (for details, see What Does the C BT Format Mean to Me? ) . For secur i ty reasons, exa m i n e es are not a l l owed t o b r i ng any p e rsonal electronic equ ipment into the testing area. Th is includes both digital and analog watches, cellular telephones, and electronic pagi ng devices. Food and beverages are also prohibited. The testing centers are monitored by audio and video surveillance equipment. H owever, most testing centers allot each examinee a small locker outside the testing area i n which he or she can store snacks, beverages, and personal items. The typical question screen i n the C BT consists of a question followed by a number of choices on which an examinee can click, together with several navigational buttons on the top of the screen . There is a countdown timer on the upper left-hand corner of the screen as well . There is also a button that allows the examinee to mark a question for review. If a given question happens to be longer than the screen (which occurs very rarely) , a scroll bar will appear on the right, allowing the examinee to see the rest of the question. Regardless of whether the examinee clicks on an answer choice or leaves it blank, he or she must click the "Next" button to advance to the next question. The U SMLE features a small number of media clips i n the form of audio and/or video. There may even be a question with a multimedia heart sound simulation. In these questions, a digital image of a torso appears on the screen, and the examinee directs a digital stethoscope to various auscultation points to l isten for heart and breath sounds. No more than five media questions will be found on any given examination, and the U S MLE orie ntation materials now include several practice questions in these new formats. During the exam tutorial, examinees are give n an opportunity to ensure that both the audio headphones and the volume are functioning properly. If you are already familiar with the tutorial and planning on skippi ng it, first skip ahead to the section where you can test your headphones. After you are sure the headphones are working properly, proceed to the exam. Recently the U S MLE introduced a sequential item test format for some questions. Sequential item questi ons a re grouped togeth e r i n the l ist of questions on the left-hand side of the screen. Questions i n a sequential item set must be completed in order. After an examinee answers the first question, he or she will be given the option to proceed to the next item but will be warned that the answer to the first question will be locked. After proceeding, examinees will not be able to change the answer selected for that question . The question stem and the answer chosen will be available to the examinee as he or she answers the next question(s) i n the sequence. No more than five sets of sequential item questions will be found in any given examination. Some Step l questions may also conta i n figures or illustrations. These are typ i cally situated to the right of the question . Although the contrast and brightness of the screen can be adjusted, there are no other ways to manipulate the picture (e.g., there is no zooming or panning) . GUIDE TO EFFICIENT EXAM PREPARATION S E C T I O N I 5 The examinee can call up a window displayi ng normal laboratory values. In order to do so, he or she must c l i ck the "Lab" icon on the top part of the screen. Afterward, the examinee will have the option to choose between "Blood," "Cerebrospinal," "Hematologic," or "Sweat and Urine." The normalvalues screen may obscure the question if it is expanded. The examinee may have to scroll down to search for the needed lab values. You might want to memorize some common lab values so you spend less time on questions that require you to analyze these. The CBT interface provides a running l ist of questions on the left part of the screen at all times. The software also permits examinees to highlight or cross out information by using their mouse. Finally, there is an "Annotate" icon on the top part of the screen that allows students to write notes to themselves for review at a later time. Being famil iar with these features can save time and may help you better organize the information you need to answer a question. What Does the CBT Format Mean t o Me? The significance of the C BT to you depends on the requirements of your school and your l evel of computer knowledge . If you are a Mac user, you might want to spend some time using a Windows-based system and pointing and clicking icons or buttons with a mouse . For those who feel they might benefit, the U SMLE offers an opportu nity to take a simulated test, or " C BT Practice Session at a Prometric center." Students are e l igible to register for th is three-and-one-half-hour practice session after they have received their schedul ing permit. The same U SMLE Step 1 sample test items ( 1 5 0 questions) available on the U S MLE Web site, www. usml e . org, are used at these sessions. No new items will be presented. The session is divided into three one-hour blocks of 50 test items each and costs about $42 . Students receive a printed percentcorrect score after completing the session . No explanations of questions are provided. You may register for a practice session online at www. usmle .org. A separate scheduling permit is issued for the practice session. Students should allow two weeks for receipt of this permit. How Do I Register to Take the Exam? Prometric test centers offer Step 1 on a year-round basis, except for the fi rst two weeks in January and major holidays . The exam is given every clay except Sunday at most c enters . Some schools administer the exam on their own campuses . Check with the test center you want to use before making your exam plans. U.S. students can apply to take Step 1 at the NBME Web site. This application allows you to select one of 1 2 overlapping three-month blocks in which to be 􀀒 Familiarize yourself with the commonly tested lab values. 􀀠 Ctri-Ait-Delete are the keys of death during the exam. Don't touch them! 􀀒 You can take a shortened CBT practice test at a Prometric center. 6 S E CT I O N I G U I D E T O E F F I C I E N T E X A M P R E PA R AT I O N 􀀣 The Prometric Web site will display a calendar with open test dates. 􀀒 The confirmation emails that Prom .tric and NBME send are not the same as the scheduling permit. 􀀒 Te5t scheduling is done on a "first-come, first-served" basis. It's important to col/ and schedule an exam date as soon as you receive your scheduling p rmit. tested ( e .g. , April-May-June, June-July-August) . C hoose your three-month el igibil ity period wisely. If you need to reschedule outside your i nitial threemonth period, you can request a one-time extension of eligibil ity for the next contiguous three-month period, and pay a rescheduling fee . The appl ication also includes a photo I D form that must be certified by an official at your medical school to verify your enr o l l ment. After the N B M E processes your application, it will send you a schedul ing permit. The scheduling permit you receive fro m the N B M E w i l l c o n t a i n your U S MLE identification number, the el igibil ity period in which you may take the exam , and two additional numbers. The fi rst of these is known as your "scheduling number." You must have this number in order to make your exam appointment with Prometric . The second number is known as the "candidate identification number," or C I N . Examinees must enter their C I N s at the Prometric workstation in order to access their exams. Prometric has no access to the codes. Do n ot lose your permit! You will not be allowed to take the exam unless you present this permit along with an unexpired , governmentissued photo ID that includes your signature (such as a driver's l icense or passport) . Make sure the name on your photo I D exactly matches the name that appears on your scheduling permit. Once you receive your schedul ing permit, you may access the Prometric Web site or call Prometric's toll-free number to arrange a time to take the exam. You may contact Prometric two weeks before the test elate if you want to confirm identification requirements. Although requests for taking the exam may be completed more than six months before the test elate, examinees will not receive their scheduling permits earlier than six months before the el igibility period. The eligibil ity period is the three-month period you have chosen to take the exam. Most medical students choose the April-June or June-August period. Because exams are scheduled on a "first-come, first-served" basis, it is recommended that you contact Prometric as soon as you receive your permit. After you 've scheduled your exa m , it's a good idea to confirm your exam appointment with Prometric at least one week before your test elate. Prometric does not provide written confirmation of exam elate, time, or location. Be sure to read the 2013 USMLE B u lletin o{ Infonnation for further details. What If I Need to Reschedule the Exam? You can change your test elate and/or c enter by contacting Prometric at 1 -800-MED-EXAM ( l -800-6 3 3-3926) or www.prometric. com . Make sure to have your CIN when rescheduling. If you are reschedul ing by phone, you must speak with a Prometric representative; leaving a voice-mail message will not suffice. To avoid a rescheduling fee , you will need to request a change at l east 3 1 calendar days before you r appoi ntment. Please note that your rescheduled test elate must fall with i n your assigned three-month el igibil ity period. GUIDE TO EFFICIENT EXAM PREPARATION S E CTI O N I 7 When Should I Register for the Exam? Although there are no deadlines for registering for Step 1 , you should plan to register at least six months ahead of your desired test elate . This will guarantee that you will get either your test center of choice or one with i n a 5 0-mile radius of your first choice. For most U. S . medical students, the desired testing window is in June, since most medical school curricula for the second year end in May or June. Thus, U . S . medical students should plan to register before January in anticipation of a June test elate . The timing of the exam is more flexible for IMGs, as it is related only to when they finish exam preparation. Talk with upperclassmen who have al ready taken the test so you have reallife experience from students who went through a similar curriculum, then formulate your own strategy. Where Can I Take the Exam? Your testing l ocation is arranged with Prometric when you call for your test elate (after you receive your scheduling permit) . For a l ist of Prometric locations nearest you, visit www. prometric.com. How Long Will I Have to Wait Before I Get My Scores? The U SMLE reports scores three to four weeks, unless there are delays i n score processing. Examinees w i l l be notified v i a email when their scores are available. By following the online instructions, examinees will be able to view, clownloacl, and print their score report. Additional information about score timetables and accessibility is available on the official USMLE Web site . What About Time? Time is of special interest on the CBT exam. Here's a breakdown of the exam schedule: 1 5 minutes 7 hours 45 minutes Tutorial (skip if familiar with test format and features) Seven 60-minute question blocks B reak time ( i ncludes time for lunch) The computer will keep track of how much time has elapsed on the exam. However, the c o m p u te r w i l l show you only how mu c h time you have remaining i n a given block. Therefore, it is up to you to determine if you are pacing yourself properly (at a rate of approximately one question per 77 seconds) . The computer will not warn you if you are spending more than your allotted time for a break. You should therefore budget your time so that you can take a short break when you need one and have time to eat. You must be especially careful not to spend too much time in between blocks (you should keep track of how much time elapses from the time you finish a block of questions to the time you start the next block). After you finish one question block, you'll need 􀀒 Register six months in advance for seating and scheduling preference. 􀀒 Gain extra break time by skipping the tutorial or finishing a block early. 8 SECT I O N I G U I D E T O E F F I C I E N T E X A M P R E PA R AT I O N 􀀣 Be careful to watch the clock on your break time. 􀀣 Nearly three-fourths of Step 1 questions begin with a description of a patient. to click on a button to proceed to the next block of questions. If you do not click to proceed to the next question block, you will automatically be entered into a break period . Forty-five minutes is the minimum break time for the clay, but you are not requ ired to use all of it, nor are you required to use any of it. You can gain extra break time (but not time for the question blocks) by skippi ng the tutorial or by finishing a block ahead of the allotted time. Any time remaining on the clock when you finish a block gets added to your remaining break time . Once a new question block has been started, you may not take a break until you have reached the end of that block. If you do so, this will be recorded as an "unauthorized break" and will be reported on your final score report. Finally, be aware that it may take a few minutes of your break time to "check out" of the secure resting room and then "check in" again to resume testing, so plan accordingly. The "check-i n " process may include fi ngerprints and pocket checks. Some students recommend pocketless cloth i ng on exam clay to streamline the process. If I Freak Out and Leave, What Happens to My Score? Your scheduling permit shows a CIN that you will enter onto your computer screen to start your exam. Entering the CIN is the same as breaking the seal on a test book, and you are considered to have started the exam when you do so. However, no score will be reported if you do not complete the exam. In fact, if you leave at any time from the start of the test to the last block, no score will be reported . The fact that you started but did not complete the exam, however, will appear on your U SMLE score transcript. Even though a score is not posted for incomplete tests, examinees can still request that their scores be calculated and reported if they desire; unanswered questions will be scored as incorrect. The exam ends when all question blocks have been completed or when their time has expired. As you leave the testing center, you will receive a printed test-completion notice to document your completion of the exam. To receive an official score, you must finish the entire exam. What Types o f Questions Are Asked? One-best-answer multiple-choice items (either singly or as part of a sequential item set) are the only question type on the exam. Most questions consist of a clinical scenario or a direct question followed by a l ist of five or more options. You are required to select the s i ngle best answer among the options given. There are no "except," "not," or matching questions on the exam. A number of options may be partially correct, i n which case you must select the option that best answers the question or completes the statement. Additionally, keep in mind that experimental questions may appear on the exam, which do not affect your score (see Difficult Questions, p. 2 0 ) . GUIDE TO EFFICIENT EXAM PREPARATION S E C T I O N I 9 How Is the Test Scored? Each Step 1 examinee receives an electronic score report that includes the examinee's pass/fail status, two test scores, and a graphic depiction of the examinee's performance by discipl i n e and organ system or s u b j e c t area. The actual organ system profi l e s reported may depend on the statistical characteristics of a given administration of the examination . The N B M E provides two overall test scores based on the total number of items answered correctly on the examination (see Figure 2). The first score, the three-digit score, is reported as a scaled score in which the mean is 2 2 5 and the standard deviation i s approximately 2 1 . This i s the only score that gets reported to residency program directors. The second score scale, the two-digit score, defines 75 as the minimum passing score (equivalent to a score of 1 88 on the first scal e ) . This score is only reported to state l icensing boards that may have statutory requ irements that the score scale have 75 as the minimum passing score . In 20 1 1 , the U SMLE stopped reporting the two-digit score to score users ( e . g . , residency programs) and now reports only the three-digit score . Throughout this book we refer to scores using the three-digit scale only. A score of 1 88 or higher is required to pass Step 1 . The NBME does not report the minimum number of correct responses needed to pass, but estimates that it is roughly 60-70%. The NBME may adj ust the minimum passing score in the future, so please check the U SMLE Web site or www. firstaidteam . com for updates. According to the U S M L E , medical schools receive a l isting of total scores and pass/fail results plus group summaries by discipl ine and organ syste m . Students c a n withhold their scores from their medical school if they wish . Official U S MLE transcripts , which can be sent on request to res idency programs, include only total scores, not performance profiles. Consult the USMLE Web site or your medical school for the most current and accurate information regarding the examination. F I G U R E 2 . 201 1 Scoring Sca les for t h e USMLE Step 1 . 3-digit score 160 170 180 188 190 200 210 220 230 240 250 260 (-2 SD) (-1 SD) (x) (+ 1 SD) (+2 SD) 􀀠 The mean Step 1 score for U. S. medical students continues to rise, from 200 in 1991 to 225 in 201 1. 1 0 SECTION I G U I D E T O E F F I C I E N T E X A M P R E PA R AT I O N TA B L E I . Passing Rates for the 201 0-201 1 USMLE Step 1 . Allopathic l st takers Repeaters Allopath ic total Osteopathic 1 st takers Repeaters Osteopathic total Total U.S./Canadian IMG 1 st takers Repeaters IMG total Total Step 1 examinees 􀀒 Practice questions may be easier than the actual exam. 201 0 201 1 No. Tested % Passing No. Tested % Passing 1 8, 1 1 6 92% 1 8, 3 1 2 94% 1 ,726 6 1 % 1 ,498 70% 1 9, 842 90% 1 9, 8 1 0 9 3 % 1 ,964 8 2 % 2 , 1 4 5 89% 75 4 1 % 66 6 5 % 2 , 0 3 9 8 0 % 2 ,2 1 1 8 8 % 2 1 ,881 89% 22,02 1 92% 1 4, 2 0 3 7 0 % 1 4, 8 5 5 7 3 % 4,6 5 6 3 3 % 4,62 1 3 6 % 1 8, 8 5 9 6 1 % 1 9,476 64% 40,740 76% 41,497 79% What Does My Score Mean? The most important point with the Step 1 score is passing versus fai l i ng. Passing essentially means, " H ey, you 're on your way to becoming a fully licensed doc." As Table 1 shows, the maj ority of students pass the exam, so remember, we told you to relax. Beyond that, the main point of having a quantitative score is to give you a sense of how well you've clone on the exam and to help schools and residencies rank their students and applicants, respectively. Official N B M E/USMLE Resources We strongly encourage students to use the materials provided by the testing agencies (see p. 2 3 ) and to study in detail the following B M E resour ces, all of wh ich are available at the U SMLE Web site, www. usmle .org: • USMLE Step 1 Compu ter-based Content and Sample Test Questions (free to all examinees) • 2013 USMLE Bu lletin of lnforma tion (free to all examinees) • Comprehensive Basic Science Self-Assessment The USMLE Step 1 Compu ter-based Conten t a n d Sample Test Questions contains approximately 1 5 0 questions that are similar in format and content to the questions on the actual U SMLE Step 1 exam. This practice test offers one of the best means of assessing your test-taking skills. However, it does not contain enough questions to simulate the full length of the examination, and its content represents a l imited sampl ing of the basic science material that may be covered on Step l . Moreover, most students felt that the questions on the actual 20 1 2 exam were more challenging than those contained in that GUIDE TO EFFICIENT EXAM PREPARATION S E CTI O N I 1 1 year's sample questions. Interestingly, some stu dents reported that they had encountered a few near-duplicates of these sample questions on the actual Step l exam. Presumably, these are "experimental" questions, but who knows? So the bottom line is, know these questions! T A B L E 2 . CBSSA to U S M L E Score The extremely detailed Step 1 Content Outline provided by the U SMLE has not proved useful for students studying for the exam. The USMLE even states that " . . . the content outl ine is not intended as a curriculum development or study guide." 1 We concur with this assessment. The 2 0 1 3 USMLE B u lletin of Info rm a tion contains detailed procedur al and policy information regarding the C B T, including descripti ons of all three Steps, scoring of the exams, reporting of scores to medical schools and residency programs, procedures for score rechecks and other inquiries, policies for irregular behavior, and test dates. The NBME also offers the C omprehensive Basic Science Self-Assessment (CBSSA) , wh ich tests users on topics covered during basic science courses in a format similar to that of the U SMLE Step l examination. Students who prepared for the examination using th is Web-based tool reported that they found the format and content h ighly i ndicative of questions tested on the Step l examination. I n addition, the C B S SA is a fair predictor of U S M LE performance (see Table 2 ) . The C B S SA exists i n two forms: a sta ndard-paced a n d a self-paced format, both of which consist of four sections of 50 questions each (for a total of 200 multiple-choice items) . The standard-paced format allows the user up to one hour to complete each section, reflecting the time limits of the actual exam. By contrast, the self-paced format places a four-hour time limit on answering the multiple-choice questions. Keep i n mind that this bank of questions is available only on the Web . The N B M E requires that users log on, register, and start the test with i n 30 clays of registra tion. Once the assessment has begun, users are required to complete the sections within 20 clays. Following completion of the questions, the C B S SA will provide a performance profile indicating each user's relative strengths and weaknesses, much l ike the report profile for the U SMLE Step l exam. It is scaled with an average score of 5 0 0 a n d a standard deviation of l 0 0 . Please note that C B S SAs do n o t provide correct answers to the questions at the end of the session. However, some forms can be purchased with an extended feedba ck option; these tests show you which questions you answered incorrectly, but do not show you the correct answer or explain why your choice was wrong. Feedback from the selfassessment takes the form of a performance profile and nothing more. The NBME charges $ 5 0 for assessments without feedback and $60 for assessments with feedback. The fees are payable by credit card or money order. For more information regarding the C B S SA, please visit the NBME's Web site at www. nbme.org and click on the link labeled "NBME Self-Assessment Services." CBS SA Score 2 0 0 2 5 0 3 0 0 3 5 0 4 0 0 4 5 0 5 0 0 5 5 0 600 6 5 0 700 7 5 0 8 0 0 Prediction. Approximate USMLE Step 1 Score 1 5 1 1 6 3 1 7 5 1 86 1 9 8 2 1 0 2 2 1 2 3 3 245 2 5 7 268 2 8 0 292 1 2 S E CTI O N I G U I D E T O E F F I C I E N T E X A M P R E PA R AT I O N 􀀣 Fourth-year medical students have the best feel for how Step 1 scores fa ctor into the residency application process. 􀀣 Some competitive residency programs place more weight on Step 1 scores in their selection process. 􀀆 D E F I N I N G Y O U R G O A L I t i s useful to define your own personal performance goal when approaching the U SMLE Step l . You r styl e and i n tensity of preparati on can then be matched to your goal . Furthermore, your goal may depend on your school's requ irements, your specialty choice, your grades to date , and your personal assessment of the test's importance. Do your best to define your goals early so that you can prepare accordingly. C e rtain h ighly competitive residency programs, such as those in plastic surgery and orthopedic surgery, have acknowledged their use of Step 1 scores in the selection process. In such residency programs, greater emphasis may be placed on attaining a high score, so students who seek to enter these programs may wish to cons ider aiming for a very h igh score on the Step 1 exam (see Figure 3 ) . At the same time, your Step 1 score is only one of a number of factors that are assessed when you apply for residency. In fact, many residency programs value other criteria such as letters of recommendation, thi rd-year clerkship grades, honors, and research experience more than a h igh score on Step l . Fourth-year medical students who have recently completed the residency application process can be a valuable resource in this regard . 􀀆 T I M E L I N E F O R S T U D Y Before Starting Your preparation for the USMLE Step 1 starts with entering medical school . Organize your studying so that wh e n the time comes to prepare for the U SMLE , you will be ready with a strong background . F 1 G u R E l . Median USMLE Step 1 Score by Specia lty for Matched U.S. Seniors. a 260 250 240 230 220 210 200 190 T T 2h 214 I 1 T 214 􀀄 T 2!0 - 211 T I .L .J.. a Vertical lines show 1nterquartile range Source: wwwnrmp.org T I I 2􀀉3 225 2 T6 I 1 I 􀆱 ...:c. ..I. T - 210 - 210 - 210 - 213 2l4 249 T .L T T I 2􀀈0 1 I 1 1 l. 2T6 2T6 2f I 1 .L 􀀅 .L GUIDE TO EFFIC IENT EXAM PREPARATION S E C T I O N I 1 3 Make a Schedule After you have defined your goals, map out a study schedule that is consistent with your obj ectives, your vacation t i m e , the difficulty of your ongoi ng cour sework, a n d your fa m i l y a n d social c o m m i tme nts ( s e e F igu r e 4 ) . Determine whether you want to spread out your study time o r concentrate it into 1 4-hour study days i n the final weeks . Then factor in your own h istory in preparing for standardized examinations ( e .g. , SAT, MCAT) . Talk to students at your school who have recently taken Step 1 . Ask them for their study schedules, especially those who have study habits and goals similar to yours. Typ ical ly, U . S . medical students allot betwee n five and seven weeks for dedicated preparation for Step 1 . The time you dedicate to exam preparation will depend on your target score as well as your success in preparing yourself dur i n g the first two years of medical school. Some students reserve about a week at the end of their study period for final review; others save j ust a few days. When you have scheduled your exam date, do your best to adhere to it. Studies show that a later testing elate does not translate into a higher score, so avoid pushing back your test date without good reason . 2 Another important consideration is when you will study each subj ect. Some subjects lend themselves to cramming, whereas others demand a substantial long-term commitment. The "crammable" subj ects for Step 1 are those for which concise yet relatively complete review books are available. ( See Section F I G U R E 4 . Typical Timeline for the USMLE Step 1 . 201 2 Nov Dec 201 3 Jan Feb Mar Apr May J u n e July Aug Sept ----1f------- Schedule test date and location f------- Expect scores 4-6 weeks after exam 􀀣 Customize your schedule. Tackle your weakest section first. 1 4 S E CT I O N I G U I D E T O E F F I C I E N T E X A M P R E PA R AT I O N 􀀠 "Crammable" subjects should be covered later and Jess crammable subjects earlier. 􀀠 Avoid burnout. Maintain proper diet exercise, and sleep habits. IV for h ighly rated review and sample examination materials . ) Behavioral science and physiology are two subj ects with concise review books . Three subj ects with longer but qu ite comprehensive review books are microbiology, pharmacology, and biochemistry. Thus, these s u b j e c ts could be covered toward the end of your schedule, whereas oth e r s u b j e c ts ( a natomy and pathology) requ ire a longer time commitment and could be studied earl ier. Many students prefer using a "syste ms-based" approach ( e . g. , G I , renal , cardiovascular) to integrate the material across basic science subj ects. See Section III to study anatomy, pathology, physiology, and pharmacology facts by organ system. Each subject may make up a different percentage of the test. For example, although anatomy may requ i re a longer time commitment to review, you may encounter fewer anatomy questions on the test than questions on pharmacology. You can find more details of the breakdown of the test at the NBME's Web site. Make your schedule real istic, and set achievable goals. Many students make the mistake of studying at a level of detail that requires too much time for a comprehensive review - reading Gray 's Ana tomy i n a couple of clays is not a real istic goal ! Have at least two catch-up clays i n your schedu l e . No matter how well you stick to your schedule, unexpected events happen . But don't let yourself procrastinate because you have catch-up clays; stick to your schedule as closely as possible and revise it regularly on the basis of your actual progress. Be careful not to lose focus. Beware of feelings of inadequacy when comparing study schedules and progress with your peers. Avoid others who stress you out. Focus on a few top-rated resources that suit you r learning style - not on some obscure books your friends may pass clown to you . Accept the fact that you cannot learn it all . You will need time for uninterrupted and focused study. Plan your personal affairs to minimize crisis situations near the elate of the test. Allot an adequate number of breaks in your study schedule to avoid burnout. Maintain a healthy lifestyle with proper diet, exercise, and sleep. Another important aspect of your preparation is your studying environment. Study where you have always been comfortable studying. Be sure to include everyth ing you need close by ( review books, notes, coffee, snacks, etc . ) . If you're the kind of person who cannot study alone, form a study group with other students taking the exam. The main point here is to create a comfortable environment with minimal distractions. Year(s) Prior Although you may be tempted to rely solely on cramming in the weeks and months before the test, you should not have to do so. The knowledge you gained dur i ng your first two years of medical school and even dur i ng your undergraduate years should provide the groundwork on which to base your test preparation. Student scores on NBME subj ect tests (commonly known as "shelf exams") have been shown to be h ighly correlated with subsequent Step GUIDE TO EFFICIENT EXAM PREPARATION S E C T I O N I 1 5 1 scores. 3 Moreover, undergraduate science GPAs as well as MCAT scores are strong predictors of performance on the Step 1 exam.4 We also recommend that you buy h i ghly rated review books early in your first year of medical school and use them as you study throughout the h¥o years. When Step 1 comes along, these books will be familiar and personalized to the way in which you learn . It is risky and intimidating to use unfamiliar review books in the final wo or three weeks preceding the exam. Some students find it helpful to personalize and annotate First A i d throughout the curriculum. Months Prior Review test elates and the appl ication procedur e . Testing for the U S M L E Step 1 is clone on a year-round basis. If you h ave a n y disabil ities or "special circumsta n c es," contact th e N B M E as early as possible to discuss test accommodations (see p . 43, First Aiel for the Student with a Disabil ity) . Before you begin to study earn estly, simulate the US MLE Step 1 under " real " conditions to pinpoint strengths and weaknesses in your knowledge , test endur a n c e , and test-taking ski l l s . B e sure th at you are well informed about the examination and that you have planned your strategy for studying. Consider what study methods you will use, the study materials you will need, and how you will obtai n your material s . Plan ahead . Do a lot of practic e questions. Get advice from third- a n d fou rth-year medical students who have recently taken the U SMLE Step 1 . There might be strengths and weaknesses in your school's curriculum that you should take into account in deciding where to focus your efforts. You might also choose to share books, notes, and study hints with classmates. That is how th is book began. Three Weeks Prior Two to four weeks before the examination is a good time to resimulate the USMLE Step 1 . You may want to do th is earl ier d epending on the progress of your review, but be sure not to do it later, when there will be little time to remedy gaps in your knowledge or test-taking ski l l s . Make use of any remaining good-quality sample U SMLE test questions, and try to simu late the computerized test conditions so that you can adequately assess your test performance. One way to simulate a full-length exam is doing a ful l , timed NBME C B S SA fol l owed by three 46-question blocks from your question bank or the free 1 5 0 questions from the U S M LE Web site. Recognize, too, that time pressure is increasing as more and m ore questions are framed as clinical vignettes. Most sample exam questions are shorter than the real th ing. Focus on reviewing the high-yield facts, your own notes, clinical images, and very short review books. Do not fall into the trap of reviewing your strengths repeatedly; spend time on your weaknesses. 􀀒 Buy review books early (first year) and use while studying for courses. 􀀒 Simulate the USMLE Step 1 under "real" conditions before beginning your studies. 􀀒 In the final two weeks, focus on review, practice questions, and endurance. Stay confident! 1 6 S E CT I O N I G U I D E TO E F F I C I E N T E X A M P R E PA R AT I O N 􀀣 One week before the test: Sleep according to the same schedule you'll use on test day • Review the CBT tutorial one last time • Call Prometric to confirm test date and time 􀀣 No notes, books, calculators, pagers, cell phones, recording devices, or watches of any kind are allowed in the testing area, but they are allowed in lockers. One Week Prior Make sure you have your C I N (found on your scheduling permit) as well as other items necessary for the day of the examination, includi ng a current driver's l icense or another form of photo ID with your signature ( make sure the name on your I D exactly matches that on your schedul i ng permit) . Confirm the Prometric testing center location and test time. Work out how you will get to the testing center and what parking and traffic problems you might encounter. If possible, visit the testing site to get a better idea of the testing conditions you will face. Determine what you will do for lunch. Make sure you have everything you need to ensure that you will be comfortable and alert at the test site. It may be beneficial to adj ust your schedule to start waking up at the same time that you will on your test day. And of course, make sure to maintain a healthy lifestyle and get enough sleep. One Day Prior Try your best to relax and rest the night before the test. Double-check your admissions and test-taking materials as well as the comfort measures discussed earl ier so that you will not have to deal with such details on the morning of the exam. At this point it will be more effective to review short-term memory material that you're already familiar with than to try to learn new material . The Rapid Review section at the end of this book is h igh yield for last-minute studying. Remember that regardless of how hard you have studied, you cannot know everything. There will be things on the exam that you have never even seen before, so do not panic. Do not underestimate your abilities. Many students report difficulty sleeping the night prior to the exam. This is often exacerbated by going to bed much earlier than usual . Do whatever it takes to ensure a good night's sleep ( e . g . , massage , exercise, warm milk, no back-lit screens at night) . Do not change your daily routine prior to the exam. Exam clay is not the clay for a caffeine-withdrawal headache. Morning o f the Exam On the morning of the Step 1 exa m , wake up at your regular time and eat a normal breakfast. If you think it will help you , have a close friend or family member check to make sure you get out of bed. Make sure you have your scheduling permit admission ticket, test-taking materials, and comfort measures as discussed earl ier. Wear loose, comfortable cloth ing. Plan for a variable temperature in the testing center. Arrive at the test site 3 0 minutes before the time designated on the admission ticket; however, do not come too early, as doing so may i ntensify your anxiety. Whe n you arrive at the test site, the proctor should give you a U SMLE information sheet that will explain critical factors such as the proper use of break tim e . The U SM LE uses the B iometric Identity Management System ( B I M S ) at some test cente r locations. BIMS converts a fingerprint, taken on test clay, to a digital image used for identification of examinees during the testing process. Seating may be assigned, but ask to be reseatecl if necessary; you need to be seated in an area G U I D E TO E F F I C I E N T E X A M P R E PA R AT I O N S E CT I O N I 1 7 that will allow you to remain comfortable and to concentrate. Get to know your testing station, especially if you have never been in a Prometric testing center before. Listen to your proctors regarding any changes in instructions or testing procedures that may apply to your test site. Finally, remember that it is natural (and even beneficial) to be a little nervous. Focus on being mentally clear and alert. Avoid panic. Avoid panic. Avoi d panic. When you are asked t o begin the exam, take a deep breath, focus o n the screen, and then begi n . Keep an eye on the timer. Take advantage o f breaks between blocks t o stretch, maybe do some j umping jacks, a n d relax for a moment with deep breathing or stretching. After the Test After you have completed the exam, be sure to have fun and relax regardless of how you may feel. Taking the test is an achievement in itself. Remember, you are much more l ikely to have passed than not. Enjoy the free time you have before your clerkships. Expect to experience some "reentry" phenomena as you try to regain a real life . Once you have recovered sufficiently from the test (or from partyi ng) , we i nvite you to send us your feedback, corrections, and suggestions for entries, facts, mnemonics, strategies, resource ratings, and the like (see p. xvii , How to Contribute ) . Sharing your experience will benefit fellow medical students and IMGs. 􀆰 S T U D Y M AT E R I A L S Quality and Cost Considerations Although an ever-increasing number of review books and software are now available on the market, the quality of such material is h ighly variable. Some common problems are as follows : • Certain review books are too detailed to allow for review in a reasonable amount of time or cover subtopics that are not emphasized on the exam. • Many sample question books were originally written years ago and have not been adequately updated to reflect recent trends. • Many sample question books use poorly written questions or contain factual errors in their explanations. • Explanations for sample questions vary in qual ity. Basic Science Review Books In selecting review books, be sure to weigh different opinions against each other, read the reviews and ratings i n Section IV of th is guide, examine the books closely i n the bookstore, and choose carefully. You are i nvesting not only money but also your l i mited study time. Do not worry about finding the "perfect" book, as many sub j ects simply do not have one, and different 􀀒 Arrive a t the testing center 30 minutes before your scheduled exam time. If you arrive more than half an hour late, you will not be allowed to take the test. 􀀒 If a given review book is not working for you, stop using it no matter how highly rated it may be or how much it costs. 1 8 S E C T I O N I G U I D E T O E F F I C I E N T E X A M P R E PA R AT I O N 􀀒 Charts and diagrams may be the best approach for physiology and biochemistry, whereas tables and outlines may be preferable for microbiology. 􀀒 Most practice exams are shorter and less clinical than the real thing. 􀀒 Use practice tests to identify concepts and areas of weakness, not just fads that you missed. students prefer different formats. Supplement your chosen books with personal notes from other sources, including what you learn from question banks. There are two types of review books : those that are stand-alone titles and those that are part of a series. Books in a series generally have the same style, and you must decide if that style works for you. However, a given style is not optimal for every subj ect. You should also find out which books are up to date . Some recent editions reflect major improvements, whereas others contain only cursory changes. Take into consideration how a book reflects the format of the U SMLE Step 1 . Pradice Tests Taking practice tests provides valuable information about potential strengths and weaknesses in your fu nd of knowl e dge a n d test-taking skills. Some students use practice examinations s imply as a means of break i ng up the monotony of studying and adding variety to their study schedule, whereas other students rely almost solely on practice tests . Your best preview of the computerized exam can be found in the practice exams on the U SMLE Web site . Some students also recommend u s i ng computerized test s i mulation programs. In addition, students report that many current practice-exam books have questions that are, on average, shorter and less cl inically oriented than those on the current U SMLE Step l . After taking a practice test, try to identify concepts and areas of weakness, not j ust the facts that you missed. Do not panic if you miss a lot of questions on a practice examination; instead, use the experience you have gained to motivate your study and prioritize those areas in which you need the most work. Use quality practice examinations to improve your test-taki ng skills. Analyze your ability to pace yourself. Clinical Review Books Keep your eye out for more clinically oriented review books; purchase them early and begin to use them. A number of students are turning to Step 2 books, pathophysiology books, and case-based reviews to prepare for the cl i n ical vignettes. Examples of such books include: • First Aid Cases for the USMLE Step 1 ( McGraw-Hill) • First Aid for the Wards (McGraw-H ill) • First Aid Clerkship series (McGraw-H ill) • B lueprints clinical series ( Lippincott Williams & Wilkins) • PreTest Physica l Diagnosis ( McGraw-H ill) • Washington Manual ( Lippincott Williams & Wilkins) • Various USMLE Step 2 review books CiUIDE TO EFFICIENT EXAM PREPARATION S E CTI O N I 1 9 Texts, Syllabi, and Notes Limit your use of textbooks and course syl l a b i for Step 1 review. Many textbooks are too deta i l ed for h igh-yield review and include material that is generally not tested on the U S M LE Step 1 ( e .g. , dru g dosages, complex chemical structure s ) . Syllab i , a l th o ugh fam i l iar, are incons istent ac ross medical schools and frequently reflect the emphasis of individual faculty, which often does not correspond to that of the U SMLE Step 1 . Syllabi also tend to be l ess organized than top-rated books and generally contain fewer diagrams and study questions. • T E S T-TA K I N G S T R AT E G I E S Your test performance will be influenced by both your knowledge and your test-taking skills. You can strengthen your performance by considering each of these factors . Test-taking skil l s and strategies should be developed and perfected well i n advance of the test elate so that you can concentrate on the test itself. We suggest that you try the following strategies to see if they might work for you . Pacing You have seven hours to compl ete 3 2 2 questi ons. Note that each onehour block contains 46 questions. Th is works out to about 77 seconds per question. If you find yourself spending too much time on a question, mark the question, make an educated guess, and move on. If time permits, come back to the question later. In the past, pacing errors have been detrimental to the performance of even h ighly prepared examinees. The bottom line is to keep one eye on the clock at all times ! Dealing with Each Question Th ere a re several establ i s h e d te c h n i qu e s fo r effi c i e n tl y approa c h i n g multiple-choice questions; find what works for you . One technique begins with identifying each question as easy, workable, or impossible. You r goal should be to answer all easy questions, resolve all workable questions i n a reasonable amount of time, and make qu ick and intell igent guesses on all impossible questions. Most students read the stem, think of the answer, and turn immediately to the choices. A second technique is to first skim the answer choices and the last sentence of the question and then read through the passage quickly, extracting only relevant information to answer the question. Try a variety of techniques on practice exams and see what works best for you . 􀀠 Practice and perfect test-taking skills and strategies well before the test date. 􀀠 Time management is an important skill for exam success. 20 SECT I O N I GUIDE TO EFFICIENT EXAM PREPARATION 􀀦 Do not dwell excessively on questions that you are on the verge of "figuring out. " Make your best guess and move on. 􀀦 Remember that some questions may be experimental. 􀀦 Your first hunch is not always correct. 􀀦 Do not terminate a question block too early Carefully review your answers if possible. Difficult Questions Because of the exam's c l i nical emphasis, you may fi n d that many of the questions on the Step l exam appear workable but take more time than is available to you. It can be tempting to dwell on such questions because you feel you are on the verge of " figuring it out," but resist th is temptation and budget your time. Answer difficult questions with your best guess, mark them for review, and come back to them only if you have time after you have completed the rest of the questions in the block. This will keep you from i nadvertently leaving any questions blank i n your efforts to "beat the clock." Another reason for not dwell i ng too long on any one question is that certain questions may be experimental or may be incorrectly phrased. Moreover, not all questions are scored . Some questions serve as "embedded pretest items" that do not count toward your overall score . I n fact, anywhere from l 0% to 20% of exam questions have been designated as experimental on past exams. Guessing There is no penalty for wrong answers . Thus, no test block should be left with unanswered questions. A hunch is probably better than a random guess. If you have to guess, we suggest selecting an answer you recognize over one with which you are totally unfamiliar. Changing Your Answer The conventional wisdom is not to change answers that you have already marked unless there is a convincing and logical reason to do so - in other words, go with your "first hunch." H owever, studies show that if you change your answer, you are twice as l ikely to change it from an incorrect answer to a correct one than vice versa. So if you have a strong "second hunch," go for it! Fourth-Quarter Effed (Avoiding Burnout) Pacing and endurance are important. Practice helps d evelop both . Fewer and fewer examinees are leaving the examination session early. Use any extra time you might have at the end of each block to return to marked questions or to recheck your answers; you cannot add the extra time to any remaining blocks of questions. Do not be too casual in your review or you may overlook serious mistakes. Remember your goals, and keep in mind the effort you have devoted to studyi ng compared with the small additional effort you will need to maintain focus and concentration throughout the examination. Never give up. If you begin to feel frustrated, try taking a 3 0-second breather. GUIDE TO EFFIC IENT EXAM PREPARATION SECTI O N I 2 1 􀀤 C L I N I C A l V I G N E T T E S T R AT E G I E S I n recent yea rs , the U S MLE Step l has become i n c reasingly c l i nically oriente d . Th i s change m i rrors the tre n d i n medical education towa rd introducing students to c l i nical problem solving dur i ng the basi c science years. The increasing clinical emphasis on Step l may be challenging to those students who attend schools with a more traditional curriculum. What Is a Clinical Vignette? A clinical vignette is a short (usually paragraph-long) description of a patient, including demographics, presenting symptoms, signs, and other information concerning the patient. Sometimes th is paragraph is followed by a brief l isting of important physical findings and/or laboratory results. The task of assimilating all this information and answering the associated question in the span of one minute can be intimidating. So be prepared to read quickly and th ink on your feet. Remember that the question is often i ndirectly asking something you already know. Strategy Remember that Step l vignettes usually describe diseases or disorders in their most classic presentation. So look for buzzwords or cardinal signs (e.g. , malar rash for SLE or nuchal rigidity for meningitis) in the narrative h istory. Be aware, however, that the question may contain classic signs and symptoms instead of mere buzzwords. Sometimes the data from labs and the physical exam will help you confirm or rej ect possible diagnoses, thereby helping you rule answer choices in or out. In some cases, they will be a dead giveaway for the diagnosis. Making a diagnosis from the history and data is often not the final answer. Not infrequently, the diagnosis is divulged at the end of the vignette, after you have just struggled through the narrative to come up with a diagnosis of your own. The question might then ask about a related aspect of the diagnosed disease. One strategy that many students suggest is to skim the questions and answer choices before reading a vignette, especially if the vignette is lengthy. Th is focuses your attention on the relevant information and reduces the time spent on that vignette . Sometimes you may not need much of the information in the vignette to answer the question. However, be careful with skimming the answer choices; going too fast may warp your perception of what the vignette is asking. 􀀦 Be prepared to read fast and think on your feet! 􀀦 Practice questions that include case histories or descriptive vignettes are critical for Step I preparation. 􀀦 Step T vignettes usually describe diseases or disorders in their most classic presentation. 􀀦 Sometimes making a diagnosis is not necessary at all. 2 2 S E C T I O N I GUIDE TO EFFICIENT EXAM PREPARATION 􀀠 If you pass Step 1, you are not allowed to retake the exam. 􀀠 Near the failure threshold, each point on the three-digit scale is equivalent to about 1.5 questions answered corredly. 6 􀀆 I F Y O U T H I N K Y O U FA I L E D After the test, many examinees feel that they have failed, and most are at the very least unsure of their pass/fail status. There are several sensible steps you can take to plan for the future in the event that you do not achieve a passing score . First, save and organize all your study materials, i n c l u d i ng review books, practice tests, and notes. Famil iarize yourself with the reappl ication procedures for Step l , including appl ication deadl ines and upcoming test elates. The CBT format allows an examinee who has failed the exam to retake it no earlier than the first clay of the month after 60 clays have elapsed since the last test elate. Examinees will, however, be allowed to take the Step l exam no more than four times within a 1 2-month period should they repeatedly fail. The performance profiles on the back of the U SMLE Step l score report provide valuable feedback concerning your relative strengths and weaknesses. Study these profiles closely. Set up a study ti meline to strength e n gaps in your knowledge as well as to maintain and improve what you already know. Do not neglect high-yield subj ects . It is normal to feel somevvhat anxious about retaking the test, but if anxiety becomes a problem, seek appropriate counsel ing. Although the NBME allows an unlimited number of attempts to pass Step l , they recommend that l icensing authorities allow a maximum of six attempts for each Step examination . 5 Aga i n , review your school's pol icy regarding retakes. 􀀆 I F Y O U FA I L E D Even i f you came out of the exam room fee l i ng that you failed, seeing that failing grade can be traumatic, and it is natural to feel upset. Different people react in different ways: For some it is a stimulus to buckle clown and study harder; for others it may "take the wind out of their sails" for a few clays; and it may even lead to a reassessment of individual goals and abilities. In some instances, however, failure may trigger weeks or months of sadness, feelings of hopelessness, social withdrawal, and inability to concentrate - in other words, true clinical depression. If you think you are depressed, please seek help. GUIDE TO EFFICIENT EXAM PREPARATION 􀀤 T E S T I N G A G E N C I E S • National Board of Medical Examiners (NBME) Department of Licensing Examination Services 3 7 5 0 Market Street Philadelphia, PA 1 9 1 04-3 1 02 ( 2 1 5 ) 5 90-9700 Fax: ( 2 1 5 ) 590-94 5 7 Email : webmail@nbme . org www. nbme. org • Educational Commission for Foreign Medical Graduates (ECFMG) 3624 Market Street Philadelphia, PA 1 9 1 04-268 5 ( 2 1 5 ) 3 86- 5900 Fax: ( 2 1 5 ) 3 86-9 1 96 Email: info@ecfmg.org www.ecfmg.org • Federation of State Medical Boards (FSMB) 400 Fuller Wiser Road , Suite 300 Euless, TX 760 39-3 8 5 6 ( 8 1 7) 868-4000 Fax: ( 8 1 7) 868-4099 Email: usmle@fsmb.org www.fsmb.org • USMLE Secretariat 3 7 5 0 Market Street Philadelphia, PA 1 9 1 04-3 1 90 ( 2 1 5 ) 5 90-9700 Fax: ( 2 1 5 ) 590-94 5 7 Email: webmail@nbme .org www. usmle .org 􀀤 R E F E R E N C E S l . United States Medical Licensing Exa m ination. Step 1 Content Description Online. Available at: http : //www.usmle.org/pdfs/step- 1 /2 0 1 2content_step 1 .pdf. Accessed September 26, 2 0 1 2 . 2 . Pohl , Charles A . , Robeson, Mary R . , H ojat, Mohammadreza, and Velosk i , J . Jon, " S ooner or Later? U S M L E Step 1 Performance a n d Test Ad m i n istration Date at the End of the Second Year," Academic Medicine, 2002 , Vol . 77, No. 10, pp. S 1 7- S 1 9. 3. Holtman, Matthew C . , Swanson, David B . , R ipkey, Douglas R . , and Case, Susan M . , "Using Basic S cience Subject Tests to Identify Students at Risk for Fa i l i ng Step 1 ," Academic Medicine, 2 00 1 , Vol . 76, No. 10, pp. S48-S 5 l . S E C T I O N I 23 24 SECTION I GUIDE TO EFFICIENT EXAM PREPARATION 4. Basco, Will iam T., Jr., Way, David P. , Gilbert, Gregory E., and Hudson, Andy, "Undergraduate Institutional MCAT Scores as Predictors of USMLE Step 1 Performance," Academic Medicine, 2002 , Vo l. 77, No. 10, pp. S13- S16. 5. United States Medical Licensing Examination. 2013 USMLE Bulletin: El igibibii lty. Ava ilable at: http://www.us mle.org/bullet in/eligibil ity. Accessed September 26, 201 2. 6. O'Donnell, M. J., Obensha in, S. Scott, and Erdmann, James B., "1: Background Essential to the Proper Use of Results of Step 1 and Step 2 of the USMLE," Academic Medic ine, October 1993, Vo l. 68, No. 10, pp. 734-7 39. SECT I ON I SUPPLEM ENT Specia l Situat ions 2 6 SECTION I S P E C I A L S I T U AT I O N S 􀀠 IMGs make up approximately 25% of the U.S. physician population. 􀀠 Mare detailed information can be found in the ECFMG Information Booklet, available at www. edmg.argjpubshome.html. 􀀠 Applicants may apply online for USMLE Step 1, Step 2 CK, or Step 2 CS at www. edmg.org. 􀀆 F I R S T A I D F O R T H E I N T E R N AT I O N A L M E D I C A L G R A D U AT E " International medical graduate" ( I M G ) i s the accepted term now used to describe any student or graduate of a non-U . S . , non-Canadian, non-Puerto Rican medical school , regardless of whether he or she is a U. S . citizen or resident. Technically the term IMG encompasses FMGs (foreign medical graduates; i . e . , medical graduates from medical schools outside the United States who are not residents of the U nited States - that is, U. S . citizens or green-card holders ) , although the terms I M G and FMC are ofte n used interchangeably. I M G's Steps to Licensure in the United States To be eligible to take the USMLE Steps, you (the applicant) must be officially enrolled in a medical school located outside the United States and Canada that is l i s ted i n the International Medical Education D irectory ( I M E D ; http ://www.faimer. org/resources/imecl. html ) , both at the time you apply for examination and on your test clay. In addition, your "Graduation Year" must be listed as "Current" at the time you apply and on your test clay. If you are an IMG, you must go through the following steps (not necessarily in this order) to apply for residency programs and become licensed to practice in the United States. You must complete these steps even if you are already a practicing physician and have completed a residency program i n your own country. • Pass U SMLE Step 1 , Step 2 C K, and Step 2 C S , as well as obtai n a medical school diploma ( n ot necessarily i n this order) . All three exams can be taken dur i ng medical school . • Apply for certification from the Educational C o mmission for Foreign M e d i c a l Graduates ( E C FM G ) after above steps are s u c c essfu l l y completed. There w i l l be a delay o f 4-8 weeks between your E C FMG application and your receipt of the ECFMG certificate; the EC FMG will not issue a certificate (even if all the U SMLE scores are submitted) until it verifies your medical diploma with your medical school . • You must have a valid ECFMG certificate before entering an accredited residency program in the United States, although you can begi n the Electroni c Residency Appl ication S e rv i c e ( E RA S ) appl ication and interviews before you receive the certificate . H owever, many programs prefer to interview IMGs who have an EC FMG certificate, so obtaining it by the time you submit your E RAS application is ideal . • Apply for residency positions i n your fields of i nterest, either di rectly or through the E RAS and the National Residency Match i ng Program (NRMP), otherwise known as "the Match ." To be entered into the Match, you need to have passed all the exa m inations necessary for EC FMG certification ( i . e . , Step 1 , Step 2 C K, and Step 2 C S ) by the rank order l ist deadl ine (usually in late February before the Matc h ) . If you do not pass these exams by the deadl ine, you will be withdrawn from the Matc h . S P E C I A L S I T U AT I O N S S E C T I O N I 2 7 • I f you are not a U . S . citizen o r green-card holder (permanent resident) , obtain a visa that will allow you to enter and work in the United Stat s . • Sign up t o receive the ECFMG a n d ERAS email newsletter t o keep up to elate with their most current policies and deadl ines. If required by the state in which your residency program is located, obtain an educational/training/l imited medical license. Your residency program may a5sist you with this appl ication . Note that medical l icensing i5 the prerogative of each individual state, not of the federal government, and that states vary with respect to their laws about licensing. • Once you have the ECFMG certification, take the USMLE Step 3 dur i ng your residency, and then obtain a full medical license . Once you have a state-issued l icense, you are permitted to practice in federal institutions such as Veterans Affairs (VA) hospitals and Indian Health Service facilities in any state. Thi5 can open the door to "moonl ighting" opportunities and possibil ities for an H 1 B visa appl ication if relevant. For details on individual state rules, write to the l icensing board in the state in question or contact the Federation of State Medical Boards ( FSMB ) . If you need to apply for an H 1 B visa for starting residency, you will need to take and pass the USMLE Step 3 exam, preferably before you Match. • Complete your residency and then take the appropriate specialty board exams if you wish to become board certified (e.g. , in internal medicine or surgery) . If you already have a specialty certification in another country, some specialty boards may grant you six months' or one year's c redit toward your total residency time. • Currently, most residency programs are accepting applications thro ugh ERAS. For more inf01 mation, see First Aid for the Match or contact: ECFMG/ERAS Program 3624 Market Street Philadelphia, PA 1 9 1 04-268 5 U SA ( 2 1 5 ) 3 86-5900 Email : eras-support@ecfmg.org www.ecfmg.org/eras • For detailed information on the U SMLE Steps, visit the U S MLE Web site at http://www. usmle.org. The USMLE and the I M Ci The U S M L E is a s e r i e s of standardized exams that give I M G s and U . S . medical graduates a level playing field. The passing marks for IMGs for Step l , Step 2 CK, and Step 2 CS are determined by a statistical distribution that is based on the scores of U. S . medical school students. For example, to pa􀐾s Step 1 , you will probably have to score h igher than the bottom 8- 1 0% of U . S . and Canadian graduates. U nder new U SMLE program rul e s , a maximum of six atte mpts will be permitted to pass any U SMLE S tep or component exam starting January l , 20 1 2 for new examinees, and J anuary 1 , 20 1 3 for previous examinees. There 􀀠 IMGs have a maximum of s1x attempts to pass any USMLE Seep, and must pass the USMLE Steps requtred for t.CJ-MG certification wtlhm a seven-year pc::ll d. I 2 8 SECTION I S P E C I A L S I T U AT I O N S 􀀠 If your clinical experience is recent, consider taking the Step 2 CK first, followed by the Step 1. 􀀠 A higher Step 1 score will improve your chances of getting into a highly competitive specialty. is a l imit of three attempts with in a 1 2-month period for any of the U SMLE Steps. Timing of the USMLE For an IMG, the timing of a complete application is critical . It is extremely i mportant that you send i n your appl ication early if you are to obtai n the maximum number of interviews . Complete all exam requi rements by August of the year in wh ich you wish to apply. Check the E C FM G Web site for deadlines to take and pass the various Step exams to be eligible for the NRMP Match. I M G appl i c a nts must pass th e U S M L E Steps requ i re d fo r E C FMG certification within a seven-year period. The U SMLE program recommends, although not all j ur isdictions impose, a seven-year limit for completion of the three-step U SMLE program. In terms of U SMLE exam order, arguments can be made for taking the Step 1 or the Step 2 CK exam first. For example, you may consider taking the Step 2 CK exam first if you have j ust graduated from medical school and the clinical topics are still fresh in your mind. H owever, keep i n mind that there is substantial overlap between Step 1 and Step 2 CK topics in areas such as pharmacology, pathophysiology, and biostatistics. You might therefore consider taking the Step 1 and Step 2 C K exams c lose togeth er to take advantage of this overlap in your test preparation. U S M LE Step 1 and the I M G Significance of the Test. Step 1 is requ ired for the E C FMG certificate as well as for registration for the Step 2 C S . S ince most U. S . graduates apply to residency with their Step 1 scores only, it may be the only objective tool available with which to compare IMGs with U . S . graduates. Eligibility Period. A three-month period of your choice. Fee. The fee for Step 1 is $790 plus an international test delivery surcharge (if you choose a testing region other than the United States or Canada ) . Statistics. In 20 1 1 -20 1 2, 7 3 % of iMG examinees passed Step 1 o n their first attempt, compared with 94% of those from the United States and Canada. Tips. Although few if any students feel totally prepared to take Step 1 , IMGs in particular require serious study and preparation in order to reach their full potential on this exam. It is also imperative that IMGs do their best on Step l , as a poor score on Step 1 is a distinct disadvantage i n applying for most residencies. Remember that if you pass Step 1 , you cannot retake it i n an attempt to improve your score . Your goal should thus be to beat the mean , because you can then assert with confidence that you have clone better than average for U . S . students . H igher Step 1 scores will also lend credibility to S P E C I A L S I T U AT I O N S S E CT I O N I 29 your residency application and help you get into highly competitive specialties such as radiology, orthopedics, and dermatology. C ommercial Review C o u r s e s . Do c o m m e rc i a l review c o ur ses h e l p improve your scores? Reports vary, and s u c h courses c a n be expensive . For some students these programs c a n provide a more structured learning environment with professional support. H owever, review courses consume a significant c h u nk of time away from i ndependent study. Many I M G s decide t o prepare for S t e p 1 on the i r o w n and then cons ider a review course only if th ey fa i l . ( For more i n formation on review courses, see Section IV. ) USM LE Step l CK and the I MG What Is the Step 2 C K? It is a computerized test of the clinical sciences consisting of up to 3 5 5 multiple-choice questions divided into eight blocks. It can be taken at Prometric centers in the United States and several other countries. Content. The Step 2 C K includes test items in the following content areas: • Internal medicine • Obstetrics and gynecology • Pediatrics • Preventive medicine • Psychiatry • Surgery • Other areas relevant to the provision of care under supervision Significance of the Test. The Step 2 CK is requ i red for th e E C F M G certificate . It reflects the level o f clinical knowledge o f the applicant. It tests clinical subjects, primarily i nternal medicine. Other areas that are tested are surgery, obstetrics and gynecology, pediatrics, orthopedics, psychiatry, E NT, ophthalmology, and medical ethics. Eligibility. Students and grad uates from medical schools that are l isted in IMED are eligible to take the Step 2 C K. Students must have completed at least two years of medical school. This means that students must have completed the basic medical science component of the medical school curriculum by the beginning of the el igibil ity period selected . Eligibility Period. A three-month period of your choice . Fee. The fee for the Step 2 C K is $790 plus an i nternational test del ivery surcharge ( i f you choose a testing region other than the United States or Canada) . Statistics. In 20 l l -20 1 2 , 84% o f E C FMG candidates passed the Step 2 C K o n their first attempt, compared with 96% o f U . S . and Canadian candidates. 􀀠 The areas tested o n the Step 2 CK relate to the clerkships provided at U. S. medical schools. 3 0 S E CTI O N I S P E C I A L S I T U AT I O N S 􀀠 Be familiar with topics that are heavily emphasized in U.S. medicine, such as cholesterol screening. 􀀠 The Step 2 CS is graded as passjfail. Tips. It's better to take the Step 2 C K after your internal medicine rotation because most of the questions on the exam give c l i nical scenarios and ask you to make medical diagnoses and cl inical decisions. I n addition, because th is is a clinical sciences exam, cultural and geographic considerations play a greater role than is the case with Step l . For exampl e , i f your medical education gave you ample exposure to malaria, bru cellosis, and malnutrition but little to alcohol withdrawal , child abuse, and cholesterol screening, you must work to familiarize yourself with topics that are more heavily emphasized in U. S . medicine. You must also have a basic understanding of the legal and social aspects of U . S . medicin e , because you will be asked questions about communicating with and advising patients. U S M LE Step l C S and the I M G What I s the Step 2 CS? The Step 2 C S is a test of clinical and communication skills administered as a one-day, eight-hour exa m . It i n c l udes 1 0 to 1 2 encounters with standardized patients ( 1 5 minutes each , with l 0 minutes to write a note after each encounter) . Content. The Step 2 C S tests the ability to communicate in E ngl ish as well as interpersonal skills, data-gathering skills, the ability to perform a physical exam, and the ability to formulate a brief note , a differential diagnosis, and a l ist of diagnostic tests. The areas that are covered in the exam are as follows: • Internal medicine • Surgery Obstetrics and gynecology • Pediatrics • Psychiatry Family medicine Unl ike the U S MLE Step l , Step 2 C K, or Step 3, there are no numerical grades for the Step 2 C S - it's si mply either a "pass" or a "fa i l ." To pass, a candidate must attain a passing performance i n each of the following three components: • Integrated Cl inical Encounter (ICE): includes Data Gathering, Physical Exam, and the Patient Note Spoken Engl ish Proficiency (SEP) Communication and Interpersonal Skills (CIS) According to the NBME, the most commonly failed component for IMGs is the C I S . Significance o f the Test. T h e Step 2 C S assesses spoken E ngl ish language proficiency and is requ ired for the ECFMG certificate . The Test of English as a Foreign Language (TOEFL) is no longer required. Eligibility. Students must have completed at least two years of medical school i n order to take the test. That means students must have completed the basic SPECIAL SITUATIONS S E C T I O N I 3 1 medical science component of the medical school curriculum at the time they apply for the exam. Fee. The fee for the Step 2 C S is $ 1 3 7 5 . Scheduling. You must schedule the Step 2 C S within four months o f the date indicated on your notification of registratio n . You must take the exam within 1 2 months of the elate indicated on your notification of registration. It is generally advisable to take the Step 2 CS as soon as possible in the year before your Match, as often the results either come in late or arrive too late to allow you to retake the test and pass it before the Match. Test Site Locations. The Step 2 C S is currently administered at the following five locations : • Philadelphia, PA • Atlanta, GA • Los Angeles, CA • Chicago, IL • Houston, TX For more information about the Step 2 C S exam, please refer to First Aid for the Step 2 CS. USMLE Step l and the I M G What Is the U S M L E Step 3 ? It is a two-clay computerized test in clinical medicine consisti ng of 480 multiple-choice questi ons and nine compute rbased case simulations (CC S ) . The exam aims at testing your knowledge and its application to patient care and clinical decision making ( i . e . , this exam tests if you can safely practice medicine independently and without supervision) . Significance o f the Test. Taking Step 3 before residency i s critical for IMGs seeking an H 1 B visa and is also a bonus that can be added to the residency appl ication. Step 3 is also requ ired to obta i n a full medical l icense i n the United States and can be taken dur i ng residency for this purpose . Fee. The fee for Step 3 is $780 in all states except Iowa ( $ 8 3 0 ) , South Dakota ($9 3 0 ) , and Vermont ( $8 1 5 ) . Eligibility. Most states requi re that appl icants have completed one, two, or three years of postgraduate training ( residency) before they apply for Step 3 and permanent state l icensur e . The exceptions are the 1 3 states mentioned below, wh ich allow IMGs to take Step 3 at the begi nning of or even before residency. So if you don't fulfill the prerequ isites to taking Step 3 in your state of choice, simply use the name of one of the 1 3 states in your Step 3 application. You can take the exam in any state you choose regardless of the state that you mentioned on your application . Once you pass Step 3, it will be recognized by all states. Basic eligibil ity requ irements for the USMLE Step 3 are as follows: 􀀠 Try to take the Step 2 CS the year before you plan to Match. 􀀠 Complete the Step 3 exam before you apply for an H 18 visa. 3 2 SECTI O N I S P E C I A L S I T U AT I O N S • Obtaining a n MD o r D O degree ( o r i ts equivalent) b y the application deadline. • Obtaining an EC FMG certifi cate if you are a grad uate of a foreign medical school or are successfully completing a "fifth pathway" program (at a elate no later than the application deadl i n e ) . • M eeting t h e requ irements i mposed by t h e i n dividual state l ic e n s i ng authority to which you are applying to take Step 3 . Please refer to www. fsmb.org for more information. The fol l ow i ng states do not h ave postgraduate tra i n i ng as an e l i g i b i l i ty requirement to apply for Step 3 : • Arkansas • California • Connecticut • Florida • Lou isiana • Maryland • Nebraska· • New York • South Dakota • Texas • Utah* • Washington • West Virginia * Requires that IMGs obtain a "valid indefinite" E C FMG certificate . The Step 3 exam is not available outside the United States. Applications can be found online at www.fsmb. org and must be submitted to the FSMB. In 20 l l -20 1 2 , 84% of iMG candidates passed the Step 3 on their first attempt, compared with 97% of U . S . and Canadian candidates. Residencies and the I M G In the Match, the number of U . S .-citizen IMG applications has grown over the past few years, while the percentage accepted has remained constant (see Table 4 ). More information about residency programs can be obtained at www.ama-assn .org. The Match and the I M G Given the growing number of IMG candidates with strong applications, you should bear in mind that good U SMLE scores are not the only way to gain a competitive edge. However, U SMLE Step l and Step 2 C K scores continue to be used as the initial screening mechanism when candi dates are being considered for interviews. S P E C I A L S I T U AT I O N S S E C T I O N I 3 3 T A B L E 4 . IMGs in the Match. Applicants 201 0 201 1 201 2 U . S .-citizen I MCs 3,695 3,769 4,279 % U. S .-citizen I MCs accepted 47 5 0 49 Non-U . S .-citizen I MCs 7, 246 6,659 6,828 % non- U . S .-citizen IMCs 40 41 41 accepted U. S . seniors (non-IMCs) 1 6 ,070 1 6, 5 59 1 6 , 5 2 7 % U . S . sen iors accepted 93 94 9 5 Source: www.nrmp.org. Based on accumulated IMG Match experiences over recent years, here are a few pointers to help IMGs maximize their chances for a residency interview: • Apply early. Program s offer a l i m i ted number of i n terviews and often select candidates on a fi rst-come, fi rst-served basis. Because of th is, you should aim to complete the entire process of applying for the ERAS token , registering with the Association of American Medical Colleges (MM C ) , mailing necessary documents t o E RA S , and completing the E RAS application before September (see Figure 5 ) . Community programs usually send out interview offers earlier than do university and university-affiliated programs. • U. S. clinical experience helps. Externsh ips and observersh ips in a U. S . hospital setting have emerged a s a n i mportant credential o n an I M G application. Externships are l ike short-term medical school internsh ips and offer hands-on c l i n i cal experi e n c e . Observerships, also called "shadowing," involve following a phys i cian and observing how he or she manages patients . S o m e p rogra ms requ i re stu d e n ts to have parti cipated in a n externsh ip or observership before applying. It is best t o gain such an experience before or at the time you apply to various programs so that you can mention it on your E RAS applicati o n . If such an experience or opportunity comes up after you apply, be sure to inform the programs accordingly. • Clinical research helps. U niversity programs are attracted to candidates who show a strong interest in clinical research and academics. They may even relax the i r appl ication c riteria for i ndividuals with u n i que backgrounds and stron g research exp e r i e n c e . P u b l i cations in wel l-kn own journals are an added bonus. • Time the Step 2 CS well. E C F M G has publ ished the new Step 2 C S score-reporting schedule for 2 0 1 2-2 0 1 3 a t http : //www. ecfmg.org/news/ category/step-2-cs . Most progra m di rectors would l ike to see a passi n g score on the Step 1 , Step 2 C K, and Step 2 C S exams before they rank an IMG on their rank order l ist i n mid-February. There have been many i nstances in which candidates have lost a potential Match - either because of delayed CS results or because they h ave been unable to retake th e 􀀦 Most U. S. hospitals allow externship only when the applicant is actively enrolled in a medical school, so plan ahead. 3 4 SECTION I S P E C I A L S I T U AT I O N S 􀀠 A good score on the Step 3 may help offset poorer scores on the Step 1 or 2 CK exams. F 1 G u R E s . IMG Ti meline for Application. J u n e Obta i n E RAS token and obtai n AAMC I D I f U S M L E Steps 1 , 2 C S , and 2 C K completed : req u est ECFMG certification J u l y Send docu ments to ERAS Aug ust September October November December January February Request l ette rs of recom m e n dation be u ploaded Complete CAF and personal statement on M y E RAS Select and apply to programs t h ro u g h MyE RAS Sched u l e and attend i nterviews Complete any p e n d i n g U S M L E Step exams Obta i n ECFMG certification (if not done earlier) Submit ran k order l ist Complete U S M L E Step 3 (if interested in H1 B) March Match resu lts (day 1 ) SOAP (days 3-5) Matched p rogram resu lts (day 5) exam on time following a failur e . It is difficult to predict a result on the Step 2 C S , since the grading process is not very transparent. Therefore , it is advisable to take the Step 2 C S as early as possible i n the appl ication year. • U. S. letters of recommendation help. Letters of recommendation from clinicians practicing in the United States carry more weight than recommendations from home countries. • Step up the Step 3. If HlB visa sponsorship is desired, aim to have Step 3 results by January of th e Match year. In addition to the visa advantage you will ga in, an early and good Step 3 score may benefit IMGs who have been away fr om clinical medicine for a while as well as those who have low scores on Step 1 and th e Step 2 CK. • Verify medical credentials in a timely manner. Do not overlook the medical school credential verification process. The EC FM G certificate arrives only after credentials have been verified and after you have passed SPECIAL SITUATIONS SECTION I 35 Step 1, the Step 2 CK, and the Step 2 CS, so you should keep track of the process and check with the ECFMG fr om time to time about your status. Don't count on a pre-Match. Of note , as of the 20 13 Match, programs parti cipating in NRMP Match can no longer offer a pre-Match. What if You Do Not Match? Fo r applicants who do not Match into a residency program, there 's SOAP (Supplemental Offe r and Ac ceptance Program). Under SOAP, unmatched appl icants will have access to the list of unfilled programs at noon Eastern time on th e Monday of Match week. The unfilled programs electing to parti cipate in SOAP will offe r positions to unmatched appl icants through the Registration, Ranking, and Results (R3) system. A series of "rounds" will begin at noon Eastern time on We dnesday of Match week until 5:00 P.M. Ea ste rn time on Friday of Match week. Detailed information about SOAP can be fo und at the NRMP We b site at http : //www. nrmp.org/res_match/pol icies/ map_ma in.html . Resources for the IMCi • EC FMG 3624 Market Street Philadelphia, PA 19104-2685 (2 15) 386- 5900 Fa x: (2 15) 386-9 196 www. ecfmg.org The ECFMG telephone number is answered only between 9:00 A. M. and 12:30 P.M. and between 1:30 P.M. and 5:00 P.M. Monday th rough Friday EST. The ECFMG often takes a long time to answer the phone, wh ich is fre quently busy at peak times of the year, and th en gives you a long voice-mail message -so it is better to write or fax early than to rely on a last-minute phone call. Do not contact th e NBME, as all IMG exam matters are conducted by the ECFMG. The EC FMG also publishes an information booklet on ECFMG certification and the USMLE program, wh ich gives deta ils on the elates and locations of fo rthcoming Step tests fo r IMGs togeth er with application fo rms. It is fr ee of charge and is also available fr om the public affairs offices of U.S. embassies and consulates worldwide as well as fr om Overseas Educational Adv isory Centers. Yo u may order si ngle copies of the handbook by calling (2 15) 386- 5900, preferably on weeke nds or between 6 P.M. and 6 A. M. Philadelphia time, or by fa xing to (2 15) 386-9 196. Requests fo r multiple copies must be made by fax or mail on org anizational letterhead . The fu ll text of the booklet is also av ailable on the ECFMG's We b site at www. ecfmg.org. 􀀠 The Scramble has been replaced by SOAP (Supplemental Offer and Acceptance Program). 3 6 SECT I O N I S P E C I A L S I T U AT I O N S • FSMB 400 Fuller Wiser Road, Su ite 300 Euless, TX 760 39 ( 8 1 7 ) 868-4000 Fax: ( 8 1 7) 868-4099 www.fsmb . org The FSMB has a number of publications availabl e , including free policy documents . To obtain these publ ications, print and mail the order form on the Web site listed above . Alternatively, write to Federation Publ ications at the above address . All orders must be prepai d w i th a personal check drawn on a U . S . bank, a cash ier's check, or a money order payable to the F S M B . Foreign orders must be accompanied by an i nternational money order or the equivalent, payable i n U . S . dollars th rough a U. S . bank o r a U. S . affil iate o f a foreign bank. For S tep 3 inquiries, the telephone number is ( 8 1 7 ) 868-404 1 . You may e-mail the F S M B at usmle@ fsmb.org or write to Examination Services at the address above . The AMA has dedicated a portion of i ts Web s i te to information on IMG demograph ics, residencies, i mmigration, and the l ike. This i n formation can be fou n d at www. ama-ass n . o rg/a m a /pub/about-a ma/our-people/membergroups- sections/international-medical-graduates.shtm l . Other resources that m a y be useful a n d of i nterest t o IMGs i n c l u d e the following: • Th e I n te rn a tio n a l Medic a l G ra du a te 's G u ide to US Medic i n e a n d Residency Training, by Patrick C . Alquire, Gerald P . Whelan, and Vi jay Rajput ( 2 009; I S B N 978 1 9 3446 5 080) . • The International Medical Gra du a te 's B est Hope , by Franck Belibi and Suzanne Bel ibi ( 2 009; ISBN 978097987 7 3 0 8 ) . 􀀤 F I R S T A I D F O R T H E O S T E O PAT H I C M E D I C A L S T U D E N T What I s the COM LEX-USA Level l ? T h e N a t i o n a l B o a r d o f Osteopath i c M e d i c a l E xa m i n e rs ( B O M E ) administers the Comprehensive Osteopath ic Medical Licensing Examination , or COMLEX-U SA. Like the U S ML E , the COMLEX-U SA is administered over three levels. The COMLEX-U SA series assesses osteopath i c m e d i c a l knowledge an d clinical skills using c l i nical presentations and physician tasks . A descriptio n of the COMLEX-U SA Written Exami nation Blueprints for each level , wh ic h outline the various clinical presentations and physician tasks that examinees will encounter, is given on the N B O M E Web site . Another stated goal of the COMLEX-U SA Level 1 is to create a more primary care-oriented exam th at integrates osteopathic principles i nto clinical situations. SPECIAL SITUATIONS To be eligible to take the COMLEX-USA Level 1, you must have satisfactorily completed your first year in an Am erican Osteopath ic Association (AOA)approvecl medical school. The office of the cl ean at each school informs th e NBOME that a student has completed his or her first year of school and is in good standing. At th is point, the NBOME sends out an email with detailed instructions on how to register fo r the exam. Fo r all three levels of the COMLEX-U SA, raw scores are converted to a percentile score and a score ra nging from 5 to 800. For Levels 1 and 2, a score of 400 is required to pass; fo r Level 3, a score of 3 50 is needed. COMLEXUSA scores are posted at the NBOME We b site 4-6 weeks after the test and usually mailed within 8 weeks after the test. The mean score is always 500. If you pass a COMLEX-USA examination, you are not allowed to retake it to improve your grad e. If you fa il, there is no specific limit to the number of times you can retake it in order to pass. However, a student may not take the exam more than fo ur times in one year. Levels 2 and 3 exams must be passed in sequential order within seven years of passing Level 1. What Is the Strudure of the COMLEX-USA Level l ? The COMLEX-USA Level 1 is a computer-based examination consisting of 400 questions over an eight-hour period in a single cl ay (nine hours if you count breaks). Most of the questions are in one-best-answer fo rmat, but a small number are matching-type questions. Some one-best-answer questions are bundled togeth er around a common qu estion stem th at usually takes the fo rm of a clinical scenario. Every section of the COMLEX-U SA Level 1 ends with either matching questions, multiple questions around a single stem, or both . ew question fo rmats may gradually be intro duced, but candidates will be noti fied if th is occurs. In 20 12, th e NBOME introduced multimedia questions and have stated that multimedia questions will continue to be a larger part of the exam. Questions are grouped into eight sections of 50 questions each in a manner similar to the USMLE . Reviewing and changing answers may be clone only in the current section. A "review page" is presented fo r each block in order to advise test takers of questions completed, questions marked fo r fu rther review, and incompl ete questi ons fo r which no answer has been given. Breaks are even more structured with COMLEX-USA than they are with the USMLE. Students are allowed to take a 10-mi nute break at the end of the second and sixth sections. Students who do not take these l 0-minute breaks can apply th e time toward their test time. After section 4, students are given a 40-m inute lunch break. These are the only times a student is permitted a break. More information about the computer-based COMLEX-USA examinations can be obta ined fr om www. nbome . org. SECTION I 37 3 8 SECTION I S P E C I A L S I T U AT I O N S 􀀣 The tP􀇵t intf'rfoce for the COML FXUSA L evel 1 is not the same as the U Ml E StPp 1 interfacP. What Is the Difference Between the U S M LE and the COM LEX-U SA? Ac cord ing to the NBOME, the COMLEX-USA Level 1 fo cuses broadly on the fo llowing categories, with osteopath ic principles and practices integrated i nto each section : Health promotion and disease prevention • Th e h istory and physical Diagnostic technologies • Management • Scientific understanding of mechanisms • Health care d el ivery Althou gh the COMLEX-U SA and th e U SMLE are similar i n scope, content, and empha sis, some differences a re worth noting. For example, the i nte rfa ce i s d i fferent; you cannot search for lab val u e s . The expectation is tha t you can make a diagnosis with out having performed testi ng. Fewer deta ils are given a bout a patient's conditi o n , so a savvy stu d e n t needs to know how to differentiate between similar pathol ogies. Al so, age, gender, and ra ce are key fa c tors for d i a gnosis on th e COMLEX-U S A . I mages are e mbedd ed in the question stem and the exa m i n ee h a s to c l i ck an attac h m ent bu tton to see the image. If you don't rea d th e question carefu l ly, the attachment buttons a re very easy to miss. COMLEX- U SA Level 1 tests osteopath i c p r i n c i p l e s i n a d d i ti o n to b a s i c s c i e n c m a te r i a l s b u t d oes not emph a s i z e l a b tec h n i q u e s . Alth o u gh both exa m􀌝 often requ ire that you apply and integrate knowledge over several a reas of ba􀌞ic science to answer a given qu estion, many stu dents wh o took both tests reported that th e questions differed somewh at in styl e . Stud ents reported, fo r e ·ample, that U S MLE qu estions genera l ly requ i red tha t the test taker reason and d raw from the i nformation given (often a two-step process ) , whereas those on the CO 1LEX-USA exam tended to be more straigh tforward . Furth ermore, USMLE questions were on average fou n d to be cons i d e rably l onger than tho'le on the COMLEX-USA. COM LEX- U S A test takers can exp e c t to h a ve only a few qu sti o n s o b i o c h e m i stry, m o l e c u l a r b i o l ogy, o r l a b tec h n i qu e . O n th e oth e r h a n d , mi c robi ology i s very heavi l y tested by c l i n i ca l presentati o n a n d by l ab identi fication . Another m a i n d i ffe re n c e i s that the C O MLEX- U SA exa m stresses osteopath ic manipulative medicine. Th erefore, qu esti on banks specific to th e U SMLE will not be ad equate, and supplementation with a question bank specific to the COMLEX-U SA i􀆯 h ighly recommen d e d . Stud ents also commented th at the COMLEX-USA utilized " buzzwords ," although limited in th eir use (e.g., "rose spots" in typhoid feve r), where a s the USMLE avoided buzzwords in fa vor of descriptions of clinical findin gs or symptoms (e.g., rose-colored papules on the abd omen rather than ro e spots). Finally, USMLE appeared to have more phot o g rap h s than did t h e COMLEX-USA. In general, the overall impression was th at the USMLE w as S P E C I A L S I T U AT I O N S S E CT I O N I 3 9 a more "thought-provoking" exam, wh ile the COMLEX-USA was more o f a "knowledge-based" exa m . Who Should Take Both the U S M LE and the COM LEX-USA? Aside from facing the COMLEX-U SA Level l , you must decide if you will also take the U SMLE Step l . We recommend that you consider taking both the USMLE and the COMLEX-U SA under the following circumstances: • If you are applying to allopathic residencies. Although there is growing acceptance of COMLEX- U SA c e rtification on th e part of a l l opath i c residencies, some all opath i c p rogra ms prefer or even requ ire passage of the U S M L E Step l . T h e s e i n c l u d e m a n y a c a d e m i c p rogra m s , programs i n competi tive specialties ( e . g. , orthopedics, ophthalmology, or dermatology) , and programs in competitive geograph i c areas (such as Vermont, Utah , and California ) . Fourth-year doctor of osteopathy ( DO ) students who have already Matched m a y be a good sour c e o f information about wh i c h programs and specialties look for U S MLE scores . I t is also a good idea to contact program di rectors at the i ns titutions you are interested in to ask about their policy regarding the COMLEX-U SA versus the USMLE. • If you are unsure about your postgraduate training plans. Successful passage of both the COMLEX- U SA Level l and the U S M LE Step l is certain to provide you with the greatest possible range of options when you are applying for internship and residency training. In addition , the COMLEX-U SA Level l has i n recent years placed increasing emphasis on questi ons related to p r i m a ry care medicine and prevention . Having a strong background in family or primary care medicine can help test takers when they face questions on preventi o n . How D o I Prepare for the C O M LEX-USA Level 1 ? Student experience suggests th at you should start studying for the COMLEXU SA four to six months before the test is give n , as an early start will allow you to spend up to a month on each subj ect. The recommendations made in Section I regarding study and testing methods, strategies, and resources, as well as the books suggested i n Section IV for the U SMLE Step l , hold true for the COMLEX-USA as wel l . Another important source of i n formation is i n the Examination Guidelines and Sample Exa m , a booklet that discusses the breakdown of each sub j ect wh ile also providing sample questi ons a n d corresponding an swers . Many students, however, felt that th is breakdown provided only a general gu idel ine and was not representative of the l evel of difficulty of the actual COMLEXU SA. The sample questions did not provide examples of c l i n i cal vignettes, wh ich made up approximately 2 5 % o f th e exa m . Yo u w i l l receive th i s 􀀣 If you're not sure whether you need to take either the COM LEX-USA Level l or the USMLE Step 1, consider taking both to keep your Match options open. 40 SECTI O N I S P E C I A L S I T U AT I O N S 􀀠 You must know the Chapman reflex points and the obscure names of physical exam signs. publication with registration materials for the COMLEX-U SA Level 1 , but you can also receive a copy and additional i n formati o n by writing: NBOME 876 5 W. H iggins Road, Su ite 200 Chicago, IL 606 3 1 -4 1 74 ( 7 7 3 ) 7 1 4-0622 Fax: (77 3 ) 7 1 4-06 3 1 or by visiting the NBOME Web page at www . nbome. org. T h e N B O M E d e ve l o p e d t h e C o m p re h e n s ive O s t e o p a th i c M e d i c a l S e l f-Assessment Exa m i nation ( C O M SAE ) series t o fi l l t h e n e e d for selfassessment on the part of osteopath i c medical students . Many students take the COMSAE exam before the COMLEX-U SA in addition to using test-bank questions and board review books. Students can purchase a copy of this exam at www. nbome .org/comsa e . asp. I n recent years, students have reported a n emphasis i n c e rt a i n areas . Fo r exampl e : • There was an increased emphasis on upper l i mb anatomy/brachial plexus . • Specifi c top i c s were repeatedly tested o n the exa m . These i n c l uded cardiovascular physiology and pathology, acid-base physiology, diabetes, benign prostatic hyperplasia, sexually transmitted diseases, measles, and rubella. Thyroid and adrenal fu nction, neurology ( head i n j ury) , specific drug treatments for bacterial infection, migraines/cluster headaches, and drug mechanisms also received heavy emphasis. • Behavioral science questions were based on psyc hiatry. • H igh-yield osteopath ic manipulative technique ( OMT) top ics included an emphasis on the sympathetic a n d parasympathetic i n n e rvations of viscera and nerve roots, rib mechanics/diagnosis, and basic craniosacral theory. Students who spend time reviewing basic anatomy, studying nerve and dermatome i n nervations, and understanding how to perform basic OMT techniques ( e . g . , muscle energy or counterstrai n ) can improve thei r scores. The COMLEX-USA Level 1 also includes multimedia-based questions. Such questions test the student's ab i l i ty to pe rform a good phys i cal exam and to elicit various physical diagnostic signs ( e . g. , Murphy's sign ) . Since topics that were repeatedly tested appeared i n a l l four booklets, students found it useful to review them i n between the two test clays . It is important to understand that the topics emphasized on the c urrent exam may not be stressed on future exams. However, some topics are heavily tested each year, so it may be beneficial to have a sol id fou ndation i n the above-mentioned topics. S P E C I A L S I T U AT I O N S SECTI O N I 4 1 • F I R S T A I D F O R T H E P O D I AT R I C M E D I C A L S T U D E N T The National B oard of Podiatric M e d i c a l Exa m i n e rs ( N B P M E ) tests are designed to assess whether a candidate possesses the kn owl edge requ i red to practice as a m i n i mally competent e ntry-level podiatrist. The N B PM E examinations are used a s part o f the l icensing process governing the practice of podiatric medicine. The NBPME exam is recognized by all 5 0 states and the District of Columbia, the U . S . Army, the U . S . avy, and the Canadian provinces of Alberta, B r i tish C o l u m b i a , and Ontario . Individual states use the exami nation scores differently; therefore, doctor of podiatric medicine (DPM) candidates should refer to the NBPME B u lletin of information: 2 0 1 2 Examinations. The N B P M E Part I is generally taken after the completion of the second year of podiatric medical educati o n . Unl ike the U S MLE Step 1 , there is no behavioral science secti o n , nor i s b i o m echanics teste d . The exam samples seven basic s c i e n c e discipl i n e s : ge n e ral a natomy ( 1 0 % ) ; l ower extre m i ty anatomy ( 2 2 % ) ; biochemistry ( 1 0% ) ; physiology ( 1 2 % ) ; medical microbiology and immunol ogy ( 1 5 % ) ; pathol ogy ( 1 5 % ) ; a n d pharmacol ogy ( 1 6 % ) . A detailed outl i n e of topics and subtopics covered on the exam can be fou n d in the NBPME Bulletin of Information, available on the N B P M E Web site . Your N BPME Appointment In early spring, your college registrar will have you fill out an appl ication for the NBPME Part I . After your appl ication and registration fees are received, you will be mailed the NBPME B u lletin of infomwtion: 2 0 1 2 Examinations. Th e exam will be offered at an i n d e p e n d e n t location i n each c i ty with a podiatr i c m e d i c a l s c h ool ( New Yo rk, P h i l adel p h i a , M i a m i , C l evel a n d , Chicago, Des Moines, Phoenix, a n d S a n Francisco ) . You may take the exam at any of these locations regardless of which school you attend. However, you must designate on your application wh ich testing location you desire . Specific instructions about exam elates and registration deadlines can be found i n the NBPME B u lletin. Exam Format The BPME Part I is a written exam consisting of 2 0 5 questions. The test consists entirely of multiple-c h o i c e questions with fou r answer c h o i c e s . Examinees have three hours in wh ich t o take t h e exam a n d a r e given scratch paper and a calculator, both of wh i c h must be tu rned i n at the end of the exam. Some questions on the exam will be "trial questions." These questions are evaluated as future board questions but are not counted in your score . 􀀠 Areas tested on the NBPME Part 1: • General anatomy • Lower extremity anatomy Biochemistry Physiology • Medical microbiology & immunology Pathology Pharmacology 42 SECTI O N I 􀅳 Know the anatomy of the lower extremity! S P E C I A L S I T U AT I O N S Interpreting Your Score Three to four weeks following the exam elate, test takers will receive their scores by mail . NBPME scores are reported as pass/fa i l , with a scaled score of at least 7 5 needed to pass. E ighty-five percent of first-time test takers pass the N B PME Part I. Failing candidates receive a report with one score between 5 5 and 74 in addition to diagnostic messages intended to help identify strengths or weaknesses in specific content areas . If you fai l the N B P M E Part I , you must retake the entire examination at a later elate . There is no l i m i t to the number of times you can retake the exa m . Preparation for the N BPM E Part I Students suggest that you begin studying for the N B P M E Part I at least three months prior to the test elate . The suggestions made in Section I regarding study and testing methods fo r th e U S MLE Step l can be ap p l i e d to the NBPME as wel l . Th is book should, however, be used as a supplement and not as the sole source of i n formati o n . Keep in mind that you need only a passing score . Neither you nor your school or futur e residency will ever see your actual numerical score . Competing with colleagues should not be an issue, and study groups are beneficial to many. A potential study method that helps many students is to copy the outl i ne of the material to be tested from the NBPME Bu lletin. Check off each topic during your study, because doing so will ensure that you have engaged each topi c . lf you are pressed for time, prioritize subj ects on the basis of their weight on the exa m . Approxi mately 2 2 % of the N B P M E Part I focuses on l ower extremity anatomy. In th is area, students should rely on the notes and material that they received from their class . Remember, lower extremity anatomy is the podiatric physician's specialty - so everyth ing about i t i s i mportant. Do not forget t study osteology. Keep your old tests and look through old lower extremity clas exams, since each of the podiatric colleges submits questions from its ow n exams. Th is strategy will give you an understanding of the types of q uestions that may be asked. On the NBPME Part I, you will see some of the same classic lower extre mity anatomy questions you were tested on in school . The N B P M E , l ike the U S M L E , requ i res that you apply a n d i n tegrate knowl edge over several areas of b a s i c s c i e n c e i n order to answer exa m q u e s t i o n s . S t u d e n ts r e p o r t t h a t m a n y q u e s t i o n s e m p h a s i z e c l i n i c a l presentati ons; h owever, the fac ts i n th i s book are ve ry usefu l i n h e l p i n g students recall the various diseases and organisms. DPM candidates should expand on the h i gh-yield pharmacol ogy section a n d study antifungal drugs and treatments for Pseudomonas, methicillin-resistant S. a u reus, candidiasi s, and erythrasma. The high-yield section focusing on pathology is very useful ; h owever, additional emphasis on diabetes m e l l itus a n d a l l i ts s e c o n d a ry manifestations, particularly peripheral neuropathy, should not be overlooked. Students should also focus on renal physiol ogy a n d d ru g e l i m i nati on, the b iochemistry of gout, and neur ophysiol ogy, all of whi c h have been noted to be important topics on the N B P M E Part I exa m . S P E C I A L S I T U AT I O N S S E CTI O N I 43 A sample set o f questions is fou n d i n the NB PME B u lletin o f Informatio n : 2012 Exa m i n a tions. These samples a r e s i m i l a r i n difficulty t o actual board questio n s . If you do not receive a n NBPME B u lletin or i f you h ave any questions rega rdi ng registrat i o n , fee s , test c enters , authorization forms, or score reports, please contact your college registrar or: NBPME P.O. Box 5 1 0 Bell efonte, PA 1 68 2 3 (8 1 4) 3 5 7-0487 Email: NBPMEOfc@aol .com or visit the NBPME Web page at www. nbpme . info . 􀀤 F I R S T A I D F O R T H E S T U D E N T W I T H A D I S A B I L I T Y The U S M L E provides a c c o m m o d a t i o n s fo r stu d e n ts with d o c u m e n ted disab i l i t i e s . The b a s i s fo r s u c h a c c o m m odations is the Ame r i c a n s w i th Disabil ities Act (ADA) of 1 99 0 . The ADA defines a disability as "a significant l imitation in one or more major life activities." This includes both "observable/ physical" disab i l ities ( e . g . , blindness, hearing loss, narcolepsy) and "h idden/ mental disab il ities" ( e . g. , atte n t i o n-d e fi c i t hyperactivity disorder, chronic fatigue syndrome , learning disab i l ities ) . To provide appropriate support, t h e administrators of the U S MLE must b e informed o f both the nature a n d the severity o f an examinee's disability. Such documentation is required for an examinee to receive testing accommodations. Accommodations include extra time on tests, low-stimulation environments, extra or extended breaks, and zoom text. Who Can Apply for Accommodations? Students or graduates of a s c h ool in th e U n i ted S tates or Canada that i s accredited b y the Liaison Committee on Medical Education ( LC M E ) or the AOA may apply for test accommodations directly from the N B M E . Requests are granted only if they meet the ADA definition of a disability. If you are a disabled student or a disabled graduate of a foreign medical school , you must contact the EC FMG (see below) . Who Is Not Eligible for Accommodations? Individuals who do not meet the ADA definition of disabled are not eligible for test accommodati o n s . D i ffi c ulties not eligible fo r test accommodations include test anxiety, slow reading without an identified underlying cognitive deficit, Engl ish as a second language, and learning difficulties that have not been diagnosed as a medically recognized disability. 􀀠 U. S. students seeking ADAcompliant accommodations must contad the NBME directly; IMGs, contad the ECFMG. 44 SECTION I S P E C I A L S I T U AT I O N S Understanding the Need for Documentation Although most learni ng-disabled medical students are all too fam i l i a r with the often exhausting process of provi ding documentati o n of their disab i l i ty, you should realize that applying for USMLE accommodation is different from these previous experiences. Th i s is because the N B M E d etermines whether an i ndividual is disabled solely on the basis of the g u ide l i n es set by the ADA. Previous accommodation does not in itself j ustify provision of an accommodation, so be sure to review the N B M E gu idelines carefully. Getting the Information The first step in applying for U SMLE special accommodations is to contact the NBME and obtain a gu idelines and questionnaire booklet. Th is can be obtained by cal l i ng or writing to : Testing Coordinator Office of Test Accommodations National Board of Medical Examiners 3 7 5 0 Market Street Philadelph ia, PA 1 9 1 04-3 1 02 ( 2 1 5 ) 590-9 5 09 Internet access to this information is also ava i l able at www. n b m e . org. Th is i n formation is also relevant for I M G s , s i n c e the information is the same as that sent by the ECFMG. Foreign graduates should contact the E C F M G to obtai n i n formation on special accommodations by calling or writing to : ECFMG 3 624 Market Street Philadelph ia, PA 1 9 1 04-268 5 ( 2 1 5 ) 3 86- 5900 Wh en you get th is i n formatio n , take some t i m e to read i t carefu l ly. The gu i d e l i nes are clear and expl i c i t about what you n e e d to d o to obta i n accommodations. SECTION II High-Yield General Principles "There comes a time when for every addition of knowledge you forget something that you knew before. It is of the highest importance, therefore, not to have useless facts elbowing out the useful ones." -Sir Arthur Conan Doyle, A Study in Scarlet "Never regard study as a duty, but as the enviable opportunity to leam." -Albert Einstein "Live as if you were to die tomorrow. Leam as if you were to live forever." -Gandhi 46 SECTION II HIGH-YIELD GENERAL PRINCIPLES 􀁞 HOW TO USE THE DATABASE The 2013 edition of First Aid for the USMLE Step 1 contains a revised and expanded database of basic science material that student authors and faculty have identified as high yield for board review. The information is presented in a partially organ-based format. Hence, Section II is devoted to pathology and the foundational principles of behavioral science, biochemistry, microbiology, immunology, and pharmacology. Section III focuses on organ systems, with subsections covering the embryology, anatomy and histology, physiology, pathology, and pharmacology relevant to each. Each subsection is then divided into smaller topic areas containing related facts. Individual facts are generally presented in a three-column format, with the Title of the fact in the first column, the Description of the fact in the second column, and the Mnemonic or Special Note in the third column. Some facts do not have a mnemonic and are presented in a two-column format. Others are presented in list or tabular form in order to emphasize key associations. The database structure used in Sections II and III is useful for reviewing material already learned. These sections are not ideal for learning complex or highly conceptual material for the first time. The database of high-yield facts is not comprehensive. Use it to complement your core study material and not as your primary study source. The facts and notes have been condensed and edited to emphasize the essential material, and as a result, each entry is "incomplete" and arguably "over-simplified." Often the more you research a topic, the more complex it gets, and certain topics resist simplification. Work with the material, add your own notes and mnemonics, and recognize that not all memory techniques work for all students. We update the database of high-yield facts annually to keep current with new trends in boards content as well as to expand our database of information. However, we must note that inevitably many other very highyield entries and topics are not yet included in our database. We actively encourage medical students and faculty to submit entries and mnemonics so that we may enhance the database for future students. We also solicit recommendations of alternate tools for study that may be useful in preparing for the examination, such as diagrams, charts, and computerbased tutorials (see How to Contribute, p. xvii). Image Acknowledgments Images marked with􀁜 are reproduced with permission of USMLE-Rx.com. Images marked with lil!l are reproduced with permission of Dr. Richard P. Usatine and the Color Atlas of Family Medicine (www.usatinemedia.com). Images marked with c are reproduced with permission of other sources. Citations are listed on page 633. HIGH-YIELD GENERAL PRINCIPLES Disclaimer The entries in this section reflect student opinions of what is high yield. Because of the diverse sources of material, no attempt has been made to trace or reference the origins of entries individually. We have regarded mnemonics as essentially in the public domain. Errors and important omissions will gladly be corrected if brought to the attention of the authors, either through our online errata process or directly by e-mail. SECTION II 4 7 4 8 SECTION II 􀁞 NOTES HIGH-YIELD GENERAL PRIN CI PLES HIGH-YIELD PRINCIPLES IN Behavioral Science "It's psychosomatic. You need a lobotomy. I'll get a saw." -Calvin, "Calvin & Hobbes" A heterogeneous mix of epidemiology, biostatistics, ethics, psychology, sociology, and more falls under the heading of behavioral science. Many medical students do not study this discipline diligently because the material is felt to be easy or a matter of common sense. In our opinion, this is a missed opportunity. Behavioral science questions may seem less concrete than questions from other disciplines, requiring an awareness of the social aspects of medicine. For example, if a patient does or says something, what should you do or say in response? These so-called quote questions now constitute much of the behavioral science section. Medical ethics and medical law are also appearing with increasing frequency. In addition, the key aspects of the doctor-patient relationship (e.g., communication skills, open-ended questions, facilitation, silence) are high yield, as are biostatistics and epidemiology. Make sure you can apply biostatistical concepts such as specificity and predictive values in a problem-solving format. 50 SECTION II BEHAVIORAL SCIENCE 􀁽 BEHAVIORAL SCIENCE-EPIDEMIOLOGY/BIOSTATISTICS 􀁽 BEHAVIORAL SCIENCE-EPIDEMIOLOGY/BIOSTATISTICS Types of studies STUDY TYPE Case-control study Observational and retrospective Cohort study Observational and prospective or retrospective Cross-sectional study Observational Twin concordance study Adoption study Clinical trial Phase I Phase II Phase Ill Phase IV DESIGN Compares a group of people with disease to a group without disease. Looks for prior exposure or risk factor. Asks, "What happened?" Compares a group with a given exposure or risk factor to a group without such exposure. Looks to see if exposure t the likelihood of disease. Can be prospective (asks, "Who will develop disease?") or retrospective (asks, "Who developed the disease [exposed vs. non exposed]?"). Collects data from a group of people to assess frequency of disease (and related risk factors) at a particular point in time. Asks, "What is happening?" Compares the frequency with which both monozygotic twins or both dizygotic twins develop same disease. Compares siblings raised by biological vs. adoptive parents. MEASURES/EXAMPLE Odds ratio (OR). " Patients with CO PD had higher odds of a history of smoking than those without CO PD had." Relative risk (RR). "Smokers had a higher risk of developing CO PD than nonsmokers had." Disease prevalence. Can show risk factor association with disease, but does not establish causality. Measures heritability. Measures heritability and influence of environmental factors. Experimental study involving humans. Compares therapeutic benefits of 2 or more treatments, or of treatment and placebo. Study quality improves when study is randomized, controlled, and double-blinded (i.e., neither patient nor doctor knows whether the patient is in the treatment or control group). Triple-blind refers to the additional blinding of the researchers analyzing the data. STUDY SAMPLE Small number of healthy volunteers. Small number of patients with disease of interest. Large number of patients randomly assigned either to the treatment under investigation or to the best available treatment (or placebo). Postmarketing surveillance trial of patients after approval. PURPOSE Assesses safety, toxicity, and pharmacokinetics. Assesses treatment efficacy, optimal dosing, and adverse effects. Compares the new treatment to the current standard of care. Detects rare or long-term adverse effects. BEHAVIORAL SCIENCE 􀁼 BEHAVIORAL SCIENCE-EPIDEMIOLOGY/BIOSTATISTICS SECTION II 5 1 Evaluation of diagnostic tests Sensitivity (truepositive rate) Specificity (truenegative rate) Positive predictive value (PPV) Negative predictive value (NPV) <1 data-blogger-escaped-.=""> a. 0 <1 data-blogger-escaped-.=""> 0.. 0 Q; ..0 E :::> z Uses 2 x 2 table comparing test results with the actual presence of disease. TP = true positive; FP =false positive; TN = true negative; F = false negative. Sensitivity and specificity are fixed properties of test; however, PPV and NPV vary with prevalence or pretest probability. Proportion of all people with disease who test positive, or the probability that a test detects disease when disease is present. Value approaching 100% is desirable for ruling out disease and indicates a low false-negative rate. Used for screening in diseases with low prevalence. Proportion of all people without disease who test negative, or the probability that a test indicates non-disease when disease is absent. Value approaching 100% is desirable for ruling in disease and indicates a low false-positive rate. Used as a confirmatory test after a positive screening test. Example: HJV testing. Screen with ELISA (sensitive, high false-positive rate, low threshold); confirm with Western blot (specific, high false-negative rate, high threshold). Proportion of positive test results that are true positive. Probability that person actually has the disease given a positive test result. Proportion of negative test results that are true negative. Probability that person actually is disease free given a negative test result. Disease ® e 􀀆:1 T P FP FN TN = T P I (TP + FN) = 1 -false-negative rate PID =Positive In Disease SNOUT = SeNsitivity rules OUT If 100% sensitivity, TP I (TP + F ) = 1, F = 0, and all negatives must be TNs = T N I (TN + FP) = 1 - false-positive rate NIH= Negative In Health SPIN= SPecificity rules IN If 100% specificity, T N I (TN+ FP) = 1, FP = 0, and all positives must be TPs = TP I (TP + FP) PPV varies directly with prevalence or pretest probability: high pretest probability-+ high PPV = TN I (FN + TN) NPV varies inversely with prevalence or pretest probability: high pretest probability-+ low NPV A 100% sensitivity Test results B practical compromise between specificity and sensitivity C 100% specificity 52 SECTION II Incidence vs. prevalence Quantifying risk Odds ratio {OR) Relative risk (RR) Attributable risk Absolute risk reduction {ARR) Number needed to treat Number needed to harm BEHAVIORAL SCIENCE • BEHAVIORAL SCIENCE-EPIDEMIOLOGY/BIOSTATISTICS # of new cases in a specified time period Incidence rate = Population at risk during same time period I) 1 # of existing cases reva en c e = ..,-------o------"'------- --o- Population at risk Prevalence"" incidence rate x average disease duration. Prevalence> incidence for chronic diseases (e.g., diabetes). Typically used in case-control studies. Odds that the group with the disease (cases) was exposed to a risk factor (a/c) divided by the odds that the group without the disease (controls) was exposed (b/d). Typically used in cohort studies. Risk of developing disease in the exposed group divided by risk in the unexposed group (e.g., if 2 1% of smokers develop lung cancer vs. 1% of nonsmokers, RR = 2 1/ 1 = 2 1). If prevalence is low, RR"" OR. The difference in risk between exposed and unexposed groups, or the proportion of disease occurrences that are attributable to the exposure (e.g., if risk of lung cancer in smokers is 21% and risk in nonsmokers is 1%, then 20% of the 2 1% risk of lung cancer in smokers is attributable to smoking). Absolute reduction in risk associated with a treatment as compared to a control (e.g., if 8% of people who receive a placebo vaccine develop flu vs. 2% of people who receive a flu vaccine, then ARR = 8%-2% = 6%). Number of patients who need to be treated for 1 patient to benefit. Calculated as !/absolute risk reduction. Number of patients who need to be exposed to a risk factor for 1 patient to be harmed. Calculated as 1/attributable risk. Incidence looks at new incidents. Prevalence looks at all current cases. Odds rat1. o = -ale = -ad b/d be Relative risk a/(a t b) = ---,-e/( e t d) Attributable risk = _a_ - _e_ 􀀅® ® I a ci18 c atb e t d Disease 8 b d BEHAVIORAL SCIENCE • BEHAVIORAL SCIENCE-EPIDEMIOLOGY/BIOSTATISTICS SECTION II 53 Precision vs. accuracy Precision Accuracy Bias Selection bias Recall bias Sampling bias Late-look bias Procedure bias Confounding bias Lead-time bias Observer-expectancy effect Hawthorne effect The consistency and reproducibility of a test (reliability). The absence of random variation in a test. The trueness of test measurements (validity). The absence of systematic error or bias in a test. Accurate Precise Random error-reduces precision in a test. t precision -+ ! standard deviation. Systematic error-reduces accuracy in a test. Accurate and precise X Not accurate, not precise Occurs when there is systematic error or favor in a particular direction. Nonrandom assignment to participation in a study group (e.g., Berkson's bias, loss to follow-up) Knowledge of presence of disorder alters recall by subjects; common in retrospective studies Subjects are not representative of the general population; therefore, results are not generalizable. A type of selection bias. Information gathered at an inappropriate time-e.g., using a survey to study a fatal disease (only those patients still alive will be able to answer survey) Subjects in different groups are not treated the same-e.g., more attention is paid to treatment group, stimulating greater adherence Occurs when factor is related to both exposure and outcome, but is not on the causal pathway; factor distorts or confuses effect of exposure on outcome Early detection confused with t survival; seen with improved screening (natural history of disease is not changed, but early detection makes it seem as though survival t) Occurs when a researcher's belief in the efficacy of a treatment changes the outcome of that treatment Occurs when the group being studied changes its behavior owing to the knowledge of being studied Ways to reduce bias: • Blind studies to limit influence of participants and researchers on interpretation of outcomes • Placebo control groups • Crossover studies (each subject acts as own control) to limit confounding bias • Randomization to limit selection bias and confounding bias • Matching to reduce confounding bias Dr. Hawthorne is watching you X 54 SECTION II I BEHAVIORAL SCIENCE 􀁼 BEHAVIORAL SCIENCE-EPIDEMIOLOGY/BIOSTATISTICS Statistical distribution Measures of central tendency= mean, median, mode. Measures of dispersion =standard deviation (SD), standard error of the mean (SEM), Z-score, confidence interval. Normal distribution Gaussian, also called bell-shaped. SO and SEM Positive skew Negative skew Statistical hypotheses Null (H0) Alternative (H1) Statistical error types Type I error (a) Type II error (􀁍) Mean =median= mode. cr = SD; n =sample size. SEM = a!-Vn.. SEM 􀄶as n t. Typically, mean > median > mode. Asymmetry with longer tail on right. Mode is least affected by outliers in the sample. Typically, mean - ""0 .a Ho V> 􀁻 Correct Also known as false-positive error. If p < .05, then there is less than a 5% chance that the data will show something that is not really there. a= you saw a difference that did not exist-e.g., convicting an innocent man. Also known as false-negative error. p =you were blind to a difference that did exist-e.g., setting a guilty man free. BEHAVIORAL SCIENCE 􀁼 BEHAVIORAL SCIENCE-EPIDEMIOLOGY/ BIOSTATISTICS SECTION II 55 Power (1- p) Meta-analysis Confidence interval t-test vs. ANOVA vs. X1 t-test AN OVA Chi-square (Xl) Pearson's correlation coefficient (r) Disease prevention Primary Secondary Tertiary Probability of rejecting null hypothesis when it is in fact false, or the likelihood of finding a difference if one in fact exists. It increases with: • t sample size • t expected effect size • t precision of measurement Pools data and integrates results from several similar studies to reach an overall conclusion. t statistical power. Range of values in which a specified probability of the means of repeated samples would be expected to fall. CI = confidence interval. CI =range from (mean- Z(SEM)] to (mean+ Z(SEM)]. The 95% CI (corresponding top= .05) is often used. For the 95% CI, Z = 1.96. For the 99% CI, Z = 2.58. Checks difference between the means of 2 groups. Checks difference between the means of 3 or more groups. Test checks difference between 2 or more percentages or proportions of categorical outcomes (not mean values). If you t sample size, you t power. There is power in numbers. Limited by quality of individual studies or bias in study selection. If the 95% CI for a mean difference between 2 variables includes 0, then there is no significant difference and H0 is not rejected. If the 95% CI for odds ratio or relative risk includes l, I-I0 is not rejected. If the Cis between 2 groups do not overlap --+ significant difference exists. If the Cis between 2 groups overlap--+ usuaiJy no significant difference exists. Mr. T is mean. ANOVA =ANalysis Of VAriance of 3 or more groups. X2 =compare percentages (%) or proportions. r is always between -1 and +l. The closer the absolute value of r is to l, the stronger the linear correlation between the 2 variables. Coefficient of determination= r2 (value that is usually reported). Prevent disease occurrence (e.g., HPV vaccination). Early detection of disease (e.g., Pap smear). Reduce disability from disease (e.g., chemotherapy). PDR: Prevent Detect Reduce disability 56 SECTION II Medicare and Medicaid BEHAVIORAL SCIENCE 􀁽 BEHAVIORAL SCIENCE-ETHICS Medicare and Medicaid-federal programs that originated from amendments to the Social Security Act. Medicare is available to patients􀃉 65 years of age,< 65 with certain disabilities, and those with end-stage renal disease. Medicaid is joint federal and state health assistance for people with very low income. MedicarE is for Elderly. MedicaiD is for Destitute. 􀁽 BEHAVIORAL SCIENCE-ETHICS Core ethical principles Patient autonomy Beneficence Nonmaleficence Justice Informed consent Consent for minors Obligation to respect patients as individuals and to honor their preferences in medical care. Physicians have a special ethical (fiduciary) duty to act in the patient's best interest. May conflict with autonomy. If the patient can make an informed decision, ultimately the patient has the right to decide. " Do no harm." However, if the benefits of an intervention outweigh the risks, a patient may make an informed decision to proceed (most surgeries and medications fall into this category). To treat persons fairly. Legally requires: • Discussion of pertinent information • Patient's voluntary agreement to the plan of care • Freedom from coercion Exceptions to informed consent: • Patient lacks decision-making capacity or is legally incompetent • Implied consent in an emergency • Therapeutic privilege-withholding information when disclosure would severely harm the patient or undermine informed decision-making capacity • Waiver-patient waives the right of informed consent Patients must have an intelligent understanding of the risks, benefits, and alternatives, which include no intervention Written consent can be revoked by the patient at any time, even orally. A minor is generally any person< 18 years of age. Parental consent laws in relation to health care vary state by state. Generally, consent must be obtained unless minor is emancipated (e.g., is married, is self-supporting, has children, or is in the military). Parental consent is not required in ( 1) emergency situations, (2) prescribing contraceptives, (3) treating ST Ds, (4) medical care of pregnancy, and (5) treatment of drug addiction. Decision-making capacity Advance diredives Oral advance directive Living will (written advance directive) Medical power of attorney Surrogate decisionmaker Confidentiality BEHAVIORAL SCIENCE • BEHAVIORAL SCIENCE-ETHICS SECTION II 57 Physician must determine whether the patient is psychologically and legally capable of making a particular health care decision. The patient's family cannot require that a doctor withhold information from the patient if patient demonstrates decision-making capacity. Components: • Patient makes and communicates a choice • Patient is informed (knows and understands) • Decision remains stable over time • Decision is consistent with patient's values and goals, not clouded by a mood disorder • Decision is not a result of delusions or hallucinations Instructions given by a patient in anticipation of the need for a medical decision. State-specific. Incapacitated patient's prior oral statements commonly used as guide. Problems arise from variance in interpretation. If patient was informed, directive was specific, patient made a choice, and decision was repeated over time to multiple people, the oral directive is more valid. Describes treatments the patient wishes to receive or not receive if he/she loses decision-making capacity. Usually, patient directs physician to withhold or withdraw life-sustaining treatment if he/ she develops a terminal disease or enters a persistent vegetative state. Patient designates an agent to make medical decisions in the event that he/she loses decision-making capacity. Patient may also specify decisions in clinical situations. Patient can revoke anytime patient wishes (regardless of competence). More flexible than a living will. If an incompetent patient has not prepared an advance directive, individuals (surrogates) who know the patient must determine what the patient would have clone if he/she were competent. Priority of surrogates: spouse, adult children, parents, adult siblings, other relatives. Confidentiality respects patient privacy and autonomy. If patient is not present or is incapacitated, disclosing information to family and friends should be guided by professional judgment of patient's best interest. The patient may waive the right to confidentiality (e.g., insurance companies). General principles for exceptions to confidentiality: • Potential harm to others is serious • Likelihood of harm to self is great • No alternative means exists to warn or to protect those at risk • Physicians can take steps to prevent harm Examples of exceptions (many are state-specific) include: • Reportable diseases (ST Ds, TB, hepatitis, food poisoning)-physicians may have a duty to warn public officials, who will then notify people at risk • The Tarasoff decision-California Supreme Court decision requiring physician to directly inform and protect potential victim from harm; may involve breach of confidentiality • Child and/or elder abuse • Impaired automobile drivers • Suicidal/homicidal patients 58 SECTION II BEHAVIORAL SCIENCE 􀁼 BEHAVIORAL SCIENCE-ETHICS Ethical situations SITUATION Patient is not adherent. Patient desires an unnecessary procedure. Patient has difficulty taking medications. Family members ask for information about patient's prognosis. A child wishes to know more about his/her illness. A 17-year-old girl is pregnant and requests an abortion. A 15-year-old girl is pregnant and wants to keep the child. Her parents want you to tell her to give the child up for adoption. A terminally ill patient requests physician assistance in ending own life. Patient is suicidal. Patient states that he/she finds you attractive. A woman who had a mastectomy says she feels "ugly" when she undresses. Patient is angry about the amount of time he/she spent in the waiting room. Patient is upset with the way he/she was treated by another doctor. A drug company offers a "referral fee" for every patient a physician enrolls in a study. A physician orders an invasive test for the wrong patient. A patient requires a treatment not covered by his/her insurance. APPROPRIATE RESPONSE Attempt to identify the patient's reason for nonadherence and determine his/her willingness to change; do not attempt to coerce the patient into adhering or refer the patient to another physician. Attempt to understand why the patient wants the procedure and address underlying concerns. Do not refuse to see the patient or refer him/her to another physician. Avoid performing unnecessary procedures. Provide written instructions; attempt to simplify treatment regimens; use teach-back method (ask patient to repeat medication regimen back to physician) to ensure patient comprehension. Avoid discussing issues with relatives without the permission of the patient. Ask what the parents have told the child about his/her illness. Parents of a child decide what information can be relayed about the illness. Many states require parental notification or consent for minors for an abortion. Unless she is at medical risk, do not advise a patient to have an abortion regardless of her age or the condition of the fetus. The patient retains the right to make decisions regarding her child, even if her parents disagree. Provide information to the teenager about the practical issues of caring for a baby. Discuss the options, if requested. Encourage discussion between the teenager and her parents to reach the best decision. In the overwhelming majority of states, refuse involvement in any form of physicianassisted suicide. Physicians may, however, prescribe medically appropriate analgesics that coincidentally shorten the patient's life. Assess the seriousness of the threat; if it is serious, suggest that the patient remain in the hospital voluntarily; patient can be hospitalized involuntarily if he/she refuses. Ask direct, closed-ended questions and use a chaperone if necessary. Romantic relationships with patients are never appropriate. Never say, "There can be no relationship while you are a patient," because this implies that a relationship may be possible if the individual is no longer a patient. Find out why the patient feels this way. Do not offer falsely reassuring statements (e.g., "You still look good."). Acknowledge the patient's anger, but do not take a patient's anger personally. Apologize for any inconvenience. Stay away from efforts to explain the delay. Suggest that the patient speak directly to that physician regarding the patient's concerns. If the problem is with a member of the office staff, tell the patient you will speak to that individual. Eligible patients who may benefit from the study may be enrolled, but it is never acceptable for a physician to receive compensation from a drug company. Patients must be told about the existence of a referral fee. No matter how serious or trivial a medical error, a physician is ethically obligated to inform a patient that a mistake has been made. Never limit or deny care because of the expense in time or money. Discuss all treatment options with patients, even if some are not covered by their insurance companies. BEHAVIORAL SCIENCE 􀁽 BEHAVIORAL SCIENCE-DEVELOPMENT SECTION II 59 􀁼 BEHAVIORAL SCIENCE-DEVELOPMENT Apgar score Low birth weight Assessment of newborn vital signs following labor via a 10-point scale evaluated at l minute and 5 minutes. Apgar score is based on Appearance, Pulse, Grimace, Activity, and Respiration (􀃉 7 =good; 4-6 =assist and stimulate;< 4 = resuscitate). If Apgar score remains< 4 at later time points, there is t risk that the child will develop long-term neurological damage. Defined as< 2500 g. Caused by prematurity or intrauterine growth retardation. Associated with t risk of SIDS, and with t overall mortality. Other problems include impaired thermoregulation and immune function, hypoglycemia, polycythemia, and impaired neurocognitive/emotional development. Complications include infections, respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage, and persistent fetal circulation. Early developmental milestones AGE Infant Birth-3 mo 7-9 mo 12-15 mo Toddler 12-24 mo 24-36 mo Preschool 3 yr 4 yr MOTOR SOCIAL Rooting reflex, holds head up, Social smile Mora reflex disappears Sits alone, crawls, transfers toys Stranger anxiety from hand to hand Walks, Babinski sign disappears Separation anxiety Climbs stairs; stacks 3 blocks at l yr, 6 blocks at 2 yr (age x 3 =no. of blocks) Feeds self with fork and spoon, kicks ball Rapprochement (moves away from and then returns to mother) Core gender identity, parallel play VERBAL/COGNITIVE Orients and responds to voice Responds to name and simple instructions, uses gestures, plays peek-a-boo Few words 200 words and 2-worcl phrases at age 2 Toilet training ("pee at age 3") Rides tricycle (rides 3-cycle at age 3); copies line or circle drawings Comfortably spends part of clay 900 words and complete Uses buttons and zippers, grooms self (brushes teeth), hops on l foot, makes simple drawings (stick figures) away from mother sentences Cooperative play, imaginary Can tell detailed stories and friends use prepositions 60 SECTION II Changes in the elderly Cirief BEHAVIORAL SCIENCE • BEHAVIORAL SCIENCE-PHYSIOLOGY Sexual changes: • Men-slower erection/ejaculation, longer refractory period • Women-vaginal shortening, thinning, and dryness Sleep patterns: 􀁻 REM and slow-wave sleep; t latency and awakenings t suicide rate (men 65-74 years of age have the highest suicide rate in the United States) 􀁻 vision, hearing, immune response, bladder control 􀁻 renal, pulmonary, Gl function 􀁻 muscle mass, t fat Sexual interest does not !. Intelligence does not􀁻- Normal bereavement characterized by shock, denial, guilt, and somatic symptoms. Can last up to 1 year. May experience illusions. Pathologic grief includes excessively intense grief; prolonged grief lasting > 2-6 months; or grief that is delayed, inhibited, or denied. May experience depressive symptoms, delusions, and hallucinations. • BEHAVIORAL SCIENCE-PHYSIOLOGY Sexual dysfundion Includes sexual desire disorders (hypoactive sexual desire or sexual aversion), sexual arousal disorders (erectile dysfunction), orgasmic disorders (anorgasmia and premature ejaculation), and sexual pain disorders (dyspareunia and vaginismus). Differential diagnosis includes: • Drugs (e.g., antihypertensives, neuroleptics, SSRis, ethanol) • Diseases (e.g., depression, diabetes) • Psychological (e.g., performance anxiety) Body-mass index {BMI) BMI is a measure of weight adjusted for height. < 18.5 underweight 18.5-24.9 normal weight 25.0-29.9 overweight BMI = weight in kg (height in meters)2 > 30.0 obesity > 35.0 severe obesity > 40.0 morbid obesity > 45.0 super obesity Sleep stages STAGE (%OF TOTAL SLEEP TIME IN YOUNG ADULTS) Awake (eyes open) Awake (eyes closed) Stage Nl (5%) Stage N2 {45%) Stage N3 {25%) REM (25%) REM sleep BEHAVIORAL SCIENCE 􀁼 BEHAVIORAL SCIENCE-PHYSIOLOGY SECTION II 6 1 DESCRIPTION Alert, active mental concentration Light sleep Deeper sleep; bruxism Deepest, non-REM sleep (slow-wave sleep); sleepwalking; night terrors; bedwetting Dreaming, loss of motor tone, possibly a memory processing function, erections, t brain 02 use EEG WAVEFORM Beta (highest frequency, lowest amplitude) Alpha Theta Sleep spindles and K complexes Delta (lowest frequency, highest amplitude) Beta Serotonergic predominance of raphe nucleus is At night, BATS Drink Blood key to initiating sleep. Sleep enuresis is treated with oral desmopressin acetate ( DDAV P), which mimics vasopressin (ADH, antidiuretic hormone); preferred over imipramine because of the latter's adverse effects. Alcohol, benzodiazepines, and barbiturates are associated with reduced REM and delta sleep. Benzodiazepines are useful for night terrors and sleepwalking. Awake Stage Nl Stage N2 Stage N3 REM K- Sleep complex spindle (Adapted, with permission, from Barrett KE et al. Ganong's Review of Medical Physiology. 23rd ed. New York: McGraw-Hill, 20 I 0, Fig. 15-7.) Occurs every 90 minutes; duration t through the night. ACh is the principal neurotransmitter in REM sleep. NE reduces REM sleep. Findings: t and variable pulse and blood pressure. Extraocular movements during REM sleep due to activity of PPRF (paramedian pontine reticular formation/ conjugate gaze center). Penile/clitoral tumescence. REM sleep is like sex: t pulse, penile/clitoral tumescence, ! frequency with age. Because REM sleep has the same EEC patterns as wakefulness, it has been termed "paradoxical sleep" and "desynchronized sleep." 6 2 SECTION II Sleep patterns of depressed patients Narcolepsy Circadian rhythm Sleep terror disorder BEHAVIORAL SCIENCE 􀁼 BEHAVIORAL SCIENCE-PHYSIOLOGY Patients with depression typically have the following changes in their sleep stages: • ! slow-wave sleep • ! REM latency • t REM early in sleep cycle • t total REM sleep • Repeated nighttime awakenings • Early-morning awakening (important screening question) Disordered regulation of sleep-wake cycles; primary characteristic is excessive daytime sleepiness. May include hypnagogic (just before sleep) or hypnopompic (just before awakening) hallucinations. The patient's nocturnal and narcoleptic sleep episodes start off with REM sleep. Cataplexy (loss of all muscle tone following a strong emotional stimulus) in some patients. Strong genetic component. Treated with daytime stimulants (e.g., amphetamines, modafinil) and nighttime sodium oxybate (GHB). Driven by suprachiasmatic nucleus (SCN) of hypothalamus. Controls ACTH, prolactin, melatonin, nocturnal NE release. SC -+ NE release -+ pineal gland -+ melatonin. SCN is regulated by environment (i.e., light). Periods of terror with screaming in the middle of the night; occurs during slow-wave sleep. Most common in children. Occurs during non-REM sleep (no memory of arousal) as opposed to nightmares that occur during REM sleep (memory of a scary dream). Cause unknown, but triggers may include emotional stress during the previous day, fever, or lack of sleep. Usually self limited. HIGH-YIELD PRINCIPLES IN Biochemistry "Biochemistry is the study of carbon compounds that crawl." -Mike Adams "We think we have found the basic mechanism by which life comes from lz·1r.e . " - Francis H . C . Crick This high-yield material includes molecular biology, genetics, cell biology, and principles of metabolism (especially vitamins, cofactors, minerals, and single-enzyme-deficiency diseases). When studying metabolic pathways, emphasize important regulatory steps and enzyme deficiencies that result in disease, as well as reactions targeted by pharmacologic interventions. For example, understanding the defect in Lesch-Nyhan syndrome and its clinical consequences is higher yield than memorizing every intermediate in the purine salvage pathway. Do not spend time on hard-core organic chemistry, mechanisms, or physical chemistry. Detailed chemical structures are infrequently tested; however, many structures have been included here to help students learn reactions and the important enzymes involved. Familiarity with the biochemical techniques that have medical relevance-such as enzyme-linked immunosorbent assay (ELISA), immunoelectrophoresis, Southern blotting, and PCR-is useful. Beware if you placed out of your medical school's biochemistry class, as the emphasis of the test differs from that of many undergraduate courses. Review the related biochemistry when studying pharmacology or genetic diseases as a way to reinforce and integrate the material. 64 S E C T I O N I I B I O C H E M I ST RY 􀂬 B I O C H E M I S T R Y - M O L E CU L A R 􀂭 BIO C HEMISTRY- MOLECULAR Chromatin structure DNA exists in the condensed, chromatin form i n order to fit i nto the nucleus. Negatively charged DNA loops twice around positively charged h istone octamer to form nucleosome "bead." H istones are rich in the amino acids lysine and argin i ne. Hl ties nucleosome beads together in a string. In mitosis, DNA condenses to form chromosomes. H eterochromatin Condensed, transcriptionally inactive, sterically inaccessible. Euchromatin Less condensed, transcriptionally active, sterically accessible. DNA methylation Template strand cytosine and adenine are methylated i n DNA repl ication , wh ich allows m ismatch repair enzymes to distinguish between old and new strands in prokaryotes. H istone methylation H istone acetylation Inactivates transcription of DNA. Relaxes DNA coiling, allowing for transcription. Nucleotides PURi nes (A, G )-2 rings. PYrimidines (C, T, U ) -1 ring. Guanine has a ketone . Thym ine has a methyl . Deamination of cytosine makes uracil. Uracil found in RNA; thym ine in DNA. G-C bond ( 3 H bonds) stronger than A-T bond (2 H bonds ) . t G-C content - t melting temperature. Purine (A, G) Pyrimidine (C, T, U) C02 Carbamoyl phosphate I Glycine Aspartate y- , , ·-, ¥ \/c....._.·;,-􀃌􀃍 \ ...... . 􀃎--;.c, : IN ::cI ;: .. ' C+N1 0-Formyl· c : c : / tetrahydrofolate 􀂎 '-. N',. ;. • >-,. N N10_Formyl-' 􀂫 . tetrahydrofolate G lutamine :. IN . c• ':: . c. 􀂏':: -􀂐=-c-1.::': t Aspartate Think of " beads on a string." 􀂞 .. • .. • o& • 􀂌 􀂍 .. • • .. I . [] Nucleosome core h i stones H2A, H2B, H3, H4 (each x2) H l is the only h istone that is not in the nucleosome core. HeteroChromatin = H igh ly Condensed . E u = true, " truly transcribed." Methylation makes DNA Mute. Acetylation m akes DNA Active. PURe As Gold. CUT the PY (pie) . Thym i n e has a met hyl . GAG -Amino acids necessary for purine synthesis : Glycine Aspartate Gluta m i ne NucleoSide = base + ribose ( Sugar) . NucleoTides = base + ribose + phosphaTe ; l i nked by 3'-5' phosphodiester bond. BIOCHEMISTRY 􀂬 BIOCHEMISTRY-M OLECULAR S E C T I O N I I 6 5 De novo pyrimidine and purine synthesis Purines Pyrimidines Make temporary base (orotic acid) Add sugar + phosphate (PRPP) Modify base Start with sugar + phosphate ( PRPP) Add base Pyrimidine base production Purine base production or (requires aspartate) Ribosle 5 -P reuse from salvag e pathway Carbamoyl (de novo requires aspartate, phosphate glycine, glutamine, and THFJ \t< / PRPP􀀠- 6-MP aod \E UMP 􀂪 IMP # U D P / 􀃉 Hyd roxyurea -0-f !f$ \ AMP GMP &!i 􀃊􀃋 d U D P CTP ! Ribonucleotides are synthesized first and are converted to deoxyribonucleotides by ribonucleotide reductase. Carbamoyl phosphate is i nvolved in 2 metabol ic pathways : de novo pyrim idine synthesis and the urea cycle. Ornithine transcarbamoylase deficiency ( OTC , key enzyme in the urea cycle) leads to a n accumulation of carbamoyl phosphate, wh ich is then converted to orotic acid. Various anti neoplastic and antibiotic d ru gs function by interfering with puri ne synthesis: • Hydroxyurea i n h ibits ribonucleotide NSNIO_ dUMP reductase Lmethylene THF􀀟􀁉􀁋 THF - DHF 􀃅r;;-t-0-5-FU Oihydrofolate >- • 6-mercaptopurine (6-MP) blocks de novo purine synthesis • 5 -Auorouracil ( 5 -FU) i n h ibits thymidylate synthase ( 􀂹 deoxythymidine m onophosphate [dTMP]) reductase dTMP 􀁌 MTX/TMP • Methotrexate ( MTX) i n h ibits d i hydrofolate reductase ( 􀂹 dTM P) • Tri methopri m (TMP) i n h ibits bacterial d i hydrofolate reductase (! dTMP) Orotic aciduria Inabil ity to convert orotic acid to UMP (de novo pyrimidine synthesis pathway) because of defect i n U M P synthase (a bifunctional enzyme). Autosomal recessive. FINDINGS TREATMENT t orotic acid in urine, megaloblastic anem ia (does not i mprove with adm i n istration of vita m i n B12 or folic acid), failure to thrive. No hyperammonem ia (vs. OTC deficiency- t orotic acid with hyperammonemia). Oral uridine admin istration. 6 6 S E C T I O N I I B I O C H E M I S T RY • B I O C H E M I S T RY-M O L E CU L A R Purine salvage deficiencies Adenosine deaminase deficiency Lesch-Nyhan syndrome Genetic code features Unambiguous Degenerate/ redundant Comma less, nonoverlapping U n iversal N ucleic acids N ucleic acids ll ll Guanylic acid (GMP) 􀁇 Inosinic acid Adenylic acid 0 I )"'""'"' (IMP) 􀁊 (AMP) o J ))''"' 􀂋 "'!{. 1 e Guani n􀀧 (} ;xanthine • Adenine, 􀁈 / 0 HGPRT t PRPP Xanthine eJ Uric acid Excess ATP and dATP imbalances nucleotide pool via feedback inh ibition of ribonucleotide reductase -+ prevents DNA synthesis and thus ! lymphocyte count. One of the major causes of SCID. Autosomal recessive. Defective purine salvage owing to absence of HGPRT, which converts hypoxanthine to IMP and guanine to GMP. Results in excess uric acid production and de novo purine synthesis. X-l i nked recessive. Findings : retardation , self-mutilation, aggression, hyperuricemia, gout, choreoathetosis. Each codon specifies only l amino acid. Most amino acids are coded by multiple codons . Read from a fixed starting point as a continuous sequence of bases. Genetic code is conserved th roughout evolution . f) APRT t PRPP (}E) Adenosine deaminase (ADA) Xanthine oxidase • Base from degraded DNA/RNA Severe C ombi ned Im m u nodeficiency Disease ( SCID ) happens to kids . lst d i sease to be treated by experimental human gene therapy. He's Got Purine Recovery Trouble. Exception s : meth ionine and tryptophan encoded by only l codon (AUG and UGG, respectively) . Exception s : some viru ses. Exception i n humans: m itochondria. B I O C H E M I S T R Y 􀂬 B I O C H E M I S T R Y - M O L E CU L A R Point mutations in DNA Severity of damage : silent< m issense< nonsense< framesh i ft. Silent Same a m i no acid, often base change in 3rd Missense Nonsense Frameshift position of codon (tRNA wobble ) . Changed amino acid (conservative -new a m i n o a c i d is similar i n chemical structure) . Change resulting in early stop codon. Stop the nonsense! Change resulting i n m i sread ing of all nucleotides downstream, usually resulting in a truncated, nonfunctional protein. S E C T I O N I I 6 7 6 8 S E C T I O N I I DNA replication Origin of replication Replication fork Helicase Single-stranded binding protei n s D N A topoisomerases Primase DNA polymerase I l l D N A polymerase I DNA ligase Telomerase B I O C H E M I S T R Y 􀂬 B I O C H E M I S T R Y - M O L E CU L A R Eukaryotic DNA repl ication is more complex than the prokaryotic process but uses many enzymes analogous to those l isted below. I n both prokaryotes and eukaryotes, DNA repl ication is semiconservative and i nvolves both continuous and d i scontinuous ( Okazaki fragment) synthesis. Particular consensus sequence of base pairs in genome where DNA repl ication begins. May be single (prokaryotes) or multiple (eukaryotes). Y-shapecl region along DNA template where lead ing and lagging strands are synthesized. Unwinds DNA template at repl ication fork. Prevent strands from reannealing. Create a n ick in the hel i x to relieve supercoils created during repl ication. Makes an RNA primer on which DNA polymerase I I I can i niti ate repl ication. Prokaryotic only. Elongates leading strand by adding cleoxynucleoticles to the 3' encl. Elongates lagging strand until it reaches primer of preceding fragment. 3' -+ 5' exonuclease activity "proofreads" each aclclecl nucleotide. Prokaryotic only. Degrades RNA primer; replaces it with DNA. Catalyzes the formation of phosphodiesterase bond within a strand of double-stranded DNA (i.e. , joins Okazaki fragments). Enzyme adds DNA to 3' ends of chromosomes to avoid loss of genetic material with every dupl ication. DNA Fluoroqui nolones - i n h ibit DNA gyrase (prokaryotic topoisomerase I I ) . DNA polymerase I I I h a s 5 ' -+ 3 ' synthesis and proofreads with 3' -+ 5' exonuclease. Has same functions as DNA polymerase I I I b u t a l s o excises RNA primer with 5 ' -+ 3' exonuclease. Seals. Lagging strand 3' s· DNA repair Single stran d Nucleotide excision repair Base excision repair Mismatch repair D o u b l e stra nd Nonhomologous end joining DNA/RNA/protein synthesis direction BIOCHEMISTRY 􀂬 BIOCHEMISTRY-MOLECULAR S E C T I O N I I 6 9 Specific endonucleases release the oligonucleotide-conta ining damaged bases; DNA polymerase and l i gase fill and reseal the gap, respectively. Repa irs bulky hel ix-distorting lesions. Mutated i n xeroderma pigmentosum, which prevents repa i r of pyri m i d i ne cli mers because of ultraviolet l i ght exposure. Specific glycosylases recogn ize and remove damaged bases, apur inic/apyrimidinic endonuclease cuts DNA at both apurinic and apyr i m i d i n i c sites, empty sugar is removed, and the gap is filled and resealed. Important i n repai r of spontaneous/toxic dea m i nation. Newly synthesized strand is recogn ized, mismatched nucleotides are removed, and the gap is filled and resealed. Mutated in hered itary nonpolyposis colorectal cancer ( H N PC C ). Bri ngs together 2 ends of DNA fragments to Mutated in ataxia telangiectasia. repa i r double-stranded breaks. No requ i rement for homology. DNA and RNA are both synthesized 5' -+ 3'. m RNA is read 5' to 3'. Remember that the 5' of the incom ing Protein synthesis is N-term inus to C -terminus. nucleotide bears the triphosphate (energy source for bond). The triphosphate bond is the target of the 3' hydroxyl attack. Drugs blocking DNA repl ication often have modified 3' O H , preventing addition o f t h e next nucleotide ( "chain term i nation"). D N A replication 5' 0 0 0 " / 5' .f'p'\... 0 o- OH H 3' DNA synthesis requ i res a free 3' OH to add the n ext nucleotide 􀃈0 )( )( \11 0-P-0-P-Q-P -Q I I I 0 0 0 OH H 7 Q S E C T I O N I I Types of RNA Start and stop codons mRNA start codons Euka ryotes P roka ryotes mRNA stop codons Fundional organization of the gene BIOCHEMISTRY • BIOCHEMISTRY- MOLECU LAR rRNA is the most abundant type. mR A is the longest type. tRNA is the smallest type. AUG (or rarely GUG ) . rampant, massive, ti ny. AUG inAUGurates protein synthesis. C odes for meth ionine, which may be removed before translation is completed. C odes for for myl methionine (f-met) . UGA, UAA, UAG . Sense/coding UGA = U Go Away. UAA = U Are Away. UAG = U Are Gone. Sta rt o f transcription (+1) 3' ) Enhancer Template strand ,_, ..􀂝-"-'-''-- ...r- 5' Promotor Coding region Termination signals Regulation of gene expression Promoter Enhancer Silencer RNA polymerases Euka ryotes P roka ryotes S ite where RNA polymerase and multiple other transcription factors bind to DNA upstream from gene locus (Kf-rich upstream sequence with TKfA and CAAT boxes) . Stretch of DNA that alters gene expression by binding transcription factors. Site where negative regulators (repressors) bind. RNA polymerase I makes rRNA (most numerous RNA, rampant) . RNA polymerase II makes mRNA (largest RNA, massive) . RNA polymerase I I I makes tR A (smallest RNA, tiny) . No proofread ing function, but can in itiate chains. RNA polymerase I I opens DNA at promotor site. l RNA polymerase (multisubunit complex) makes all 3 kinds of RNA. Promoter mutation commonly results in dramatic ! in amount of gene transcribed. Enhancers and silencers may be located close to, far from , or even with i n (in an i ntron) the gene whose expression it regulates. I, I I , and I I I are numbered as their products are used in protein synthesis. a-amanitin, found i n Amanita phalloides (death cap mushroom s ) , i n h ibits RNA polymerase I I . Causes severe hepatotoxicity if ingested. RNA processing (eukaryotes) Cap Coding 5' _......., Gppp i) 3' < c:t::::::::;; :=:;)=: HO-AAAAA ...., Tail Splicing of pre-mRNA lntrons vs. exons B I O C H E M I S T RY 􀂬 B I O C H E M I S T R Y - M O L E CU L A R S E C T I O N I I 7 1 Initial transcript is called heterogeneous nuclear RNA ( h n R NA) . hnRNA destined for translation is called pre-m R A. Processing occurs i n nucleus. After transcription: • Capping on 5' end (addition of 7-methylguanosine cap) • Polyadenylation on 3' end ("" 200 1\s) • Splicing out of i ntrons Capped, ta iled, and spliced transcript is called m RNA. 0 Primary transcript combines with snRNPs and other proteins to form spliceosome. f) Lariat-shaped ( looped) intermediate is generated. €) Lariat is released to remove intron precisely and join 2 exons. Patients with lupus m ake antibodies to spliceosomal snRNPs. Exons conta i n the actual genetic information coding for protein. lntrons are i ntervening noncoding segments of DNA. Only processed RNA is transported out of the nucleus. Poly-A polymerase does not requ i re a template. AAUAAA = polyadenylation signal. intron 􀂊 snRNPs.... 0 􀃆®-GU-A-AG􀃇 lariat intermediate lntrons are interveni ng sequences and stay in the nucleus, whereas exons exit and are expressed. Different exons can be combined by alternative spl icing to make u nique proteins i n d i fferent tissues (e.g., 􀃅-thalasse m i a mutations) . l ntrons Exons j Transcription and splicing 72 SECTION II tRNA Structure Charging tRNA wobble BIOCHEMISTRY 􀂬 BIOCH EMISTRY-MOLECULAR 75-90 nucleotides, zo structure, cloverleaf fo rm, CCA: C an Carry Amino acids. ant icodon end is opposite 3' aminoacyl encl. All tRNAs, both eukaryotic and prokaryotic, have CCA at 3' end along with a high percentage of chemically modified bases. The amino acid is covalently bound to the 3' end of the tRNA. Aminoacyl-tRNA synthetase (l per amino acid, "match m aker," uses ATP) scrutinizes amino acid before and after it bi nds to tRNA. If incorrect, bond is hyd rolyze d. The amino acid-tRNA bond has energy for for mation of peptide bond. A mischarged tRNA reads usual codon but inserts wrong amino ac id. Methionine "- Ace 3' Aminoacyl-tRNA synthetase Methionine "- Ace 3' AT P AMP+ PP """'..,r-\,.􀁇 􀁈􀁉 Aminoacyl -tRNA synthetase and binding of charged tRNA to the co don are responsible for accuracy of amino acid selection. Tetracycl ines bind 30S subunit, preve nting attach ment of aminoacyl-tRNA. IF2 (initiation factor) Methionine "- Ace 3' AC Ill Ill 􀁗 AUG """"-- 5' 􀈏 '--,-' 􀂝 3' mANA Codon Accurate base pairing is requ ired only in the first 2 nucleotide positions of an mR A codon, so codons diffe ring in the 3rd "wobble" position may code for the same tRNA/amino acid (as a result of degeneracy of genetic code). Protein synthesis Initiation Elongation Termination B I O C H E M I S T R Y 􀂬 B I O C H E M I S T R Y - M O L E CU L A R S E CTI O N I I 73 Activated by GTP hydrolysis, in itiation factors (eukaryotic I Fs) help assemble the 40S ribosomal subunit with the in itiator tRNA and are released when the mRNA and the ribosomal subunit assemble with the complex. l. A m inoacyl-tRNA binds to A site (except for in itiator meth ion ine) 2. R ibosomal rRNA ( "ribozyme") catalyzes peptide bond form ation , transfers growing polypeptide to a m i no acid in A site 3 . Ribosome advances 3 nucleotides toward 3' end of m RNA, moving peptidyl tRNA to P site (translocation) Stop codon is recogn ized by release factor, and completed protein is released from ribosome. Eukaryotic ribosom e 60S 3' Eukaryotes : 40S + 60S -+ 80S (Even) . PrOkaryotes : 30S + 50S ---70S (Od d). ATP- tRNA Activation (charging) . GTP- tRNA Gripping and Going places (translocation ) . T h i n k of "going APE": A site = i ncom i n g Am i noacyl-tRNA. P site = accommodates growing Peptide. E site = holds Empty tRNA as it Exits. Many antibiotics act as protein synthesis inhibitors : • Aminoglyc;osides bind 30S and inh ibit formation of i n iti ation complex and cause m isread i n g of m RNA • Tetracycl i nes bind 30S and block a m inoacyl tRNA from entering the acceptor site • Chloramphenicol binds 50S and i n h ibits peptidyl transferase • Macrolides bind 50S and prevent release of uncharged tRNA after it has donated its a m ino acid Posttranslational modifications Trimming Covalent a lterations Proteasomal degradation Removal of N- or C-term i nal propeptides from zymogens to generate mature proteins. Phosphorylation, glycosylation , hydroxylation , methylation , and acetylation . Attachment of ubiguitin to defective proteins to tag them for breakdown. 7 4 S E C T I O N I I B I O C H E M I S T RY 􀂬 B I O C H E M I S T R Y - C E L LU L A R 􀂬 B I O C H E M I S T RY - C E L LU L A R Cell cycle phases Checkpoints control transitions between phases of cell cycle. This process is regulated by cycl i ns, CDKs, and tumor suppressors. M itosis (shortest phase): prophase-metaphase-anaphase-telophase. G1 and G0 are of variable duration. REGULATION OF CELL CYCLE CDKs Cycli n-dependent kinases; constitutive and inactive. Cyclins Regulatory proteins that control cell cycle events; phase specific; activate CDKs. Cyclin-CDK complexes Must be both activated and inactivated for cell cycle to progress. Tumor suppressors CELL TYPES Permanent Stable (quiescent) Labile Rough endoplasmic reticulum Smooth endoplasmic reticulum p 5 3 and hypophosphorylated Rb normally i n h ibit G1 -to-S progression ; mutations in these genes result in unrestrained cell division. Rem a i n in G0, regenerate from stem cells. Enter G1 from G0 when stimulated. Never go to G0, d ivide rapidly with a short G1 . S ite of synthesis of secretory (exported) proteins and of N-l inked ol igosaccharide addition to many protei ns. Nissl bodies ( RER in neurons) - synthesize enzymes (e.g. , ChAT [chol ine acetyltransferase] makes ACh) and peptide neu rotra nsm i tters. Free ribosomes-unattached to any membrane; site of synthesis of cytosolic and organellar protei ns. Site of steroid synthesis and detoxification of drugs and poisons. G = Gap or Growth. S = Synthesis. Interphase (G1, S, G2) Neurons, skeletal and cardi ac muscle, RBCs. Hepatocytes, lymphocytes. Bone m arrow, gut epithel i u m , ski n, ha i r foll icles, germ cells. Mucus-secreting goblet cells of the small i ntestine and antibody-secreting plasma cells are r ich in RER. Liver hepatocytes and steroid hormoneproducing cells of the adrenal cortex are rich in SER. Cell trafficking Key: 􀀦 Clath rin 'rO COPI 􀀥 COPII Endoplasmic reticulum BIOCHEMISTRY • B IOCHE MIST RY- C E LLU L AR S E C T I O N I I 7 5 Golgi is the d istribution center for proteins and l ipids from the ER to the vesicles and plasma membrane. Modifies N-ol igosaccharides on asparagine. Adds 0-ol igosaccharides on seri ne and threon ine. Adds mannose-6-phosphate to protei ns for trafficki n g to lysosomes. Endosomes are sorting centers for material from outside the cell or from the Gol g i , send i n g it to lysosomes for destruction or back to the membrane/Golgi for fur ther use. 1-cell disease ( inclusion cel l d isease) - inherited lysosomal storage d isorder; failure of addition of mannose-6-phosphate to lysosome proteins (enzymes are secreted outside the cell i nstead of being targeted to the lysosome). Results in coarse facial features, clouded corneas, restricted joint movement, and h igh plasma levels of lysosomal enzymes. O ften fatal i n ch ildhood . Vesicu l a r t raffick i n g prote i n s C O P I : Golgi -+ Golgi (retrograde); Golgi - ER. COPI I : Golgi - Golgi (anterograde); ER - Gol g i . Clath r i n : trans-Golgi - lysosomes; plasma membrane -+ endosomes (receptormediated endocytosis). N u cl ear enve lope Peroxisome Proteasome Membrane-enclosed organelle i nvolved in catabol ism of very long fatty acids and am ino acids. Barrel-shaped protei n complex that degrades damaged or u n necessary protei ns tagged for destruction with ubiqu itin. 7 6 S E C T I O N I I Microtubule a-Tubulin 􀃄-Tu bulin Protofilament Negative end(-) Cilia structure Cytoskeletal elements Actin and myosin M icrotubule Intermediate filaments Plasma membrane composition Immunohistochemical stains for intermediate filaments B I O C H E M I ST RY 􀂬 B I O C H E M I S T R Y - C E L LU L A R Cyl indrical structure composed o f a hel ical array of polymerized climers of a- and 􀃅-tubulin. Each climer has 2 GTP bound. Incorporated into flagella, cilia, mitotic spindles. Grows slowly, collapses qu ickly. Also involved in slow axoplasm ic transport in neurons. Molecula r motor proteins - transport cellular cargo toward opposite ends of m icrotubule tracks. • Dyne in =retrograde to m icrotubule ( + ..... -). • K inesin =anterograde to m icrotubule (- ..... +) . 9 + 2 arrangement of m icrotubules. Axonemal clynein -ATPase that links peripheral 9 doublets and causes bend ing of cilium by d i fferential sl iding of doublets. Drugs that act on m icrotubules: • Mebenclazole/th iabenclazole (antihel m inth ic) • Griseofulvin (antifungal) • Vi ncristine/vinblastine (anti-cancer) • Pacl itaxel (anti-breast cancer) • Colch icine (anti-gout) Chediak- H igashi syndrome - mutation in the lysosomal trafficking regulator gene (LYST), whose product is required for the m icrotubuledependent sorting of enclosomal proteins into late multivesicular enclosomes. Results in recurrent pyogen ic i n fections, partial albin ism , and peripheral neuropathy. Kartagener's syndrome (primary ciliary dyskinesia) - i mmotile cil i a clue to a clynein arm defect. Results i n male i n fertil ity ( i m motile sperm) and ! female ferti l ity, bronch iectasis, and recurrent sinusitis (bacteria and particles not pushed out); associated with situs i nversus. M icrovilli, muscle contraction , cytokinesis, aclherens junctions. Movement. C i l i a , flagella, mitotic spi ndle, axonal trafficking, centrioles. Structure. Vimentin, clesm in, cytokeratin, lamins, gl ial fibrillary acid proteins ( G FAP), neurofilaments. Asym metric l ipid bilayer. Contains cholesterol , phosphol ipids, sph ingol ipicls, glycol ipicls, and proteins. STAIN CELL TYPE Vimentin Connective t issue Desm in Muscle Cytokeratin Epithel ial cells GFAP NeuroGl i a Neurofilaments Neurons Sodium-potassium pump Collagen Type I Type I I Type I l l Type I V BIOCHEMISTRY 􀂬 BIOCHEMISTRY-C ELLUL AR S E C T I O N I I 77 Na+ -K+ ATPase is located i n the plasma membrane with ATP site on cytosol ic side. For each ATP consumed, 3 Na+ go out and 2 K+ come in. During cycle, pump is phosphorylated. Extracel l ular side Cytosolic side Ouabain i n h ibits by binding to K+ site. Card iac glycosides (digoxi n and digitoxi n) d irectly i n h ibit the Na+-K+ ATPase, wh ich leads to i n d i rect i n hibition of Na+f C a2+ exchange -+ t [Ca2+L - t card i ac contracti l i ty. 3Na+(o o 2K+ Most abundant protein i n the human body. Be ( So Totally) Cool, Read Books. Extensively modified by posttranslational mod ification. Organizes and strengthens extracellular matrix . Most common (90%)-Bone, Skin, Tendon, Type I: bone. dentin , fascia, cornea , late wound repair. Cartilage ( i ncluding hyaline), vitreous body, nucleus pulposus. Reticu l i n-ski n, blood vessels, uterus, fetal tissue, granulation tissue. Basement membrane or basal lamina. Defective i n osteogenesis i mperfecta. Type II: cartwol age. Type III: defective i n Ehlers-Danlos (ThreE D). Type IV: under the floor ( basement membrane) . Defective i n Alport syndrome . 7 8 S E C T I O N I I B I O C H E M I ST RY 􀂬 B I O C H E M I S T RY - C E L LU L A R Collagen synthesis a n d strudure Inside fibroblasts 1. Synthesis (RER) 2. Hyd roxylation (ER) 3. Glycosylation (ER) 4. Exocytosis Outside fibroblasts 5. P roteolytic processing 6. Cross- l i nking Osteogenesis imperfeda Ehlers-Danlos syndrome Translation of collagen a cha ins (preprocollagen) - usually Gly-X-Y (X and Y are prol ine or lysine). Hydroxylation of specific prol ine and lysine residues (requires vitamin C; deficiency ..... scurvy). Glycosylation of pro-a-chain hyclroxylysine residues and formation of procollagen via hydrogen and d isulfide bonds (triple helix of 3 collagen a cha i ns). Problems form ing triple heli x -+ osteogenesis i mperfecta. Exocytosis of procollagen into extracellular space. Cleavage of d isulfide-rich terminal regions of procollagen, transforming it into i nsoluble tropocollagen. Reinforcement of many staggered tropocollagen molecules by covalent lysine-hyclroxylysine cross-linkage ( by Cu2+ -containing lysyl oxidase) to make collagen fibrils. Problems with cross-l inking -+ Ehlers-Danlos. Genetic bone d isorder (brittle bone disease) caused by a variety of gene defects. Most common form is autosomal dom inant with abnormal type I collagen, causing: • Multiple fractures with m i n imal traum a ; m a y occur during t h e birth process • Blue sclerae r.J clue to the translucency of the connective tissue over the choroidal vems • Hearing loss (abnormal m iddle ear bones) • Dental i mperfections clue to lack of dentin Faulty col lagen synthesis causing hyperextensible ski n , tendency to bleed (easy bru ising) , and hypermobile joints. 6 types. Inheritance and severity vary. Can be autosomal dom inant or recessive. May be associated with joint d islocation , berry aneu rysms, organ rupture. OH OH OH OH Hydroxylation Inhibited in scurvy Glycosylation (pro a chain) rl Osteogenesis imperfecta 􀃅 Triple helix (procollagen) c(1·) Peptide cleavage + Ehlers-Danlos 􀂉􀃄􀂈􀃃􀃂􀃁􀃀􀂿􀂾􀂇 Collagen fibrils 1 with cross-links M ay be confused with child abuse. I ncidence is 1 : 10,000. Type I or Type V coll agen most frequently affected i n severe classic Ehlers-Danlos syndrome. Alport syndrome Elastin BIOCHE MISTRY 􀂭 BIOCHEMI STRY-LABORATORY TECHNIQUES S E C T I O N I I 79 Due to a variety o f gene defects resulting i n abnormal type I V collagen. Most com mon form is X-I inked recessive. Characterized by progressive hered itary nephritis and deafness. May be associated with ocular d isturbances. Stretchy protei n with i n skin, lungs, large arteries, elastic l i gaments, vocal cords, l i ga menta fl ava (connect vertebrae-+ relaxed and stretched conformations). Rich in prol ine and glycine, nonhyclroxylatecl forms. Tropoelastin with fibril l i n scaffold i ng. Cross-l inking takes place extracellularly and gives elastin its elastic properties. Broken clown by elastase, which is normally inh ibited by a1-antitrypsin . 1ype I V collagen i s an i mportant structural component of the basement membrane of the kidney, ears, and eyes. M ad a n's syndrome - caused by a defect i n fibri l l i n . Emphysema - can be caused b y a1-antitrypsin deficiency, resulting in excess elastase activity. Wri nkles of aging are clue to reduced collagen and elastin production . 􀂭 B I O C H E M I S T R Y -LA B O R AT O R Y T E C H N I QUE S Polymerase chain readion Molecular biology laboratory procedure used to ampl i fy a desired fragment of DNA. Steps: 1 . Denaturation-DNA is denatured by heating to generate 2 separate strands 2. Annea l i ng- during cool ing, excess premacle DNA primers anneal to a specific sequence on each strand to be amplified. 3. Elongation-heat-stable DNA polymerase repl icates the DNA sequence following each pnmer. These steps are repeated multiple times for DNA sequence ampl i fication. Agarose gel electrophoresis- used for size separation of P C R products (smaller molecules travel further); compared agai nst DNA ladder. 80 S E C T I O N I I Blotting procedures Southern blot Northern blot Western blot Southwestern blot Microarrays BIOCHEMISTRY 􀂬 BIOC H E M I S TRY- LABORATORY TECHNIQUES A DNA sample i s electrophoresed o n a gel and then transferred to a filter. The filter is then soaked i n a denaturant and subsequently exposed to a radiolabeled D A probe that recogn izes and anneals to its complementary strand. The resulting double-stranded, labeled piece of DNA is visualized when the filter is exposed to fi l m . S i m i lar t o Southern blot, except that an RNA sample is electrophoresed . Useful for studying mRNA levels. Sample protei n is separated via gel electrophoresis and transferred to a filter. Labeled antibody is used to bind to relevant protein. Identifies DNA-binding proteins (e.g., transcription factors) using labeled ol igonucleotide probes. SNoW DRoP: Southern = D A Northern = RNA Western =Protei n Thousands o f nucleic acid sequences are arranged i n grids o n glass o r sil icon . DNA o r R N A probes are hybrid ized to the ch ip, and a scanner detects the relative amounts of complementary binding. Used to profile gene expression levels of thousands of genes simultaneously to study certa in d iseases and treatments. Able to detect single nucleotide polymorph isms ( S N Ps) for a variety of appl ications including genotyping, forensic analysis, pred isposition to d isease, cancer mutations, and genetic l inkage analysis. Enzyme-linked A rapid immunologic techn ique testing for Used in many l aboratories to determine whether a particular antibody (e.g., anti-H I V) is present in a patient's blood sample. Both the sensitivity and the specificity of E LI SA approach 100% , but both false-positive and false-negative results do occur. immunosorbent assay antigen-antibody reactivity. Patient's blood sample is probed with either l. Indirect E LISA: uses a test antigen to see if a specific antibody is present in the patient's blood ; a secondary antibody coupled to a color-generating enzyme is added to detect the first antibody; or 2 . D i rect ELISA: uses a test antibody coupled to a color-generating enzyme to see if a specific antigen is present in the patient's blood. If the target substance is present in the sample, the test solution will have an intense color reaction, ind icating a positive test result. Fluorescence in situ hybridization (FISH) Cloning methods Gene expression modifications Karyotyping BIOCHEMISTRY 􀂩 BIOCHEMISTRY- LABORATO RY TECHNIQUES S E C TI O N I I 8 l Fluorescent DNA or RNA probe binds to specific gene site of interest on chromosomes. Used for speci fic locali zation of genes and d i rect visual ization of anomal ies (e.g., m icrodeletions) at molecular level (when deletion is too small to be visual i zed by karyotype). Fluorescence = gene is present; no fluorescence = gene has been cleletecl . Clon ing i s the production o f a recombinant DNA molecule that is self-perpetuating. Steps: l. Isolate eukaryotic m RNA (post-RNA processing steps) of i nterest. 2. Expose m R NA to reverse transcriptase to produce eDNA. 3 . Insert eDNA fragments into bacterial plasm ids conta i n i n g antibiotic resistance genes. 4. Surviving bacteria on antibiotic medium produce eDNA l ibrary. Transgenic strategies in m ice involve: • Random i nsertion of gene into mouse genome • Targeted insertion or deletion of gene through homologous recombination with mouse gene Cre-lox system-Can i nducibly manipulate genes at specific developmental points usi ng an antibiotic-controlled promoter (e.g., to study a gene whose deletion causes embryon ic death). RNA interference ( R NAi) - dsRNA is synthesized that is complementary to the m RNA sequence of interest. When transfected into human cells, dsRNA separates and promotes degradation of target mRNA, knocking clown gene expression . Knock-out = removing a gene, tak ing it out. Knock-in =inserting a gene. A process in wh ich metaphase chromosomes are sta ined, ordered, and numbered accord ing to morphology, size, arm-length ratio, and band ing pattern . Can be performed on a sample of blood, bone marrow, amn iotic fluid, or placental tissue. Used to d i agnose chromosomal imbalances (e.g., autosomal trisomies, sex chromosome d isorders). 8 2 S E C T I O N I I B I O C H E M I S T RY 􀂬 B I O C H E M I S T RY - G E N E T I C S 􀂭 B I O C H E M I S T R Y - G E N E T I C S Genetic terms TERM DEFIN ITION Codominance Both alleles contribute to the phenotype of the heterozygote. Variable expressivity Phenotype varies among ind ividuals with same genotype. I ncomplete Not all individuals with a mutant genotype penetrance show the mutant phenotype. Pleiotropy One gene contributes to multiple phenotypic effects. Imprinting D i fferences in gene expression depend on whether the mutation is of maternal or paternal origin. Anticipation I ncreased severity or earlier onset of disease i n succeed ing generations. loss of h eterozygosity I f a patient inherits or develops a mutation in Dominant negative mutation Linkage disequilibrium Mosaicism locus heterogeneity Heteroplasmy a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. This is not true of oncogenes . Exerts a dominant effect. A heterozygote produces a nonfu nctional altered protein that also prevents the normal gene product from functioning. Tendency for certa i n alleles at 2 l inked loci to occur together more often than expected by chance. Measured in a population, not in a fam ily, and often varies in different populations. Occurs when cells i n the body d i ffer in genetic makeup clue to postfertil ization loss or change of genetic information dur i n g m itosis. Can be a germ-l ine mosaic (gonadal mosaicism ) , which may produce d isease that is not carried by parent's somatic cel ls. Mutations at d i fferent loci can produce the same phenotype. Presence of both normal and mutated mtDNA, resulting in variable expression in m itochondrial inherited disease. EXAMPLE Blood groups A, B, A B . 2 patients with neurofibromatosis type 1 ( Fl) may have varying disease severity. BRCA l gene mutations do not always result in breast or ovarian cancer. PKU causes many seemingly unrelated symptoms, ranging from mental retardation to hair/ski n changes. Prader-Wil l i and Angel man's syndromes. Huntington's d isease. Retinoblastoma and the " two-h it hypothesis." Mutation of a transcription factor i n its allosteric site. Nonfunctioni n g mutant can still bind DNA, preventing w ild-type transcription factor from binding. Mutation in the embryonic precursor of the bone marrow stem cell -+ a hematologic mosaic individual. A chimeric ind ividual is derived from 2 zygotes that subsequently fuse. Marfa n's syndrome, M E N 2 B , and homocystinuri a ; all cause marfanoicl habitus. Albin i s m . BIOCHEMISTRY 􀂩 BIOCHEMISTRY-GENETI C S S E C T I O N I I 8 3 Genetic terms (continued) TERM Uniparental disomy DEFIN ITION Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent. Heteroclisomy ( heterozygous) indicates a meiosis I error. I soclisomy (homozygous) indicates a meiosis II error or postzygotic chromosomal duplication of one of a pai r of chromosomes, and loss of the other of the original pair. Hardy-Weinberg If a population is in H ardy-Weinberg population genetics equilibrium and if p and q are the frequencies of separate al leles, then : p2 + 2pq + q2 = 1 and p + q = 1, which implies that: p2 = frequency of homozygosity for allele p q2 = frequency of homozygosity for allele q 2pq = frequency of heterozygosity (carrier frequency, i f an autosomal recessive d isease ) . T h e frequency of an X-l i nked recessive disease in males = q and in females = q2 . Imprinting At some loci, only 1 allele is active ; the other is inactive ( i mprinted/inactivated by methylation) . With 1 al lele i nactivated, deletion of the active allele - d isease. Prader-Wil l i syndrome Paternal allele is not expressed. AngeiMan's syndrome Maternal allele is not expressed . EXAMPLE Uniparental is eUploid (correct number of chromosomes) , not aneuploid. Most occurrences of UPD -+ normal phenotype. Consider UPD i n a n individual m a n i festing a recessive disorder when only one parent is a earner. H ardy-Wei nberg law assumes: • No mutation occur r i n g at the locus • No selection for any of the genotypes at the locus • Completely random mating • No net migration Both Prader-Wil l i and Angel man's syndromes clue to inactivation or deletion of genes on chromosome 1 5. Can also occur as a result of u n iparental cli somy. Mental retardation, hyperphagia, obesity, hypogonad ism, hypoton i a . Mental retardation , seizures, ataxia, inappropriate laughter. 84 S E C T I O N I I Modes of inheritance Autosomal dominant Autosomal recessive X-linked recessive X-linked dominant M itochondrial inheritance B I O C H E M I S T RY 􀂬 B I O C H E M I S T R Y - G E N E T I C S Often due to defects i n structural genes. Many generations, both male and female, affected. 25% of offspr i n g from 2 carrier parents are affected. Often due to enzyme deficiencies. Usually seen in only l generation. Sons of heterozygous mothers have a 50% chance of being affected. No male-to-male transm ission. Transmitted through both parents. Either male or female offspring of the affected mother may be affected, whereas all female offspring of the affected father are affected. Transm itted only through mother. All offspring of affected females may show signs of d isease. Often due to failures in oxidative phosphorylation . Often pleiotropic. Fam i ly history cru c i a l to d iagnosis. Com monly more severe than dominant d isorders ; patients often present in childhood. Commonly more severe i n males. Females usually must be homozygous to be affected. Hypophosphatemic rickets - formerly known as vita m i n 0-resistant r ickets. Inherited d isorder resulting in t phosphate wasting at proximal tubule. Results in rickets-l i ke presentation. Variable expression i n population due to heteroplasmy. M itochondrial myopathies - group of rare d isorders resulting from mutations affecting m itochondrial function . Often present with myopathy and C N S disease. Muscle biopsy often shows "ragged red fibers." BIOC HEMISTRY 􀂩 BIOCHEMISTRY-G ENETICS SECTION II 8 5 Autoso mal-dominant diseases Ach ondroplasia Autosomal-dominant polycystic kidney disease (ADP KD) Fa milial adenomatous polyposis Fa milial hypercholesterolemia (hyperlipidemia type IIA) Hereditary hemorrhag ic telangiectasia (Osler-Weber-Rendu syndrome) Hereditary spherocytosis Huntington's disease Marfa n's syndrome Multiple endocrine neoplasias (MEN) Neurofi bromatosis type 1 (von Recklinghausen's disease) Neurofi bromatosis type 2 Tu berous sclerosis von Hippei-Lindau disease Cell-signaling defect of fibroblast growth fa ctor (FGF) receptor 3. Results in dwarfism ; short limbs, larger head, but trunk size is normal. Associated with advanced paternal age. Fo rmerly known as adult polycystic kidney disease. Always bilatera l, massive enlargement of k idneys clue to multiple large cysts. Patients present with flank pain, hematuria, hypertension, progressive renal fa ilure. 85% of cases are due to mutation in PKD1 (chromosome 16 ; 16 lette rs in "polycys tic kidney"). Associated with polycys tic liver disease, berry aneurysms, mitral valve prolapse. Infantile fo rm is recessive. Colon becomes covered with adenomatous polyps after puberty. Progresses to colon cancer unless colon is re sected. Mutations on chromosome 5 (APC gene); 5 letters in "polyp." Elevated LDL cl ue to defective or absent LDL receptor. Heterozygotes (l :500) have cholesterol "' 300 mg/c! L. Homozygotes (very rare) have cholesterol "' 700+ mg/dL, severe atherosclerotic disease early in life, and te ndon xanthomas (classically in the Ach illes tendon); Ml may develop before age 20. Inherited disorder of blood vessel s. Findings : telangiectasia, recurrent epistaxis, sk in discolorations, arteriovenous malformations (AVM s). Spheroid eryth rocytes clue to spectrin or ankyrin defect; hemolytic anem ia; t MCHC. Splenectomy is curative. Findings: depression, progressive dementia, choreiform movements, caudate atrophy, and ! levels of GABA and AC h in the brain. Symptoms manifest in affected individuals between the ages of 20 and 50. Gene located on chromosome 4 ; trinucleotide repeat disorder: (CAG \, . " Huntin g 4 fo od." Fibrill in-1 gene mutation --+ connective tissue disorder affecting skel eton , heart, and eyes. Findings: tall with long extremities, pectus excavatum, hypermobile joints, and long, tapering fingers and to es (arachnodactyly) ; cystic medial necrosis of aorta --+ aortic incompeten ce and dissecting aortic aneurysm s; floppy mitral valve. Subluxation of lenses. Severa l distinct syndromes (1, 2A, 2B) characterized by fa milial tumors of endocrine glands, including those of the pancreas, parathyroid, pituitary, thyroid, and adrenal medulla. MEN 2A and 2B are associate d with ret gene. Findings : cafe-au-la it spots, neural tumors, Lisch nodules (pigmented iris hamartomas) . Also marked by skeletal disorders (e.g., scoliosis) and optic pathway gl iomas. On long arm of chromosome 17; 17 letters in "von Recklinghausen." Bilateral acoustic schwannomas, juvenile cataracts. NF2 gene on chromosome 22 ; type 2 = 22. Findings : fa cial lesions (adenoma sebaceum), hypopigmentecl "ash leaf spots" on sk in, cortical and retinal hamartom as, seizures, mental retardation , renal cysts and renal angiomyol ipomas, cardiac rhabdomyomas, t incidence of astrocytom as. Incomplete penetrance, variable presentation. Findings: hemangioblastomas of retina/cerebellum/medulla; the majority of affected individuals develop multiple bilatera l renal cell carcinomas and other tumors. Associated with deletion of VHL gene (tumor suppressor) on chromosome 3 (3p ). Re sults in constitutive expression of HIF (transcription fa ctor) and activation of angiogenic growth fa ctors. Von Hippel-Lindau = 3 words fo r chromosome 3 . 8 6 S E C T I O N I I Autosomal-recessive diseases Cystic fibrosis X-linked recessive disorders Muscular dystrophies Duchenne's Becker's BIOCHEMISTRY • BIOCHE MISTRY- GENETICS Albi nism, ARPKD (formerly known as infantile polycystic kidney d isease) , cystic fibrosis, glycogen storage d iseases, hemochromatosis, mucopolysaccharidoses (except Hunter's ) , phenylketonuria, sickle cell anemias, sphingolipidoses (except Fabry's), thalassem ias. Autosomal-recessive defect in CFTR gene on chromosome 7, commonly deletion of Phe 508. CFTR channel actively secretes CJ- in lungs and Gl tract and actively reabsorbs C)from sweat. Defective Cl- channel --+ secretion of abnormally th ick mucus that plugs lungs, pancreas, and l iver --+ recurrent pulmonary infections (Pseudomonas species and S. aureus), chronic bronch itis, bronch iectasis, pancreatic insufficiency (malabsorption and steatorrhea) , nasal polyps, and mecon ium ileus in newborns. Mutation often causes abnormal protein folding, resulting in degradation of channel before reaching cell surface. I n ferti l ity i n males due to bilateral absence of vas deferens . Fat-soluble vita m i n deficiencies (A, D, E , K) . Can present as fa i l ure to thrive in i n fancy. Most common lethal genetic d i sease of white population . t concentration of Cl- ions i n sweat test is d iagnostic. Treatment: N-acetylcysteine to loosen mucous plugs (cleaves d i sulfide bonds with in mucous glycoproteins) . Bruton's agammaglobulinemia, Wiskott-Aidrich Be Wise, Fool 's GOLD Heeds Si l ly HOpe. syndrome, Fabry's disease, G6PD deficiency, Ocular albinism, Lesch-Nyhan syndrome, Duchenne's (and Becker's) muscular dystrophy, Hunter's Syndrome, Hemoph ilia A and B , Orn ith ine transcarbamoylase deficiency. Female carriers may be affected, and may have less severe symptoms clue to random X chromosome inactivation in each cell. X-l i nkecl framesh ift mutation --+ deletion of dystroph in gene - accelerated muscle breakdown. Weakness begins in pelvic girdle muscles and progresses superiorly. Pseudohypertrophy of calf muscles clue to fibrofatty replacement of muscle; card iac myopathy. Use of Cowers' maneuver, requiring assistance of the upper extremities to stand up, is characteristic. Onset before 5 years of age. X-linked mutated clystrophin gene. Less severe than Duchenne's . Onset in adolescence or early adulthood . Duchenne's = deleted dystroph i n . Dystroph i n gene (DMD) i s t h e longest known human gene --+ t rate of spontaneous mutation. Dystrophin helps anchor muscle fibers, primarily i n skeletal and card iac muscle. D iagnose muscular dystroph ies by t CPK and muscle biopsy. Fragile X syndrome Trinucleotide repeat expansion diseases BIOC HEMISTRY • BIOCHEMISTRY- GENETICS S E C TI O N I I 87 X-l inked defect affecting the methylation and expression of the FMRI gene. The 2nd most common cause of genetic mental retardation (after Down synd rome) . Findings: macroorch idism (enlarged testes), long face with a large jaw, large everted ears, autism, m itral valve prolapse. Huntington's d i sease, myoton ic dystrophy, Friedreich 's ataxia, fragile X syndrome. Fragile X syndrome = ( C GG ) 11 • Frieclreich 's ataxia = ( GAA) 11 • Huntington's d isease = ( CAG ) 11 • Myotonic dystrophy = (CTG) 11 • Tri nucleotide repeat d isorder ( C G G ) 11 • Fragile X = eXtra large testes, j aw, ears. Try (trinucleotide) hunting for my fried e ggs (X). X-Gi rlfriend 's First Aiel Helped Ace My Test. May show genetic anticipation (disease severity t and age of onset 􀂹 in successive generations) . 8 8 S E C T I O N I I Autosomal trisomies Down syndrome (trisomy 2 1 ), 1 :700 Edwards' syndrome (trisomy 1 8), 1 : 8000 Patau's syndrome (trisomy 1 3), 1 : 1 5,000 Robertsonian translocation BIOCHEMISTRY 􀂩 BIOCHEMIST RY-G ENET ICS Findings : mental retardation, flat facies, pro m i nent epicanthal folds, simian crease, gap between 1 st 2 toes, duodenal atresia, congenital heart d isease (most commonly ostium primum-type ASD ) . Associated with t risk of ALL and Alzheimer's d isease (> 35 years of age ) . 9 5 % o f cases cl u e t o meiotic nond isjunction of homologous chromosomes (associated with advanced m aternal age ; from 1 : 1 500 in women < 20 to 1 : 2 5 i n women > 45). 4% of cases clue to Robertson ian translocation. 1% of cases clue to Down mosaicism (no maternal association ) . Find ings : severe mental retardation , rockerbottom feet, m icrognath ia (small jaw) , low-set Ears, clenched hands, prom inent occiput, congenital heart d i sease. Death usually occurs within 1 year of birth. Findings : severe mental retardation, rockerbottom feet, m icrophthalmia, m icrocephaly, cleft l iP/Palate, holoProsencephaly, Polydactyly, congenital heart disease. Death usually occurs within 1 year of birth. Drinking age (2 1 ) . Most common viable chromosomal d isorder and most common cause of genetic mental retardation . Results of pregnancy quad screen : ! a-fetoprotei n , t 􀃅-hCG , ! estriol , t i n h ib i n A . Ultrasound shows t nuchal i n fi r s t tri mester translucency. Election age ( 1 8 ) . Most common trisomy resulting i n l ive bi rth after Down syndrome. Results of pregnancy quad screen : ! a-fetoprote i n , ! 􀃅-hCG , ! estriol , normal inhibin A . Puberty ( 1 3 ) . Results of fi rst-trimester pregnancy screen : ! free 􀃅-hCG, ! PAPP-A, and t nuchal translucency. Meiotic nondisju nction )\ u u n + 1 n+1 Anaphase I )\ Anaphase I I n-1 n-1 X )\ n n-1 n + 1 X n n Normal Nonreciprocal chromosomal translocation that commonly i nvolves chromosome pairs 1 3, 14, 1 5, 2 1 , and 2 2 . One of the most common types of translocation . Occurs when the long anns of 2 acrocentric chromosomes (chromosomes with centromeres near their ends) fuse at the centromere and the 2 short arms are lost. Balanced translocations normally do not cause any abnormal phenotype. Unbalanced translocations can result in m iscarriage, stillbirth, and chromosomal i mbalance (e.g., Down syndrome, Patau's syndrome) . Cri-du-chat syndrome Williams syndrome llq 1 1 deletion syndromes BIOCHEMISTRY 􀂩 BIOCH EMISTRY-GENETICS S E C TI O N I I 8 9 Congenital microcleletion of short arm of chromosome 5 ( 46,XX or XY, 5p-) . Find ings : m icrocephaly, moderate to severe mental retardation, h igh-pitched crying/mewing, epicanthal folds, cardiac abnormalities (VS D ) . Cri d u chat = c r y of the cat. Congenital m icrocleletion of long arm of chromosome 7 (deleted region i ncludes elastin gene) . Findings : distinctive "elfin" facies, intellectual disabil ity, hypercalce m i a (t sensitivity to vitamin D ) , well-developed verbal skills, extreme friend l i ness w i t h stra ngers, card iovascular problems. Variable presentation, including Cleft palate, Abnormal facies, Thym ic aplasia -+ T-cell deficiency, Cardiac defects, Hypocalcemia zo to parathyroid aplasia, clue to m icrocleletion at chromosome 22g ll. D iG e o rge syn d ro m e -thym ic, parathyroid, and card iac defects. V e l o c a rd iofa c i a l synd ro m e -palate, facial, and cardiac defects. CATC H-2 2 . Due t o aberrant development of 3 r d and 4th branch ial pouches. 90 S E C T I O N I I BIOCHEMISTRY • BIOCHEMISTRY-NUTRITION • BIOCHEMIST R Y -NUTRITIO N Vitamins: fat soluble A, D, E, K. Absorption dependent on gut (i leum) and pancreas. Toxicity more common than for water-soluble vitam ins, because these accumulate in fat. Vitamins: water soluble B1 (th i a m i n e : TPP) Vitamin A (retinol) FUNCTION DEFICIENCY EXCESS Vitamin B1 (thiamine) FUNCTION DEFICIENCY B2 (riboflavin : FAD, FMN) B3 (niacin : NAD+) B5 (pantothenic acid: CoA) B6 (pyridoxi n e : PLP) B7 (biotin) B9 (folate) B1 2 (cobalamin) C (ascorbic acid) Antioxidant; constituent of visual pigments (retinal ) ; essential for normal differentiation of epithel ial cells into specialized tissue (pancreatic cells, mucus-secreting cells); prevents squamous metaplasia. Used to treat measles and AML, subtype M 3 . Night blindness, d r y ski n . Arthralgias, fatigue, headaches, skin changes, sore throat, alopecia. Teratogenic (cleft palate, cardiac abnormal ities), so a negative pregnancy test and rel iable contraception are needed before isotretinoin is prescribed for severe acne. I n thiamine pyrophosphate (TPP) , a cofactor for several enzymes in decarboxylation reaction s : • Pyruvate dehydrogenase (l inks glycolysis to TCA cycle) • a-ketoglutarate dehydrogenase (TCA cycle) • Transketolase ( H M P shunt) • Branched-chain amino acid dehydrogenase Impaired glucose breakdown ..... ATP depletion worsened by glucose infusion ; highly aerobic tissues (bra i n and heart) are affected first. Wern icke-Korsakoff syndrome and beriberi . Seen in mal nutrition a s wel l a s alcohol ism (2° to malnutrition and malabsorption) . Malabsorption syndromes (steatorrhea), such as cystic fibrosis and sprue, or m ineral oil intake can cause fat-soluble vita m i n deficiencies. All wash out easily from body except B1 2 and folate (stored in l iver) . B -complex deficiencies often result in dermatitis, glossitis, and d iarrhea. Retinol i s vita m i n A, so think retin-A (used topically for wrinkles and acne) . Found in l iver and leafy vegetables. a-ketoglutarate D H , Transketolase, and Pyruvate DH required for ATP synthesis. Spell beriberi as Beri Beri to remember vitamin Bl . Wernicke- Korsa koff- confusion, ophthal moplegia , ataxia (classic triad) + confabulation, personal ity change, memory loss (permanent) . Damage to medial dorsal nucleus of thalamus, mammillary bodies. D ry beri beri -polyneuritis, symmetrical muscle wasting. Wet beriberi - h igh-output cardiac fa i lure (dilated card i omyopathy) , edema . Vitamin B1 (riboflavin) FUNCTION DEFICIENCY Vitamin 83 (niacin) FUNCTION DEFICIENCY EXCESS BIOCHEMISTRY 􀂩 BIOCHEMISTRY- NUTRITION S E C T I O N I I 9 1 Cofactor in oxidation and reduction (e.g., FADH 2 ) . Chei losis (inflam mation o f l ips, scal ing and fissures at the corners of the mouth) , Corneal vascularization. Constituent of NAD+, ADP+ (used i n redox reactions) . Derived from tryptophan. Synthesis requ i res vita m i n B6. Glossitis. S evere deficiency leads to pellagra, which can be caused by Hartnup d isease (! tryptophan absorption), malignant carcinoid syndrome (t tryptophan metabol ism), and INH U vita m i n B6) . Symptoms of pellagra : Diarrhea, Dementia, and Dermatitis. Facial flush ing (clue to pharmacologic closes for treatment of hyperl ipidem ia) . FAD and FMN are derived from riboFlavin ( B2 = 2 KfP) . The 2 C 's of B2 . NAD derived from Ni aci n ( B 3 = 3 ATP) . The 3 D's of B 3 : Di arrhea , Dermatiti s, Dementia . Vitamin 85 (pantothenate) FUNCTION DEFICIENCY Vitamin 86 (pyridoxine) FUNCTION DEFICIENCY Essential component of CoA (a cofactor for acyl B 5 is "pento" thenate . transfers) and fatty a c i d synthase. Dermatitis, enteritis, alopecia, adrenal insufficiency. Converted to pyridoxal phosphate, a cofactor used in transa m i n ation (e.g., ALT and AST ) , decarboxylation reactions, glycogen phosphorylase. Synthesis of cystathion i ne, heme, n iacin, h ista m i ne, and neurotransmitters including serotonin, epineph rine, norepinephrine, and GABA. Convulsions, hyperirritabi l ity, peripheral neuropathy (deficiency inducible by I N H and oral contraceptives) , sicleroblastic anemias clue to impaired hemoglob i n synthesis and iron excess. 9 2 SECTION II Vitamin 87 (biotin) FUNCTION DEFICIENCY Vitamin 89 (folic acid) FUN CTION DEFICIENCY BIOCHEMISTRY • BIOCHEMISTRY-NUTRITION Cofactor for carboxyl ation enzymes (which add "Avidin in egg wh ites avid ly binds biotin." a 1-carbon group) : • Pyruvate carboxylase: pyruvate (3C) - oxaloacetate (4C ) • Acetyl-CoA carboxylase : acetyl-CoA (2C) - malonyl- CoA (3C) • Propionyl- CoA carboxylase: propionyl-CoA (3C) - methylmalonyl-CoA (4C ) Relatively rare . Dermatitis, alopec ia, enteritis. Caused by antibiotic use or excessive ingestion of raw eggs. Converted to tetra hydrofolate (THF), a coen zyme for 1-carbon transfer/methylation reactions. Important fo r the synthesis of nitrogenous bases in DNA and RNA. Macrocytic, megaloblastic anemia; no neurologic symptoms (as opposed to vitamin B12 deficiency) . Most common vitamin deficiency in the United States. Seen in alcohol ism and pregnancy. Found in leafy green vegetables. Folate from fo l iage. Small reserve pool stored primarily in the liver. Deficiency can be caused by s evera l drugs (e.g., phenytoin, sulfonamides, MTX) . Supplemental fo lic acid in early pregnancy reduces neural tube defects. Vitamin 812 (cobalamin) FUNCTION DEFICIENCY BIOCHEMISTRY 􀂩 BIOCHEMISTRY- NUTRITION SECTION II 9 3 Cofactor for homocysteine methyltra nsferase (transfers CH3 groups as methylcobalamin) and methylmalonyl-CoA mutase. Macrocytic, megaloblastic anemia, hypersegmentecl PMNs, neurologic symptoms (paresthesias, subacute combined degeneration) clue to abnormal myel in. Prolonged deficiency leads to irreversible nervous system damage. Fo und in animal products. Synthe sized only by microorganisms. Ve ry large reserve pool (several years) stored primarily in the liver. Deficiency is usually caused by malabsorption (sprue, enteritis, Diphyllobothrium latum), lack of intrinsic fa ctor (pernicious anem ia, gastric bypass surgery) , or absence of terminal ileum (Crohn's disease) . CH3 for anabolic reactions Odd #C fatty acids Use Schilling test to detect the etiology of the deficiency. 1 Methyl malonyl-GoA 5-adenosyl-methionine AT P +methionine -+ SA M. SAM transfers methyl units. Regeneration of methionine (and thus SAM ) is dependent on vitamin B12 and fo late . SAM the methyl donor man. Requ ired for the conversion of NE to epinephrine. AT P CH /f \ SAM 􀈎 3 􀂅 ---------􀂆 Anabolic pathways Methionine Homocysteine 􀀤 THF methyltransferase CH3 THF B ,2 9 4 S E C T I O N I I Vitamin C (ascorbic acid) FUNCTION DEFICIENCY EXCESS Vitamin D FUNCTION DEFICIENCY EXCESS Vitamin E FUNCTION DEFICIENCY BIOCHEMISTRY 􀂬 BIOCHEMISTRY- NUTRITION Antioxidant. Also facil itates iron absorption by keeping iron in Fe 2 + reduced state. Necessary for hydroxylation of prol ine and lysine in collagen synthesis. Necessary for dopamine 􀂽-hydroxylase, wh ich converts dopamine to N E . Scu rvy- swollen gums, bruising, hemarthrosis, anemia, poor wound heal i ng. Weakened immune response. Nausea, vom iting, diarrhea, fatigue, sleep problems. Can t risk of iron toxicity in predisposed i ndividuals (e.g. , those with transfusions, hereditary hemochromatosis). D2 = ergocalciferol - ingested from plants. D3 = cholecalciferol - consumed in m ilk, formed in sun-exposed skin. 2 5 -0H D3 = storage form. 1 ,2 5 - (0H)2 D3 (calcitriol) = active form. t i ntestinal absorption of calcium and phosphate, t bone m ineral ization . Rickets fJ in children (bone pain and deform ity) , osteomalacia in adults (bone pain and muscle weakness) , hypocalcemic tetany. Breast milk has ! vitam in D (supplement in dark-skinned patients) . Hypercalcem ia, hypercalciur ia, loss of appetite, stupor. Seen in sarcoidosis (t activation of vitamin D by epithel ioid macrophages) . Antioxidant (protects erythrocytes and membranes from free-radical damage). t fragil ity of erythrocytes (hemolytic anem ia), muscle weakness, posterior column and spinocerebellar tract demyel ination. Found i n fru its and vegetables. Pronounce "absorbic" acid. Vita m i n C deficiency causes sCurvy clue to a Collagen synthesis defect. Drinking milk (fortified with vita m i n D ) i s good for bones. Rickets. X-ray of legs in toddler shows bowing of femurs (genu varum). C E is for Erythrocytes. Vitamin K FUNCTION DEFICIENCY Zinc FUNCTION DEHCIENCY Ethanol metabolism Cytosol BIOCHEMISTRY • BIOC HEMIST R Y- N UTRIT ION S E C T I O N I I 9 5 Catalyzes y-carboxylation of glutamic acid residues on various proteins concerned with blood clotting. Synthesized by intestinal Aora . Neonatal hemorrhage with t PT and t aPTT but normal bleed ing time (neonates have sterile intestines and are unable to synthesize vitamin K). Can also occur after prolonged use of broad-spectru m antibiotics. K is for Koagulation. Necessary for the synthesis of clotting factors II, VI I , IX, X, and proteins C and S . Warfarin -vita m i n K a ntagonist. Not in breast m ilk; neonates are given vita m i n K injection at bi rth to prevent hemorrhage. Essential for the activity of 100+ enzymes. Important in the formation of zinc fingers (transcription factor motif) . Delayed wound heali ng, hypogonad ism, ! adult hair (axillary, facial, pubic) , dysgeusia, anosmia. May predispose to alcohol ic cirrhosis. Mitochondria Eth I Alcohol dehydrogenase ano A t ld h d 7 "'\ • ce a e y e Acetaldehyde dehydrogenase 7 "'\ • Ac eta t e Fomepizol e - i n h ibits alcohol dehydrogenase and is an antidote for methanol or ethylene glycol poisoni n g. NAD' NADH Ethanol hypoglycemia NAD' NADH NAD + is the l i m iting reagent. Alcohol dehydrogenase operates via zero-order kinetics. Disulfiram (Antabuse) - in h ibits acetaldehyde dehydrogenase (acetaldehyde accumulates, contributing to hangover symptoms) . Ethanol metabol ism t NADH /NAD+ ratio in l iver, causing d iversion of pyruvate to lactate and OAA to malate, thereby inhibiting gluconeogenesis and stimulating fatty acid synthesis. --+ hypoglycemia and hepatic fatty change (hepatocel lular steatosis) seen i n chron ic alcoholics. Overproduction of lactate --+ acidosis. Depletion of oxaloacetate shuts down the TCA cycle, shunting acetyl-CoA i nto ketone production . Breakdown of excess malate t NADPH and thus fatty acid synthesis. N A D H NAD+ Pyruvate --"'----=-./'---�)! lactate Glycolysis NADH NAD+ Oxaloacetate --"---�-./--�)1 malate TCA cycle 9 G S E CT I O N I I Malnutrition Kwashiorkor Marasmus BIOCHEMISTRY 􀂭 BIOCHEMIST RY - MET ABOLISM Protein malnutrition resulting in skin lesions, edema, l iver malfunction (fatty change clue to ! apolipoprotein synthesis) . Cl i n ical picture is small child with swollen belly. E nergy malnutrition resulting in tissue and muscle wasting, loss of subcutaneous fat, and variable edema. Kwashiorkor results from a proteindeficient MEAL : Malnutrition Edem a Anemia Liver (fatty) Marasmus results in Muscle wasting. 􀂭 B I O C H E M I ST R Y - M E TA B O L I SM Metabolism sites M itochondria Cytoplasm Both Enzyme terminology Kinase Phosphorylase Phosphatase Dehydrogenase Carboxylase Fatty acid oxidation ( 􀂽-oxidation) , acetylGoA production , TCA cycle, oxidative phosphorylation. Glycolysis, fatty acid synthesis, HMP shunt, protein synthesis ( RER), steroid synthesis ( SE R) , cholesterol synthesis. Heme synthesis, Urea cycle, Gluconeogenesis . HUGs take two (i.e., both ) . A n enzyme's name often describes its function. For example, glucok inase i s a n enzyme that catalyzes the phosphorylation of glucose using a molecule of KrP. The following are commonly used enzyme descriptors. Uses AT P to add high-energy phosphate group onto subs trate (e.g., phosphofru ctokinase) Adds inorganic phosphate onto subs trate without using KrP (e.g., glycogen phosphorylase) Removes phosphate group from substrate (e.g., fru ctose- 1,6-bisphosphatase) Catalyzes oxidation-reduction reactions (e.g. , pyruvate clehycl rogenase) Transfers C02 groups with the help of biotin (e.g., pyruvate carboxylase) BIOCHEMISTRY 􀂭 BIOCH EMIST RY- METABOLISM S E C T I O N II 9} Rate-determining enzymes of metabolic processes PROCESS ENZYME Glycolysis Phosphofructo k i n a se-] (PFK- 1 ) Gluconeogenesis TCA cycle Glycogen synthesis Glycogenolysis I-I MP shunt De novo pyrimidine synthesis De novo purine synthesis Urea cycle Fatty acid synthesis Fatty acid oxidation Ketogenesis Cholesterol synthesis Fructose- 1 , 6- bi sphosphatase lsocitrate dehydrogenase Glycogen synthase G lycogen phosphorylase G l u cose-6- phosphate dehydrogenase (G6PD) Carbamoyl phosph ate synthetase I I G l utam i n e- PRPP a m idotra nsferase Carba moyl phosphate synthetase I Acetyl- CoA ca rboxylase (ACC) Carnitine acyltra n sfe rase I H M G - CoA synth a se H M G- CoA reductase REGU LATORS AMP EB, fructose-2 ,6-BP EB, ATP 8, citrate 8 ATP EB, AMP 8, fructose-2 ,6-BP 8 ADP EB, ATP 8, NAD H 8 Glucose EB, i ns u l i n EB, epinephrine 8, glucagon 8 AMP EB, epineph rine EB, glucagon EB, i ns u l i n 8, ATP 8 NADP+ EB, NADPH 8 AMP 8, I M P 8, CMP 8 N-acetylglutamate EB In sul in EB, citrate EB, glucagon 8, palm itoyl-CoA 8 Malonyl-C oA 8 Insul i n EB, thyroxine EB, glucagon 8, cholesterol 8 9 8 S E C T I O N I I B I O C H E M I S T R Y 􀂭 B I O C H E M I S T R Y- M E TA B O L I S M Summary of pathways Galactose !O Galactose- 1 -phosphate G l ucose Glycogen ------...__ !c. i 􀂻 􀈍 i Acetyl-CoA TCA cycle (Krebs cycle) Pyruvate -+ acetyl-CoA produces l NADH, l C02 . Pyruvate 13C) 5:1-c8 ATP 5' 8 Acetyl-CoA 8 NADH Acetyl-CoA I2C) FATP Oxalo- 􀈌O t.-,• .....--........ Suconyl - o>'(0 AMP + PP; Cytoplasm (liver) Ornithine Argininosuccinate To kidney +--Urea U rea NH/ -----+- NH2 I C02 -----+- C = 0 I Aspartate -----+- NH2 Arginine Transport of ammonium by alanine and glutamate 􀀡 Muscle Liver Amino acids Alanine Alanine 1'"'' ) ( •·""''"""" ) c ::􀀙r .. -- A - 1 - an - in _ e _ c - yc - le-.... G,::::) (''""'"""" a-Ketoacids Glutamate ( N H3l Pyruvate Cori cycle Pyr!vate Glutamate ( N H3l ! t ! Hyperammonemia Ornithine transcarbamoylase deficiency B I O C H E M I S T RY 􀂬 B I O C H E M I S T R Y - M E TA B O L I S M S E C T I O N I I 1 07 Can be acqu ired (e.g., l iver disease) or hereditary (e.g., urea cycle enzyme deficiencies) . Results in excess N H4 +, which depletes a-ketoglutarate, leading to inh ibition of TCA cycle. Treatment: l i m it protein in d iet. Benzoate or phenylbutyrate (both of wh ich bind amino acid and lead to excretion) may be given to ! ammonia levels. Lactulose to acidify the GI tract and trap NH4 + for excretion . A m m o n i a i ntoxicati o n -tremor (asterixis), slurring of speech, somnolence, vom iting, cerebral edema, blurring of vision. Most common urea cycle d isorder. X-linkecl recessive (vs. other urea cycle enzyme deficiencies, which are autosomal recessive) . Interferes with the body's :1bil ity to el i m i n ate ammonia. Often evident in the first few clays of life, but may present with late onset. Excess carbamoyl phosphate is converted to orotic acid (part of the pyrimidine synthesis pathway) . Findings: t orotic acid in blood and urine, ! BUN, symptoms of hyperammonem ia. Amino acid derivatives Phenyla l a n i ne Tryptophan H isti d i n e G lycine A rg i n i n e G l utamate Thyroxine Melanin BH4 t BH4 t Vitamin 86 Vitamin c SAM -- Tyrosine -Dopa-- Dopa m i n e -- NE -- Epi Y. Niacm -- NAD+/NADP+ 􀀺 Seroto n i n -- Melato n i n B 􀂠 H istamine B 􀂟 Po rphyrin -- Heme 􀂳 C reatine -- Urea 􀁽 N itric oxide 􀁻 GABA 􀁼 G l u tathione 1 0 8 S E C T I O N I I B I O C H E M I S T R Y 􀂩 B I O C H E M I S T R Y - M E TA B O L I S M Catecholamine synthesis/tyrosine catabolism Pheny l a l a n i n e Dihydropteridine reductase )( ) NADP• T H B 1 NADPH DHB Phenylalan ine hydroxylase Tyrosine N A D P • 􀈅?f T H B \ 1 Dihydropteridine reductase / \.. v NADPH DHB Tyrosine hyd roxylase Phenylketonuria D i hydroxypheny l a l a n i ne, aka "dopa" Vitamin 861 Dopa m i ne Vitam in C 1 N"'::rMn• Epinephrine e carbidopa ® cortisol Dopa decarboxylase Dopamine 􀂜-hyd roxylase Phenylethanolamine N-methyltransferase Due to 􀂹 phenylalanine hydroxylase or 􀂹 tetrahydrobiopterin cofactor (malignant phenylketonuria) . Tyrosine becomes essential. t phenylalanine leads to excess phenylketones m unne. Findings : mental retardation, growth retardation, seizures, fa ir skin, eczema, musty body odor. Treatment: 􀂹 phenylalanine (contained in aspartame [e.g., NutraSweet] ) and t tyrosine i n d iet. Maternal PKU - lack of proper d ietary therapy during pregnancy. Findings in infant: m icrocephaly, mental retardation, growth retardation, congenital heart defects. E nzyme legen d : • Hydroxylase adds O H • Decarboxylase removes COOH · SAM adds CH3 B reakdown prod ucts via MAO and COMT: Dopam i n e 􀂚 HVA Norepi nephrine 􀂛 VMA Epinephrine 􀂛 Metanephrine Autosomal recessive. I ncidence "" 1 :10,000. Screened for 2-3 days after birth (normal at birth because of maternal enzyme during fetal l i fe) . Phenylketones-phenylacetate, phenyllactate, and phenylpyruvate. D isorder of aromatic amino acid metabol ism --+ musty body odor. Alkaptonuria (ochronosis) Congenital deficiency of homogentisic acid oxidase in the degradative pathway of tyrosi ne to fumarate. Autosomal recessive. Ben ign d isease. Albinism Findings: clark connective tissue, brown pigmented sclera , urine turns black on prolonged exposure to air. May have debil itating arthralgias ( homogentisic acid toxic to cartil age) . Congenital deficiency of either of the following: • Tyrosi nase ( inabil ity to synthesize melanin from tyrosine) - autosomal recessive • Defective tyrosine transporters ( 􀂹 amounts of tyrosine and thus melanin) Can result from a lack of migration of neural crest cells. Lack of melanin results i n a n t risk of ski n cancer. Variable i nheritance clue to locus heterogeneity (vs . ocular albinism -X-l i nked recessive) . Homocystinuria Cystinuria Maple syrup urine disease Hartnup disease B I O C H E M I S T R Y 􀂩 B I O C H E M I S T R Y - M E TA B O L I S M S E C T I O N I I 1 09 3 forms (all autosomal recessive ) : • Cystath ion ine synthase deficiency (treatment: ! Met and t Cys, and t B12 and folate in d iet) • ! affi n ity of cystathionine synthase for pyridoxal phosphate (treatment: t t vitam i n B6 in d iet) • Homocysteine methyltransferase (requires Bd deficiency All forms result i n excess homocysteine. Cysteine becomes essential. Findings : t t homocysteine i n urine, mental retardation , osteoporosis, tall stature, kyphosis, lens subluxation (downward and inward ) , and atherosclerosis (stroke and M I ) . Homocysteine Cystathionine Methionine methyltransferase . synthase Homocysteme .........-;:; • Cystathionine---Cysteine B12 / B6 Serine Hereditary defect of renal tubular amino acid transporter for cysteine, ornithine, lysine, and argin ine in the PCT of the kidneys. Excess cystine i n the urine can lead to precipitation of hexagonal crysta ls and renal staghorn calcul i . Blocked degradation of branched amino acids (lie, Leu, Val) due to ! a-ketoacid dehydrogenase ( B 1 ) . Causes t a-ketoacids in the blood, especially Leu. Causes severe CNS defects, mental retardation, and death . Autosomal recessive. Common ( 1 :7000). Treatment: good hydration and urinary alkal i n ization. Cystine i s made of 2 cysteines connected by a d i sulfide bond. Autosomal recessive. Urine smells l i ke maple syrup. I Love Vermont maple syrup from maple trees (with branches) . An autosomal-recessive d isorder characterized by defective neutral a m i no acid transporter on renal and i ntestinal epithelial cells. Causes tryptophan excretion in urine and ! absorption from the gut. Leads to pellagra. 1 1 0 S E C T I O N I I BIOC HEMISTRY 􀂬 BIOCH EMISTRY-METABOLISM Glycogen regulation by insulin and glucagon/epinephrine Ca2+ I calmodulin i n muscle activates phosphorylase kinase so that glycogenolysis is coordinated with muscle activity 1 Glycoge n phosphorylase kinase (inactive) Glucagon Epinephrine (liver) 􀀖 (liver and muscle) Adenylyl cyclase cAMP I Protei n kinase A P, Glycogen phosphorylase kinase (active) Protein phosphatase Receptor tyrosine kinase dimerizes -------------' l Insulin Branches have a ( 1 ,6) bonds; linkages have a ( 1 ,4) bonds. Glycogenolysis l Glycogen phosphorylase (active) Glycogen Skeletal muscle Glycogen undergoes glycogenolysis -+ glucose- 1-phosphate -+ glucose-6-phosphate, wh ich is rapidly metabol ized dur i n g exercise. Hepatocytes Glycogen is stored and undergoes glycogenolysis to maintai n blood sugar at appropriate levels. Glucose-6-phosphate Jt Glucose-1-phosphate oJ U DP-glucose aJ o • • • • --• Storage form of glycogen Limit dextrin Note : A small amount of glycogen is degraded in lysosomes by a- 1 ,4-glucosidase. 0 UDP-glucose pyrophosphorylase f) Glycogen synthase E) Branching enzyme 0 Glycogen phosphorylase 0 Debranching enzyme B I O C H E M I S T R Y • B I O C H E M I S T RY - M E TA B O L I S M S E C T I O N I I 1 1 1 Glycogenolysis/glycogen synthesis G LYCOG E N Lysosomal deg radation 􀀕------------- Limit dextri n (4 g l ucose residues i n branched configu ration) Debra n c h i n g enzyme (type Ill) Branching enzyme \ G lycogen synthase J I t GLUCOSE ----- Glucose-6-phosphate --:::===;:=: =::=:;:: 􀂲-Glucose + P; G l u cokinase G l ucose-6- Glycogen storage diseases DISEASE Von Gierke's disease (type I) Pompe's disease (type I I ) Cori's disease (type I l l ) McArdle's disease (type V) phosphatase (type I) 12 types, all resulting in abnormal glycogen metabolism and an accumulation of glycogen with i n cells. Very Poor Carbohydrate Metabol i sm . F I N D I NGS Severe fasting hypoglycem ia, t t glycogen i n l iver, t blood lactate, hepatomegaly Cardiomegaly and systemic findings lead ing to early death M i lder form of type I with normal blood lactate levels t glycogen in muscle, but cannot break it clown, leading to painfu l muscle cramps, myoglobinuri a with strenuous exercise DEFICI ENT ENZYME Glucose-6-phosphatase Lysosomal a-1 ,4-glucosidase (acid maltase) Debranching enzyme ( a-1 ,6-glucosidase) Skeletal muscle glycogen phosphorylase COMMENTS Autosomal recessive. Autosomal recessive. Pompe's trashes the Pump (heart, l iver, and muscle). Autosoma 1 recessive. Gluconeogenesis is i ntact. Autosomal recessive. McArdle's = Muscle. 1 1 2 S E C T I O N I I B I O C H E M I S T RY 􀂬 B I O C H E M I S T R Y - M E TA B O L I S M Lysosomal storage diseases Each is caused by a deficiency in one of the many lysosomal enzymes. Results in an accumulation of abnormal metabolic products. DISEASE Sphi ngol ipidoses Fabry's disease Gaucher's disease Niemann-Pick disease lay-Sachs d isease Krabbe's disease Metachromatic leukodystrophy FINDINGS Peripheral neuropathy of hands/feet, angiokeratomas, card iovascular/renal d isease Most common . , Hepatosplenomegaly, aseptic necrosis of femur, bone crises, Gaucher's cells rJ (macrophages that look like crumpled tissue paper) Progressive neurodegeneration, hepatosplenomegaly, cherry-red spot on macula, foam cells rn Progressive neurodegenera tion, developmental delay, cherry-red spot on macula, lysosomes with onion skin, no hepatosplenomegaly (vs. Niemann-Pick) Peripheral neuropathy, developmental delay, optic atrophy, globoid cells Central and peripheral demyel ination with ataxia, dementia DEFICIENT ENZYME a-galactosidase A Glucocerebrosidase Sph ingomyelinase Hexosa m i n idase A Galactocerebrosidase Arylsulfatase A ACCUMU LATED SU BSTRATE Ceramide trihexoside Glucocerebroside Sphingomyel i n GM2 gangl ioside Galactocerebroside Cerebroside sulfate I N H ERITANCE X R AR AR AR AR AR M ucopolysaccharidoses H urler's syndrome Developmental delay, gargoyl ism, a-L-iduron idase Heparan sulfate, AR a irway obstruction, corneal cloud ing, hepatosplenomegaly dermatan sulfate H unter's syndrome M ild Hurler's + aggressive behavior, no lduronate sulfatase corneal cloud ing Heparan sulfate, XR dermatan sulfate G M 2 Tay-Sachs t S u l fatides GM3 Ce ra m i d e tri h exosi d e Metach romatic t 􀀹 􀂱 leu kodystrophy / G l u cocerebros i d e Fabry's G a l a ctoce rebroside t G h , ')( auc er s Krabbe 's ' '\..... . ....---\--- S p hingomyelin Ce r a m l d e N ieman n -Pick No man picks (Niemann-Pick) his nose with his sphinger (sphingomyel i nase) . Tay-SaX l acks heXosa m i n idase. Hunters see clearly (no corneal clouding) and aim for the X (X-l i nked recessive ) . t i ncidence of Tay-Sachs, Niemann-Pick, and some forms of Gaucher's disease i n Ashkenazi Jews. Fatty acid metabolism Ketone bodies B I O C H E M I S T R Y 􀂩 B I O C H E M I S T RY - M E TA B O L I S M S E CT I O N I I 1 1 3 Fatty acid degradation occurs where its products will be consumed-in the m itochondrion . Carnitine deficiency: i nabil ity to transport LCFAs i nto the m itochondria, resulting in toxic accumulation. Causes weakness, hypotonia, and hypoketotic hypoglycem ia. Mitochondrial matrix Synthesis Fatty acid synthesis (palmitate, a 16C FA) l Malonyi-CoA }- C02 (biotin) Acetyi-CoA lATP citrate lyase Citrate shuttle Cit1ra te In the liver, fatty acids and amino acids are metabol ized to acetoacetate and 􀃅-hydroxybutyrate (to be used in muscle and bra i n ) . I n prolonged starvation a n d diabetic ketoacidosis, oxaloacetate is depleted for gluconeogenesis. In alcohol ism, excess ADH shunts oxaloacetate to malate. Both processes stall the TCA cycle, which shunts glucose and F FA toward the production of ketone bodies. Made from H M G -CoA. Metabol ized by the brai n to 2 molecules of acetyl-CoA. Excreted 1 1 1 unne. Acyi-CoA dehydrogenase deficiency: t dicarboxyl ic acids, ! glucose and ketones. " SYtrate" = SYnthesi s . CARn it i ne = CARnage of fatty acids. Degradation Fatty acid + CoA I Fatty acid CoA synthetase Acyi-CoA !1-0--Malonyi-CoA Carnitine shuttle I Acyi-CoA ! 13-oxidation (breakdown to acetyi-CoA groups) /"-. Ketone TCA bodies cycle Breath smel ls l i ke acetone (fru ity odor) . Urine test for ketones does not detect 􀃅-hydroxybutyrate (favored by h i gh redox state) . 1 1 4 SECTION II Metabolic fuel use Exercise 1 00% (!) 􀈄 :::> 0 (/) >. e> (!) c w BIOCHEMISTRY 􀂬 BIOCHEMISTRY-METABOLISM M i n utes--­ D u ration of exercise Hours --- 1 g protein or carbohydrate = 4 kcal . 1 g fat = 9 kca l . Fasting a n d starvation Priorities are to supply sufficient glucose to the brain and RBCs and to preserve prote i n . F e d state (afte r a meal) Fasting (between meals) Sta rvation days 1 -3 Starvation after day 3 Cholesterol synthesis Glycolysis and aerobic respiration . Hepatic glycogenolysis (major) ; hepatic gluconeogenesis, adipose release of FFA (m inor) . Blood glucose level maintained by: • Hepatic glycogenolysis • Adipose release of FFA • Muscle and l iver, which shift fuel use from glucose to F FA • Hepatic gluconeogenesis from peripheral tissue lactate and alanine, and from ad ipose tissue glycerol and propionylCoA (from odd-cha in FFA- the only triacylglycerol components that contribute to gluconeogenesis) Ad ipose stores (ketone bodies become the main source of energy for the bra in and heart) . After these are depleted, vital protein degradation accelerates, lead ing to organ fa ilure and death. Rate-l im iting step is catalyzed by HMGCoA reductase, which converts HMG-CoA to mevalonate. % of plasma cholesterol is esterified by lecithi n-cholesterol acyl transferase ( LCAT) . Insulin stimulates storage of l ipids, proteins, glycogen . Glucagon, adrenaline stimulate use of fuel reserves. Glycogen reserves depleted after clay 1. RBCs lack m itochondria and s o cannot use ketones. Amount of adipose stores determines survival time. Statins (e.g., lovastatin) inhibit HMG-CoA reductase. , BIOCHEMI S T RY 􀂩 BIO CHEMISTRY - MET A BOLISM S E CT I O N I I 1 1 5 Lipid transport, key enzymes Major apolipoproteins Apo l i poprotei n E A-1 C-1 1 B-48 B-1 00 _ Dietary fat+ cholesterol --• Chylomicro n s LPL , Chylomicron ""\ remnants VLDL F FA 􀂙 IS \ Ill t1ssues Y Periphera l (with L D L receptors) l F FA -LP)--L • ID---I L--- LDL I HL I L:: Pancreatic l ipase - degradation of d ietary TG i n small intestine. Lipoprotein l ipase ( L PL) - degradation of TG circulating i n chylomicrons and VLDLs. Hepatic TG l ipase ( H L) - degradation of TG remai n i n g i n IDL. Hormone-sensitive l ipase - degradation of TG stored i n adipocytes. CETP Transfe r of cholesterol este rs to VLDL, I D L , LDL Lecithin-cholesterol acyl transferase ( LCAT) - c atalyzes esterification of cholesterol . Cholesterol ester transfer protein (CETP) -mediates transfer of cholesterol esters to other l ipoprotein particles. Chyl o m i cron Function Chyl om icron re m n a n t V L D L I D L L D L Mediates remnant uptake X X X X Activates LCAT Lipoprotein l ipase cofactor X X Med iates chylomicron X X secretion Binds LDL receptor X X X H D L X X X l l 6 S E C T I O N I I Lipoprotein fundions Chylomicron VLDL IDL LDL HDL Familial dyslipidemias TYPE 1-hyperchylomicronemia lla-familial hypercholesterolemia IV-hypertriglyceridemia Abetalipoproteinemia B I O C H E M I S T R Y 􀂬 B I O C H E M I S T R Y - M E TA B O L I S M Lipoproteins are composed of varying proportions of cholesterol , triglycericles (TGs) , and phosphol ipids. LDL and H DL carry most cholesterol . LDL transports cholesterol from l iver to tissues. HDL transports cholesterol from periphery to l iver. LDL is Lousy. HDL is Healthy. Del ivers d ietary TGs to peripheral tissue. Del ivers cholesterol to l iver in the form of chylomicron remnants, which are mostly depleted of their triacylglycerols. Secreted by intestinal epithel ial cel ls. Delivers hepatic TGs to peripheral tissue. Secreted by l i ver. Formed i n the degradation ofVLDL. Del ivers triglycerides and cholesterol to l iver. Del ivers hepatic cholesterol to peripheral tissues. Formed by hepatic l ipase modification of i D L in the peripheral tissue. Taken up by target cells via receptor-mediated endocytosis. Mediates reverse cholesterol transport from periphery to l iver. Acts as a repository for apoC and apoE (wh ich are needed for chylom icron and VLDL metabol i s m ) . Secreted from both l iver and i ntestine. I NCREASED B L O O D LEVEL Chylomicrons, TG, cholesterol LDL, cholesterol VLDL, TG PATHOPHYSIOLOGY Autosomal recessive. Lipoprote i n l ipase deficiency or altered apol ipoprotein C -I I . Causes pancreatitis, hepatosplenomegaly, and eruptive/pruritic xanthomas (no t risk for atherosclerosis) . Autosomal dominant. Absent or 􀂹 LDL receptors. Causes accelerated atherosclerosis, tendon (Achilles) xanthomas, and corneal arcus. Autosomal domi nant. Hepatic overproduction of VLDL. Causes pancreatitis. Autosomal recessive mutation i n m icrosomal triglyceride transfer protein ( MTP) gene -+ 􀂹 B-48 and B-100 -+ 􀂹 chylomicron and VLDL synthesis and secretion. Symptoms appear i n the fi rst few months of l i fe. I ntestinal biopsy shows l ipid accumulation within enterocytes clue to i n abil ity to export absorbed l ipid as chylomicrons. Findings : failur e to thrive, steatorrhea , acanthocytosis, ataxia, night blindness. HIGH-YIELD PRINCIPLES IN Microbiology "Support bacteria. They're the only culture some people have." -Anonymous "What lies behind us and what lies ahead of us are tiny matters compared to what lies within us." - Ol iver Wendell Holmes This high-yield material covers the basic concepts of microbiology. The emphasis in previous examinations has been approximately 40% bacteriology (20% basic, 20% quasi-clinical), 25% immunology, 25% virology (10% basic, 15% quasi-clinical), 5% parasitology, and 5% mycology. Microbiology questions on the Step l exam often require two (or more) steps: Given a certain clinical presentation, you will first need to identify the most likely causative organism, and you will then need to provide an answer regarding some feature of that organism. For example, a description of a child with fever and a petechial rash will be followed by a question that reads, "From what site does the responsible organism usually enter the blood?" This section therefore presents organisms m two major ways: in individual microbial "profiles" and in the context of the systems they infect and the clinical presentations they produce. You should become familiar with both formats. When reviewing the systems approach, remind yourself of the features of each microbe by returning to the individual profiles. Also be sure to memorize the laboratory characteristics that allow you to identify microbes. Additional tables that organize infectious diseases and syndromes according to the most commonly affected hosts and the most likely microbes are available on the First Aid team blog at www. firstaiclteam.com. 11 8 SE CTION II MI CROBIOLOGY 􀃛 MICROBIOLOGY-BASIC BACTERIOLOGY 􀃚 MICROBIOLOGY-BASIC BACTERIOLOGY Bacterial structures STRUCTURE FUNCTION Pept idoglycan Gives rigid support, protects against osmotic pressure. Cell wall/cell Major surface antigen. membrane (gra m positives) Oute r membrane (gram Site of endotoxin (lipopolys accharide [LPS ]); negatives) major surface antigen. Pla sma membrane Site of ox idative and transport enzymes. Ribosome Prote in synthesis. Periplasm Space between the cy topl asmic membrane and outer membrane in gram-negative bacteria. Capsule Prote cts against phagocytosis. Pilus/fi mbria Mediate adherence of bacteria to cell surface ; sex pilus for ms attachment between 2 bacteria during conjugation. Flagellum Motility. Sp ore Resistant to dehydration, heat, and chemicals. Plasmid Contains a variety of genes for antibiotic resistance, enzymes, and toxins. Glycocalyx Mediates adherence to surfaces, especially fore ign surfaces (e.g., indwelling catheters). CHEMICAL COMPOSITION Sugar backbone with peptide side chains crosslinked by transpeptidase. Pe ptidoglycan for support. Lipote ichoic acid induces T F and IL-l. Lipid A induces TNF and IL-l; 0 polysaccharide is the antigen. Lipoprotein bilayer. 50S and 30S subunits. Contains many hydrolytic enzymes, including 􀄊-lactamases. Polysac charide (except Bacillus anthracis, which conta ins D-glutamate) . Glycoprotein. Prot ein. Kerati n-like coat; dipicoli nic acid ; peptidoglyc an. DNA. Polysaccharide. Cell wa lls Unique to gram-positive Common to both Unique to gram-negative organisms Lipoteichoic acid (combi nation of lipids and teichoic acids) 1------ Pilus------; Peri plasm Gram-positive Gram-negative (Adapted, with permission, from Levinson W, Jawetz E. Medical Microbiology and Immunology: Examination ond Boord Review. 9th ed. New York: McGraw-Hill, 2006: 7.) MI CROBIOLOGY 􀃚 MICROBIOLOGY-BASIC BACTERIOLOGY SE CT I O N I I 1 1 9 Baderial taxonomy MORPHOLOGY Ci rcular (coccus) Gram-positive exa mples Staphylococcus Streptococcus G ra m-negative examples Neisseria Rod (bacillus) Clostridium Corynebacterium Bacillus Listeria Mycobacterium (acid fast) Gardnerella ( Gram variable) Bra nch ing fila m entous Actinomyces Nocardia (weakly acid fast) Enteric s : • E. coli • Shigella • Salmonella • Yersinia • Klebsiella • Proteu s • Enterobacter • Serra tia • Vibrio • Campylobacter • Helicobacter • Pseudomonas • Bacteroides Respiratory: • Haemophilus (pleomorphic) • Legionella (silver) • Bordetella Zoonotic: • Francisella • Brucella • Pasteurella • Bartonella Pleomorphic R ickettsiae (Giem sa) Chlamydiae ( G ie msa) Spi ral Spirochete s : N o cell wall Mycoplasma (does not Gram stain) Baderia with unusual cell membranes/walls Mycoplasma Mycobacteria Contai n sterols and have no cell wal l . Contai n mycol ic a c i d . H igh l ipid conteht. • Leptospira • Borrelia ( Giemsa) • Treponema 1 2 Q SE C T I O N I I M I CRO B I O L O G Y 􀃚 MICROBIOLOGY-BASIC BACTERIOLOGY Gram stain limitations These bugs do not Gram sta i n wel l : Stains Giemsa PAS (periodic acid-Schiff) Treponema (too thin to be visualized) . Rickettsia (intracel lular parasite ) . Mycobacteria ( h igh l ipid content in c e l l wall detected by carbolfuchsin i n acid-fast sta i n ) . Mycoplasma ( n o c e l l wall) . Legionella pnewnophila (primarily i ntracellular) . Chlamydia (intracellular parasite ; lacks muramic acid in cell wall) . Chlamydia, Borrelia, Rickettsiae, Trypanosomes, Plasmodium . Stains glycogen, mucopolysaccharicles; used to d iagnose Whipple's disease (Tropheryma whipplei) . Ziehi- Neelsen (ca rbol Acid-fast organisms (Nocardia, Mycobacterium) . fuchsin) India i nk Cryptococcus neoformans (mucicarmine can also be used to stain thick polysaccharide capsule reel ) . Silver stai n Fungi (e.g., Pneunwcystis) , Legionella, Helicobacter pylori. Special culture requirements BUG MEDIA USED FOR ISOLATION These Rascals May Microscopically Lack Color. Treponemes - dark-fielcl m icroscopy and fluorescent a ntibody sta i n i ng. Legionella -silver sta in. Certai n Bugs Really Try my Patience. PASs the sugar. H. influenzae Chocolate agar with factors V ( NAD+) and X ( hematin) N. gonorrhoeae, N. meningitidis B. pertussis C. diphtheriae M. tuberculosis M. pneumoniae Lactose-f e r m enti ng enterics Legion ella Fungi Thayer-Martin (or VPN) media-Vancomycin (inhibits gram-positive organisms) , Polymyx i n (inhibits gram-negative organ isms except Neisseria) , a n d Nystati n (inh ibits fun gi ) ; " to connect to Neisseria, please use your VPN client" Borclet-Gengou (potato) agar (Bordet for Bordetella) Tellurite plate, Loffler's media Lowenstein-Jensen agar Eaton's agar Pink colon ies on MacConkey's agar (fermentation produces acid, turning colony pink) ; E. coli i s a l s o grown o n eosin-methylene blue ( E M B ) agar as colonies with green metallic sheen Charcoal yeast extract agar buffered with cysteine and iron Sabouraud 's agar. " Sab 's a fun guy! " Obligate aerobes Obligate anaerobes Intracellular bugs Obligate i ntracellular Facultative i ntracellular Encapsulated baderia Catalase-positive organisms MICROBIOLOGY 􀃙 MICROBIOLOGY-BASIC BACTERIOLOGY SE C T I O N I I 1 2 1 Use an 02-dependent system to generate ATP. Examples include Nocardia, Pseudomonas aeruginosa, Mycobacterium tuberculosis, and Bacillus. Reactivation of M. tuberculosis (e.g., after i m mune compromise or TNF-a inh ibitor use) has a predilection for the apices of the lung, which have the h i ghest Po2 . Examples include Clostridium, Bacteroides, and Actinomyces. They lack catalase and/or superoxide d i smutase and are thus susceptible to oxidative damage. Generally foul smell ing (short-cha i n fatty acids), are difficult to culture, and produce gas in tissue (C02 and Hz) . Rickettsia, Chlamydia. Can't make own ATP. Salmonella, Neisseria, Brucella, Mycobacterium, Listeria, Francisella, Legionella, Yersinia pestis. Positive quellung reaction - if encapsulated bug is present, capsule swells when specific anticapsular antisera are added. Examples are Streptococcus pneumoniae, Haemophilus infiuenzae type B , Neisseria meningitidis, Escherichia coli, Salmonella, Klebsiella pneumoniae, and group B Strep. Their capsules serve as an antiphagocytic · virulence factor. Capsule + protein conjugate serve as an antigen in vaccines. Nagging Pests Must Breathe . P. aeruginosa is a n aerobe seen i n burn wounds, compl ications of d i abetes, nosocom i a l pneumon i a , a n d pneumon ias i n cystic fibrosis patients. Anaerobes Can't Breathe Ai r. Anaerobes are normal flora in GI tract, pathogenic elsewhere. Amin02glycosides are ineffective against a naerobes because these antibiotics require 02 to enter i nto bacterial cel l . Stay inside (cells) when i t is Real ly C old. Some Nasty Bugs May Live FacultativeLY Quellung = capsul a r "swellung." S HiNE S Ki S . Are opson ized, and then cleared by splee n . Asplenics have decreased opsonizing abil ity and are at risk for severe i n fections. G ive S. pneumoniae, H. infiuenzae, N. meningitidis vaccmes. Catalase degrades H 202 before it can be You need PLAC E S S for your cats . converted to microbicidal products by the enzyme myeloperoxidase. People with chronic granulomatous d isease ( NADPH oxidase deficiency) have recurrent infections with these m icrobes because they degrade the l i m ited H202 . Examples : Pseudomonas, Listeria, Aspergillus, Candida, E. coli, S. aureus, Serratia. 1 22 SE C T I O N I I Vaccines Urease-positive bugs Pigment-producing bacteria Bacterial virulence factors Protein A lgA protease M protei n MI CRO B I O L O G Y • MICROBIOLOGY-BASIC BACTERIOLOGY For vaccines containing polysaccharide capsule antigens, a protein is conjugated to the polysaccharide antigen to promote T-cell activation and subsequent class switching. A polysaccharide antigen alone cannot be presented to T cell s ; therefore, only IgM antibodies would be produced. Cryptococcus, H. pylori, Proteus, Vreaplasma, Nocardia, Klebsiella, S. epidermidis, S. saprophyticus. Actinomyces israelii-yellow "sulfur" granules, which are composed of filaments of bacteria. Pneumovax (polysaccharide vaccine with no conjugated protein) and Prevnar (conjugated vaccine) H. influenzae type B (conjugated vaccine) Meningococcal vaccines (conjugated vaccines) C Huck Norris hates PUNKSS. Israel has yellow sand. S. aureus-yellow pigment. aureus (Latin) = gold. Pseudomonas aeruginosa-blue-green pigment. Aerugula is green. Serratia marcescens-red pigment. Serratia marcescens-think red maraschino cherries. These promote evasion of host immune response. Binds Fe region of Ig. Prevents opson ization and phagocytosis. Expressed by S. au reus. Enzyme that cleaves IgA. Secreted by S. pnewnoniae, H. influenzae type B , and Neisseria (SH iN) in order to colonize respiratory mucosa. Helps prevent phagocytosis. Expressed by group A streptococci. MI CROBIOLO GY 􀃚 MICROBIOLOGY-BASI C BACTERIOLOGY SECTION II 123 Main features of exotoxins and endotoxins PROPERTY SOURCE SECRETED FROM CELL CHEMISTRY lOCATION OF GENES TOXICITY CliNICAl EFFECTS MODE OF ACTION ANTIGENICITY VACC INES HEAT STABiliTY TYPICAl DISEASES Exotoxin Certain species of some gram-positive and gram-negative bacteria Yes Polypeptide Plasmid or bacteriophage High (fatal dose on the order of l pg) Va rious effects (see below) Va rious modes (see below) Induces high-titer antibod ies called antitoxins To xoids used as vaccines Destroyed rapidly at 60°C (except staphylococcal enterotox in) Te tanus, botulism, diphtheria Endotoxin Outer cell membrane of most gram-negative bacteria No Lipopolysaccharide (structural part of bacteria; released when lysed) Bacterial chromosome Low (fatal dose on the order of hundreds of micrograms) Fe ver, shock Induces TNF and IL-l Poorly antigenic No toxoids fo rmed and no va ccine ava ilable Stable at l00°C for l hour Meningococcemia; sepsis by gram-negative rods 1 2 4 SECT I O N I I M I CRO B I O L O G Y 􀃚 MICROBIOLOGY-BASIC BACTERIOLOGY Bugs with exotoxins BACTERIA In h i b it protei n synthesis Corynebacterium diphtheriae Pseudomonas aeruginosa Shigella spp. Enterohemorrhagic E. coli ( E H EC), including 01 57:H7 strai n Increase fluid secreti o n Enterotoxigenic E. coli ( ETEC) Bacillus anthracis Vibrio cholerae In h i bit phagocytic a b ility TOX I N MECHANISM Diphtheria toxin3 I nactivate elongation factor Exotoxi n N ( E F-2) Sh iga toxi n ( ST) Shiga-like toxi n ( S LT) Heat-labile toxi n ( LT)a Heat-stable toxi n ( ST) Edema factor Cholera toxin3 Inactivate 60S ribosome by removing aden ine from rRNA Overactivates adenylate cyclase (t cAMP) - t C)secretion in gut and H 20 efflux Overactivate guanylate cyclase (t cGMP) -+ ! resorption of NaCI and H 20 i n gut M i m ics the adenylate cyclase enzyme (t cAM P) Overactivates adenylate cyclase (t cAM P) by permanently activating G5 -+ t cJ- secretion in gut and H 20 efflux Bordetella pertussis Pertussis toxina Overactivates adenylate cyclase (t cAM P) by d i sabl ing Gi, impairing phagocytosis to permit survival of m icrobe In h i bit release of n eurotra n s m itter Clostridium tetani Tetanospasmin Clostridium Botulinum toxi n botulinum Cleave SNARE protein required for neurotransm itter release MAN I FESTATION Pharyngitis with pseudomembranes i n throat and severe lymphadenopathy (bull neck) Host cell death GI mucosal damage -+ dysentery; ST also enhances cytokine release, causing H U S SLT enhances cytokine release, causing H US; unl ike Shigella , E H E C does not i nvade host cells Watery diarrhe a : labile i n the Ai r (Adenylate cyclase), stable on the Ground (Guanylate cyclase) . Likely responsible for characteristic edematous borders of black eschar i n cutaneous anthrax Voluminous "rice-water" diarrhea Whoopi ng cough: child coughs on expiration and "whoops" on inspiration (toxi n may not actually be a cause of cough; can cause " 1 00-day cough " i n adults) Muscle rigidity and " lock j aw"; toxi n prevents release of inhibitory ( GABA and glycine) neurotransm itters i n spinal cord Flaccid paralysis, Aoppy baby; toxi n prevents release of stimulatory (ACh) signals at neuromuscular junctions -+ Aaccid paralysis 3Toxin is an ADP ribosylating A-B toxin : B (binding) component binds to host cell surface receptor, enabling endocytosis; A (active) component attaches ADP-ribosyl to disrupt host cell proteins. MICROBI OLOGY 􀃙 MICROBIO LOGY- BASIC BACTERIO LOGY SECT I O N I I 1 2 5 Bugs with exotoxins (continued) BACTERIA TOXI N Lyse cell m e mbranes Clostridium perfringens Streptococcus pyogenes Alpha toxi n Streptolysi n 0 Superantigen s causing s hock Staphylococcus Toxi c shock au reus Streptococcus pyogenes syndrome toxi n (TSST-l) Exotoxi n A M ECHANISM Phosphol ipase that degrades tissue and cell membranes Protein that degrades cell membrane Bring MHC I I and TC R in proxim ity to outside of antigen binding site to cause overwhelming release of i FN-y and I L-Z -+shock M A N I FESTAT I O N Degradation of phosphol ipid C -+ myonecrosis ( "gas gangrene") and hemolys i s ( "double zone" of hemolysis on blood agar) Lyses R B C s ; contributes to 􀄊-hemolys i s ; h o s t antibodies against toxi n (ASO) u s e d to d i agnose rheumatic fever (do not confuse with i m mune complexes of poststreptococcal glomerulonephritis) Toxic shock syndrom e : fever, rash , shock; other toxi n s cause scalded skin syndrome (exfoliative toxin) and food poison ing (enterotoxin) Toxic shock syndrome : fever, rash , shock Endotoxin A l ipopolysaccharide found in outer membrane ENDOTOXIN : of gram-negative bacteria. Edema Endotoxin (especially lipid A) I t I Activates complement I I 't 't C3a C5a .J, .J, Hypotension, Neutrophil edema chemotaxis Coagulation cascade .J, DIC (Adapted, with permission, from Levinson W. Review of Medical Microbiology and Immunology, 1 2th ed. New York: McGraw-Hill, 20 1 2: Fig. 7-4.) Baderial growth curve Lag phase Metabol ic activity without division. Exponential/log phase Rapid cell d ivision. Penicillins and cephalosporins act here as peptidoglycan is being made. Stationary phase Nutrient depletion slows growth . Spore formation in some bacteria. Death Prolonged nutrient depletion and buildup of waste products lead to death . Nitric oxide DIC /Death Outer membrane TN F-a 0-antigen eXtremely heat stable I L-l Neutrophi l chemotaxis Stationary phase Exponential growth phase Time 1 2 6 SECT ION I I Bacterial genetics Transformation Conjugation F+ X FHfr x FTra nsposition Transduction Gen e ralized Specialized Lysogeny, specialized transduction M I CROB I O LOG Y 􀃘 MICROBIOLOGY-BASIC BACTERIOLOGY Abi l ity to take up naked DNA (i.e., from cell lysis) from environment (also known as "competence" ) . A feature of many bacteria, especially S. pneumoniae, H. influenzae type B, and Neisseria ( SH iN ) . Any DNA can be used. Adding deoxyribonuclease to environment will degrade naked DNA i n medium -+ no transformation seen. P plasmid contains genes required for sex pilus and conjugati on. Bacteria without this plasmid a re termed F-. Plasmid (dsDNA) is repl icated and transferred through pilus from P cell. No transfer of chromosomal genes. P plasmid can become incorporated into bacterial chromosomal DNA, termed high-frequency recombination ( H fr) cel l . Repl ication of incorporated plasmid DNA may i nclude some flanking chromosomal DNA. Transfer of plasm id and chromosomal genes. Segment of DNA that can " jump" (excision and reintegration) from one location to another, can transfer genes from plasmid to chromosome and vice versa. When excision occurs, may i nclude some flanking chromosomal DNA, wh ich can be incorporated i nto a plasmid and transferred to a nother bacterium. A "packaging" event. Lytic phage infects bacterium, leading to cleavage of bacterial DNA. Parts of bacterial chromosomal DNA may become packaged in viral capsid. Phage infects a nother bacterium, transferring these genes. An "excision" event. Lysogenic phage infects bacterium; viral DNA i ncorporates i nto bacterial chromosome. When phage DNA i s excised, flanking bacterial genes may be excised with it. DNA is packaged i nto phage viral capsid and can infect another bacterium. Genes for the following 5 bacterial toxins encoded i n a lysogenic phage : • ShigA-l ike toxi n • Botu l i nu m toxi n (certai n strains) • Cholera tox i n • D iphtheria toxi n • Erythrogenic toxi n o f Streptococcus pyogenes ABC DE MI CROBIOLOGY 􀃚 MI CROBI OLOGY-CLINICAL BACTERI O LOGY SECTION II 1 2 7 􀃚 MI CRO BIOLOGY-C LINIC AL BACTERIOLOGY Gram-positive lab algorithm Clostridium (anaerobe) Corynebacterium Listeria Bacillus (aerobe) Mycobacterium (acid-fast) Catalase<±) (clusters) Staphylococcus Catalase8 (chains) Streptococcus Coagulase8 Novobiocin se nsitive S. epidermidis Novobiocin resi stant S. saprophyticus Important pathogens are in bold type. Note: Enterococcus is either a- or y-hemolytic. Identification of gra m-positive cocci Staphylococci NOvobiocin -Saprophyticus is Res i s tant ; Epidermidis is S en s itive. I Nocardia ! S. pneumoniae Capsule ( <±) quellung) Optochin se nsitive Viridans st reptococci (e.g., S. mutans) No capsu le Optochin re sistant Group A S.pyogenes Bacitrac in se nsitive Complete l3 1-; hemolysis 0􀆆& (clear) '?. oj..&· 􀆅 Group B (S. agalactiae) Bacitracin re si stant Gro up D (Enterococcus) y Growth in bile and 􀆇-􀆈 6.5% NaCI (E. faecalis) Non ente rococcus Growth in bile, not 6.5% NaCI (S. bovis) On the office's staph retreat, there was NO S t RESs . Streptococci O p toch in-Viridans is Resi s tant; Pnewnoniae is OV RPS (overpass) . a- hemolytic baderia S e n s itive. Bacitracin - gr oup B strep are Re s i stant ; group A strep are Sen sitive. B - BRAS. Fo rm green ring around colon ies on blood agar. Include the fo llowing organisms: • Streptococcus pnewnoniae (catalase negative and optochin sensitive) • Viridans streptococci (catalase negative and optoch in resistant) l 2 8 SECT I O N I I P-hemolytic baderia Staphylococcus aureus fJ Staphylococcus epidermidis Streptococcus pneumoniae I I , ,-. ' Viridans group streptococci M I C R O B I O L O GY • M I C R O B I O L O G Y - C LI N I C A L B A C TE R I O L O G Y Form clear area of hcmolysi s on blood agar. Include the following orga n i sms: • Staphylococcus aureus (catalase and coagulase positive) • Streptococcus {Jyogenes-group A strep (catalase negative and bacitracin sensitive) • Streptococcus agalactiae-group B strep (catalase negative and bacitracin resistant) • Listeria monocytogenes (tumbling motil ity, meningitis in newborns, unpasteurized m i lk) Gram-positive cocci in clusters (J. Protein A (virulence factor) binds Fc-lgG, inh ibiting complement fixation and phagocytosis. Cause s : • Inflammatory disease-skin infections, organ abscesses, pneumonia • Toxi n-mediated d i sease-toxic shock syndrome (TSST- 1 ) , scalded ski n syndrome (exfol iative toxin), rapid-onset food poisoning (enterotoxins) • M RSA (meth icill in-resistant S. aureus) i n fection-important cause of serious nosocom ial and community-acqu ired i n fection s ; resistant to P-lactams because of altered penicillin-bi nding protein TSST is a superantigen that binds to M HC II and T-cell receptor, resulting i n polyclonal T-cell activation. Presents as fever, vom iti ng, rash, desquamation, shock, end-organ fai lure. S. aureus food poisoning i s clue to ingestion of preformed tox i n . Causes acute bacterial endocard itis, osteomyelitis. Staph make catalase because they have more "staff." Bad staph (aureus) make coagulase and toxins. Forms fibrin clot around self; can lead to abscess. I n fects prosthetic devices and i ntravenous catheters by producing adherent biofi l m s . Component of normal skin flora; conta m inates blood cultur e s . M o s t c o m m o n cause of: • Meningitis • Otitis media (in children) • Pneumon ia • Sinusitis Lancet-shaped, gram-positive d iplococci (J. Encapsulated. I gA protease. Viriclans streptococci are a-hemolytic. They are normal flora of the oropharynx and cause dental caries (Streptococcus mutans) and subacute bacterial endocard itis at damaged valves (S. sanguis) . Res istant to optoch in, differentiating them from S. pneumoniae, wh ich is a-hemolytic but is optoch i n sensitive. S. pnewn oniae MOPS are Most OPtoch in Sensitive. Pneumococcus i s associated with "rusty" sputum , sepsis i n sickle cell anem ia and splenectomy. No virulence w ithout capsule. Sanguis = blood . T here i s lots of blood in the heart (endocarditis) . S. sanguis sticks to damaged valves by making glycocalyx. Viriclans group strep l ive in the mouth because they are not afraid of-the-chin (op-to-chin resistant) . Streptococcus pyogenes (group A streptococci) Streptococcus agaladiae (group B streptococci) Enterococci (group D streptococci) Streptococcus bovis (group D streptococci) MICROBIOLOGY 􀃙 MIC ROBIOLOGY-CLINICAL BACTERI O LOGY SECTION II 1 2 9 Causes: • Pyogenic-pharyngitis, cellulitis, impetigo • To xigenic-scarlet fe ver, toxic shock-like syndrome, necrotizing fa sciitis • Immunologic-rheumatic fe ver, acute glomerulonephritis Bacitracin sensitive. Antibodies to M protein enhance host defenses against S. pyoge nes but can give rise to rh eumatic fe ver. ASO titer detects recent S. pyogenes infection. Bacitracin re sistant, 􀄊-hemolytic, colon izes vagina; causes pneumon ia, meningitis, and sepsis, mainly in babies. Produces CAMP fa ctor, which enlarges the area of hemolysis fo rmed by S. au re us. (Note : CAM P stands fo r the authors of the test, not cyclic AMP.) Hippurate test positive. Screen pregnant women at 35-37 weeks. Patients with positive culture rece ive intrapa rtum penicillin prophylaxis. Enterococci (Enterococcus fa ecalis and E. fa ecium) are normal colonic flora that are penicillin G resistant and cause UTI, biliary tract infections, and subacute endocarditis. Lancefield group D includes the enterococci and the nonenterococcal group D streptococc i. La ncefield grouping is based on diffe rences in the C carbohydrate on the bacterial cell wa ll. Va riable hemolysis. VRE (vancomycin-resistant enterococci) are an important cause of nosocom ial infection . J¥NES criteria to diagnose rheumatic fever: J oints-polya rthritis ¥-carditis Nodules (subcutaneous) E r y thema marginatum S ydenham's chorea Ph aryngitis can result in rheumatic "p h ever" and glomeru lonephritis . Impetigo more commonly precedes glomerulonephritis than pharyngitis. Scarlet fe ve r: scarlet rash sparing fa ce, strawberry (scarlet) tongue, scarlet throat Group B for B abies ! Enterococci, hardier than nonenterococcal group D, can grow in 6.5% NaCl and bile (lab test) . En tero = inte stine, fa eca lis = fe ces, strepto = twisted (chains), coccus= berry. Colonizes the gut. Can cause bacteremia and Bovis in the blood = c ancer in the colon . subacute endocarditis in colon cancer patients. 1 3 0 SECT I O N I I Corynebaderium diphtheriae Spores: bacterial Clostridia (with exotoxins) C. tetani C. botulinum C. perfringens C. difficile MICRO BIO LOGY • MICROBIOLOGY-CLINICAL BACTERIOLOGY Causes d iphtheria via exotoxin encoded by 􀄊-prophage. Potent exotoxin inh ibits protein synthesis via ADP-ribosylation of EF-2 . Symptoms i nclude pseudomembranous pharyngitis (grayish-wh ite membrane) with lymphadenopathy, myocarditis, and arrhythmias. Lab d iagnosis based on gram-positive rods with metachromatic (blue and reel) granules and Elek's test for toxin. Toxoid vaccine prevents diphtheria. Some bacteria can form spores at the end of the stationary phase when nutrients are l i m ited . Spores are h ighly resistant to heat and chem icals. H ave cl ipicol inic acid in thei r core. H ave no metabol ic activity. Must autoclave to kill spores (as is clone to surgical equipment) by steaming at 1 2 l ° C for 1 5 m inutes. Coryne = club shaped. Black colon ies on cystine-tellur i te agar. ABCDEFG : ADP-ribosylation Beta-prophage Corynebacterium Diphtheria Elongation Factor 2 Granules Spore-forming gram-positive bacteria found in soi l : Bacillus anthracis, Clostridium perfringens, C. tetani. Other spore formers include B. cereus, C. botulinum, Coxiella burnetii. Gram-positive, spore-forming, obl igate anaerobic bac i l l i . Produces tetanospasm in, an exotoxin causing tetanus. Tetanus toxin (and botulinum toxin) are proteases that cleave releasing proteins for neurotransmitters. Produces a preformed , heat-labile toxin that inh ibits ACh release at the neuromuscular j unction, causing botulism. In adults, disease is caused by ingestion of preformed toxin. In babies, ingestion of spores in honey causes d i sease (floppy baby syndrome) . Produces a toxi n ( " lecithinase," a phosphol ipase) that can cause myonecrosis (gas gangrene) and hemolysis. Produces 2 toxins. Toxin A, enterotoxin, binds to the brush border of the gut. Toxin B, cytotoxi n , destroys the cytoskeletal structure of enterocytes, causing pseudomembranous col itis. Often 2 ° to antibiotic use, especially clinclamycin or ampicill i n . Diagnosed by detection of one or both toxins in stool . Tetanus is tetanic paralysis (blocks glycine and GABA release [ i n h ibitory neurotransmitters] ) from Renshaw cells i n spinal cord . Causes spastic paralysis, trismus (lockjaw) , and risus sarclonicus. Botulinum is from bad bottles of food and honey (causes a flaccid paralysis) . Perfringens perforates a gangrenous leg. Diffzcile causes diarrhea . Treatment: metron idazole or oral vancomycin. Anthrax Cutaneous anthrax Pulmonary anthrax Bacillus cereus Listeria monocytogenes Adinomyces vs. Nocardia MI CROBIOL OGY 􀃚 MIC R OBIOLOGY- C LINI CAL BACTERIOLOGY S E C T I O N I I 1 3 1 Caused by Bacillus anthracis, a gram-positive, spore-form i n g rod that produces anthrax tox i n . The only bacterium with a polypeptide capsule (conta i n s D-glutamate) . Contact --+ black eschar (pa inless ulcer) ; can progress to bacteremia and death . Inhalation of spores - flu-like symptoms that rapidly progress to fever, pul monary hemorrhage, med iastinitis, and shock. Causes food poisoning. Spores survive cooking rice. Keeping rice warm results in germination of spores and enterotoxi n formation. Emetic type usually seen with rice and pasta . Nausea and vom iting with i n l-5 hour s . Caused b y cereul i de, a preformed toxin. Diarrheal type causes watery, nonbloody d i arrhea and GI pain in 8-1 8 hour s . Black s k i n lesions - black eschar (necrosis) surrounded by edematous ring. Caused by lethal factor and edema factor. Woolsorters' d i sease - inhalation of spores from conta m i nated wool . Reheated rice syndrome. Facultative intracellular m icrobe; acqu ired by ingestion of unpasteuri zed milk/cheese and deli meats or by vaginal transm ission dur i n g birth. Form "acti n rockets" by wh ich they move from cell to cel l . Characteristic tumbl ing motility. Can cause amn ionitis, septicem ia, and spontaneous abortion in pregnant women ; granulomatosis infantiseptica ; neonatal meningitis ; men i ngitis in i m munocompro m i sed patients ; m i l d gastroenteritis in healthy individuals. Treatment: gastroenteritis usually sel f-l i m ited ; ampicillin i n infants, immunocomprom ised patients, a n d t h e elderly in empirical treatment of men i ngitis. Both form long, branching filaments resembl ing fungi. Actinomyces Gram-positive anaerobe Not acid fast Normal oral fl ora Causes oral /facial abscesses that drain th rough sinus tracts, forms yellow "sulfur granules" Treat with penicillin Nocardia Gram-positive aerobe Acid fast Found i n soil Causes pulmonary i n fections i n i m m u nocompromised and cutaneous infections after traum a i n i m munocompetent Treat with sulfona m ides 1 3 2 SECTIO N I I MICROBIOLOGY 􀃙 MICROBIOLOGY- C LINICAL BACTER IOLOGY 1 o and 2° tuberculosis r Infection with Mycobacterium tuberculosis Nonimmune host (usually child) l Hilar nodes Ghon focus J Ghon (usually in mid complex zone of lung) Partially immune hypersensitized host (usually adult) l Reinfection I Secondary tuberculosis j-.-----, Fibrocaseous cavitary lesion (} (usually !:!.£per · lobes) t] Reactivation tuberculosis of the lungs Heals by fibrosis Progressive Severe bacteremia Preallergic lymphatic or hematogenou1 dissemination t lung disease Immunity and (HIV, malnutrition) hypers;nsitivity ! 􀁾 Miliary tuberculosis 􀃖 Tuberculin positive Death (rare) Death Dormant tubercle bacilli in several organs Extrapulmonary tuberculosis 􀃗 Reactivation in • CNS (parenchymal tuberculoma or meningitis) adult life • Vertebral body (Pott's disease) 1+------------' • Lymphadenitis • Renal • Gl Mycobacteria Mycobacterium tuberculosis (TB , often resistant to multiple dru gs) . M. kansasii (pul monary TB-l ike symptoms) . M. avium-intracellulare (causes cl issem i nated, non-TB d isease i n AIDS ; often resistant to multiple drugs) . Prophylactic treatment with azithromycin. All mycobacteria are acid-fast organ isms rJ. PPD+ if current i n fection, past exposure, or BCG vacci nated. PPD- i f no i n fection or anergic (steroids, mal nutrition, immunocompromise) and i n sarcoidosis. 􀁿􀂀􀂁􀂂􀂃-􀂄􀂅􀂆􀂇-􀂈􀂉􀂊􀂋 caseating granuloma. With multinucleated Langhan's giant cell (arrow).li!l TB symptoms include fever, n ight sweats, weight loss, and hemoptysis. Cord factor in virulent strains inhibits macrophage maturation and i nduces release of TNF-a. Sulfatides (surface glycolipids) i n h ibit phagolysosomal fusion. MICRO BIOLOGY 􀃙 MI C ROBI OLOGY-CLINICAL BACTERIO LOGY SECT I O N I I 1 3 3 Leprosy (Hansen's disease) Nasal collapse Lumpy earlobe "Leonine facies" of lepromatous leprosy Caused by Mycobacterium leprae, an acid-fast bacillus that l ikes cool temperatures (infects skin and superficial nerves-"glove and stocki ng" loss of sensation) and cannot be grown i n vitro. Reservoir in United State s : armadillos. Hansen's d i sease has 2 forms : • Lepromatous -presents diffusely over skin rn and i s communicable; characterized by low cell-mediated i m mun ity with a humoral Th2 response. • Tu bercu loid -l i m ited to a few hypoesthetic, hairless skin plaque s ; characterized by h igh cell-mediated immunity with a largely Th 1 - type i m mune response. Multidrug therapy consisting of dapsone and rifampin for 6 months for tuberculoid form and dapsone, rifampin, and clofazim ine for 2-5 years for lepromatous form. Gram-negative lab algorithm Maltose fermenter Diplococci Neisseria meningitidis, N. gonorrhoeae Maltose nonfermenter N. meningitidis N. gonorrhoeae Important pathogens are in bold type. "Coccoid" rods Haemophilus influenzae (requires factors V and X) Pasteurella-animal bites Brucella-brucellosis Bordetella pertussis Fast fermenter Klebsiella Lactose fermenter E. coli Enterobacter Slow fermenter Citrobacter Serratia Others OxidaseG Shigella Salmonella Proteus I Vibrio cholerae I Lactose nonfermenter Oxidase @ Pseudomonas H. pylori 1 3 4 SECTI O N II Lactose-fermenting enteric bacteria Penicillin and gram-negative bugs Neisseria Haemophilus influenzae MI CRO B I O L O G Y 􀃛 MICROBIOLOGY-CLINICAL BACTERIOLOGY Grow pink colon ies on MacConkey's agar. Examples i nclude Citrobacter, Klebsiella, E . coli, Enterobacter, and Serratia. E. coli produces 􀄊-gal actosidase, which breaks down lactose into glucose and galactose. Lactose is KEE . Test with MacCon KEE' S agar. EMB agar-lactose fermenters grow as purple/black colonies. E. coli grows purple colonies with a green sheen. Gram-negative bacilli are resistant to penicillin G but may be susceptible to penicillin derivatives such as ampicil l i n and amoxicillin. The gram-negative outer membrane layer inh ibits entry of penici l l i n G and vancomycin. Gram-negative d iplococci . Both ferment glucose and produce IgA proteases. N. gonorrhoeae within polymorphonuclear leukocytes rJ. Gonococci No polysaccharide capsule No maltose fermentation No vaccine (clue to rapid antigen ic variation of pilus proteins) Sexually transm itted Causes gonorrhea, septic arthritis, neonatal conjunctivitis , PID, and Fitz- Hugh-Curtis syndrome Treatment: ceftriaxone + (azithromycin or doxycycline) for possible chlamydia co infection HaEMOPhilus causes Epiglottitis ( "cherry reel " in children) , Meningitis, Otitis med ia, and Pneumon ia. Small gram-negative (coccobacillary) rod . Aerosol transmission. Most i nvasive d isease caused by capsular type B. Nontypeable stra i ns cause mucosal infections (otitis media, conjunctivitis, bronch itis) . Produces I gA protease. Culture on chocolate agar requires factors V ( NAD+) and X ( hematin) for growth ; can also be grown with S. aureus, wh ich provides factor V. Treat meningitis with ceftriaxone. Rifampin prophylaxis i n close contacts. MeninGococci ferment Maltose and Glucose . Gonococci ferment Glucose. Meningococci Polysaccharide capsule Maltose fermentation Vaccine (none for type B ) Respiratory and oral secretions Causes meningococcem i a and meningitis, Waterhouse-Friclerichsen syndrome Rifampin, ciproAoxaci n , or ceftriaxone prophylaxis in close contacts Treatment: ceftriaxone or penicillin G When a ch ild has "Au," mom goes to five ( V) and cl ime (X) store to buy some chocolate. Vaccine contains type B capsular polysaccharide (polyribosyl ribitol phosphate) conjugated to d iphtheria toxoid or other protein. Given between 2 and 18 months of age. Does not cause the Au (influenza virus does) . Legionella pneumophila Pseudomonas aeruginosa E. coli STRAIN E IEC ETEC E PEC E H EC M I C R OB I OLO G Y 􀃚 M I C R O B I O L O G Y - C LIN I CAL BACTE RIO L O G Y SECT I O N I I 1 3 5 Legi o n n a i res' d isease = severe pneumon ia, fever, GI and C N S symptoms. Po ntiac fever = mild Au-like syndrome. Gram-negative rod. Gram stains poorly-use silver sta i n . Grow on charcoal yeast extract culture with iron and cysteine. Detected clinically by presence of antigen in urine. Aerosol transm ission from environmental water source h abitat. o person-to-person transmission. Treatment: macrol ide or qui nolone. PSE UDOmonas is associated with wound and burn infections, Pneumonia (especially i n cystic fibrosis), Sepsi s (black lesions on ski n ) , External otitis (swim mer's ear) , UTI , Drug use and Diabetic Osteomyelitis, and hot tub foll iculitis. Mal ignant otitis externa i n diabetics. Aerobic gram-negative rod. Non-lactose fermenting, oxidase positive. Produces pyocyanin (blue-green) pigment; has a grape-l ike odor. Water source. Produces endotoxi n (fever, shock) and exotoxin A (inactivates E F-2 ) . Treatment: a m inoglycoside plus extendedspectrum penic i l l i n (e.g., piperacillin, ticarci l l i n ) . Think of a French legionnaire (soldier) with his silver helmet, sitting around a campfire (charcoal) with h i s iron dagger- he is no sissy (cysteine). Labs show hyponatremia. Aeruginosa - aerobic. Think water connection and blue-green pigment. Think Pseudomonas i n burn victi m s . Chronic pneumonia i n C F patients is associated with biofi l m . E. coli virulence factors : fimbriae- cystitis a n d pyelonephriti s ; K capsule-pneumonia, neonatal meningiti s ; LPS endotoxin- septic shock . TOXI N AND M ECHANISM M icrobe i nvades intestinal mucosa and causes necrosis and inflam mation. No toxins produced. Clin ical manifestations similar to Shigella . Labile toxi n /stable toxin. No inflammation or i nvasion . No toxi n produced. Adheres to apical surface, fl attens villi, prevents absorption. O l 57: H 7 i s the most common serotype. Produces Shiga-l ike toxi n and Hemolytic-uremic syndrome (triad of anem ia, th rombocytopenia, and acute renal failure) . Endothel ium swells and narrows lumen , leading to mechanical hemolysis and reduced renal blood flow; damaged endothelium consumes platelets. PRESENTATION Invasive ; dysentery. Traveler's d i arrhea (watery) . D i arrhea usually i n children (Ped iatrics) . Dysentery (toxin alone causes necrosi s and inflam mation ) . D o e s n o t ferment sorbitol (d istingu ishes it from other E. coli) . 1 3 6 SECTI O N II Klebsiella Salmonella vs. Shigella MI CRO B I O L O G Y 􀃚 MIC R O BIO L OGY - C LINIC AL BACTERIO L O G Y An i ntestinal flora that causes lobar pneumonia in alcoholics and diabetics when aspirated . Very mucoid colonies caused by abundant polysaccharide capsule. Red "currant jelly" sputum . A l s o cause of nosocomial UTis. Salmonella H ave flagella (salmon swim) Can disseminate hematogenously H ave many animal reservoirs Pro duce hydrogen sul fide Antibiotics may prolong symptoms I nvades intestinal mucosa and causes a monocytic response Can cause bloody diarrhea Does not ferment lactose 4 A's : Aspiration pneumonia Abscess i n lungs and l iver Alcohol ics d i-A-betics Shigella No flagel la Cell to cell transm ission ; no hematogenous spread Only reservoirs are humans and primates Does not produce hyd rogen sulfide Antibiotics prolong excretion of organism i n feces I nvades intestinal mucosa and causes PMN infiltration Often causes bloody diarrhea Does not ferment lactose Salmonella typhi Causes typhoid fever. Found only in humans. Characterized by rose spots on the abdomen, fever, headache, and d iarrhea. Can remain in gallbladder and cause a carrier state . Campylobader jejuni Major cause of bloody diarrhea, especially i n children. Fecal-oral transmission through foods such as poultry, meat, unpasteurized milk. Comma or S-shaped, oxidase positive, grows at 42 °C ( "Campylobacter l ikes the hot campfire" ) . Common antecedent to Guillain-Barre syndrome and reactive arth ritis. Vibrio cholerae Produces profuse rice-water diarrhea via toxin that permanently activates G5, t cAM P. Comma shaped, oxidase positive, grows in alkaline media. Endemic to developing countries. Prompt oral rehydration is necessary. Yersinia enterocolitica Usually trans m itted from pet feces (e.g., puppies), contaminated milk, or pork. Causes mesenteric adenitis that can mimic Crohn's or append icitis. Helicoboder pylori Spirochetes MICROBIOLOGY 􀃙 MIC RO BIO L OGY - C LINICAL BACTERIO LO GY SECTI O N II 1 3 7 Causes gastritis and up to 90% of duodenal ulcers. Risk factor for peptic ulcer, gastric adenocarcinoma, and lymphoma. Curved gram-negative rod. Urease positive (can use urea breath test for d iagnosis) . Creates alkaline environment. Most common in itial treatment is triple therapy: proton pump inh ibitor; clarithromyc i n ; amoxici l l i n or metron idazole. The spirochetes are spiral-shaped bacteria with BLT. axial filaments and include Borrelia (big size), B i s B ig. Leptospira, and Treponema. Only Borrelia can be visualized using anil ine dyes (Wright's or Giemsa stain) i n l ight m icroscopy. Treponema is visualized by dark-field m icroscopy. Leptospira interrogons Found in water conta m inated with animal urine, causes leptospirosi s : flu-l i ke symptoms, jaundice, photophobia with conjunctivitis . Prevalent among surfers and i n tropics (i .e., Hawa i i ) . Lyme disease Weil's d i sease (icterohemorrhagic leptospirosis) - severe form with jaundice and azote m i a from l iver and kidney dysfunction ; fever, hemorrhage, and anemi a . Caused b y Borrelia burgdorferi, which is transmitted by the tick Ixodes (also vector for Babesia ) . Natural reservoir is the mouse. M ice are i mportant to tick life cycle. Common in northeastern Un ited States. Treatment: doxycycline, ceftriaxone. 3 stages of Lyme d isease : • Stage ! - erythema chron icum m igrans (expanding "bull's eye" red rash with central clearing) , flu-l ike symptoms. • Stage 2 - neurologic (facial nerve palsy) and cardiac (AV nodal block) manifestations . • Stage 3 - musculoskeletal (chronic monoarthritis and m igratory polyarthritis), neurological (encephalopathy and polyneuropathy) , and cutaneous manifestations. FAKE a Key Lyme pie: Facial nerve palsy (typically bilateral) Arthritis Kardiac block Erythem a m igrans 1 3 8 SECT I O N I I M I C RO B I OLO G Y 􀃘 MICROBIOLOGY-CLINICAL BACTERIOLOGY Syphilis 1° syphilis r syphilis . B ; · * 3° syphi l i s Congenital syphilis Caused by spirochete Treponema pallidum. Localized d isease presenting with pain less chancre [l Screen with VORL and confirm d iagnosis with FTA-ABS. D i ssem i nated disease with constitutional symptoms, maculopapular rash (palms and soles ) , condylomata lata. Treponemes are present in chancres of 1 o and condylomata lata of zo syph ilis and may be directly visual ized through clark-field m icroscopy (I). Screen with VORL and confirm diagnosis with FTA-ABS. S econdary syph ilis = System ic. Gummas (chronic granulomas), aortitis (vasa vasorum destruction) , neurosyph ilis (tabes dorsal is), Argyl l Robertson pupi l . Signs : broad-based ataxia, positive Romberg, Charcot joint, stroke without hypertension. Test spinal fluid with VORL. Saber shins, saddle nose, C VI I I deafness, Hutchinson's teeth, mulberry molars. Early prevention is key, as placental transmission typically occurs after first trimester. Argyll Robertson pupil Argyll Robertson pupil constricts with accommodation but is not reactive to l ight. Associated with 3 ° syph i l i s . V D R L false positives VORL detects nonspecific antibody that reacts with beef card iol ipin. Used for diagnosis of syph ilis, but many false positives, including viral infection (mononucleosis, hepatitis) , some drugs, rheumatic fever, SLE , and leprosy. Treatment: pen i c i l l i n G . "Prostitute's pupil " -accommodates b u t d o e s not react. VORL : Vi ru ses (mono, hepatitis) D rugs Rheumatic fever Lupus and leprosy Jarisch-Herxheimer readion Flu-l i ke syndrome immediately after antibiotics are started- due to killed bacteria releasing pyrogens . M I C R O B I O L O G Y 􀃙 MIC R O BIO L O G Y - C LINI C A L B A C T E R I O LO G Y SE C T I O N I I 1 3 9 Zoonotic baderia Zoonos i s : I n fectious d isease transmitted between animals and humans. SPECIES Bartonella spp. Borrelia burgdorferi Borrelia recurrentis Brucella spp. Campylobacter Chlamydophila psittaci D I SEASE Cat scratch d i sease Lyme d isease Recurrent fever Brucellosis/undulant fever Bloody d iarrhea Psittacosis Coxiella burnetii Q fever Ehrlichia chaffeensis Ehrlichiosis Francisella tularensis Tularemia Leptospira spp. Leptospirosis Mycobacterium leprae Leprosy Pasteurella multocida Cellulitis, osteomyel itis Rickettsia prowazekii Epidemic typhus Rickettsia rickettsii Rocky Mounta i n spotted fever Rickettsia typhi Endemic typhus Yersinia pestis Plague Gardnerella vagina/is A pleomorph ic, gram-variable rod that causes vaginosis presenting as a gray vaginal d ischarge with a fishy smel l ; nonpainful. Associated with sexual activity, but not an STD. Bacterial vaginosis is characterized by overgrowth of certa in bacteria i n vagina. Clue cells, or vaginal epithelial cells covered with bacteria, are visible under the m icroscope (arrow) f.J. Treatment: metronidazole. TRANSM I S S I O N A N D SOURCE Cat scratch Ixodes ticks ( l ive on deer and m ice) Louse (recurrent because of variable surface antigens) Unpasteurized dairy Puppies, livestock (fecal- oral , ingestion of u ndercooked meat) Parrots, other bird s Aerosols of cattle/sheep a m niotic fluid Lone Star tick Ticks, rabbits, deer fly Animal urine Armad illos and humans with lepromatous leprosy Animal bite, cats, dogs Louse Dermacentor tick bite Fleas Fleas (rats and prairie clogs a re reservoirs) I don't have a clue why I smell fish i n the vagina garden ! 1 40 SE C T I O N I I Rickettsial diseases and vedor-bome illness Rash No rash M I C R O B I O L O G Y 􀃛 MIC R O BIO LO G Y - C LINI C AL B A C TE R I O L O G Y Treatment for all : doxycycline. Rocky Mountain spotted fever (tick) -Rickettsia rickettsii. Broadly d istributed in US (in spite of name) . Rash typically starts at wrists and ankles and then spreads to trunk, palms, and soles. Rickettsiae are obligate intracellular organisms that need CoA and NAD +. Typhu s : • Endemic (fleas) -R. typhi. • Epidemic (human body louse) -R. prowazekii. Rash starts centrally and spreads out, sparing palms and soles. Ehrlichiosis (tick) -Ehrlichia. Monocytes with morula (berry-l ike inclusions) in cytoplasm. Anaplasmosis (tick) -Anaplasma. Granulocytes with morula i n cytoplasm . Q fever (tick feces and cattle placenta release spores that are inhaled as aerosols) -Coxiella bumetii. No arthropod vector. Presents as pneumoma. Classic triad -headache, fever, rash (vasculiti s ) . "Rickettsi i on t h e wRi sts , Typhus o n the Trunk." Palm and sole rash is seen in Coxsackieviru s A infection (hand, foot, and mouth d i sease) , Rocky Mountain spotted fever, and secondary Syph il is (you drive CARS using your palms and soles) . Q fever is Queer because it has no rash or vector and its causative organ ism can survive outside i n its endospore for m . Not i n the Rickettsia genus, but closely related. Chlamydiae M I C R O B I O L O G Y 􀃙 MI C R O BIO LO G Y - C LI N I C A L B A C T E RI O L O G Y SECTI O N II 1 4 1 Chlamydiae cannot make their own ATP. They are obl igate i ntracellular organisms that cause mucosal infections. 2 forms: • Elementary body (small , dense) i s " Enfectious" and Enters cell via Endocytosi s . • Reticulate b o d y Repl icates i n c e l l b y fission ; form seen on tissue culture. Chlamydia trachomatis causes reactive arthritis, conjunctivitis, nongonococcal urethritis, and PID. C. pneumoniae and C. psittaci cause atypical pneumonia; transm itted by aerosol . Treatment: azithromycin (favored because onetime treatment) or doxycycline. Chla mys = cloak (intracellular) . Chla mydophila psittaci-notable for an avian reservOir. Lab d iagnosi s : cytoplasmic inclusions seen on Giemsa or fluorescent antibody-stained smear. The chlamydia] cell wal l is unusual in that it lacks m uram ic acid. Attach ment and entry Elementary bodies of elementary body Reorganization of reticulate bod ies into elementary bodies Cell nucleus Formation of reticulate body M u ltipl ication of Chlamydia trachomatis serotypes Types A, B, and C Chronic infection, cause blindness clue to Types 0-K Types Ll , Ll, and L3 fol l icular conjunctivitis i n Africa. Urethritis/Fl O, ectopic pregnancy, neonatal pneumonia (staccato cough) , or neonatal conjunctivitis. Lymphogranuloma venereum. ABC = Africa/Bl indness/Ch ronic infection . D-K = everything else. Neonatal d isease can be acqu i red during passage through infected birth canal. 1 4 2 SECTI O N II Mycoplasma pneumoniae MI C R O B I O L O G Y 􀃚 MIC RO BIO LO G Y - C LINI C A L B A C TE RIO LO G Y Classic cause of atypical "walking" pneumon ia (insidious onset, headache, nonproductive cough, d i ffuse i nterstitial i nfiltrate) . X-ray looks worse than patient. H igh titer of cold agglutinins (IgM ) , wh ich can agglutinate or lyse RBCs. Grown on Eaton's agar. Treatment: macrol ide or fluoroquinolone (penicil l i n ineffective since Mycoplasma have no cell wal l ) . N o cell wall . N o t seen o n Gram sta i n . Bacterial membrane contains sterols for stabil ity. Mycoplasmal pneumonia is more common in patients < 30 years of age. Frequent outbreaks i n m i l itary recruits and pnsons . M I CRO B I O L O G Y 􀃙 MIC R O BIO L OGY- MYC O L OGY SECT I O N I I 14 3 􀃙 MIC R O BIO L OGY- MYC O L OGY Systemic mycoses DISEASE Histoplasmosis Coccidioidomycosis Paracoccidioidomycosis 'I All of the following can cause pneumonia and can d isse m i nate. All arc caused by d imorphic fun g i : cold (20°C ) = mold; heat (37°C) = yeast. The only exception i s coccidioidomycosis, wh ich is a spherule (not yeast) in tissue. Treatment: fluconazole or itraconazole for local i n fection ; amphoteri c i n B for systemic infection. Systemic mycoses can m im i c TB (granuloma formation), except, unl ike TB, have no person-person transm ission . E N D E M I C lOCAT I O N AND PATHOlOGIC FEATURES M i ssissippi and Ohio River valleys. Causes pneumom a . Macrophage fi l l e d w i t h HistofJlasma (smal ler than R B C ) fJ. States east of M ississippi R iver and Central America. Causes inflammatory lung d isease and can d issem i nate to skin and bone. Forms granulomatous nodules. Broad-base budd ing (same size as RBC) [J. Southwestern United States, California. Causes pneumon ia and meningiti s ; can d isseminate to bone and skin. Case rate t after earthquakes (spores i n dust are thrown up in the air and become spherules i n lungs) . Spherule fi lled with endospores (much larger than R B C ) [!1. Latin America. Budd ing yeast with "captain's wheel " formation (much larger than RBC) [!]. N OTES H i sto h ides (with in m acrophages). B i rd or bat droppings. Blasto buds (broadly) . C occidio crowds . San Joaqu in Valley or desert (desert bu mps) "valley fever." "Capta in's wheel " appearance. Paracoccidio parasails with the captain's wheel all the way to Latin America . \ 44 S E CTIO N II Cutaneous mycoses Tinea versicolor Other ti neae M I C R O B I O L O G Y 􀃙 M I C R O B I O L O G Y - MY C O L O G Y Caused b y Malassezia fmfur. Degradation of lipids produces acids that d a mage melanocytes and cause hypopigmented and/or hyperpigmented patches. Occurs i n hot, humid weather. Treatment: topical m iconazole, selenium sulfide ( Selsun) . " Spaghetti and meatba l l " appearance on KOH prep rJ. Includes tinea ped i s (foot) , tinea cruris (groin ) , tinea corpori s (ringworm, on body) , tinea capitis (head, scalp ) , tinea unguium (onychomycosis, on fingernails). Pruritic lesions with central clearing resembl ing a ring, caused by dermatophytes (Microspontm, Trichophyton, and Epidermophyton) . See mold hyphae in KOH prep, not d i morphic. M I C R O B I O L O G Y 􀃙 M I C R O B I O L O G Y - M Y C O L O G Y S E C T I O N I I 1 4 5 Opportunistic fungal i nfections Candido olbicons rJ alba= white. Aspergillus fumigotus [l] Cryptococcus neoformons 􀆬 Mucor [!] a n d Rhizopus spp. Systemic or superficial fungal infection. Oral and esophageal thrush in i m munocomprom ised (neonates , steroids, d i abetes, A I D S ) , vulvovaginitis (diabetes, use of antibiotics ) , diaper rash, endocard itis in IV drug users, disseminated cand idiasis (to any orga n ) , chronic mucocutaneous candidiasis. Treatment: topical azole for vaginal ; fluconazole or caspofungin for oral/esophageal ; fluconazole, amphotericin B, or caspofungin for systemic. I nvasive aspergillosis, especially i n i m munocompromised and those with chronic granulomatous disease. Allergic bronchopulmonary aspergillosis (AB PA) : with asthma or C F. Aspergillomas in lung cavities, especially after TB infection . Some species of Aspergillus produce aflatoxins, which are associated with HCC. Think "A:.' for Acute Angles in Aspergillus. Not d imorphic. C ryptococcal meningitis, cryptococcosis. Heavily encapsulated yeast. Not d i morph ic. Found i n soil, pigeon droppings . Acquired through inhalation with hematogenous d issemi n ation to meninges. Culture on Sabour a u d 's agar. Stains with India ink. Latex agglutination test detects polysaccharide capsular antigen and is more specific. " Soap bubble" lesions in brain. Mucormycosis. Disease mostly in ketoacidotic d i abetic and leukemic patients . Fungi prol iferate i n blood vessel walls when there is excess ketone and glucose, penetrate cribriform plate, and enter brain. Rhi nocerebra l , frontal lobe abscesses. Headache, facial pain, black necrotic eschar on fac e ; may have cranial nerve involvement. Candido olbicons. Dimorphic yeast Pseudohyphae and budding yeasts at 2o•c (left). EI Germ tubes at 3 rc (right).D Aspergillus fumigatus. Septate hyphae that branch at 45• angle (left).li!f Conidiophore with radiat1ng chains of spores (right).D Cryptococcus neofonnons. 5-1 0 􀂞m yeasts with wide capsular halos and unequal budding 1n lnd1a mk sta1n D Mucor. Irregular, broad, nonseptate hyphae branch1ng at wide angles (arrows). a 1 46 SECT I O N I I M I CRO B I O L O G Y 􀃚 MI C R O BIO L O G Y - MY C O L O G Y Pneumocystis jirovecii Causes Pneumocystis pneumon ia ( PCP) , a diffuse interstitial pneumonia. Yeast (originally classified as protozoan) . Inhaled. Most infections are asymptomatic. Immunosuppression (e.g., AIDS) predisposes to d isease. Diffuse, bilateral CXR appearance. D i agnosed by lung biopsy or l avage. D isc-shaped yeast forms on methenamine silver stain of lung tissue f:l Treatment: TMP-SMX, pentamidine, dapsone. Start prophylaxis when CD4 drops < 2 0 0 cel l s /mm3 in H I V patients. Sporothrix schenckii Sporotrichosis. D imorphic, cigar-shaped bmlcling yeast that l ives on vegetation rJ. When spores are traumatically i ntroduced into the skin, typically by a thorn ( "rose gardener's" d i sease), causes local pustul e or ulcer with nodules along draining lymphatics (ascending lymphangitis) . Little systemic i l l ness. Treatment: itraconazole or potassium iodide. " Plant a rose in the pot." MICROBIOLOGY 􀃙 MICROBIOLOGY-PARASITOLOGY SECTION I I 1 4 7 􀃙 MI CROBIO LOGY-PARASITO LOGY Protozoa-GI infections ORGAN ISM D ISEASE TRANSM ISSION Giardia Iamblia Giardiasis: bloating, flatulence, Cysts in water Entamoeba histolytica fou l-smel l ing, fatty diarrhea (often seen i n campers/hikers) - think fat-rich Ghirardell i chocolates for fatty stools o f Giardia Amebiasi s : bloody d i arrhea Cysts in water (dysentery) , l iver abscess ( "anchovy paste " exudate ) , R U Q pain ( h istology shows flask-shaped ulcer if submucosal abscess of colon ruptu res) Cryptosporidium Severe diarrhea i n A I D S Cysts in water M i l d d isease (watery d iarrhea) in non i m m unocomprom ised D IAGNOSIS TREATMENT Trophozoites rn or Metronidazo l e cysts (arrow) m in stool S erology and/or Metron idazol e ; trophozoites (with iodoqui nol for RBCs in the asymptomatic cyst cytoplasm) 􀆬 or passers cysts (with m ultiple nuclei) I!] i n stool D Cysts on acid-fast sta i n I] Prevention ( by fi l tering city water suppl ies); n itazoxanide in i mmunocompetent hosts 1 4 8 SECT I O N I I M I C R O B I O L O GY 􀃛 MIC R O BIO L O G Y - PA R A S ITO L O G Y Protozoa-eN S infedions ORGANISM D I SEASE Toxoplasma gondii Brain abscess i n H I V (seen as ring-enhancing brain lesions on CT/M R I ) ; congenital toxoplasmosis = "classic triad " of chorioretin itis, hydrocephalus, and i ntracranial calci fications TRANSMISSION Cysts i n meat or cat feces; crosses placenta (pregnant women should avoid cats) Noeglerio fowleri Rapidly fatal meningoencephalitis Swimming in Trypanosoma brucei T. gambiense T. rhodesiense African sleeping sickness : enlarged lymph nodes, recurring fever (clue to antigenic variation) , somnolence, coma freshwater lakes (think Nalgene bottle filled with freshwater containing Naegleria); enters via cribriform plate Tsetse fly, a painful bite DIAGNOSIS Serology, biopsy rJ Amoebas i n spinal fluid m Blood smear n TREATMENT Sulfad iazine + pyrimetham ine Amphotericin has been effective for a few survivors Sura m i n for bloodborne d i sease or melarsoprol for C N S penetration ( " it sure i s nice to go to sleep"; melaton i n helps with sleep) M I C R O B I O L O G Y 􀃙 MIC R O BI O L O G Y - PARA S IT O L O G Y Protozoa-Hematologic infections ORGANISM D ISEASE TRANSMISSION D I AGNOSIS Plasmodium Malaria : fever, headache, anem ia, Mosqu ito Blood smear, P. vivaxjovale splenomegaly (Anopheles) trophozoite ring P. falciparum P. vivax/ovale - 48-hr cycle (tertian ; for m fJ, R B C P. ma/ariae includes fever on first day and schizont with third clay, thus fevers are actually merozoites rn 48 hr apart) ; dormant form ( hypnozoite) i n l iver P. falciparum - severe ; irregular fever patterns; parasitized RBCs occlude capillaries i n brain (cerebral malaria) , k idneys, lu ngs P. malariae-72-hr cycle (quartan) Babesia Babesios i s : fever and hemolytic Ixodes tick (same as Blood smear, ring anem i a ; predom inantly in Borrelia burgdorferi for m m, " M altese northeastern Un ited States; of Lyme disease; cross" m; PCR asplenia t risk of severe d i sease may often coinfect humans) SECT I O N I I 1 4 9 TREATMENT Begin with chloroquine, which blocks Plasmodium heme polymerase ; if resistant, use mefloquine I f l i fe-threatening, use intravenous quinid ine (test for G6PD deficiency) Vivaxlovale - add primaquine for hypnozoite (test for G6PD deficiency) Atovaquone + azith romycin 1 50 SECTI O N II MI CROB I O L O G Y 􀃘 MICRO BIOLO G Y - PARASITOLO G Y Protozoa-Others ORGANISM Visceral i nfectio n s Trypanosoma cruzi Leishmania donovani STDs Trichomonas vagina/is D I S EASE Chagas' d isease : d ilated cardiomyopathy, megacolon, megaesophagu s ; predom inantly in South America Visceral leishmaniasis (kala-azar) : spiking fevers, hepatosplenomegaly, pancytopen i a Vaginiti s : foul-smell ing, greenish d ischarge ; itching and bur n ing; do not confuse with Gardnerella vaginalis, a gram-variable bacterium that causes vaginosis TRANSMISSION DIAGNOSIS Reduviid bug Blood smear fJ ( " kissing bug" ) , a painless bite (much l ike a kiss) Sandfly M acrophages containing amastigotes rn Sexual (cannot exist Trophozoites outside human (motile) on wet because it cannot mount form cysts) TREATMENT Nifu rtimox Sodium stibogluconate Metron idazole for patient and partner (prophylaxis) M I CRO B I O L O G Y 􀃚 MICROBIOLOGY-PARASITOLOGY SECT I O N I I 1 5 1 Nematodes (roundworms) ORGANISM Intestinal Enterobius vermicularis (pinworm) Ascaris lumbricoides (giant roundworm) Strongyloides stercora/is Ancylostoma duodenale, Necator america nus (hookworms) Tissue Dracunculus medinensis Onchocerca volvulus Loa loa TRANSMISSION D ISEASE Food conta m i nated with eggs Intestinal infection causing anal pruritus (d iagnosed via the Scotch Tape test) Fecal-ora l ; eggs visible in feces Intestinal infection under microscope Larvae in soil penetrate the Intestinal infection causing skin vom iting, diarrhea, anemia Larvae penetrate skin I ntestinal infection causing I n drinking water Female blackfly bite Deer fly, horse fly, m ango fly anem ia by sucking blood from i ntestinal wal l s S k i n inflammation and ulceration Hyperpi gmented skin and river bl indness ( black flies, black skin nodules, " black sight"; allergic reaction to m icrofilaria possible Swell ing in ski n , worm in conjunctiva TREATMENT B endazoles or pyrantel pamoate (worms are bendy; treat with mebendazole) Bendazoles or pyrantel pamoate lvermectin or albendazole Bendazoles or pyrantel pamoate Slow extraction of worm lvermectin ( ivermectin for river bl indness) D iethylcarbamazine Wuchereria bancrofti Female mosquito Blocks lymphatic vessels : Diethylcarbamazine Toxocara canis Nematode routes of infection Food contaminated with eggs elephantiasis ; takes 9 mo-l yr after bite to become symptom a tic Visceral larva m igrans Albendazole or mebendazole I ngested- En terobius, Ascaris, Trichinella. Cutaneou s - Strongyloides, Ancylostoma, Necator You ' l l get sick if you EAT these ! These get into your feet from the SANd . 1 52 SECT I O N I I Cestodes (tapeworms) ORGANISM Taenia so/ium Diphyllobothrium Ia tum Echinococcus granulosus Trematodes (flukes) ORGANISM Schistosoma Clonorchis sinensis Paragonimus westermani Parasite hints M I C R O B I O L O G Y 􀃙 M I C R O B I O L O G Y - PA R A S I T O L O G Y TRANSMISSION I ngestion of larvae encysted in unclercookecl pork I ngestion of eggs Ingestion of larvae from raw freshwater fish I ngestion of eggs from clog feces TRANSMISSION Snails are host; cercariae penetrate ski n of humans Unclercookecl fish Unclercookecl crab meat FINDI NGS Brain cysts, seizures Liver cysts Vitamin B1 2 deficiency DISEASE T REATM ENT Intestinal infection Praziquantel Cysticercosis, Praziquantel ; -benclazoles for neurocysticercosis neurocysticercosis Vitamin B1 2 deficiency Praziquantel (tapeworm competes for B 1 2 in intestine) --+ anemia Cysts in l iver, causing -benclazoles anaphylaxis if antigens released (surgeons preinject with ethanol to kill cysts before removal) D ISEASE TREATMENT Liver and spleen granulomas, Praziquantel fibrosis, and inflammation Chron ic infection with S. haematobium can lead to squamous cell carcinoma of the bladder Bil iary tract inflam mation Praziquantel --+ pigmented gallstones Associated with cholangiocarcinoma Lung inflammation and zo Praziquantel bacterial infection, with hemoptysis ORGANISM B i liary tract d i sease, cholangiocarcinoma Hemoptysis Taenia soliwn (cysticercosis) Echinococcus granulosus Diphyllobothrium latum Clonorchis sinensis Paragonimus westermani Schistosoma mansoni Schistosoma haematobium Ancylostoma, Necator Enterobius Portal hypertension Hematuria, bladder cancer M icrocytic anemia Perianal pruritus M I C R O B I O L O G Y 􀃙 MIC R O BIO L O G Y - VIRO L O G Y SECTI O N I I 1 53 􀃙 MIC R O BIO L O G Y - VIR O L O G Y Viral strudure-genera l features Viral genetics Recombination Reassortment Complementatio n Phenotypic mixing Viral vaccines Live attenuated vaccines Ki lled Recombinant DNA viral genomes Naked virus with icosahedral capsid Enveloped virus with icosahedral capsid Enveloped virus with helical capsid Helical capsid with n u cleic acid inside Exchange of genes between 2 chromosomes by crossing over with i n regions of significant base sequence homology. When viruses with segmented genomes (e.g., influenza virus) exchange segments. H igh-frequency recombi nation. Cause of worldwide influenza pandemics. When 1 of 2 viruses that infect the cell has a mutation that results i n a nonfunctional protein. The nonmutated virus "complements" the mutated one by making a functional protein that serves both viruses. Occurs with simultaneous infection of a cell with 2 viru ses. Genome of virus A can be partially or completely coated (forming pseudovirion) with the surface proteins of virus B . Type B protein coat determines the tropism (infectivity) of the hybrid virus. H owever, the progeny from th i s infection have a type A coat that is encoded b y i t s type A genetic material . I nduce humoral and cell-mediated immun ity but h ave reverted to virulence on rare occasion s . Killed/inactivated vaccines induce only humoral immunity but are stable. Live attenuated - smallpox, yellow fever, chickenpox (VZV) , Sabin's polio viru s , MMR, Influenza (intranasal) . Rabies , Influenza (injected), Salk Polio, and HAV vaccines. H BV (antigen = recombinant H BsAg), H PV (types 6, 1 1 , 1 6 , and 1 8 ) . A l l D A viru ses except the Parvoviridae are dsDNA. All are l inear except pap i l loma-, polyoma-, and hepadnaviru ses (circular) . N o booster needed for l ive attenuated vaccines. Dangerous to give l ive vacc i nes to immunocomprom ised patients or their close contacts. "Live ! One n ight only! See small yellow chickens get vaccinated with Sabin's and MMR! It's incredible ! " M M R = measles, mumps, rubella ( l ive attenuated vaccine that can be given to H I Vpositive patients who do not show signs of i mmunodeficiency) . Sal K = Ki lled . RIP Always. All are dsDNA ( l ike our cells) , except "part-of-avirus" (parvovirus) is ssDNA. Parvus = small. 1 54 SECT I O N I I RNA viral genomes Naked viral genome infedivity Virus ploidy Viral replication DNA viruses RNA viruses Viral envelopes DNA virus charaderistics MI CRO B I O L O G Y • MICROBIOLOGY-VIROLOGY All RNA viruses except Reoviridae are ssRNA. Positive-stranded RNA viru ses : I went to a retro (retrovi ru s) toga (togaviru s) party, where I drank flavored (flaviviru s) Corona ( coronav i ru s) and ate hippy ( hepeviru s) California (calicivirus) pickles (picornaviru s) . All are ssRNA ( l ike our m RNA) , except "repeato-vi ru s" (reoviru s) is dsRNA. Purified nucleic acids of most dsDNA (except poxviru ses and H BV) and (+) strand ssR A ("" mRNA) viruses are infectious. Naked nucleic acids of (- ) strand ssRNA and dsRNA viruses are not infectious. They require polymerases conta ined in the complete virion. All viruses are haploid (with I copy of DNA or RNA) except retroviru ses, wh ich have 2 identical ssRNA molecules ("" d iploid) . All repl icate in the nucleus (except poxvi rus) . All repl icate in the cytoplasm (except influenza virus and retroviruses) . Naked (nonenveloped) viruses include Papillomavi rus, Adenoviru s, Picornavirus , Polyomaviru s, Calcivirus, Parvovi rus, Reovirus , and Hepeviru s . Generally, enveloped viru ses acqu ire their envelopes from plasma membrane when they exit from cell. Exceptions include herpesviruses, wh ich acquire envelopes from nuclear membrane. Some general rules-all DNA vi ruses : GENERAL RULE Are H HAPPPPy viruses Are double stranded Are l i near Are icosahedral Repl icate in the nucleus Give PAPP smears and CPR to a naked Heppy ( hippy) . DNA = PAPP; RNA = CPR and hepev i ru s . COMMENTS Hepadna, Herpes, Adeno, Pox, Parvo, Papilloma, Polyoma. Except parvo (single strande d ) . Except papilloma and polyoma (circular, supercoiled) and hepadna (circular, incomplete ) . Except p o x (complex) . Except pox (carries own DNA-dependent RNA polymerase) . DNA viruses V I RAL FAM I LY ENV ELOPE Herpesviruses Yes Hepadnavirus Yes Adenovirus No Parvovirus No Papillomavirus No Polyomavirus No Poxvirus Yes DS, double-strande d ; S S , single-stranded M I C R O B I O L O G Y 􀃙 MIC R O BI O L O G Y - VI R O L O G Y SECT I O N I I 1 5 5 DNA STRUCTU RE M E D I CA L I M PORTANCE D S and l i near HSV- 1 - oral (and some gen ital) lesions, spontaneous temporal lobe encephalitis, keratoconjunctivitis HSV-2 - gen ital (and some oral) lesions VZV ( H H V-3 ) - ch ickenpox, zoster (sh i ngles) ; vaccine avai l able E BV ( I-J HV-4) - mononucleosis, Burkitt's lymphoma, Hodgkin's lymphoma CMV ( H H V-5 ) - in fection in i m m unosuppressed patients (AI D S ret i n itis) , especially transplant rec ipients ; congen ital defects ( "sightomegalovi ru s") H H V- 6 - roseola (exanthem subitum ) H H V-7-less c o m m o n c a u s e of roseola H H V- 8 - Kaposi 's sarcoma-associated herpesvirus ( K S H V) DS and partial circular H BV: • Acute or chronic hepatitis • Vaccine ava i l abl e - conta ins H BV surface antigen Not a retrovirus but has reverse transcriptase DS and l i near Febrile pharyngitis- sore throat; acute hemorrhagic cystitis Pneu monia Conjunctivitis-"pink eye" S S and l i near (-) B19 viru s - aplastic crises i n sickle cell d i sease, (smallest D A viru s ) "slapped cheeks" rash i n child ren - erythema infectiosum (fifth d isease) , RBC destruction i n fetus leads to hydrops fetal i s and death, pure RBC aplasia and rheumatoid arthritis-l i ke symptoms in adults D S and circular H PV-warts ( 1 , 2, 6 , 1 1 ) , CIN, cervical cancer ( 1 6 , 18) vaccine ava i l able DS and circular JC virus- progressive multifocal leukoencephalopathy ( P M L) in H I V B K v i ru s - transplant patients, commonly targets kidney ( JC : Junky C erebrum ; BK: Bad Kidney) DS and l i near Smallpox, although erad icated, could be used in (largest DNA virus) germ warfare Vacci n i a - cowpox ( " m i l k m a i d 's bl isters") Molluscum contagiosu m - Aesh-colored dome lesions with central d imple 1 56 SECT I O N I I Herpesviruses V I RUS H SV-1 H SV-2 vzv E BV CMV H HV-6 H HV-8 M I C R O B I O L O G Y 􀃙 MIC R O BIO L O G Y - VI R O L O G Y D I S EASES Gingivostomatitis, keratoconjunctivitis, temporal lobe encephalitis (most common cause of sporadic encephalitis in the Un ited States) , herpes labialis fJ. Latent in trigeminal gangl ia. Herpes gen ital i s fl], neonatal herpes. Latent in sacral gangl i a . Varicella-zoster (chickenpox, sh ingles) 􀆬' encephalitis, pneumonia. Latent in dorsal root or trigem inal gangl ia. Infectious mononucleosis, Burkitt's/I-Ioclgkin's lymphoma , nasopharyngeal carcinoma. Latent in B cel l s . Congenital infection, mononucleosis (negative Monospot) , pneumonia, retinitis. Infected cells have characteristic "owl 's eye" inclusions [!]. Latent in mononuclear cells. Roseola : h igh fevers for several clays that can cause seizures, fol lowed by a diffuse macular rash. Kaposi 's sarcoma ( H IV patients ) . Zoster. Hemorrhag1c vesicles and pustules i n dermatomal distribution. ROUTE OF TRANSMISSION Respi ratory secretions, sal iva Sexual contact, perinatal Respiratory secretions Respi ratory secretions, saliva Congenital, transfusion, sexual contact, sal iva , urine, transplant Not determined Sexual contact CMV. Renal tubular cells 1 n a neonate with congemtal CMV infection Note the "owl's eye" 1nclusions (arrows). li!J HSV identification EBV M I C R O B I O L O G Y • MI C R O BIO L O G Y - VI R O L O G Y S E C T I O N I I l 57 PCR i s test of choice. Tzanck test- a smear of an opened skin vesicle to detect multi nucleated giant cells commonly seen i n HSV- 1 , H SV-2 , and VZV. Infected cells also have i ntranuclear Cowdry A inclusions. A herpesviru s . Can cause mononucleosis. Infects B cells. Characterized by fever, hepatosplenomega ly, pharyngitis, and lymphadenopathy (especially posterior cervical nodes) . Peak incidence 1 5-20 years of age . Atypical lymphocytes seen o n peripheral blood smear r1] are not infected B cells but rather reactive cytotoxic T cells. Positive Monospot test-heterophile antibodies detected by agglutination of sheep or horse RBCs. Also associated with development of Hodgkin's and endemic Burkitt's lymphomas as well as nasopharyngeal carcinoma. Tzanck heavens I do not h ave herpes. Most common during peak kissing years ( " kissing d i sease " ) . Atypical lymphocytes. Seen with EBV infection. Note "hugging" of RBCs (arrow). D 1 5 8 SE CT I O N II RNA viruses VIRAL FAM I LY Reoviruses Picornaviruses Hepevirus Caliciviruses Flaviviruses Togaviruses Retroviruses Coronaviruses Orthomyxoviruses Paramyxoviruses Rhabdoviruses Filovi ruses Arenavi ruses Bu nyaviruses Delta virus M I C R OBI O L O G Y 􀃚 MIC RO BIO LOGY - VI R O LOGY CAPSID ENVELOPE RNA STRUCTURE SYMM ETRY MEDICAL I M P O RTANCE No OS l inear Ieos a heel ra 1 Coltivirusa - Coloraclo tick fever 1 0- 1 2 segments (double) Rotavirus - # 1 cause of fatal diarrhea i n children No SS EEl l inear Icosa heel ra 1 Poliovi ru s -polio-Salk/Sabin vacc i nes - I PV/OPV Echovirus - aseptic meningitis Rh inoviru s -"common col d " Coxsack ieviru s - aseptic meningitis; herpangina (mouth bl i sters, fever) ; hand, foot, and mouth disease; myocard itis HAY- acute viral hepatitis PERCH No S S EEl l i near Icosahedral H EY No SS EEl l inear Icosahedral Norovirus-viral gastroenteritis Yes S S EEl l i near Icosahedral I-ICY Yellow fever" Dengue St. Louis encephalitis3 West Nile virus" Yes SS EEl l i near Icosahedral Rubella Eastern equine encephalitis3 Western equine encephal itis" Yes SS EEl l inear Icosahedral Have reverse transcriptase ( HTLV), HTLV-T-cell leukemia complex H IV-A I D S a n d conical ( I-I IV) Yes SS E8 l i near Helical Coronaviru s - "common col d " and SARS Yes SS 8 linear Helical I n fluenza virus 8 segments Yes SS 8 l inear Hel ical PaRaMyxovirus : Nonsegmented Parainfluenza - croup RSV- bronch iolitis in babies; Rx-ribavirin Measles, Mumps Yes SS 8 l i near Helical Rabies Yes SS 8 l i near Hel ical Ebola/Marburg hemorrhagic fever-often fatal ! Yes SS 8 circular Hel ical LCMV-lymphocytic choriomen ingitis virus 2 segments Lassa fever encephalitis- spread by mice Yes SS 8 circular Helical California encephal itis3 3 segments SanclAy/Rift Valley fevers" Crimean-Congo hemorrhagic fever" Hantaviru s -hemorrhagic fever, pneumonia Yes SS 8 circular Uncertain H OY i s a " defective" virus that requires H BV co-infection SS, single-stranded; OS, double-stranded; EE>, positive sense ; 8, negative sense ; "= arbovirus, transmitted by arthropods (mosquitoes, ticks). (Adapted, with permission, from Levinson W , Jawetz E. Medical Microbiology a n d Immunology: Examination a n d Boord Review, 6th e d . N e w York: McGraw-Hill, 2000: 1 82 .) Negative-stranded viruses Segmented viruses Picornavirus Rhinovirus Yellow fever virus Rotavirus I M I C R O B I O L O G Y 􀃙 MIC R O BIO LO G Y - VI RO L O G Y S E C T I O N I I 1 59 Must transcribe negative strand to positive. Virion brings its own RNA-dependent RNA polymerase. They include Arenavi ru ses, Bu nyavi ru ses, Paramyxoviruses, Orthomyxoviruses, Filoviru ses , and Rhabdovi ruses. All are RNA viruses. They include Bunyavi ruses , Orthomyxoviruses (inAuenza viru ses) , Arenaviruses , and Reovi ruses . I ncludes Poliovirus, Echovirus , Rhinovirus, Coxsack ieviru s , HAY. RNA is translated into 1 large polypeptide that is cleaved by proteases i nto functional viral proteins. Can cause aseptic (viral) meningitis (except rhinovirus and HAY ) . All are enterovi ruses (fecal-oral spread) except rh i novi rus. Always Bring Polymerase Or Fail Replication . BOAR PicoRNAvi ru s = small RNA virus. PERC H on a "peak" (pica) . A picornavi rus . Nonenveloped RNA virus. Rhino has a runny nose. Cause of common col d ; > 1 0 0 serologic types. Acid labile - destroyed by stomach acid; therefore, does not infect the GI tract (unl ike the other picornaviru ses) . A flaviviru s (also an arbovirus) transm itted by Aedes mosquitoes . Virus has a monkey or human reservoir. Symptom s : h igh fever, black vom itus, and jaundice. Rotavirus rJ, the most important global cause of infantile gastroenteritis, is a segmented dsRNA viru s (a reovirus) . Major cause of acute diarrhea in the Un ited States dur i ng winter, especially in day-care centers, ki ndergartens. Villous destruction with atrophy leads to ! absorption of Na+ and loss of K+. Flavi = yellow, jaundice. ROTAvi ru s = Right Out The Anus . C D C recom mends routine vacc ination o f a l l infants. l 60 S E CT I O N I I Influenza viruses G enetic shift /antigenic shifts Genetic d rift Rubella virus Paramyxoviruses M I C R O B I O L O G Y 􀃙 M I C R O B I O L O G Y - V I R O L O G Y Orthomyxoviru ses. E nveloped, negative singlestranded RNA viruses with 8-segment genome. C ontain hemagglutinin (promotes viral entry) and neura m i n idase (promotes progeny virion release) antigens. Patients at risk for fatal bacterial superinfection. Rapid genetic changes. Causes pandemics. Reassortment of viral genome; segments undergo high-frequency recombination, such as when human Au A virus recombines with swine Au A viru s . Causes epidem ics. M i nor (antigen ic drift) changes based on random mutation. Killed viral vaccine i s major mode of protection ; reformulated vaccine offered each fal l . Vaccine conta i n i ng l ive, temperature-sensitive m utant that repl icates i n the nose but not in the lung is also available. Used i n childre n . Sudden sh i ft i s more deadly t h a n gradual drift. A togavirus. Causes rubella, once known as German ( 3 -clay) measles. Fever, postauricular adenopathy, lymphadenopathy, arthralgias, fine truncal rash that starts at head and moves clown. Causes mild d i sease i n children but serious congenital d isease (a ToRC H e S i n fection ) . Paramyxoviruses cause d isease in children. They include those that cause para i nfluenza (croup : seal-l ike barking cough), mumps, and measles as well as RSV, which causes respiratory tract infection (bronch iolitis, pneumonia) in infants. All conta i n surface F (fusion) protein, which causes respi ratory epithel ial cells to fuse and form multinucleated cells. Pal ivizu m ab (monoclonal antibody against F protein) prevents pneumon ia caused by RSV infection i n premature infants. Measles virus Mumps virus M I C R O B I O L O G Y 􀃕 M I C R O B I O L O G Y - V I R O L O G Y S E C T I O N I I 1 6 1 A paramyxovirus that causes measles. Kopl ik spots lZ) (red spots with blue-wh ite center on buccal mucosa) and descending maculopapular rash 1IJ are characteristic. SSPE (subacute sclerosing panencephal itis, occurring years later) , encephalitis (l : 2 0 0 0 ) , and giant c e l l pneumonia (rarely, in immunosuppressed) are possible sequelae. Rash presents last and spreads from head to toe. I ncludes hands and feet (vs. truncal rash in rubella) . Do not confuse with roseola (caused by H H V-6) . Koplik spots. Note small white lesions with an erythematous halo that precede the measles rash by 1 -2 days. m A paramyxovirus. Sympto m s : Parotitis rJ, Orch itis (inAammation of testes), and aseptic Meningitis . Can cause steril ity (especially after puberty) . 3 C 's of measles : C ough C oryza Conjunctivitis Rash of measles. Discrete erythematous rash becomes confluent as it progresses downward. m Mumps makes your parotid glands and testes as big as POM-poms. 1 6 2 S E C T I O N I I M I C R O B I O L O Ci Y 􀃙 MIC R O BI O L O G Y - VI R O L O G Y Rabies virus Bullet-shaped viru s [J. Negri bodies are characteristic cytoplasmic inclusions in neurons infected by rabies viru s ; commonly found i n Purkinje cel ls of cerebel lum II). Rabies has long incubation period (weeks to months) before symptom onset. Postexposure treatment is wound cleansing and vaccination ± rabies immune globulin. Travel s to the CNS by migrating in a retrograde fashion up nerve axons. Progression of d i sease : fever, malaise ..... agitation, photophobia, hydrophobia ..... paralysis, coma ..... death . More com monly from bat, raccoon, and skunk bites than from dog bites in the United States. Hepatitis viruses V I RUS HAVa RNA HCV . . picornavnus DNA hepaclnavirus RNA flaviviru s TRANSMISSION Fecal-oral Parenteral, sexual, maternalfetal CARRIER No Yes Primarily Yes blood, IVDU, posttransfusion INCUBATION Short (weeks) Long (month s) Long HCC RISK No Yes : integrates into host genome, acts as oncogene N OTES Asymptomatic (usually) , Acute, Alone (no carriers) Yes : from chro nic Ch ron ic, C i rrhosis , inflam mation C arcinoma , Carrier H DV RNA delta virus Parentera l , Yes Superinfection- Yes D efective vi rus Dependent on H BV; superinfection ..... ! sexual, maternalfetal RNA hepeviru s Fecal-ora l , No especially with waterborne epidemics short Co-infection long Short No prognosis H igh mortal ity in pregn a nt women ; Enteric, Expectant mothers, Epidemic Signs and symptoms of all hepatitis v i ruses : episodes of fever, jaundice, elevated ALT and AST. aHAV and H EY are fecal-ora l : The vowels hit your bowels. Naked viruses do not rely on an envelope so they are not destroyed by the gut. bi n H BV, the virus uses its own DNA-dependent DNA polymerase to make full double-stranded DNA. The host RNA polymerase transcribes m R A from viral DNA and then makes viral proteins from the m RNAs. M I C R O B I O L O G Y 􀃛 MICROBIOLOGY-VIROLOGY SECT I O N I I 1 63 Hepatitis serologic markers Anti-HAV (lgM) lgM antibody to HAV; best test to detect active hepatitis A. Anti- H AV ( lgG) IgG antibody indicates prior HAV infection and/or prior vaccination ; protects against reinfection. H BsAg Antigen found on surface of H BV; ind icates hepatitis B infection. Antibody to H B sAg; ind icates immunity to hepatitis B. Antigen associated with core of H BV. Anti - H B s H BcAg Anti- H Bc Antibody to H B cAg; IgM = acute/recent infection ; IgG = prior exposure or chronic infection. Positive during window period. H BeAg A second, different antigenic determ inant in the H BV core. H B eAg indicates active viral replication and therefore h igh transm issibility. Anti - H Be Antibody to e antigen ; indicates low transmissibility. 1 Coat protei n (H BsAg) 42 nm j DNA polymerase Vi rus particle In viral hepatitis, AL T > AST. In alcoholic hepatitis, AST > ALT. SECES: SE are antigens, CES are antibodies; labeled on figure in order of appearance. Acute H BV Window Chronic H BV (h igh i nfectivity) Chron ic H BV (low i nfectivity) Recovery I m munized H B sAg + + + 0 I mportant diagnostic tests I ncubation Prod rome, period acute disease H BsAg (anti-HBc) 2 3 DNA polymerase HBV particles 4 5 Convalescence 6 Late Anti-HBs (anti-H Bc) 7 8 Anti-HBc Anti-HBs Anti - H Be 0 2 3 4 5 6 7 8 Months after expos u re Anti-H Bs H BeAg Anti-HBe Anti-HBc + IgM + lgM + IgG + IgG + + IgG + l 64 S E C T I O N I I H IV gp41 H IV diagnosis M I C R O B I O L O G Y 􀃙 MICRO B I O L O G Y - VIRO L O G Y Lipid membrane Presumptive d iagnosis made with ELISA (sensitive, h igh false-positive rate and low threshold, rule out test) ; positive results are then confirmed with Western blot assay (specific, h igh false-negative rate and high threshol d , rule in test) . H I V PCR/viral load tests determine the amount of viral RNA in the plasma . H igh viral load associated with poor prognosis. Also use viral load to mon itor effect of drug therapy. AIDS d iagnosis ::; 200 CD4+ cells/mm3 (normal : 500-1 5 0 0 cells/mm3 ) . HIV positive with AIDS-defining condition (e.g., Pneumocystis pneumonia, or PCP) or CD4/ C D S ratio < 1 . 5 . Diploid genome ( 2 molecules o f RNA) . The 3 structural genes (protein coded for) : • env (gp l 2 0 and gp4l ) : • Formed from cleavage o f gpl60 to form envelope proteins. • gpl 2 0 - attachment to host CD4+ T cel l . • gp4 l - fusion and entry. • gag (p24) - capsid protein. • pol- reverse transcriptase, aspartate protease, i ntegrase. Reverse transcriptase synthesizes dsDNA from RNA ; dsDNA i ntegrates into host genome. Virus binds CCR5 (early) or CXC R4 (late) co-receptor and CD4 on T cel l s ; binds C C R 5 a n d CD4 o n m acrophages. Homozygous CCR5 m utation = immunity. Heterozygous C C R 5 mutation = slower course. E LI SA/Western blot tests look for antibodies to viral proteins; these tests often are fal sely negative i n the fi rst l -2 months of H I V infection a n d falsely positive i nitially i n babies born to i n fected mothers (anti-gp l 20 crosses placenta ) . M I C R O B I O L O G Y 􀃙 MIC R O BIO L O G Y - VI R O L O G Y S E C T I O N I I 1 6 5 Time course of H IV infection 1 200 1 1 00 ±Acute HIV syndrome Wide dissemination of virus Seeding of lymphoid organs Opportunistic diseases - Constitutional symptoms Four stages of infection : 1 . Flu-l ike (acute) 2. Feel i ng fine ( latent) 3. Fa l l i ng count 4. Final crisis 1 000 1 01 D ur ing latent phase, viru s repl icates in lymph 'E 900 Clinical latency E ]! 800 a; 700 S- c::J 600 0 " 500 '<!'+ 0 @QQJ (.) 300 [gQQ] 1 00 0 0 2 3 􀀓􀀔􀀕􀀖􀀗--􀀘-7r-􀀙􀀚 2 --􀀛 3 -- 4 L􀀠 5 --􀀡 6 -- 7 L􀀠 8 --􀀡 9 􀀜 1 􀀝 0 􀀞 11 􀀟 102 Months Years Red line = CD4+ T-lymphocyte count (cells/mm3 ) ; blue l i ne = H I V R A copies/mL plasma. Blue boxes ind icate i mmunocompromise (< 400 CD4+ cel l /mm3 ) and when AIDS-defining illnesses emerge (< 200 CD4+ cells/mm3 ) . nodes. 1 6 6 SE C T I O N I I Common diseases of H IV-positive adults CliN ICAl PRESENTATION Systemic MI CROB I O L O G Y 􀃘 MICRO BIOLO G Y - VIROLO G Y A s C D 4 count !, risk o f reactivation of past infections (e.g., T B , H SV, sh ingles), dissemination of bacterial infections and fungal infections (e.g., coccidioidomycosis) , and non-Hodgkin's lymphomas t. F I N D I NGS/LABS PATHOGEN Low-grade fevers, cough, Oval yeast cells with in macrophages, CD4 Histoplasma capsulatum (causes only pulmonary symptoms i n i m m unocompetent hosts) hepatosplenomegaly, < 100 cells/mm3 tongue ulcer Dermatologic Fluffy white cottagecheese lesi o n s Superfi cial vascula r proliferation Gastrointestinal Chronic, watery d i a rrhea Neurologic Encephalopathy Abscesses M e n i ngitis Retinitis Dementia Oncologic Pseudohyphae, commonly oral if CD4 < 400 cells/mm3, esophageal if CD4 < 1 0 0 cells/mm3 Biopsy reveals neutroph i l ic inAammation C. albicans (causes thru sh) Bartonella henselae (causes bacillary angiomatosis) Acid-fast cysts seen i n stool especially when CD4 Cryptosporidiwn spp. < 200 cells/mm3 Due to reactivation of a latent virus; results in JC virus reactivation (cause of PML) demyel i nation, CD4 < 200 cells/mm3 Many ring-enhancing lesions on imaging, CD4 Toxoplasma gondii < 1 0 0 cells/mm3 India ink stain reveals yeast with narrow-based Cryptococcus neoformans budding and large capsule, CD4 < 50 cells/mm3 Cotton-wool spots on funduscopic exam and CMV may also occur with esophagitis, CD4 < 50 cells/mm3 Must differentiate from other causes D i rectly associated with H I V Supe rfi cial n e oplasti c Biopsy reveals lymphocytic inAammation H H V-8 (causes Kaposi's sarcoma), do not confuse with bacillary angiomatosis caused by B. henselae prolife ration of vasculature Hairy leukoplakia Often on lateral tongue No n- Hodgk i n 's Often on oropharynx (Waldeyer's ring) lymphoma (la rge cell type) Squa m ous cell Often in anus (men who have sex with men) or c a rci n o m a cervix (females) Pri m a ry CNS lymph o m a Focal or multiple, differentiate from toxoplasmosis Respiratory Interstitial pneum o n i a Invasive a spe rgillosis Pneum o n i a Tuberculosis-like d isease Biopsy reveals cells with i ntranuclear (owl 's eye) i nclusion bodies Pleuritic pain, he moptysis, infiltrates on imaging Especially with CD4 < 200 cells/mm3 Especially with C D 4 < 50 cells/mm3 E BV May be associated with E BV H PV Often associated with E BV CMV Aspergillus fum igatus Pneumocystis jirovecii Mycobacterium avium-intracellulare Prions M I C R O B I OLO G Y 􀃙 MIC RO BIO LO GY- S Y S TE M S SE C T I O N I I 1 6 7 Prion diseases are caused by the conversion of a normal cellular protein termed prion protein ( PrPc) to a 􀃑-pleated form ( Prpsc) , which is transmissible. Prpsc resists degradation and fac i litates the conversion of still more Prpc to PrPsc. Accumulation of Prpsc results in spongiform encephalopathy and dementia, ataxia, and death. It can be sporadic (Creutzfeldt-Jakob d isease rapidly progressive dementia) , inherited (Gerstmann-Straussler-Scheinker syndrome) , or acqu i red (kur u ) . 􀃙 MICRO BIO LOGY- S YS TE M S Normal flora : dominant Bugs causing food poisoning Bugs that can mimic appendicitis LOCATION Skin Nose Oropharynx Dental plaque Colon Vagina M I CROORGA N I S M Staphylococcus epidermidis S. epidermidis; colon ized by S. aureus Viridans group streptococci Streptococcu s m u tans Bacteroides fragilis > E . coli Lactobacillus, colon ized by E. coli and group B strep Neonates del ivered by cesarean section have no Aora but are rapidly colonized after birth. S. aureus and B . cereus food poisoning starts qu ickly and ends quickly. M I C ROORGANISM Vibrio parahaemolyticus and V vulnificusa Bacillus cereus S. aureus Clostridium {Jerfringens C. botu linu m E . coli O l 57: H 7 Salmonella SOURCE OF I N FECTION Conta m in ated seafood Reheated rice. " Food poison ing from reheated rice? Be serious ! " (B. cereus) Meats, m ayonnaise, custard ; preformed tox i n Reheated m e a t d i shes Improperly canned foods (sign is bulging cans) Undercooked meat Poultry, meat, and eggs "V vulnificus can also cause wound infections from contact with conta m i n ated water or shellfish. Yersinia enterocolitica is most common cause of mesenteric aden itis, a d i sease that m i m ics append icitis. Nontyphoidal Salmonella can also be a cause. Camplyobacter jejun i m ay also m i m ic appendicitis. 1 6 8 SECT I O N I I Bugs causing diarrhea M I C R O B I O L O G Y 􀃙 MIC R O BIO L O G Y - S Y S TE M S Comma- or S-shaped organisms; growth a t 42 °C Bloody diarrhea Campylobacter Salmonella Shigella Entero h e morrhagic Lactose negative ; flagellar motil ity; has animal reservoir, especially poultry and eggs Lactose negative ; very low 1050; produces Shiga toxi n (human reservoir only) O l 5 7 : H 7; can cause H U S ; makes Shiga-l ike toxi n E. coli Enteroinvasive E. coli Yersinia enterocolitica Entamoeba histolytica Watery dia rrhea Ente rotoxigenic E. coli Vibrio cholerae I nvades colonic mucosa Day-care outbreaks, pseucloappenclicitis Protozoan Traveler's d iarrhe a ; produces ST and LT toxins Comma-shaped organisms; rice-water diarrhea C. difficile C. perfringens Protozoa Viruses Can also cause bloody d iarrhea. Pseudomembranous colitis Also causes gas gangrene Giardia, Cryptosporidium (in immunocomprom ised) Rotavi ru s , norovirus Common causes of pneumonia NEONATES (< 4 WK) C H I LDREN (4 WK- 1 8 YR) Group B streptococci Viruses ( RSV) E. coli Mycoplasma Specia l groups Chlamydia trachomatis (infants-3 yr) C. pneumon iae (school-age children) Streptococcus pneumoniae Runts May Cough Chunky Sputum ADULTS ( 1 8-40 YR) Mycoplasma C. pneumoniae S. pneumoniae Nosocomial (hospital Staphylococcus, enteric gram-negative rods acquired) ADULTS (40-65 YR) S. pnewnon iae H. influenzae Anaerobes Viruses Mycoplasma ELDERLY S. pneumoniae Influenza virus Anaerobes H. influenzae Gram-negative rods l m munocompromised Aspiration Alco h olic/ IV d rug user Cystic fibrosis Staphylococcus, enteric gram-negative rods, fu ngi, viruses, Pneumocystis jirovec ii-with HIV Anaerobes Postviral Atypical S. pneumoniae, Klebsiella, Staphylococcus Pseudomonas, S. aureus, S. pneumoniae Staphylococcus, H. influenzae, S. pnewnoniae Mycoplasma, Legionella, Chlamydia M I C R O B I O L O G Y 􀃙 MIC R O BI O L O GY - S Y S TE M S SECTI O N I I 1 6 9 Common causes of meningitis NEWBORN (0-6 MO) C H I LDREN (6 M0-6 YR) 6-60 YR 60 YR + Group B streptococci E. coli Listeria Streptococcus pneumoniae Neisseria meningitidis Haemophilus influenzae type B Enteroviruses S. pneumoniae N. meningitidis (# 1 i n teens) Enteroviruses HSV S. pnewnoniae Gram-negative rod s Listeria Give ceftriaxone and vancomycin empirically (add ampicillin if Listeria is suspected). Viral causes of meningitis -enteroviruses (esp. coxsack ievirus) , I-ISV-2 (I-ISV- 1 = encephalitis), 1-I IV, We st ile virus, VZV. In 1-II V- Cryptococcus, CMV, toxoplasmosis (brain abscess) , JC virus (PML). Note : I ncidence of H. influenzae meningitis has 􀈰 greatly with i ntroduction o f the conj ugate H . influenzae vaccine i n last 10-1 5 years. Today, cases are usually seen in unimmunizecl children. CSF findings in meningitis Bacterial Funga i/TB Viral Osteomyelitis Urinary trad infedions OPEN I NG PRESSURE Normallt CONDITION CELL TYPE t PMNs t lymphocytes t lymphocytes Assume if no other information is available Sexually active D iabetics and IV d ru g users Sickle cell Prosthetic replacement Vertebral d isease Cat and clog b ites or scratches Most osteomyel itis occurs i n children . Elevated C R P and ESR classic but nonspecific. PROT E I N SUGAR Normallt Normal CAUSE S. a ureus Neisseria gonorrhoeae (rare ) , septic arthritis more common Pseudomonas aeruginosa, Serratia Salmonella S. aureus and S. epidermidis Mycobacterium tuberculosis ( Pott's d i sease) Pasteurella m u .ltocida Cystitis presents with dysuria, frequency, urgency, suprapubic pain, and WBCs (but not WBC casts) in urine. Primarily caused by ascension of microbes from urethra to bladder. Malesinfants with congenital defects, vesicoureteral reflux. Elderly- enlarged prostate. Ascension to kidney results in pyelonephritis, which presents with fever, chills, Aank pain, CVA tenderness, hematuri a , and WBC casts. Ten times more common in women (shorter urethras colon ized by fecal flora) . Other predisposing factors include obstruction , kidney surgery, catheterization, G U malformation , diabetes, and pregnancy. Diagnostic markers : positive leukocyte esterase test = bacterial UTI ; positive n itrite test = gramnegative bacterial UTI . 1 70 SECT I O N I I UTI bugs SPECIES Escherichia coli Staphylococcus saprophyticus Klebsiella pneumoniae Serratia marcescens Enterobacter cloacae Proteus mirabilis Pseudomonas aeruginosa M I CROB I OLO G Y 􀃛 MICROBIOLOGY-SYSTEMS FEATURES Lead ing cause of UTI . Colon ies show green metallic sheen on E M B agar. 2nd leading cause of community-acqu ired UTI in sexually active women. 3rd leading cause of UTI. Large mucoid capsule and viscous colonies. Some strains produce a red pigment; often nosocom ial and dru g resistant. Often nosocom ial and drug resistant. Motil ity causes "swarming" on agar; produces urease; associ ated with struvite stones. Blue-green pigment and fruity odor; usually nosocom ial and drug resistant. COMMENTS Diagnostic markers : (f) Leukocyte esterase = bacterial. (f) Nitrite test = gram negative. (f) Urease test = urease-producing bugs (e.g., Proteus, Klebsiella) . 8 Urease test = E . coli, E n terococcus. M I C R O B I O L O G Y 􀃛 MI C RO BIO LO G Y - S Y S TE M S SECT I O N I I 1 7 1 ToRCHeS infections M icrobes that may pass from mother to fetus. Transm i ssion is transplacental i n most cases, or via del ivery (especially H SV-2 ) . Nonspecific signs common to many ToRCHeS i n fections i nclude hepatosplenomegaly, jaundice, thrombocytopenia, and growth retardation. Other i mportant infectious agents include Streptococcus agalactiae (group B streptococci ) , E . coli, and Listeria monocytogenes -all causes of meningitis in neonates. Parvovirus B l 9 causes hydrops fetal i s . AGENT MODE O F TRANSMISSION Toxoplasma gondii Cat feces or ingestion of u ndercooked meat Rubella Respiratory droplets CMV Sexual contact, organ transplants H IV Sexual contact, needlestick Herpes simplex virus-2 Skin or mucous membrane contact Syphilis Sexual contact MATERNAL MAN I FESTATIONS Usually asymptomatic ; lymphadenopathy (rarely) Rash , lymphadenopathy, arthritis Usually asymptomatic ; mononucleosis-like i l l ness Variable presentation depending on CD4+ count Usually asymptomati c ; herpetic (vesicular) lesions Chancre ( 1 ° ) and disseminated rash ( 2 ° ) are the two stages l i kely to result in fetal infection NEONATAL M A N I FESTIO N S Classic triad : chorioretin itis, hydrocephalus, and i ntracranial calcifications Classic triad : PDA (or pulmonary artery hypoplasia), cataracts, and deafness ± "blueberry muffin" rash Hearing loss, seizures, petechial rash, "blueberry muffin" rash Recurrent i n fections, chron ic d i arrhea Encephal itis, herpetic (vesicular) lesions Often results i n stillbirth, hydrops fetal is; if child survives, presents with facial abnormalities rJIJ (notched teeth , saddle nose, short maxilla) , saber shins, C N V I I I deafness Congenital syphilis facies. Skin is dry, wrinkled with yellow-brown hue. Note the hemorrhagic rhinitis. D Hutchinson's teeth. Note the centrally notched, widely spaced central incisors. D 1 72 S E C T I O N I I Red rashes of childhood AGENT Rubella virus Measles virus vzv HHV-6 Parvovirus B 1 9 Streptococcus pyogenes Coxsackievirus type A M I C R O B I O L O G Y 􀃙 M I C R O B I O L O G Y - S Y S TE M S ASSOCIATED SYNDRO M E/DISEASE Rubella Measles Chickenpox Roseola Erythema infectiosum Scarlet fever Hand-foot-mouth d i sease CLINICAL PRESENTAT I O N Rash begins at head and moves clow n ; -+ fi ne truncal rash ; postauricular lymphadenopathy A para myxoviru s ; beginning at head and moving clown ; rash is preceded by cough , coryza, conjunctivitis, and blue-wh ite ( Kopl ik) spots on buccal mucosa Vesicular rash begins on trunk; spreads to face and extrem ities with lesions of different age A macular rash over body appears after several clays of high fever; can present with febrile seizure s ; usually affects infa nts " Slapped cheek " rash on face r.:J (can cause hydrops fetal i s i n pregnant women) Erythematous, sandpaper-l ike rash with fever and sore throat Vesicular rash on palm s and soles [I); ulcers i n oral mucosa M I C R O B I O L O G Y 􀃕 M I C R O B I O L O G Y - S Y S TE M S S E C T I O N I I 1 73 Sexually transmitted diseases DISEASE Gonorrhea 1° syphilis 2° syphilis 3 ° syphilis Chancroid Genital herpes Chlamyd ia Lymphogra n u loma venereum Trichomoniasis AIDS Condylomata acum inata Hepatitis B Bacterial vaginosis Pelvic inflammatory disease CLIN I CAL FEATURES Urethritis, cervicitis, PID, prostatitis, epididym itis, arthritis, creamy purulent d i scharge Pa inless chancre Fever, lymphadenopathy, skin rashes, condylomata l ata Gummas, tabes dorsalis, general paresis, aortitis, Argyll Robertson pupil ORGAN I S M Neisseria gonorrhoeae Treponema pallidum Pai n ful genital ulcer, inguinal adenopathy I-Iaemophilus ducreyi (it's so painfu l , you "do cry" ) Pa inful penile, vulvar, o r cervical vesicles and H SV-2 , less commonly H SV- 1 ulcers ; can cause systemic symptoms such as fever, headache, myalgia Urethritis, cervicitis, conjunctivitis, Reiter's Chlamydia trachomatis (0-K) syndrome, PI D I n fection of lymphatics ; genital ulcers, C. trachomatis ( L l -L3) lymphadenopathy, rectal strictures Vagin itis, strawberry-colored mucosa, motile in Trichomonas vaginalis wet prep Opportun istic infections, Kaposi 's sarcoma, H I V lymphoma Gen ital warts, koi locytes H PV-6 and - 1 1 Jaundice Non i n fl a m m atory, m alodorous d ischarge (fishy smel l ) ; positive wh iff test, clue cells, not exclusively an STD Top bugs - Chlamydia trachomatis (subacute, often undiagnosed ) , Neisseria gonorrhoeae (acute ) . C. trachomatis -the most common bacterial STD in the United States. Cervical motion tenderness (chandelier sign ) , purulent cervical d i scharge. PID m a y include salpingitis, endometritis, hydrosalpinx, and tuba-ovarian abscess. Can lead to FitzHugh- Curtis syndrome - infection of the l iver capsule and "violi n string" adhesions of parietal peritoneu m to l iver. H BV Gardnerella vaginalis Salpingitis is a risk factor for ectopic pregnancy, infertil ity, chron ic pelvic pain, and adhesions. l 7 4 SECT I O N II MI C R OBI OLO G Y 􀃚 MIC RO BIO LO G Y - S Y S TE M S Nosocomial infedions PATHOGEN RISK FACTOR CMV, RSV Newborn nursery E. coli, Proteus mirabi/is Urinary catheterization Pseudomonas Respiratory therapy equ ipment aeruginosa H BV Candida albicans Legionella Work in renal d ialysis unit Hyperal imentation Water aerosol s Bugs affeding unimmunized children CliNICAL PRESENTATI O N F I N D INGS/LABS Dermatologic Rash Begi n n i ng at h ead and moving clown with postauricular lymphadenopathy N OTES The 2 most common causes of nosocomial infections are E. coli (UTI) and S. a ureus (wound infection) . Presume Pseudomonas "airuginosa " when air or burns are involved. Legionella when water source is i nvolved. PATHOGEN Rubella virus Beginning at head and moving clown ; rash Measles virus Neurologic Meni ngitis Respiratory Pha ryngitis Epiglottitis preceded by cough, coryza, conjunctivitis, and blue-white ( Kopl ik) spots on buccal mucosa M icrobe colonizes nasopharynx Can also lead to myalgia and paralysis Grayish oropharyngeal exudate ( "pseuclomembranes" may obstruct airway) ; painfu l throat Fever with dysphagia, drool ing, and d i fficulty breath ing clue to edematous "cherry reel " epiglottis H. influenzae type B Poliovirus Corynebacterium diphtheriae (elaborates toxin that causes necrosis i n pharynx, card iac, and CNS tissue) H. influenzae type B (also capable of causing epiglottitis i n fully i m mu n ized children) Bug hints (if all else fails) MICROBIOLOGY 􀃚 MICROBIOLOGY-SYSTEMS SE C T I O N I I 1 7 5 CHARACTERISTIC Pus, empyema, abscess Ped iatric infection Pneumonia in cystic fibrosis, burn infection Branch ing rods i n oral infection, sulfur granules Traumatic open wound Surgical wound Dog or cat bite "Cur rant j elly" sputu m Positive PAS stain Sepsis/meni ngitis i n newborn Health care provider Fungal infection in diabetic or i m munocomprom ised patient Asplenic patient Chronic granulomatous disease Neutropenic patients Facial nerve palsy ORGA N I S M S. aureus Haemophilus influenzae (including epiglottitis) Pse udomonas aeruginosa Actinomyces israelii Clostridium perfringens S. a ureu s Pasteurella m ultocida Klebsiella Tropheryma wh ipplei (Wh ipple's disease) Group B strep H BV (from needle stick) Mucor or Rhizofnts spp. Encapsulated m i crobes, especially S H iN (S. pnewnoniae, H. influenzae type B , N . meningitidis) Catalase-positive m icrobes, especially S. aureus Candida a lbicans (system ic) , Aspergillus Borrelia burgdorferi ( Lyme d i sease) 1 7 6 SECTI O N II M I C R O B I O L O G Y 􀃚 MIC R O BI O L O G Y - ANTIMIC R O BIA L S 􀃚 MI CROBIOLOGY-ANTIMIC ROBIALS Antimicrobial therapy Penicillin MECHANISM C L I N ICAL USE TOXICITY RESISTANCE MECHANISM OF ACTION 0 Block cell wall synthesis by inh ibition of peptidoglycan cross-l inking f) Block peptidoglycan synthesis E) Block nucleotide synthesi s by inhibiting folic acid synthesis ( involved i n methylation) 0 Block DNA topoisomerases 0 Block m RNA synthesis 0 Damage DNA 0 Block protein synthesis at 50S ribosomal subunit (l) Block protein synthesis at 30S ribosomal subunit 0 􀃔- lacta ms f) Vancomycin and bacitraci n E) SMX, TMP 0 Tetracycli nes, a m i noglycosides DRUGS Peni c i l l i n , meth i c i l l i n , ampic i l l i n , piperac i l l i n , cephalosporins, aztreonam, i mipenem Bacitracin, vancomycin Sulfonamides, trimethopri m Fluoroqui nolones Rifampin Metronidazole Chloramphenicol, macrol ides, cl indamyc i n , streptogra m i n s (qui nupristin , dalfopristin), l i nezol i d Ami noglycosides, tetracycl i nes 0 Macrolides, chloramphen icol, clindamycin, linezolid, streptogra m i n s Pen icillin G ( I V and I M form), pen icillin V (oral) . Prototype P-lactam a ntibiotics. Bind penicill in-binding proteins (transpeptidases) Block transpeptidase cross-l inking of peptidoglycan Activate autolytic enzymes Mostly used for gram-positive organisms (S. pneumoniae, S. pyogenes, Actinomyces) . Also used for Neisseria meningitidis, Treponema pallidum, and syph i l i s . Bactericidal for gram-positive cocc i , gram-positive rods, gram-negative cocci, a n d spirochetes . N o t pen icillinase res istant. Hypersensitivity reactions, hemolytic anem ia. P-lactamases cleave P-lactam ring. MICROBIOLOGY 􀃙 MIC ROBIOLOGY-AN TI MIC RO BIALS S E C T I O N I I 1 77 Oxacillin, nafcillin, dicloxacillin (penicillinase-resistant penicillins) MECHANISM CliN ICAL USE TOXICITY Same as pen icil l i n . Narrow spectrum; pen icillinase resistant because bulky R group blocks access of 􀃑-lactamase to 􀃑-lactam ring. S. au reus (except MRSA; resistant because of altered penicill in-binding protein target site) . Hypersensitivity reactions, interstitial nephritis. "Use naf (nafcillin) for staph." Ampicillin, amoxicillin (am inopenicillins) MECHANISM CliNICAL USE TOXICITY RESISTANCE Same as pen i c i l l i n . Wider spectrum ; AMinoPenicillins are AMPed-up pen icill i n . penicill inase sensitive. Also combine with clavulanic acid to protect against 􀃑-lactamase. Am Oxicillin has greater Oral bioavai labil ity than ampic i l l i n . Extended-spectrum penicillin - Haemophilus Coverage : ampici l l i n /amoxic i l l i n HELPSS kill influenzae, E. coli, Listeria monocytogenes, enterococci . Proteus mirabilis, Salmonella, Shigella, enterococci. Hypersensitivity reactions ; ampicillin rash ; pseudomembranous colitis. 􀃑-lactamases cleave 􀃑-lactam ring. Ticarcillin, piperacillin (antipseudomonals) MECHANISM Same as penici l l in. Extended spectrum. CliNICAL USE TOXICITY Pseudomonas spp. and gram-negative rod s ; susceptible to penicil l i na s e ; use with clavulanic acid. Hypersensitivity reactions. 􀂕-ladamase inhibitors I nclude Clavulanic Acid, Sulbactam , Tazobacta m . Often added to penici llin antibiotics to protect the antibiotic from destruction by 􀃑-lactamase (pen icill inase) . CAST. l 7 8 SECTI O N II Cephalosporins MECHANISM CliNICAl USE TOXICITY Aztreonam MECHANISM CliN ICAl USE TOXICITY MI CROBI OLO G Y 􀃘 MICROBIOLOGY-ANTIMICROBIALS 􀃑-lactam drugs that inhibit cell wall synthesis but are less susceptible to pen icill inases. Bactericidal . Organisms typically not covered by cephalosporins are LAME : Listeria, Atypicals (Chla mydia, Mycoplasma) , MRSA, and Enterococci. Exception : ceftarol ine covers MRSA . 1 st generation (cefazol i n , cephalexin) -gram- 1 st generation - PEcK. positive cocci, Proteus mirabilis, E. coli, Klebsiella pnewnoniae. Cefazol in used prior to surgery to prevent S. aureus wound infections . 2nd generation (cefoxitin, cefaclor, 2nd generation - HEN PEcKS. cefuroxime) - gram-positive cocci , Haemophilus influenzae, Enterobacter aerogenes, Neisseria spp., Proteus mirabilis, E. coli, Klebsiella fJneumoniae, Serratia marcescens. 3rd generation (ceftriaxone, cefotaxime, ceftazidime) - serious gram-negative infections resistant to other 􀃑-lactams. 4th generation (cefepime) -t activity against Pseudomonas and gram-positive organisms. Hypersensitivity reactions, vitamin K deficiency. Low cross-reactivity with pen icillins. t nephrotoxicity of a m inoglycosides. C eftriaxone-meningitis and gonorrhea. Ceftazid i me- Pseudomonas. A monobactam resistant to 􀃑-lactamases. Prevents peptidoglycan cross-l inking by binding to PBP3. Synergistic with aminoglycosicles. No cross-allergenicity with penicillins. Gram-negative rods only-No activity against gram-positives or anaerobes. For penicill i n-allergic patients and those with renal insufficiency who cannot tolerate a m inoglycosicles. Usually nontoxic ; occasional GI upset. lmipenem/ cilastatin, meropenem MECHANISM C l i N I CAl USE TOXICITY I m ipenem is a broad-spectrum , 􀃑-lactamaseresistant carbapenem . Always adm inistered with cilastatin (inh ibitor of renal clehyclropepticlase I) to ! inactivation of drug in renal tubules. Gram-positive cocci, gram-negative rods, and anaerobes. Wiele spectru m , but the sign ificant side effects l i m it use to life-threatening infections, or after other drugs have failed. Meropenem, however, has a reduced risk of seizures and is stable to dehyclropepticlase I. GI d istress, ski n rash, and CNS toxicity (seizures) at h igh plasma levels. With i m ipenem, " the kill is lastin' with cilastatin." ewer carbapenems i nclude ertapenem and cloripenem. Vancomycin MECHANISM CLIN ICAL USE TOXICITY RESISTANCE Protein synthesis inhibitors M I C R O B I O L O G Y • MICRO BIOLO G Y - ANTI MI C RO BIAL S S E C T I O N I I 1 79 I n h ibits cell wall peptidoglycan formation by binding 0-ala 0-ala portion o f cell wall precursors. Bactericidal . Cram positive only- serious, amulticlru g-resi stant organisms, including M RSA, e nterococc i , and Clostridium diffi.cile (oral close for pseudomembranous colitis) . Neph rotoxicity, Ototoxicity, Thrombophlebitis, d i ffuse fl ush i n g- red m a n syn d ro m e (can largely prevent by pretreatment with antihistam ines and slow infusion rate ) . Well tolerated in genera l does N O T have many problems. Occurs with amino acid change of D-ala D-ala to 0-ala 0-lac. " Pay back 2 D -alas (dollars) for vandalizing (vancomycin) ." Specifically target smaller bacterial ribosome (70S, made of 30S and 50S subun its), leaving human ribosome ( 80 S ) unaffected. "Buy AT 30, CCEL (sell) at 50." 3 05 i n h i b itors A = Am inoglycosicles [bactericidal ] T = Tetracycl i nes [bacteriostatic] 5 05 i n h i b itors C = Chloramphen icol, Clinclamycin [bacteriostatic] E = Erythromycin (macrol icles) [bacteriostatic] L = Li nezol icl [variable] m R N A linezolid (50S) Z.l J 􀀊 I n itiator tRNA Ribosomal A&P site ,-A---., PA I n itiation 1 . . complex t-0-- Am1 noglycos1d es ( 30S)a formation PA 􀀋 Macrolides (erythromycin ) (505) a Also causes misreading of mRNA. Clindamycin (50S) 1 80 S E CT I O N I I Aminoglycosides MECHANISM CLINICAL USE TOXICITY RESISTANCE Tetracyclines MECHANISM CLIN ICAL USE TOXICITY RESISTANCE Macrolides MECHANISM CLIN ICAL USE TOXICITY RESISTANCE MICROBIOLOGY 􀃙 MICROBIOL OGY- ANT IMI CROBIAL S Gentamicin, Neomycin, Am ikacin , Tobramyci n, Streptomycin. Bactericida l ; i n h ibit formation of in itiation complex and cause m isread ing of m RNA. Also block translocation. Require 02 for uptake ; therefore ineffective against anaerobes. Severe gram-negative rod infections. Synergistic with P-lactam antibiotics. Neomycin for bowel surgery. Nephrotoxicity (especially when used with cephalosporins ) , Neuromuscular blockade, Ototoxicity (especially when used with loop d iuretics) . Teratogen. Transferase enzymes that inactivate the drug by acetylation , phosphorylation, or adenylation. Tetracycline, doxycycline, demeclocycl ine, m i nocycl ine. Bacteriostatic; bind to 3 0 S and prevent attachment of aminoacyl-tRNA; lim ited CNS penetration. Doxycycline is fecally el i m inated and can be used i n patients with renal failure. Do not take with milk, antacids, or ironcontaining preparations because divalent cations i n h ibit its absorption in the gut. Borrelia burgdorferi, M. pnewnoniae. Drug's abil ity to accumulate intracellularly makes it very effective against Rickettsia and Chlamydia . Gl d i stress, discoloration of teeth and inh ibition of bone growth in children, photosensitivity. Contraindicated in pregnancy. ! uptake into cells or t efflux out of cell by plasmid-encoded transport pumps. Azithromyc i n , clarithromycin, erythromycin. "Mean" (arninoglyc oside) GNATS caNNOT kill anaerobes. A " i n itiates" the Alphabet. Demeclocycl i ne-ADI-1 antagonist; acts as a Diuretic in SIAD H . Rarely used as antibiotic. I n h ibit protein synthesis by blocking translocation ( "macrosl ides" ) ; bind to the 23S rRNA of the 50S ribosomal subunit. Bacteriostatic. Atypical pneumonias (Mycoplasma, Chlamydia, Legionella) , STDs (for Chla mydia), and grampositive cocci (streptococcal infections in patients allergic to penici l l i n ) . MACRO : Moti l ity issues, Arrhythmia caused b y prolonged QT, acute Cholestatic hepatitis, Rash, eOsi noph i l ia . I ncreases serum concentration of theophyll ines, oral anticoagulants. Methylation of 23S rRNA binding site. Chloramphenicol MECHAN ISM CLINICAL USE TOXICITY RESISTANCE Clindamycin MECHANISM CLIN ICAL USE TOXICITY Sulfonamides MECHANISM CLINICAL USE TOXICITY RESISTANCE MICROBIOLOGY 􀃕 MICROBIO L OGY- ANTI MI C R OBIA LS Blocks peptidyltransferase a t 50S ribosomal subunit. Bacteriostatic. S E C T I O N I I 1 8 1 Meningitis (Haemoph ilus influenzae, Ne isseria meningitidis, Streptococcus pneumoniae). C on servative use owing to toxicities but often still used in developing countries because of low cost. Anemia (close dependent) , aplastic anem ia (close independent) , gray baby syndrome (in premature infants because they lack l iver UDP-glucuronyl transferase) . Plasmid-encoded acetyltransferase that inactivates d rug. Blocks peptide transfer (transpeptidation) at 50S ribosomal subunit. Bacteriostatic. Anaerobic infections (e.g., Bacteroides fragilis, Clostridium perfringens) in aspiration pneumonia or lung abscesses. Also oral infections with mouth anaerobes. Treats anaerobes above the diaphragm vs. metronidazole (anaerobic i n fections below d i aphragm) . Pseudomembranous colitis ( C . difficile overgrowth) , fever, diarrhea. Sulfa methoxazole ( SMX), sulfisoxazole, sulfadiazine. PABA anti metabol ites i n h ibit d i hydropteroate synthase. Bacteriostatic. Gram-positive, gram-negative, Nocardia, Chlamydia. Triple sulfas or SMX for simple UTI . Hypersensitivity reactions, hemolysis if G6PD deficient, neph rotoxicity (tubulointerstitial nephritis) , photosensitivity, kernicterus in infants, d isplace other d rugs from album i n (e.g., warfarin) . Altered enzyme ( bacterial d ihydropteroate synthase ) , 􀃓 uptake, or t PABA synthesis. PABA + Pteridine Dihydro t p h teroate syn ase t I. Sulfonamides I Dihydropteroic acid 1 Dihyd rofolic acid Dihydrofolate t ' li -r - i m - e - th _ o _ p _r - i m -, ' reductase pyrimethamine Tetrahydrofolic acid (THF) 1 N5N 1 0-methylene T H F / 1 􀀓 Pu rines Thymidine Methionine 􀁨 􀁨 􀁨 DNA, RNA DNA P rotein (Adapted, with permission, from Katzung BG. Basic and Clinical Pharmacology, 7th ed. Stamford, Cf: Appleton & lange, 1 997: 762.) 1 8 2 SECTI O N II Trimethoprim MECHANISM CLI N I CAL USE TOXICITY Fluoroquinolones M ECHAN ISM CLINICAL USE TOXICITY RESISTANCE Metronidazole MECHAN ISM CLIN ICAL U S E TOXICITY MI C R OBI OLO G Y 􀃚 MICROBIOLOGY-ANTI MICROBIALS I n h ibits bacterial d i hydrofolate reductase. Bacteriostatic. Used i n combination with sulfonamides (trimethoprim-sulfamethoxazole [TMPSMX] ) , causing sequential block of folate synthesis. Combination used for UTis, Shigella, Salmonella, Pneumocystis jirovecii pneumonia (treatment and prophylaxis ) . Megaloblastic anem ia, leukopenia, Abbreviated TMP. granulocytopenia. ( May alleviate with TMP: Treats Marrow Poorly. supplemental fol inic acid [leucovorin rescue ] . ) CiproAoxaci n , norAoxacin, levoAoxacin, oAoxacin, sparAoxaci n , moxiAoxac i n , gatiAoxaci n , enoxacin (Auoroquinolones), nalidixic acid (a quinolone). I n h ibit DNA gyrase (topoisomerase I I ) and topoisomerase IV Bactericidal. Must not be taken with antacids. Gram-negative rods of urinary and GI tracts (including Pseudomonas ) , Neisseria, some gram-positive organisms. GI upset, superinfections, skin rashes, headache, d i zziness. Less common ly, can cause tendon itis, tendon rupture, leg cramps, and myalgias. Contra i nd icated in pregnant women and i n children because animal studies show damage to cartilage. Some may cause prolonged QT i nterval. May cause tendon rupture i n people > 60 years old and in patients taking predn isone. Chromosome-encoded mutation i n DNA gyrase, plasm id-mediated resistance, efflux pumps. Forms free radical toxic metabol ites in the bacterial cell that damage DNA. Bactericidal, antiprotozoal. Treats Giardia, Entamoeba, Trichomonas, Gardnerella vagina/is, Anaerobes (Bacteroides, C. difficile) . Used with a proton pump inh ibitor and clarithromycin for " triple therapy" against H. Pylori. Disulfiram-l i ke reaction with alcohol ; headache, meta II ic taste . Fluoroquinolones h u r t attachments t o your bones. GET GAP on the Metro with metron idazole ! Treats anaerobic infection below the d i aphragm vs. clindamyci n (anaerobic infections above diaphragm ) . MI CROBI OLOGY 􀃚 MICROBIOLOGY-ANTI MICROBIALS SE C T I O N I I 1 83 Antimycobaderia l d rugs BACTERIUM PROPHYLAXIS M. tuberculosis I son iazid M. avium-intracellulare Azithromycin M. leprae Isoniazid (I N H) MECHAN ISM CLINICAL USE TOXICITY Rifampin MECHANISM CLINICAL USE TOXICITY N/A l synthesis of mycol ic acids . Bacterial catalaseperoxidase ( KatG) needed to convert INH to active metabolite. Mycobacterium tuberculosis. The only agent used as solo prophylaxis against T B . Neurotoxicity, hepatotoxicity. Pyridoxine (vita m i n B6) can prevent neurotoxicity, lupus. I n h ibits DNA-dependent R A polymerase. Mycobacterium tuberculosis; delays resistance to dapsone when used for leprosy. Used for meningococcal prophylaxis and chemoprophylaxis i n contacts of children with Haemophilus inf/.uenzae type B . M inor hepatotoxicity a n d drug interactions ( t P-4 5 0 ) ; orange body Auids (nonhazardous side effect) . TREATM ENT Rifampin , Ison iazid , Pyrazi n a m i de, Ethambutol ( R IPE for treatment) Azithromyc i n , rifampin, ethambutol , streptomycin Long-term treatment with dapsone and rifampin for tuberculoid for m . Add clofa z i m ine for lepromatous for m . I N H Inj ures Neurons and H epatocytes . Different I H half-lives in fast vs. slow acetyla tors. Rifampin's 4 R's : RNA polymerase i n h ibitor Revs up m icrosomal P-45 0 Red /orange body Auids Rapid resistance i f used alone Pyrazinamide M ECHAN ISM Mechanism u ncerta i n . Thought to acid ify intracel lular environ ment via conversion to pyrazinoic acid. Effective in acidic pH of phagolysosomes, where TB engulfed by m acrophages is found. CLINICAL U S E TOXICITY Ethambutol MECHANISM CLINICAL USE TOXICITY Mycobacterium tuberculosis. Hyperuricem ia, hepatotoxicity. l carbohyd rate polymerization of mycobacterium cell wall by blocking arabinosyltransfera sc. Mycobacterium tuberculosis. Optic neuropathy (red-green color blindness ) . 1 84 S E C T I O N I I Antimicrobial prophylaxis H IV prophylaxis CELL COUNT CD4 < 200 cel ls/m m3 M I C R O B I O L O G Y 􀃙 MI C RO BIO LO G Y - ANTI MIC R O B IA L S CONDITION Meningococcal infection MED ICATION Ciprofloxacin (drug of choice) , rifampin for children Gonorrhea Ceftriaxone Syph i l i s Benzathine penicillin G H istory of recurrent UTis TMP-SMX Endocarditis with surgical or dental pro cedures Pen icillins Pregnant woman carrying group B strep Ampicillin Prophylaxis of strep pharyngitis in child with Oral penicillin prior rheumatic fever Prevention of postsurgical infection clue to Cefazol i n S. aureus Prevention of gonococcal or chlamydia! Erythromyc i n ointment conjunctivitis in newborn PROPHYLAXIS I N FECTION TMP-SMXa Pneumocystis pneumon ia CD4 < 1 00 cel ls/m m3 TMP-SMXa Pnewnocystis pneu monia and toxoplasmosis CD4 <50 data-blogger-escaped----="" data-blogger-escaped--::lating="" data-blogger-escaped--="" data-blogger-escaped--auorouracil="" data-blogger-escaped-.="" data-blogger-escaped-0="" data-blogger-escaped-187="" data-blogger-escaped-1="" data-blogger-escaped-20.="" data-blogger-escaped-2003="" data-blogger-escaped-5-fiucytosine="" data-blogger-escaped-5="" data-blogger-escaped-6="" data-blogger-escaped-8="" data-blogger-escaped-:="" data-blogger-escaped-a="" data-blogger-escaped-abnormal="" data-blogger-escaped-accumulates="" data-blogger-escaped-acid="" data-blogger-escaped-acyclovir="" data-blogger-escaped-aerosolized="" data-blogger-escaped-against="" data-blogger-escaped-aids="" data-blogger-escaped-aj.="" data-blogger-escaped-all="" data-blogger-escaped-allow="" data-blogger-escaped-altered="" data-blogger-escaped-amphotericin="" data-blogger-escaped-amphoterrible="" data-blogger-escaped-analogs="" data-blogger-escaped-and="" data-blogger-escaped-anemia="" data-blogger-escaped-anidu="" data-blogger-escaped-anti="" data-blogger-escaped-antifungal="" data-blogger-escaped-antihelminthic="" data-blogger-escaped-antiprotoz:oan="" data-blogger-escaped-antiviral="" data-blogger-escaped-aper="" data-blogger-escaped-arrhythm="" data-blogger-escaped-arrow="" data-blogger-escaped-artemether="" data-blogger-escaped-artisunate.="" data-blogger-escaped-as="" data-blogger-escaped-aspergillosis="" data-blogger-escaped-atophytes="" data-blogger-escaped-atovaquone="" data-blogger-escaped-aucytosine="" data-blogger-escaped-aush="" data-blogger-escaped-aviwn="" data-blogger-escaped-azithromycin="" data-blogger-escaped-azoles="" data-blogger-escaped-b.="" data-blogger-escaped-b="" data-blogger-escaped-baderia="" data-blogger-escaped-bake="" data-blogger-escaped-be="" data-blogger-escaped-because="" data-blogger-escaped-bg="" data-blogger-escaped-binds="" data-blogger-escaped-biosynthesis="" data-blogger-escaped-blastomyces="" data-blogger-escaped-blocked="" data-blogger-escaped-blocks="" data-blogger-escaped-brucei="" data-blogger-escaped-but="" data-blogger-escaped-by="" data-blogger-escaped-c="" data-blogger-escaped-cal="" data-blogger-escaped-candida.="" data-blogger-escaped-candida="" data-blogger-escaped-candidal="" data-blogger-escaped-candidiasis.="" data-blogger-escaped-candidiasis="" data-blogger-escaped-carcinogenic="" data-blogger-escaped-caspofungin="" data-blogger-escaped-caused="" data-blogger-escaped-cell="" data-blogger-escaped-cells="" data-blogger-escaped-chills="" data-blogger-escaped-chloroquine="" data-blogger-escaped-chronic="" data-blogger-escaped-clin="" data-blogger-escaped-clinical="" data-blogger-escaped-clotrimazole="" data-blogger-escaped-coccidioides="" data-blogger-escaped-combination="" data-blogger-escaped-complex="" data-blogger-escaped-concentration="" data-blogger-escaped-concurrently.="" data-blogger-escaped-confusion="" data-blogger-escaped-conversion="" data-blogger-escaped-converts="" data-blogger-escaped-crobi="" data-blogger-escaped-cruzi="" data-blogger-escaped-cryptococcal="" data-blogger-escaped-cryptococcus="" data-blogger-escaped-cytochrome="" data-blogger-escaped-cytosine="" data-blogger-escaped-d="" data-blogger-escaped-dalfopristin="" data-blogger-escaped-dapted="" data-blogger-escaped-deaminase.="" data-blogger-escaped-deposits="" data-blogger-escaped-derm="" data-blogger-escaped-dermatophytoses="" data-blogger-escaped-detoxification="" data-blogger-escaped-diethylcarbamazine="" data-blogger-escaped-disrupts="" data-blogger-escaped-dna="" data-blogger-escaped-due="" data-blogger-escaped-dysfunction="" data-blogger-escaped-e.g.="" data-blogger-escaped-e="" data-blogger-escaped-early="" data-blogger-escaped-electrolytes.="" data-blogger-escaped-elsewhere="" data-blogger-escaped-enzyme="" data-blogger-escaped-epoxidase.="" data-blogger-escaped-ergosterol.="" data-blogger-escaped-ergosterol="" data-blogger-escaped-esp.="" data-blogger-escaped-especially="" data-blogger-escaped-falciparum="" data-blogger-escaped-falciparwn="" data-blogger-escaped-fe-threatening="" data-blogger-escaped-fections.="" data-blogger-escaped-fever="" data-blogger-escaped-finger="" data-blogger-escaped-fluconazole="" data-blogger-escaped-flucytosine="" data-blogger-escaped-flukes="" data-blogger-escaped-for="" data-blogger-escaped-form="" data-blogger-escaped-forming="" data-blogger-escaped-forms="" data-blogger-escaped-frequency="" data-blogger-escaped-from="" data-blogger-escaped-function="" data-blogger-escaped-fungal="" data-blogger-escaped-fungi="" data-blogger-escaped-furti="" data-blogger-escaped-g="" data-blogger-escaped-gi="" data-blogger-escaped-glucan.="" data-blogger-escaped-griseofulvin="" data-blogger-escaped-growth="" data-blogger-escaped-gy-="" data-blogger-escaped-gynecomastia="" data-blogger-escaped-h="" data-blogger-escaped-headaches="" data-blogger-escaped-helminths.="" data-blogger-escaped-heme="" data-blogger-escaped-hemozoin.="" data-blogger-escaped-highly="" data-blogger-escaped-histam="" data-blogger-escaped-histoplasma.="" data-blogger-escaped-histoplasma="" data-blogger-escaped-holes="" data-blogger-escaped-hydration="" data-blogger-escaped-hypotension="" data-blogger-escaped-i="" data-blogger-escaped-ias="" data-blogger-escaped-ibit="" data-blogger-escaped-ibiting="" data-blogger-escaped-ibition="" data-blogger-escaped-ibits="" data-blogger-escaped-ical="" data-blogger-escaped-icity="" data-blogger-escaped-icl="" data-blogger-escaped-iconazole="" data-blogger-escaped-icrotubule="" data-blogger-escaped-idine="" data-blogger-escaped-if="" data-blogger-escaped-igh="" data-blogger-escaped-ii="" data-blogger-escaped-ine="" data-blogger-escaped-infection="" data-blogger-escaped-infections="" data-blogger-escaped-influenza="" data-blogger-escaped-ingitis.="" data-blogger-escaped-ingitis="" data-blogger-escaped-inh="" data-blogger-escaped-inhibiting="" data-blogger-escaped-inhibitors="" data-blogger-escaped-inhibits="" data-blogger-escaped-interferes="" data-blogger-escaped-into="" data-blogger-escaped-ique="" data-blogger-escaped-is="" data-blogger-escaped-ism.="" data-blogger-escaped-ism="" data-blogger-escaped-isturbances.="" data-blogger-escaped-itosis.="" data-blogger-escaped-itraconazole="" data-blogger-escaped-ity.="" data-blogger-escaped-iv="" data-blogger-escaped-iver="" data-blogger-escaped-ivermecti="" data-blogger-escaped-ize="" data-blogger-escaped-k="" data-blogger-escaped-katzung="" data-blogger-escaped-keratin-contai="" data-blogger-escaped-ketoconazole="" data-blogger-escaped-l="" data-blogger-escaped-lanosterol="" data-blogger-escaped-late="" data-blogger-escaped-leakage="" data-blogger-escaped-leishmaniasis="" data-blogger-escaped-less="" data-blogger-escaped-lfts="" data-blogger-escaped-lfu="" data-blogger-escaped-liposomal="" data-blogger-escaped-lo="" data-blogger-escaped-local="" data-blogger-escaped-ltraconazole="" data-blogger-escaped-lumifantrine="" data-blogger-escaped-m="" data-blogger-escaped-malaria="" data-blogger-escaped-mammalian="" data-blogger-escaped-may="" data-blogger-escaped-mcgraw-hill="" data-blogger-escaped-mebendazole="" data-blogger-escaped-mechan="" data-blogger-escaped-mechanism="" data-blogger-escaped-melarsoprol="" data-blogger-escaped-membrane="" data-blogger-escaped-men="" data-blogger-escaped-meningitis="" data-blogger-escaped-metabol="" data-blogger-escaped-mg="" data-blogger-escaped-mi="" data-blogger-escaped-mic="" data-blogger-escaped-micafungin="" data-blogger-escaped-miconazole="" data-blogger-escaped-micr="" data-blogger-escaped-microbials="" data-blogger-escaped-microbiology-anti="" data-blogger-escaped-microbiology="" data-blogger-escaped-mm3="" data-blogger-escaped-mmobil="" data-blogger-escaped-mop:="" data-blogger-escaped-mox="" data-blogger-escaped-mphotericin="" data-blogger-escaped-mrsa-vancomycin.="" data-blogger-escaped-mucor.="" data-blogger-escaped-mycobacterium="" data-blogger-escaped-mycoses.="" data-blogger-escaped-n="" data-blogger-escaped-nafine="" data-blogger-escaped-naftifine="" data-blogger-escaped-nail="" data-blogger-escaped-neph="" data-blogger-escaped-nephrotoxicity="" data-blogger-escaped-neuraminidase="" data-blogger-escaped-new="" data-blogger-escaped-nezol="" data-blogger-escaped-ngin="" data-blogger-escaped-ngworm="" data-blogger-escaped-not="" data-blogger-escaped-ns="" data-blogger-escaped-ntracellular="" data-blogger-escaped-ntrathecally="" data-blogger-escaped-nucleic="" data-blogger-escaped-nvasive="" data-blogger-escaped-nystatin="" data-blogger-escaped-o="" data-blogger-escaped-obio="" data-blogger-escaped-obiology="" data-blogger-escaped-of="" data-blogger-escaped-olo="" data-blogger-escaped-one="" data-blogger-escaped-onychomycosis-fungal="" data-blogger-escaped-or="" data-blogger-escaped-oral="" data-blogger-escaped-oseltamivir="" data-blogger-escaped-other="" data-blogger-escaped-p-45="" data-blogger-escaped-p-4="" data-blogger-escaped-p.="" data-blogger-escaped-packaging="" data-blogger-escaped-pamoate="" data-blogger-escaped-patient="" data-blogger-escaped-patients="" data-blogger-escaped-pentam="" data-blogger-escaped-permeabil="" data-blogger-escaped-permission="" data-blogger-escaped-phlebitis="" data-blogger-escaped-phormocology="" data-blogger-escaped-plasmodia.="" data-blogger-escaped-plasmodial="" data-blogger-escaped-pores.="" data-blogger-escaped-pores="" data-blogger-escaped-praziquantel="" data-blogger-escaped-prevent="" data-blogger-escaped-proguan="" data-blogger-escaped-protein="" data-blogger-escaped-pump="" data-blogger-escaped-purine="" data-blogger-escaped-pyrantel="" data-blogger-escaped-pyrimethamine="" data-blogger-escaped-pyrimidine="" data-blogger-escaped-quinidine="" data-blogger-escaped-quinine="" data-blogger-escaped-quinupristin="" data-blogger-escaped-r="" data-blogger-escaped-rash="" data-blogger-escaped-reduces="" data-blogger-escaped-release="" data-blogger-escaped-renal="" data-blogger-escaped-resi="" data-blogger-escaped-resistance="" data-blogger-escaped-resistant="" data-blogger-escaped-retinopathy.="" data-blogger-escaped-reverse="" data-blogger-escaped-rgosterol="" data-blogger-escaped-ri="" data-blogger-escaped-ribavirin="" data-blogger-escaped-rna="" data-blogger-escaped-robial="" data-blogger-escaped-robials="" data-blogger-escaped-robiology-anti="" data-blogger-escaped-rood="" data-blogger-escaped-rotoxicity.="" data-blogger-escaped-rug.="" data-blogger-escaped-rypanosoma="" data-blogger-escaped-s="" data-blogger-escaped-same="" data-blogger-escaped-schistosoma.="" data-blogger-escaped-sect="" data-blogger-escaped-secti="" data-blogger-escaped-section="" data-blogger-escaped-serious="" data-blogger-escaped-shake="" data-blogger-escaped-sodium="" data-blogger-escaped-species="" data-blogger-escaped-squalene="" data-blogger-escaped-st="" data-blogger-escaped-stance="" data-blogger-escaped-sterol="" data-blogger-escaped-stibogluconate="" data-blogger-escaped-streptogram="" data-blogger-escaped-such="" data-blogger-escaped-superficial="" data-blogger-escaped-supplement="" data-blogger-escaped-suppression.="" data-blogger-escaped-suppression="" data-blogger-escaped-sur="" data-blogger-escaped-swallow="" data-blogger-escaped-swish="" data-blogger-escaped-synthes="" data-blogger-escaped-synthesis="" data-blogger-escaped-systemic="" data-blogger-escaped-t="" data-blogger-escaped-tears="" data-blogger-escaped-teratogenic="" data-blogger-escaped-terbi="" data-blogger-escaped-terbinafine="" data-blogger-escaped-testosterone="" data-blogger-escaped-than="" data-blogger-escaped-that="" data-blogger-escaped-the="" data-blogger-escaped-therapy="" data-blogger-escaped-this="" data-blogger-escaped-thrush="" data-blogger-escaped-tinea="" data-blogger-escaped-tissues="" data-blogger-escaped-tmp-smx="" data-blogger-escaped-to="" data-blogger-escaped-toe="" data-blogger-escaped-tolerate="" data-blogger-escaped-too="" data-blogger-escaped-topical="" data-blogger-escaped-tox="" data-blogger-escaped-toxic="" data-blogger-escaped-toxicity.="" data-blogger-escaped-toxicity="" data-blogger-escaped-toxoplasmosis="" data-blogger-escaped-transcriptase="" data-blogger-escaped-treat="" data-blogger-escaped-treatment="" data-blogger-escaped-trematodes="" data-blogger-escaped-trevor="" data-blogger-escaped-tubule="" data-blogger-escaped-types.="" data-blogger-escaped-u.="" data-blogger-escaped-u="" data-blogger-escaped-ucleic="" data-blogger-escaped-un="" data-blogger-escaped-unable="" data-blogger-escaped-upset="" data-blogger-escaped-use.="" data-blogger-escaped-use="" data-blogger-escaped-used="" data-blogger-escaped-usmle="" data-blogger-escaped-v="" data-blogger-escaped-vaginal="" data-blogger-escaped-voriconazole.="" data-blogger-escaped-voriconazole="" data-blogger-escaped-vre="" data-blogger-escaped-wall="" data-blogger-escaped-warfarin="" data-blogger-escaped-with="" data-blogger-escaped-without="" data-blogger-escaped-y="" data-blogger-escaped-york:="" data-blogger-escaped-zanamivir="">.;�"'-- and _ synthesis and assembly processing t Blocked by f---� rifampin (vaccinia) --r--; Blocked by protease inhibitors (Adapted, with permission, from Katzung BG, Trevor AJ. USMLE Road Map: Pharmacology, 1st ed. New York: McGraw-Hill, 2003 : 120.) Inhibit influenza neuraminidase, decreasing the release of progeny virus. Treatment and prevention of both influenza A and B. Inhibits synthesis of guanine nucleotides by competitively inhibiting IMP dehydrogenase. RSV, chronic hepatitis C. Hemolytic anemia. Severe teratogen. Monophosphorylated by HSV/VZV thymidine kinase. Guanosine analog. Triphosphate fo rmed by cellular enzymes. Preferentially inhibits viral DNA polymerase by chain terminati on. HSV and VZV. We ak activity against EBV. No activity against CMV. Used fo r HSVinduced mucocutaneous and genital lesions as well as for encephalitis. Prophylaxis in immunocompromised patients. No effect on latent fo rms of HSV and VZV. Va lacyclovir, a prodrug of acyclovir, has be tter oral bioavailability. For herpes zoster, use a related agent, fa mciclovir. Few serious adverse effects. Mutated viral thymidine kinase. 1 8 8 SECTION II Cianciclovir MECHANISM CliNICAL USE TOXICITY MECHANISM OF RESISTA NCE Foscamet MECHANISM CLINICAL USE TOX ICITY MECHANISM OF RESISTA NCE Cidofovir MECHANISM CLINICAL USE TOX ICITY MICROBIOLOGY 􀃛 MICRO BIO LOG Y-ANTIMIC ROBIA LS 5'-monophosphate fo rmed by a CMV viral kinase. Guanosine analog. Triphosphate fo rmed by cellular kinases. Preferentially inh ibits viral DNA polymerase. CMV, especially in immunocompromised patients. Va lganciclovir, a prodrug of ga nciclovir, has better oral bioavailabil ity. Leuko penia, neutropenia, thrombocytopenia, renal toxicity. More toxic to host enzymes than acyclovir. Mutated CMV DNA polymerase or lack of viral kinase. Viral DNA polymerase inhibitor that binds to Foscarnet = pyro fosphate analog. the pyrophosphate-binding site of the enzyme. Does not require activation by viral kinase. CMV re tinitis in immunocompromised patients when ganciclovir fa ils; acyclovir-resistant HSV. ephrotoxicity. Mutated DNA polymerase. Preferentially inhibits viral DNA polymerase. Does not require phosphorylation by viral kinase. CMV retinitis in immunocompromised patients ; acyclovir-resistant HSV. Long half-l ife. Nephrotoxic ity (coadminister with probenecid and IV saline to reduce toxicity) . H IV therapy DRUG Protease i n h i bitors Lopinavir Atazanavir Darunavi r Fosamprenavir Saquinavir R itonavi r l n d inavir N RTis Tenofovir (TDF) Emtricitabine (FTC) Abacav i r (ABC) Lamivudine (3TC) Zidovudine (ZDV, formerly AZT) Didanosine (ddl) Stavud i n e ( d4T) N N RTis Nevirapine Efavi renz Delavirdine lntegrase inhibitors Ra ltegravi r Interferons MECHAN ISM CLINICAL USE TOXICITY MICROBIOLOGY 􀃕 MICR OBIOL O G Y - ANTIMICROB IALS S E C T I O N I I 1 8 9 H ighly active antiretroviral therapy ( HAART) : in itiated when patients present with A I D S -defi n i n g illness, l o w C D4 c e l l counts (< 500 cells/m m3) , or h igh vira l l o a d . Regi men consists of 3 d ru gs to prevent resistance : [2 nucleoside reverse transcriptase inh ibitors ( N RTis)] + [ l n on-nucleoside reverse transcriptase i n h ibitor ( N N RT I ) OR l protease inh ibitor OR l i ntegrase i n h ibitor] M ECHAN ISM Assembly of virions depends on HIV-l protease (pol gene), wh ich cleaves the polypeptide products of HIV mR A i nto their functional parts. Thus, protease i n h ibitors prevent maturation of new viruses. R itonavir can " boost" other drug concentrations by inh ibiting cytochrome P-450. All protease inh ibitors end in -navir. Navir ( never) tease a protease. Competitively inhibit nucleotide binding to reverse transcriptase and terminate the D A chai n ( lack a 3' OH group) . Tenofovir is a nucleotide analog and does not have to be activate d ; the others are nucleoside analogs and do need to be phosphorylated to be active. ZDV is used for general prophylaxis and dur i n g pregnancy t o reduce r i s k of fetal transm ission . Have you dined (vudine) with my nuclear (nucleosides) fam i ly? Bind to reverse transcriptase at site different from RTis. Do not require phosphorylation to be active or compete with nucleotides. I n h ibits HIV genome integration i nto host cell chromosome by reversibly inhibiting HTV integrase. TOXI C I TY Hyperglycemia, G I i ntolerance (nausea, d i a rrhea) , l ipodystrophy. Neph ropathy, hematuria (indinav i r) . Bone marrow suppression (can be reversed with G - C S F and erythropoieti n ) , peripheral neuropathy, lactic acidosis (nucleosides ) , rash (non-nucleosides), anemia (ZDV ) . S a m e as N RT J s . I-Iypercholesterolem i a . Glycoproteins synthesized b y virus-infected cells ; block repl ication of b o t h R N A and D N A viruses. I FN-a - chronic hepatitis B and C , Kaposi 's sarcoma . I FN-􀄊 - M S . I FN-y- NADPH oxidase deficiency. Neutropenia, myopathy. l 9 0 SECTION II MICROBIOLOGY 􀃙 MIC ROBIO LOGY -ANTIMIC ROBIALS Antibiotics to avoid i n ANT I B IOTIC ADVERSE EFFECT 􀁓􀁔􀁕􀁖----------------------􀁗􀁘􀁙􀁚􀁛---------------------- pregnancy Sulfona m ides Kern icterus Am i noglycosides Fl uoroqui nolones Clarithromycin Tetracyclines Ribavirin (antiviral ) Griseofulvin (antifungal) Chloramphenicol SAFe Ch ild ren Take Really Good Care. Ototoxicity Cartilage damage Embryotoxic D iscolored teeth, inhibition of bone growth Teratogenic Teratogenic "Gray baby" HIGH-YIELD PRINCIPLES IN Immunology "I hate to disappoint you, but my rubber lips are immune to your charms." -Batman & Robin "No State shall abridge the privileges or immunities of its citizens." -The United States Constitution The immunology content on USMLE exams has been expanded and reclassified into a new category called the immune system. Mastery of the basic principles and facts in this area will be useful. Cell surface markers are important to know because they are clinically useful (e.g., in identifying specific types of immune deficiency or cancer) and are functionally critical to the jobs immune cells carry out. By spending a little extra effort here, it is possible to turn a traditionally difficult subject into one that is high yield. l 9 2 SECTION II IMMUNOLOGY 􀀼 IMMUNOLOGY-LYMPHOID STRUCTURES 􀀽 IMMUNOLOGY-LYMPHOID STRUCTURES Lymph node Follicle Medulla Paracortex Lymph drainage A zo lymphoid organ that has many afferents, l or more efferents. Encapsulated, with trabeculae. Functions are nonspecific filtration by macrophages, storage and activation of B and T cells, antibody production. Site of B-cell localization and proliferation. In outer cortex. l o follicles are dense and dormant. zo follicles have pale central germinal centers and are active. Consists of medullary cords (closely packed lymphocytes and plasma cells) and medullary sinuses. Medullary sinuses communicate with efferent lymphatics and contain reticular cells and macrophages. Houses T cells. Region of cortex between follicles and medulla. Contains high endothelial venules through which T and B cells enter from blood. In an extreme cellular immune response, paracortex becomes greatly enlarged. Not well developed in patients with DiGeorge syndrome. ARE A OF BODY Upper limb, lateral breast Stomach Duodenum, jejunum Sigmoid colon Rectum (lower portion) of anal canal (above pectinate line) Anal canal (below pectinate line) Testes Scrotum Thigh (superficial) Lateral side of dorsum of foot Subcapsular Capillary Postcapillary sinus supply (high endothelial} venules Afferent lymphatic Medullary sinus (macrophages) X... ;I!S......... it--Trabecula Efferent ---..c. lymphatic Artery Vein Medullary cords (plasma cells) Paracortex (T cells) Paracortex enlarges in an extreme cellular immune response (i.e., viral). 1° lYMPH NODE DRAINA GE SITE Axillary Celiac Superior mesenteric Colic --+ inferior mesenteric Internal iliac Superficial inguinal Superficial and deep plexuses --+ para-aortic Superficial inguinal Superficial inguinal Popliteal Right lymphatic duct-drains right arm, right chest, and right half ofhead. Thoracic duct-drains everything else. Sinusoids of spleen IMMUNOLOGY 􀀼 IMMUNOLOGY-LYMPHOCYTES Long, vascular channels in red pulp with fenestrated "barrel hoop" basement membrane. Macrophages found nearby. SECTION II 1 9 3 Arterial supply T cells are found in the periarterial lymphatic sheath (PALS) within the white pulp of the spleen. B cells are found in follicles within the white pulp of the spleen. Germinal center (B cells) Central arteriole Section of white pulp PALS (T cells) 􀀤't'-'t--- Marginal zone (APCs) Venous drainage Macrophages in the spleen remove encapsulated bacteria. Splenic dysfunction: 􀀻 IgM -+ 􀀻 complement activation -+ 􀀻 C3b opsonization -+ t susceptibility to encapsulated organisms: • Streptococcus pneumoniae • Haemophilus influenzae type B • Neisseria meningitidis • Salmonella • Klebsiella pneumoniae • Group B Streptococci (SHiN SKiS) Postsplenectomy: • Howell-Jolly bodies (nuclear remnants) • Target cells • Thrombocytosis (Reproduced, with permission, from Junqueira LC, Carneiro J: Basic Histology: Text and Atlas, lith ed. New York: McGraw· Hill, 2005.) Thymus Site of T-cell differentiation and maturation. Encapsulated. From epithelium of 3rd branchial pouches. Lymphocytes of mesenchymal origin. Cortex is dense with immature T cells; medulla is pale with mature T cells and epithelial reticular cells containing Hassall's corpuscles. Positive selection (MHC restriction) occurs in the cortex and negative selection (nonreactive to self) occurs in the m eel ull a. T cells = Thymus. B cells = Bone marrow. 􀀼 IMMUNOLOGY-LYMPHOCYTES Innate vs. adaptive immunity Innate Adaptive Receptors that recognize pathogens are germline encoded. Response to pathogens is fast and nonspecific. No memory. Consists of neutrophils, macrophages, dendritic cells, natural killer cells (lymphoid origin), and complement. Receptors that recognize pathogens undergo V(D)J recombination during lymphocyte development. Response is slow on first exposure, but memory response is faster and more robust. Consists ofT cells, B cells, and circulating antibody. l 9 4 SECTION II MHC I and I I M HCI M HC II IMMUNOLOGY 􀀼 IMMUNOLOGY-LYMPHOCYTES MHC =major histocompatibility complex, encoded by human leukocyte antigen (l-ILA) genes; present antigen fragments to T cells and bind T CR. HLA-A, BLA-B, HLA-C. Binds TCR and CDS. Expressed on all nucleated cells. Not expressed on RBC. Antigen is loaded in RER with mostly intracellular peptides. Mediates viral immunity. Pairs with 􀂀2-microglobulin (aids in transport to cell surface). HLA-DR, HLA-DP, HLA-DQ. Binds TCR and CD4. Expressed only on antigen-presenting cells (APCs). Antigen is loaded following release of invariant chain in an acidified endosome. Peptide-binding H L A subtypes associated with diseases A3 Hemochromatosis. 827 DQ2/DQ8 DR2 DR3 DR4 DRS Natural killer cells Psoriasis, Ankylosing spondylitis, Inflammatory PAIR. bowel disease, Reiter's syndrome. Celiac disease. Multiple sclerosis, hay fever, SLE, Goodpasture's. Diabetes mellitus type l, Graves' disease. Rheumatoid arthritis, diabetes mellitus type l. Pernicious anemia -+ B12 deficiency, Hashimoto's thyroiditis. Use perforin and granzymes to induce apoptosis of vi rally infected cells and tumor cells. Only lymphocyte member of innate immune system. Activity enhanced by IL-2, IL-12, IFN-􀂀, and lFN-a. Induced to kill when exposed to a nonspecific activation signal on target cell and/or to an absence of class I MI-IC on target cell surface. IMMUNOLOGY 􀀼 IMMUNOLOGY-LYMPHOCYTES SECTION II 1 9 5 Major functions of B and T cells B cell functions T cell functions Differentiation of T cells Bone marrow T-cell precursor Make antibody-opsonize bacteria, neutralize viruses (IgC); activate complement (IgM, IgC); sensitize mast cells (IgE). Allergy (type I hypersensitivity): IgE. Cytotoxic (type II) and immune complex (type III) hypersensitivity: IgC. Hyperacute and llllmorally mediated acute and chronic organ rejection. CD4+ T cells help B cells make antibody and produce cytokines to activate other cells of immune system. CDS+ T cells kill virus-infected cells directly. Delayed cell-mediated hypersensitivity (type IV). Acute and chronic cellular organ rejection. Thymus Lymph node COStT cell I I .I Cytotoxic T cell (kills virus-infected, neoplastic, and donor graft cells) CD4tCDSt Tcell Th, cell 0 : I 􀀃 CD4+Tcell Helper T cell y T- cell receptor (binds MHC I orMHCII ) 'l CDS 'l CD4 Positive selection Negative selection Cortex (positive selection) Medulla (negative selection) 􀀂 Thymic cortex. T cells expressing TCRs capable of binding surface self MHC molecules survive. Medulla. T cells expressing TCRs with high affinity for self antigens undergo apoptosis. l 9 6 SECTION II IMMUNOLOGY 􀀼 IMMUN OLOGY-LYMPHOCYTES T and B cell adivation Antigen-presenting cells (APCs): • Dendritic cell (only APC that can activate naive T-cell) • Macrophage • B cell Two signals are required for T cell activation and B cell activation and class switching. Naive T cell activation l. Foreign body is phagocytosed by dendritic cell. 2. Foreign antigen is presented on MHC II and recognized by TCR on Th (helper) cell. Antigen is presented on MHC I to Tc (cytotoxic) cells (signal!). 3. "Costimulatory signal" is given by interaction of B7 and CD28 (signal 2). 4. Th cell activates and produces cytokines. Tc cell activates and is able to recognize and kill virusinfected cell. B cell activation and l. Helper T cell activation as above. class switching 2. B cell receptor-mediated endocytosis; foreign antigen is presented on MHC II and recognized by Helper T cells TCR on Th cell (signal 1). 3. CD40 receptor on B cell binds CD40 ligand on Th cell (signal 2). 4. Th cell secretes cytokines that determine Ig class switching of B cell. B cell activates and undergoes class switching, affinity 1:naturation, and antibody production. Secretes lFN-y Activates macrophages Inhibited by IL-4 and IL-10 (from Th2 cell) Secretes IL-4, IL-5, IL-10, IL-13 Recruits eosinophils for parasite defense and promotes IgE production by B cells Inhibited by IF N-y (from Th1 cell) Macrophage-lymphocyte interaction-activated lymphocytes (release IFN-y) and macrophages (release IL-l, TNF-a) stimulate one another. Helper T cells have CD4, which binds to MHC I I on APCs. Cytotoxic T cells Regulatory T cells Antibody structure and function Fab IMMUNOLOGY • IMMUNOLOGY-LYMPHOCYTES Kill virus-infected, neoplastic, and donor graft cells by inducing apoptosis. SECTION II 197 Release cytotoxic granules containing preformed proteins (perforin-helps to deliver the content of granules into target cell; granzyme-a serine protease, activates apoptosis inside target cell; granulysin-antimicrobial, induces apoptosis). Cytotoxic T cells have CDS, which binds to MHC I on virus-infected cells. Help maintain specific immune tolerance by suppressing CD4 and CDS T-cell effector functions. Express CD3, CD4, CD25 (a chain ofiL-2 receptor) cell surface markers. Activated regulatory T cells produce anti-inflammatory cytokines like IL-10 and TGF- 􀂀. Variable part of L and H chains recognizes antigens. Fe portion of lgM and IgG fixes complement. Heavy chain contributes to Fe and Fab fractions. Light chain contributes only to F ab fraction. Fab: • Antigen-binding fragment • Determines idiotype: unique antigenbinding pocket; only l antigenic specificity expressed per B cell Fe: Constant • Carboxy terminal Complement binding • Complement binding at C112 (IgG + IgM only) Fe Macrophage ::::::: binding (Adapted, with permission, from Ganong WF. Review of Medical Physiology, 22nd ed. New York: McGraw-Hill, 2005: 528.) Opsonization Antibody promotes phagocytosis Neutralization Antibody prevents bacterial adherence Complement activation Antibody activates complement, enhancing opsonization and lysis • Carbohydrate side chains • Determines isotype (IgM, IgD, etc.) Antibody diversity is generated by: • Random "recombination" of VJ (light-chain) or V (D)J (heavy-chain) genes • Random combination of heavy chains with light chains • Somatic hypermutation (following antigen stimulation) • Addition of nucleotides to DNA during recombination (see lst entry in this list) by terminal deoxynucleotidyl transferase 1 9 8 SECTION II Immunoglobulin isotypes lgG lgA lgM lgD lgE IMMUNO LOGY 􀀺 IMMUNOLOGY-LYMPHOCYTES Mature B lymphocytes express IgM and IgD on their surfaces. They may differentiate by isotype switching (gene rearrangement; mediated by cytokines and CD40 ligand) into plasma cells that secrete IgA, IgE, or IgG. Main antibody in zo (delayed) response to an antigen. Most abundant isotype. Fixes complement, crosses the placenta (provides infants with passive immunity), opsonizes bacteria, neutralizes bacterial toxins and viruses. Prevents attachment of bacteria and viruses to mucous membranes; does not fix complement. Monomer (in circulation) or dimer (when secreted). Crosses epithelial cells by transcytosis. Found in secretions (tears, saliva, mucus) and early breast milk (known as colostrum). Picks up secretory component from epithelial cells before secretion. Produced in the 1 o (immediate) response to an antigen. Fixes complement but does not cross the placenta. Antigen receptor on the surface of B cells. Monomer on B cell or pentamer. Shape of pentamer allows it to efficiently trap free antigens out of tissue while humoral response evolves. Unclear function. Found on the surface of many B cells and in serum. Binds mast cells and basophils; cross-links when exposed to allergen, mediating immediate (type I) hypersensitivity through release of inflammatory mediators such as histamine. Mediates immunity to worms by activating eosinophils. Lowest concentration in serum. Antigen type and memory Thymus-independent antigens Thymus-dependent antigens Antigens lacking a peptide component; cannot be presented by MHC to T cells (e.g., lipopolysaccharide from cell envelope of gram-negative bacteria and polysaccharide capsular antigen). Stimulate release of antibodies and do not result in immunologic memory. Antigens containing a protein component (e.g., diphtheria vaccine). Class switching and immunologic memory occur as a result of direct contact of B cells with Th cells (CD40-CD40 ligand interaction). IM MUNO LOGY 􀀺 IMMUNOLOGY-IMMUNE RESPONSES SECTION II 1 9 9 􀀺 IMMUNOLOGY-IMMUNE RESPONSES Complement Overview Activation Functions Opsonins Inhibitors Alternative Spontaneous and microbial surfaces Classic Antigen-antibody complexes System of interacting proteins that play a role in innate immunity and inflammation. Membrane attack complex (MAC) of complement defends against gram-negative bacteria. Classic pathway-IgG or IgM mediated. Alternative pathway-microbe surface molecules. Lectin pathway-mannose or other sugars on microbe surface. C3b-opsonization. C3a, C5a-anaphylaxis. C5a-neutrophil chemotaxis. C5b-9-cytolysis by MAC. C3b and IgG are the two l o opsonins in bacterial defense; C3b also helps clear immune complexes. Decay-accelerating factor (DAF) and Cl esterase inhibitor help prevent complement activation on self cells (e.g., RBC). 􀀁􀀂 C3 C3􀀪 C3b C4a C4 C4b C1􀀪 C2 C2a C3 C2b GM makes classic cars. C3b binds bacteria. C6-C9 t 􀁠 LYSIS, CSb 􀁿 MAC CYTOTOXICITY 2 00 SECTION II Complement disorders C1 esterase inhibitor deficiency C3 deficiency C5-C9 deficiencies OAF (GPI anchored enzyme) deficiency lmportant cytokines SECRETED BY MACROP HAGES IL-1 IL-6 IL-8 IL-12 TN F-a SECRETED BY ALL T CELLS IL-2 IL-3 FROM Th1 CELLS lnterferon-y FROM Th2 CELLS IL-4 IL-5 IL-10 IM MUNO LOGY 􀀺 IMMUNOLOGY-IMMUNE RESPONSES -+ hereditary angioedema. ACE inhibitors are contraindicated. -+ severe, recurrent pyogenic sinus and respiratory tract infections; t susceptibility to type III hypersensitivity reactions. -+ recurrent Neisseria bacteremia. -+ complement-mediated lysis of RBCs and paroxysmal nocturnal hemoglobinuria (PNH). An endogenous pyrogen. Causes fever, acute inflammation. Activates endothelium to express adhesion molecules; induces chemokine secretion to recruit leukocytes. An endogenous pyrogen. Also secreted by Th2 cells. Causes fever and stimulates production of acute-phase proteins. Major chemotactic factor for neutrophils. Induces differentiation of T cells into Th1 cells. Activates NK cells. Also secreted by B cells. Mediates septic shock. Activates endothelium. Causes leukocyte recruitment, vascular leak. Stimulates growth of helper, cytotoxic, and regulatory T cells. Supports the growth and differentiation of bone marrow stem cells. Functions like GM-CSF. Activates macrophages and T h1 cells. Suppresses Th2 cells. Has antiviral and antitumor properties. Induces differentiation into Th2 cells. Promotes growth of B cells. Enhances class switching to IgE and IgG. Promotes differentiation of B cells. Enhances class switching to IgA. Stimulates the growth and differentiation of eosinophils. Modulates inflammatory response. Inhibits actions of activated T cells and Th1 . Also secreted by regulatory T cells. "Hot T-Bone stEAk": IL-l: fever (hot). IL-2: stimulates T cells. IL-3: stimulates Bone marrow. IL-4: stimulates IgE production. IL-5: stimulates IgA production. "Clean up on aisle 8." Neutrophils are recruited by IL-8 to clear infections. TGF- 􀂀 has similar actions to IL-10, because it is involved in inhibiting inflammation. IMMUNOLOGY 􀀼 IMMUNOlOGY-IMMUNE RESPONSES SECTION II 2 Q 1 Interferon mechanism Interferons (a, 􀂀, y) are proteins that place Interferes with viruses: Cell surface proteins T cells Helper T cells Cytotoxic T cells B cells Macrophages NK cells Anergy Effects of bacterial toxins Antigen variation uninfected cells in an antiviral state. Interferons induce the production of a ribonuclease that inhibits viral protein synthesis by degrading viral mRNA (but not host mRNA). All cells except mature RBCs have MHC I. TCR (binds antigcn-MI-IC complex) CD3 (associated with TCR for signal transduction) CD28 (binds B7 on APC) CD4, CD40 ligand CDS Ig (binds antigen) CD19, CD20, CD21 (receptor for EBV ), CD40 MHC II, B7 CD14, CD40 MHC II, B7 Fe and C3b receptors (enhanced phagocytosis) CD16 (binds Fe of lgC), CD56 (unique marker for NK) • a- and 􀂀-interferons inhibit viral protein synthesis. • y-interferons t MHC I and II expression and antigen presentation in all cells. • Activates K cells to kill virus-infected cells. You can drink Beer at the Bar when you're 21: B cells, Epstein-Barr virus; CD-21. Self-reactive T cells become nonreactive without costimulatory molecule. B cells also become anergic, but tolerance is less complete than in T cells. Superantigens (S. pyogenes and S. aureus) -cross-link the 􀂀 region of the T-cell receptor to the MHC class II on APCs. Can activate any T cell, leading to massive release of cytokines. Endotoxins/lipopolysaccharide (gram-negative bacteria) -directly stimulate macrophages by binding to endotoxin receptor CD14; Th cells are not involved. Classic examples: • Bacteria-Salmonella (2 flagellar variants), Borrelia (relapsing fever), Neisseria gonorrhoeae (pilus protein). • Virus-influenza (major= shift, minor= drift). • Parasites-trypanosomes (programmed rearrangement). Some mechanisms for variation include DNA rearrangement and RNA segment reassortment (e.g., influenza major shift). 202 SECTION II I M MUNOLOGY 􀀺 IMMUNOLOGY-IMMUNE RESPONSES Passive vs. adive immunity MEANS OF ACQUISITION ONSET DURATION EXAMPLES NOTES Vaccination VACCINE TYPE Live attenuated vaccine Inactivated or killed vaccine Passive Receiving preformed antibodies Rapid Short span of antibodies (half-life= 3 weeks) IgA in breast milk, antitoxin, humanized monoclonal antibody After exposure to Tetanus toxin, Botulinum toxin, HBV, or Rabies virus, patients are given preformed antibodies (passive)-"To Be Healed Rapidly" Active Exposure to foreign antigens Slow Long-lasting protection (memory) Natural infection, vaccines, toxoid Combined passive and active immunizations can be given in case of hepatitis B or rabies exposure. Vaccines are used to induce an active immune response (humoral and/or cellular) to specific pathogens. DESCRIPTION Microorganism loses its pathogenicity but retains capacity for transient growth within inoculated host. Mainly induces a cellular response. Pathogen is inactivated by heat or chemicals; maintaining epitope structure on surface antigens is important for immune response. Humoral immunity induced. PROS/CONS Pro: induces strong, often life-long immunity. Con: may revert to virulent form. Pro: stable and safer than live vaccines. Con: weaker immune response; booster shots usually required. EXAMPLES Measles, mumps, polio ( Sabin), rubella, varicella, yellow fever. Cholera, hepatitis A, polio ( Salk), rabies. IMMUNOLOGY 􀀼 IMMUNOLOGY-IMMUNE RESPONSES SECTION II 2 0 3 Hypersensitivity types Type I Anaphylactic and atopic-free antigen crosslinks lgE on presensitized mast cells and basophils, triggering release of vasoactive Mast cell or basophil J ..,, Type II 􀁟 = complement Type Ill Type IV Antigenpresenting cell Fe receptor amines that act at postcapillary venules (i.e., 9 histamine). Reaction develops rapidly after antigen exposure because of preformed antibody. Cytotoxic (antibody mediated) -lgM, lgC bind to fixed antigen on "enemy" cell, leading to cellular destruction. 3 mechanisms: • Opsonization leading to phagocytosis or complement activation • Complement-mediated lysis • Antibody-dependent cell-mediated cytotoxicity (ADCC), usually due to NK cells Immune complex-antigen-antibody (lgC) complexes activate complement, which attracts neutrophils; neutrophils release lysosomal enzymes. Serum sickness-an immune complex disease (type III) in which antibodies to the foreign proteins are produced (takes 5 days). 􀁞 Immune complexes form and are deposited in membranes, where they fix complement (leads to tissue damage). More common than Arthus reaction. Arthus reaction-a local subacute antibodymediated hypersensitivity (type III) reaction. Intradermal injection of antigen induces antibodies, which form antigen-antibody complexes in the skin. Characterized by edema, necrosis, and activation of complement. Delayed (T-cell-mediated) type-sensitized T lymphocytes encounter antigen and then release lymphokines (leads to macrophage activation; no antibody involved). Th cells First (type) and Fast (anaphylaxis). Types I, II, and III are all antibody mediated. Test: skin test for specific lgE. Type II is cy-2-toxic. Antibody and complement lead to membrane attack complex (MAC). Test: direct and indirect Coombs'. In type III reaction, imagine an immune complex as 3 things stuck together: antigenantibody- complement. Most serum sickness is now caused by drugs (not serum) acting as haptens. Fever, urticaria, arthralgias, proteinuria, lymphadenopathy 5-10 days after antigen exposure. Antigen-antibody complexes cause the Arthus reaction. Test: immunofluorescent staining. 4th and last-delayed. Cell mediated; therefore, it is not transferable by serum. 4 T's = T lymphocytes, Transplant rejections, TB skin tests, Touching (contact dermatitis). Test: patch test, PPD. ACID : Anaphylactic and Atopic (type I) Cytotoxic (antibody mediated) (type II) Immune complex (type Ill) Delayed (cell mediated) (type IV ) 2 0 4 SECTION II IMMUNOLOGY 􀀼 IMMUNOLOGY-IMMUNE RESPONSES Hypersensitivity disorders REACTION Type I Type II Type Ill Type IV EXA MPLES Anaphylaxis (e.g., bee sting, some food/drug allergies) Allergic and atopic disorders (e.g., rhinitis, hay fever, eczema, hives, asthma) Autoimmune hemolytic anemia (AIHA) Pernicious anemia Idiopathic thrombocytopenic purpura Erythroblastosis fetal is Acute hemolytic transfusion reactions Rheumatic fever Goodpasture's syndrome Bullous pemphigoid Pemphigus vulgaris SLE Polyarteritis nodosa Poststreptococcal glomerulonephritis Serum sickness Arthus reaction (e.g., swelling and inflammation following tetanus vaccine) Multiple sclerosis Guillain-Barre syndrome Graft-versus-host disease PPD (test forM. tuberculosis) Contact dermatitis (e.g., poison ivy, nickel allergy) Blood transfusion readions TYPE PATHOGENESIS Allergic reaction Type I hypersensitivity reaction against plasma proteins in transfused blood. Anaphylactic reaction Severe reaction. IgA-deficient individuals must receive blood products that lack IgA. Febrile nonhemolytic Type II hypersensitivity reaction. Host transfusion reaction antibodies against donor HLA antigens and (FNHTR) leukocytes. Acute hemolytic 1ype II hypersensitivity reaction. Intravascular transfusion reaction hemolysis (ABO blood group incompatibility) (HTR) or extravascular hemolysis (host antibody reaction against foreign antigen on donor RBCs). PRESENTATION Immediate, anaphylactic, atopic Disease tends to be specific to tissue or site where antigen is found Can be associated with vasculitis and systemic manifestations Response is delayed and does not involve antibodies (vs. types I, II, and III) CLINICAL PRESENTATION Urticaria, pruritus, wheezing, fever. Treat with anti histamines. Dyspnea, bronchospasm, hypotension, respiratory arrest, shock. Fever, headaches, chills, flushing. Fever, hypotension, tachypnea, tachycardia, flank pain, hemoglobinemia (intravascular), jaundice (extravascular hemolysis). IMMUNOLOGY 􀀼 IMMUNOLOGY-IMMUNE RESPONSES SECTION II 2 0 5 Autoantibodies AUTOANTIBODY Antinuclear antibodies (ANA) Anti-dsDNA, anti-Smith Anti histone Rheumatoid factor, anti-CCP Anticentromere Anti-Scl-70 (anti-DNA topoisomerase I) Antimitochondrial lgA antiendomysial, lgA anti-tissue transglutaminase Anti-basement mem brane Anti-desmoglein Antimicrosomal, antithyroglobulin Anti-Jo-1, anti-SR P, anti-Mi-2 Anti-SSA (anti-Ro) Anti-SSB (anti-La) Anti-Ul RNP (ribonucleoprotein) Anti-smooth muscle Anti-glutamate decarboxylase c-ANCA (PR3-ANCA) p-ANCA ( M PO-ANCA) Infections in immunodeficiency PATHOGEN NO T CELLS NO B CELLS Bacteria Sepsis Encapsulated: Streptococcus pnewnoniae, Haemophilus influenzae type B, Neisseria meningitidis, Salmonella, Klebsiella pnewnoniae, group B Strep (SHiN SKiS) Virus CMV, EBV, VZV, Enteroviral chronic infection encephalitis, with respiratory/GI poliovirus viruses (live vaccine contraindicated) Fungi/parasites Candida, PCP GI giardiasis (no IgA) ASSOCIATED DISORDER SLE, nonspecific SLE Drug-induced lupus Rheumatoid arthritis Scleroderma (CREST syndrome) Scleroderma (diffuse) 1° biliary cirrhosis Celiac disease Goodpasture's syndrome Pemphigus vulgaris Hashimoto's thyroiditis Polymyositis, dermatomyositis Sjogren's syndrome Sjogren's syndrome Mixed connective tissue disease Autoimmune hepatitis Type l diabetes mellitus Granulomatosis with polyangiitis (Wegener's) Microscopic polyangiitis, Churg-Strauss syndrome NO G RANULOCYTE NO COMPLEMENT Staphylococcus, Neisseria (no Burkholderia cepacia, membrane attack Serratia, Nocardia complex) N/A N/A Candida, Aspergillus N/A ote: B-cell deficiencies tend to produce recurrent bacterial infections, whereas T-cell deficiencies produce more fungal and viral infections. 2 0 6 SECTION II IMMUNOLOGY 􀀼 IMMUNOLOGY-IMMUNE RESPONSES Immune deficiencies DISEASE DEFEC T B-cell disorders X-linked (Bruton's) X-linked recessive (t in Boys). agammaglobulinemia Defect in BTK, a tyrosine kinase gene - no B cell maturation. Selective lgA Unknown. Most common deficiency primary immunodeficiency. Common variable Defect in B-cell maturation; immunodeficiency many causes. (CVID) T-cell disorders Thymic aplasia (DiGeorge syndrome) IL-12 receptor deficiency Hyper-lgE syndrome (Job's syndrome) Chronic mucocutaneous candidiasis 22qll deletion; failure to develop 3rd and 4th pharyngeal pouches. ! Th1 response. T h1 cells fail to produce IF -y - inability of neutrophils to respond to chemotactic stimuli. T-cell dysfunction. PRESENTATION Recurrent bacterial infections after 6 months (! maternal IgG) as a result of opsonization defect. Majority asymptomatic. Can see sinopulmonary infections, GI infections, autoimmune disease, Anaphylaxis to IgA-containing blood products. Can be acquired in 20s-30s; t risk of autoimmune disease, lymphoma, sinopulmonary infections. Tetany (hypocalcemia), recurrent viral/fungal infections (T-cell deficiency), congenital heart and great vessel defects. Disseminated mycobacterial infections. FATED: coarse Facies, cold (noninflamed) staphylococcal Abscesses, retained primary Teeth, t IgE, Dermatologic problems (eczema). Candida albicans infections of skin and mucous membranes. FINDINGS Normal pro-B, ! maturation, ! number of B cells, ! immunoglobulins of all classes. IgA < 7 mg/dL with normal IgG, IgM, and IgG vaccine titers. False-positive 􀂀-HCG tests due to presence of heterophile antibody. Normal number of B cells; ! plasma cells, immunoglobulin. Thymus and parathyroids fail to develop- ! T cells, ! PTH, ! Ca2+. Absent thymic shadow on CX R. ! IF N-y. t IgE. IMMUNOLOGY 􀀺 IMMUNOLOGY-IMMUNE RESPONSES SECTION II 207 Immune deficiencies (continued) DISEASE DEFECT B- and T-cell disorders Severe combined immunodeficiency (SCI D) Ataxia-telangiectasia Hyper-lgM syndrome Wiskott-Aidrich syndrome Phagocyte dysfunction Leukocyte adhesion deficiency (type 1) Chediak-Higashi syndrome Chronic granulomatous disease Several types: defective IL-2 receptor (most common, X-linked), adenosine deaminase deficiency. Defects in the ATM gene, which codes for DNA repair enzymes. Most commonly defective CD40L on helper T cells = inability to class switch. X-linked; in WAS gene on X chromosome -+ T cells unable to reorganize actin cytoskeleton. Defect in LFA-1 integrin (CD18) protein on phagocytes. Autosomal recessive; defect in lysosomal trafficking regulator gene (LYST). Microtubule dysfunction in phagosomelysosome fusion. Lack of NADPH oxidase -+ ! reactive oxygen species (e.g., superoxide) and absent respiratory burst in neutrophils. PRESENTATION Failure to thrive, chronic diarrhea, thrush. Recurrent viral, bacterial, fungal, and protozoal infections. Absence of thymic shadow, germinal centers (lymph node biopsy), and B cells (peripheral blood smear). Treatment: bone marrow transplant (no allograft rejection). Triad: cerebellar defects (ataxia), spider angiomas (telangiectasia), IgA deficiency. Severe pyogenic infections early in life. Triad (TIE): Thrombocytopenic purpura, Infections, Eczema. Recurrent bacterial infections, absent pus formation, delayed separation of umbilical cord. Recurrent pyogenic infections by staphylococci and streptococci; partial albinism, peripheral neuropathy. t susceptibility to catalasepositive organisms (e.g., S. aureus, E. coli, Aspergillus). FINDINGS ! T-cell recombinant excision circles (T RECs). Absence of thymic shadow, germinal centers (lymph node biopsy), and T cells (flow cytometry). t AFP. t IgM; ! ! IgG, IgA, IgE. t IgE, IgA; ! IgM. Thrombocytopenia. Neutrophilia. Giant granules in neutrophils. Abnormal dihydrorhodamine (DHR) flow cytometry test. Nitroblue tetrazolium dye reduction test no longer preferred. 2 0 8 SECTION II Grafts Autograft Syngeneic graft Allograft Xenograft Transplant rejection TYPE OF REJECTION Hyperacute Acute Chronic Graft-versus-host IMMUNOLOGY 􀀺 IMMUNOLOGY-IMMUNE RESPONSES From self. From identical twin or clone. From nonidentical individual of same species. From different species. ONSET AFTER TRANSPLANTATION Within minutes Weeks later Months to years Varies PATHOGENESIS Antibody mediated (type II) because of the presence of preformed anti-donor antibodies in the transplant recipient. Cell-mediated due to CTLs reacting against foreign MHCs. Reversible with immunosuppressants (e.g., cyclosporine, muromonabCD3). Class 1-M HCnon-self is perceived by CTLs as class 1-M HCself presenting a nonself antigen. Grafted immunocompetent T cells proliferate in the irradiated immunocompromised disease host and reject cells with "foreign" proteins, resulting in severe organ dysfunction. FEATURES Occludes graft vessels, causing ischemia and necrosis. Vasculitis of graft vessels with dense interstitial lymphocytic infiltrate. Irreversible. rf'-cell and antibody-mediated vascular damage (obliterative vascular fibrosis); fibrosis of graft tissue and blood vessels. Maculopapular rash, jaundice, hepatosplenomegaly, and diarrhea. Usually in bone marrow and liver transplant (organs rich in lymphocytes). Potentially beneficial in bone marrow transplant. IMMUNOLOGY 􀀺 IMMUNOLOGY-IMMUNOSUPPRESS ANTS SECTION II 209 􀀹 IM MUNOLOGY-IM M UNOSUPPRESSANTS Cyclosporine MECHANISM CLINICAL USE TOXICITY Tacrolimus {FK-506) MECHANISM CLINICAL USE TOXICITY Sirolimus (rapamycin) MECHANISM CLINICAL USE TOXICITY Azathioprine MECHANISM CLINICAL USE TOXICITY Muromonab-CD3 {OKT3) MECHANISM CLINICAL USE TOXICITY Binds to cycloph il ins. Complex blocks the d i fferentiation and activation of T cells by i n h ibiting calc i neurin, thus preventing the production of i L-2 and its receptor. Suppresses organ rejection after transplantation ; selected auto i m mune d isorders. Nephrotoxicity, hypertension, hyperl ipidemia, hyperglyce m i a, trem or, gingival hyperplasia, h i rsutism . S i m i l a r to cyclospori n e ; binds to FK-binding protein, i n h ibiting calcineur i n and secretion of I L-2 and other cytokines. Potent immunosuppressive used in organ transplant recipients. S i m ilar to cyclosporine except no gingival hyperplasia and h i rsuti sm. Inh ibits mTOR. I n h ibits T-cell prol iferation in response to I L-2 . I m munosuppression after kidney transplantation in combination with cyclosporine and corticosteroids. Also used with drug-eluting stents. Hyperl ipidemia, thrombocytopenia, leukopen ia. Antimetabol ite precursor of 6-mercaptopurine that i nterferes with the metabol ism and synthesis of nucleic acids. Toxic to prol iferating lymphocytes. Kidney transplantation, autoim mune disorders (including glomeru lonephritis and hemolytic anemia) . Bone marrow suppression. Active metabol ite mercaptopurine is metabol ized by xanth ine oxidase ; thus, toxic effects may be increased by allopurinol. Monoclonal antibody that binds to CD3 (epsilon chain) on the surface of T cel l s . Blocks cellular i nteraction with C D 3 protein responsible for T-cel l signal transduction. I mmunosuppression after k idney transplantation . Cytokine release syndrome, hypersensitivity reaction. 2 1 0 SECTION II IM MUN OLOGY 􀀺 IMMUNOLOGY- IMMUNOSUPPRESSANTS Recombinant cytokines 􀀭A􀀮G􀀯E􀀰N􀀱T ___________ _____ 􀀲CL􀀳I N􀀴I􀀵C A􀀶L􀀷U􀀸S􀀹ES􀀺--------------------------- and clinical uses Aldesleukin (interleukin-2 ) Renal cell carcinoma, metastatic melanoma Epoetin alfa (erythropoietin) Anem ias (especially in renal fai lure) Filgrastim (granulocyte colony-stimulating Recovery of bone m arrow Therapeutic antibodies factor) Sargramostim (granulocyte-macrophage colonystimulating factor) a-interferon 􀁕-interferon y-interferon O prelvekin (interleu k i n- l l ) Throm bopoietin A GENT TARGET Muromonab-CD3 CD3 (O KT3) Digoxin I m mune Fab Digoxin lnfliximab TNF-a Adalimumab TNF-a Abciximab Glycoprotein J i b / I l ia Trastuzumab H E R 2 ( Herceptin) Rituximab CD20 O malizumab IgE Recovery of bone marrow Hepatitis B and C, Kapos i 's sarcoma, leuke m ias, mal ignant melanoma Multiple sclerosis Chron ic granulomatous d isease Thrombocytopen i a Thrombocytopenia CLINI C AL USE Prevent acute transplant rej ection Antidote for d igoxi n i ntoxication Crohn's d i sease, rheumatoid arthritis, psoriatic arthritis, ankylosing spondyl itis Crohn's d isease, rheumatoid arthritis, psoriatic arthritis Prevent card iac ischem i a in unstable angina and i n patients treated with percutaneous coronary intervention H E R2-overexpressing breast cancer B -cell non-Hodgkin's lymphoma Add itional l ine of treatment for severe asthma HIGH-YIELD PRINCIPLES IN Pathology "Digressions, objections, delight in mockery, carefree mistrust are signs of health; everything unconditional belongs in pathology." -Friedrich Nietzsche The fundamental principles of pathology are key to understanding diseases in all organ systems. Major topics such as inflammation and neoplasia appear frequently in questions across different organ systems, and such topics are definitely high yield. For example, the concepts of cell injury and inflammation are key to understanding the inflammatory response that follows myocardial infarction, a very common subject of board questions. Simi larl y, a familiarity with the early cellular changes that culminate in the development of neoplasias-for example, esophageal or colon cancer- is critical. Finally, make sure you recognize the major tumor-asso c iate d genes and are comfortable with key cancer concepts such as tumor staging and metastasis. 2 1 2 SECTION II PATHOLOGY 􀀤 PATHOLOGY-INFLAMMATION 􀀤 PATHOLOGY-INFLAMMATION Apoptosis Intrinsic pathway Extrinsic pathway Necrosis Programmed cell death; AT P required. Intrinsic or extrinsic pathway; both pathways -+ activation of cytosolic caspases that mediate cellular breakdown. No significant inflammation. Characterized by cell shrinkage, nuclear shrinkage (pyknosis) and basophilia, membrane blebbing, nuclear fragmentation (karyorrhexis), and formation of apoptotic bodies, which are then phagocytosed. Involved in tissue remodeling in embryogenesis. Intrinsic Fas- Occurs when a growth factor is withdrawn from a proliferating cell population (e.g., l IL-2 after a completed immune reaction -+ apoptosis of proliferating effector cells). Also occurs after exposure to injurious stimuli (e.g., radiation, toxins, hypoxia). CD95 (Fas-R) jl · ···· . \􀀁gaod Changes in proportions of anti- and pro-apoptotic factors lead to increased mitochondria permeability and cytochrome c release. 2 pathways: • Ligand receptor interactions (Fas ligand binding to Fas [CD95]). • Immune cell (cytotoxic T-cell release of perforin and granzyme B). Cytosolic caspases aclivated ! + Cellular breakdown Enzymatic degradation and protein denaturation of a cell resulting from exogenous injury. Intracellular components extravasate. Inflammatory process (unlike apoptosis). Types of necrosis: • Coagulative-heart, liver, kidney • Liquefactive-brain, bacterial abscess, pleural effusion • Caseous-TB, systemic fungi • Fatty-peripancreatic fat (saponification via lipase) • Fibrinoid-blood vessels • Gangrenous-dry (ischemic coagulative) or wet (with bacteria); common in limbs and in Gl tract ) Cell injury Ischemia: susceptible areas Infarcts: red vs. pale PATHOLOGY 􀀤 PATHOLOGY-INFLAMMATION SECTION II 2 1 3 REVERSIBLE WITH 0 􀁽 AT P synthesis Cellular swelling (no AT P-+ impaired Na+fK+ pump) Nuclear chromatin clumping 􀁽glycogen Fatty change Ribosomal detachment ( 􀁽 protein synthesis) IRREVERSIBLE Nuclear pyknosis, karyolysis, karyorrhexis Ca2+ influx -+ caspase activation Plasma membrane damage Lysosomal rupture Mitochondrial permeability Areas susceptible to hypoxia and ischemia/infarction: ORGAN Brain Heart Kidney Liver LOCATION ACA/MCA/PCA boundary areasa,b Subendocardium (LV) Straight segment of proximal tubule (medulla) Thick ascending limb (medulla) Area around central vein (zone III) Colon Splenic flexure,3 rectuma 3Watershed areas receive dual blood supply from most distal branches of 2 arteries, which protects these areas from single-vessel focal blockage. However, these areas are susceptible to ischemia from systemic hypoperfusion. bHypoxic ischemic encephalopathy (HIE) affects pyramidal cells of hippocampus and Purkinje cells. Red (hemorrhagic) infarcts occur in loose tissues with collaterals, such as liver, lungs, or intestine, or following reperfusion. Pale infarcts occur in solid tissues with a single blood supply, such as heart, kidney, and spleen. Red = reperfusion. Reperfusion injury is clue to damage by free radicals. Heart Kidney infarcts 2 1 4 SECTION II Shock Atrophy Inflammation Vascular component Cellular component Acute Chronic PATHOLOGY • PATHOLOGY-INFLAMMATION Hypovolemic/cardiogenic Low-output failure t T PR Low cardiac output Cold, clammy patient (vasoconstriction) Septic High-output failure ! T PR Dilated arterioles, high venous return Hot patient (vasodilation) Reduction in the size or number of cells. Causes include: • ! hormones (uterus/vagina) • ! innervation (motor neuron damage) • ! blood flow • ! nutrients • t pressure (nephrolithiasis) • Occlusion of secretory ducts (cystic fibrosis) Characterized by rubor (redness), dolor (pain), calor (heat), tumor (swelling), and functio laesa (loss of function). t vascular permeability, vasodilation, endothelial injury. Neutrophils extravasate from circulation to injured tissue to participate in inflammation through phagocytosis, degranulation, and inflammatory mediator release. Neutrophil, eosinophil, and antibody mediated. Acute inflammation is rapid onset (seconds to minutes), lasts minutes to days. Outcomes include complete resolution, abscess formation, and progression to chronic inflammation. Mononuclear cell mediated: characterized by persistent destruction and repair. Associated with blood vessel proliferation, fibrosis. Granuloma: nodular collections of epithelioid macrophages and giant cells. Outcomes include scarring and amyloidosis. Leukocyte extravasation Free radical injury PATHOLOGY 􀀤 PATHOLOGY-INFLAMMATION SECTION II 2 1 5 Neutrophils exit from blood vessels at sites of tissue injury and inflammation in 4 steps: STEP 0 Rolling @T ight binding E) Diapedesis-leukocyte travels between endothelial cells and exits blood vessel 0 Migration-leukocyte travels through interstitium to site of injury or infection guided by chemotactic signals VASCULATURE/STROMA E-selectin P-selectin ICAM-1 PECAM-1 Bacterial products: C5a, IL-8, L TB4 and Kallikrein ( C ILK) LEUKOCYTE Sialyl-Lewisx LFA-1 ("integrin") PECAM-1 Various 0 Rolling -----. @Tight binding ----+ E) Diapedesis---+ 0 Migration ----+ Phagocytosis Vessel lumen Endothelium Interstitium _.�..._.. ____ Free radicals damage cells via membrane lipid peroxidation, protein modification, and DNA breakage. Initiated via radiation exposure, metabolism of drugs (phase 1), redox reaction, nitric oxide, transition metals, leukocyte oxidative burst. Free radicals can be eliminated by enzymes (catalase, superoxide dismutase, glutathione peroxidase), spontaneous decay, antioxidants (vitamins A, C, E). Pathologies include: • Retinopathy of prematurity Bronchopulmonary dysplasia • Carbon tetrachloride, leading to liver necrosis (fatty change) • Acetaminophen overdose (fulminant hepatitis) • Iron overload (hemochromatosis) Reperfusion after anoxia (e.g., superoxide), especially after thrombolytic therapy 2 1 6 SECTION II PATHOLOGY 􀀤 PATHOLOGY-INFLAMMATION Wound healing PHASE Inflammatory (immediate) Proliferative {2-3 days after wound) Remodeling (1 week after wound) Granulomatous diseases MEDIATORS Platelets, neutrophils, macrophages Fibroblasts, myofibroblasts, endothelial cells, keratinocytes, macrophages Fibroblasts Mycobacterium tuberculosis Fungal infections (e.g., histoplasmosis), coccidioidomycosis) Treponema pallidum (syphilis) M. leprae (leprosy) Bartonella henselae (cat scratch disease) Sarcoidosis Crohn's disease Granulomatosis with polyangiitis (Wegener's) Churg-Strauss syndrome Berylliosis, silicosis Transudate vs. exudate Transudate Hypocellular Protein poor Specific gravity< 1 .01 2 Due to: • t hydrostatic pressure • ! oncotic pressure • a+ retention CHARACTERISTICS Clot formation, t vessel permeability and neutrophil migration into tissue; macrophages clear debris 2 days later Deposition of granulation tissue and collagen, angiogenesis, epithelial cell proliferation, dissolution of clot, and wound contraction (mediated by myofibroblasts) 1ype III collagen replaced by type I collagen, t tensile strength of tissue Th1 cells secrete y-interferon, activating macrophages. TNF-a from macrophages induce and maintain granuloma formation. Anti-TNF drugs can, as a side effect, cause sequestering granulomas to breakdown, leading to disseminated disease. Exudate Cellular Protein rich Specific gravity> 1 .020 Due to: • Lymphatic obstruction • Inflammation Erythrocyte sedimentation rate Iron poisoning MECHANISM SYMPTOMS Amyloidosis COMMON TYPES AL (primary) AA (secondary) Dialysis-related Heritable Age-related (senile) systemic Organ-specific PATHOLOGY • PATHOLOGY-INFLAMMATION SECTION II 2 1 7 Products of inflammation (e.g., fibrinogen) coat RBCs and cause aggregation. When aggregated, RBCs fall at a faster rate within the test tube. t ESR Infections Inflammation (e.g., temporal arteritis) Cancer Pregnancy SLE 􀁽 ESR Sickle cell (altered shape) Polycythemia (too many) CHF (unknown) One of the leading causes of fatality from toxicologic agents in children. Cell death due to peroxidation of membrane lipids. Acute-gastric bleeding. Chronic-metabolic acidosis, scarring leading to GI obstruction. Abnormal aggregation of proteins or their fragments into 􀂔-pleated sheet structures, leading to cell damage and apoptosis (J. Affected tissue has waxy appearance. DESCRIPTION Amyloidosis. Note the apple-green birefringence (Congo red sta1n) of the amyloid deposits 1n the artery wall.􀁜 Due to deposition of proteins from Ig Light chains. Can occur as a plasma cell disorder or associated with multiple myeloma. Often multiple organ sytem impact, including renal (nephrotic syndrome), cardiac (heart failure, arrhythmia), hematologic (easy bruising), hepatomegaly, and neuropathy. S een with chronic diseases like RA, IBD, spondyloarthropathy, chronic infections. Fibrils composed of serum Amyloid A. Often multisystem like AL amyloidosis. Fibrils composed of 􀂔rmicroglobulin in patients with ESRD and long-term dialysis. Often presents as carpal tunnel syndrome and other joint issues. Heterogeneous group of disorders. Example is AT TR neurologic/cardiac amyloidosis due to transthyretin (TTR or prealbumin) gene mutation. Due to deposition of normal (wild-type) TTR in myocardium and other sites. Slower progression of cardiac dysfunction vs. AL amyloidosis. Amyloid deposition localized to a single organ. Most important form is amyloidosis in Alzheimer's disease due to deposition of amyloid-􀂔 protein cleaved from amyloid precursor protein (APP). 2 1 8 SECTION II PATHOLOGY 􀀤 PATHOLOGY-NEOPLASIA 􀀤 PATHOLOGY-NEOPLASIA Neoplastic progression Hallmarks of cancer-evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, sustained angiogenesis, limitless replicative potential, tissue invasion, and metastasis. Normal 􀀢 i(OJ[QJ[Q)I$[Q) fE][QJLQ)[Qj[£) 􀀃􀀄0 􀀉 0 0 Q 0 0􀀃 0 Carcinoma in situ/ preinvasive 􀀢 Invasive carcinoma 􀀢 membrane Blood or lymphatic vessel • Normal cells with basal 􀀒 apical differentiation • Cells have increased in number-hyperplasia • Abnormal proliferation of cells with loss of size, shape, and orientation-dysplasia Carcinoma in situ • Neoplastic cells have not invaded basement membrane • High nuclear/cytoplasmic ratio and clumped chromatin • Neoplastic cells encompass entire thickness • Cells have invaded basement membrane using collagenases and hydrolases (metalloproteinases) • Can metastasize if they reach a blood or lymphatic vessel Metastasis-spread to distant organ • Must survive immune attack • "Seed and soil" theory of metastasis • Seed =tumor embolus • Soil =target organ---jiver, lungs, bone, brain, etc. -plasia definitions REVERSIBLE Hyperplasia Metaplasia Dysplasia IRREVERSIBLE Anaplasia Neoplasia Desmoplasia Tumor grade vs. stage Grade Stage Tumor nomenclature CELL TYPE Epithelium Mesenchyme Blood cells Blood vessels Smooth muscle Striated muscle Connective tissue Bone PATHOLOGY 􀀤 PATHOLOGY-NEOPLASIA SECTION II 2 1 9 t in number of cells. One adult cell type is replaced by another. Often zo to irritation and/or environmental exposure (e.g., squamous metaplasia in trachea and branch i of smokers). Abnormal growth with loss of cellular orientation, shape, and size in comparison to normal tissue maturation; commonly preneoplastic. Abnormal cells lacking differentiation; resemble primitive cells of same tissue, often equated with undifferentiated malignant neoplasms. Little or no resemblance to tissue of origin. A clonal proliferation of cells that is uncontrolled and excessive. Neoplasia may be benign or malignant. Fibrous tissue formation in response to neoplasm. Degree of cellular differentiation based on histologic appearance of individual tumor. Usually graded l-4; l = low grade, well differentiated to 4 =high grade, poorly differentiated, anaplastic. Degree of localization/spread based on site and size of l o lesion, spread to regional lymph nodes, presence of metastases; spread of tumor in a specific patient. Based on clinical (c) or pathology (p) findings. Example: cT 3NlMO BENIGN Adenoma, papilloma Hemangioma Leiomyoma Rhabdomyoma Fibroma Osteoma Stage usually has more prognostic value than grade. TNM staging system (Stage= Spread): T =Tumor size N =Node involvement M =Metastases (important prognostic factor) MALIGNANT" Adenocarcinoma, papillary carcinoma Leukemia, lymphoma Angiosarcoma Leiomyosarcoma Rhabdomyosarcoma Fibrosarcoma Osteosarcoma Fat Lipoma Liposarcoma "The term carcinoma implies epithelial origin, whereas sarcoma denotes mesenchymal origin. Both terms imply malignancy. 2 20 SECTION II Tumor differences Benign Malignant Cachexia Disease conditions associated with neoplasms PATHOLOGY 􀀤 PATHOLOGY-NEOPLASIA Usually well differentiated, slow growing, well demarcated, no metastasis. May be poorly differentiated, erratic growth, locally invasive/diffuse, may metastasize. Weight loss, muscle atrophy, and fatigue that occur in chronic disease (e.g., cancer, AIDS, heart failure, tuberculosis). Mediated by TNF-a (nicknamed cachectin), IFN-y, and IL-6. CONDITION Down syndrome Xeroderma pigmentosum, albinism Chronic atrophic gastritis, pernicious anemia, postsurgical gastric remnants Tuberous sclerosis (facial angiofibroma, seizures, mental retardation) Actinic keratosis Barrett's esophagus (chronic GI reflux) Plummer-Vinson syndrome (l iron) Cirrhosis (alcoholic, hepatitis B or C) Ulcerative colitis Paget's disease of bone Immunodeficiency states AIDS Autoimmune diseases (e.g., Hashimoto's thyroiditis, myasthenia gravis) Acanthosis n igricans (hyperpigmentation and epidermal thickening) Dysplastic nevus Radiation exposure NEOPLASM ALL ("we ALL fall Down"), AML Melanoma, basal cell carcinoma, and especially squamous cell carcinomas of skin Gastric adenocarcinoma Giant cell astrocytoma, renal angiomyolipoma, and cardiac rhabdomyoma S quamous cell carcinoma of skin Esophageal adenocarcinoma S quamous cell carcinoma of esophagus Hepatocellular carcinoma Colonic adenocarcinoma zo osteosarcoma and fibrosarcoma Malignant lymphomas Aggressive malignant lymphomas (nonI- Iodgkin's) and Kaposi's sarcoma Lymphoma Visceral malignancy (stomach, lung, uterus) Malignant melanoma Leukemia, sarcoma, papillary thyroid cancer, and breast cancer. Oncogenes GENE obi c-myc bc/-2 HER2/neu (c-erb82) ros L-myc N-myc ret c-kit Tumor suppressor genes GENE Rb p5l BRCAI BRCA2 p16 BRAF APC WTI NFI NF2 DPC4 DCC PATHOLOGY 􀀤 PATHOLOGY-NEOPLASIA SECTION II 2 2 1 Gain of function -+ t cancer risk. Need damage to only l allele. ASSOCIATED TUMOR GENE PRODUCT CML Burkitt's lymphoma Follicular and undifferentiated lymphomas (inhibits apoptosis) Breast, ovarian, and gastric carcinomas Colon carcinoma Lung tumor Neuroblastoma Multiple endocrine neoplasia (MEN) types 2A and 2B Gastrointestinal stromal tumor (GIS T ) Tyrosine kinase Transcription factor Anti-apoptotic molecule Tyrosine kinase GTPase Transcription factor Transcription factor Tyrosine kinase Cytokine receptor Loss of function -+ t cancer risk; both alleles must be lost for expression of disease. ASSOCIATED TUMOR Retinoblastoma, osteosarcoma Most human cancers, Li-Fraumeni syndrome Breast and ovarian cancer Breast and ovarian cancer Melanoma Melanoma Colorectal cancer (associated with FAP) Wilms' Tumor (nephroblastoma) NeuroFibromatosis type l NeuroFibromatosis type 2 Pancreatic cancer Colon cancer GENE PRODUCT Inhibits E2F; blocks Gl -+ S phase Transcription factor for p2l, blocks Gl -+ S phase DNA repair protein DNA repair protein B-raf RAS GT Pase activating protein (RAS -GAP) Merlin (schwannomin) protein DPC-Deleted in Pancreatic Cancer DCC-Deleted in Colon Cancer 2 2 2 SECTION II Tumor markers PSA Prostatic acid phosphatase CEA a-fetoprotein 􀀽-hCG PATHOLOGY • PATHOLOGY-NEOPLASIA Prostate-specific antigen. Used to follow prostate carcinoma. Can also be elevated in BPH and prostatitis. Questionable risk/benefit for screening. Prostate carcinoma. CarcinoEmbryonic Antigen. Very nonspecific but produced by- 70% of colorectal and pancreatic cancers; also produced by gastric, breast, and medullary thyroid carcinomas. Normally made by fetus. Hepatocellular carcinomas. Nonseminomatous germ cell tumors (e.g., testis, ovary). Hydatidiform moles and Choriocarcinomas (Gestational trophoblastic disease). CA-125 Ovarian cancer. S-100 Melanoma, neural tumors, schwannomas. Alkaline phosphatase Metastases to bone, liver, Paget's disease of Bombesin T RAP CA-19-9 Calcitonin Oncogenic microbes bone. Neuroblastoma, lung and gastric cancer. Tartrate-Resistant Acid Phosphatase (TRAP). Hairy cell leukemia-a B-cell neoplasm. Pancreatic adenocarcinoma. Medullary thyroid carcinoma. Microbe HTLV-1 HBV, HCV EBV HPV HHV-8 ( Kaposi's sarcoma-associated herpesvirus) H. pylori Schistosoma haematobium Liver fluke (Clonorchis sinensis) Tumor markers should not be used as the 1 o tool for cancer diagnosis. They may be used to confirm diagnosis, to monitor for tumor recurrence, and to monitor response to therapy. hCG is commonly associated with pregnancy. TRAP the hairy animal. Associated cancer Adult T-cell leu kem ia/lymphoma Hepatocellular carcinoma Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal carcinoma, CNS lymphoma (in immunocompromised patients) Cervical carcinoma (16, 18), penile/anal carcinoma, upper respiratory sec Kaposi's sarcoma, body cavity Auicl B-cell lymphoma Gastric adenocarcinoma and lymphoma Bladder cancer (squamous cell) Cholangiocarcinoma PATHOLOGY 􀀣 PATHOLOGY-NEOPLASIA SECTION II 2 2 3 Chemical carcinogens TOXIN ORGAN Aflatoxins (Aspergillus) Liver Vinyl chloride Liver Carbon tetrachloride Liver Nitrosamines (smoked Stomach foods) Cigarette smoke Larynx Lung Kidney Bladder Pancreas Asbestos Lung Arsenic Skin Liver Naphthalene (aniline) Bladder dyes Alkylating agents Blood Paraneoplastic syndromes HORMONE/AGENT EFFECT ACTH or ACTH-Iike Cushing's syndrome peptide ADH PTHrP 1 ,25-(0H)2 D3 ( calcitriol) Erythropoietin Antibodies against presynaptic Ca2+ channels at NMJ Psammoma bodies SIADI-I Hypercalcemia Hypercalcemia Polycythemia Lambert-Eaton syndrome (muscle weakness) Laminated, concentric, calcific spherules seen 111: • Papillary adenocarcinoma of thyroid • S erous papillary cystadenocarcinoma of ovary • Meningioma • Malignant mesothelioma IMPACT Hepatocellular carcinoma Angiosarcoma Centrilobular necrosis, fatty change Gastric cancer Squamous cell carcinoma Squamous cell and small cell carcinoma Renal cell carcinoma Transitional cell carcinoma Pancreatic adenocarcinoma Bronchogenic carcinoma> mesothelioma Squamous cell carcinoma Angiosarcoma Transitional cell carcinoma Leukemia NEOPLASM($) Small cell lung carcinoma Small cell lung carcinoma and intracranial neoplasms Squamous cell lung carcinoma, renal cell carcinoma, breast cancer Hodgkin's lymphoma, some non-Hodgkin's lymphomas Renal cell carcinoma, hemangioblastoma, hepatocellular carcinoma, pheochromocytoma Small cell lung carcinoma PSaMMoma: Papillary (thyroid) Serous (ovary) Meningioma Mesothelioma 2 2 4 SECTION II Cancer epidemiology Incidence Mortality Common metastases SITE OF METASTASIS Brain Liver Bone PATHOLOGY 􀀤 PATHOLOGY-NEOPLASIA MALE Prostate (32%) Lung (16%) Colon/rectum (12%) Lung (33%) Prostate (13%) l0TUMOR FEMALE Breast (32%) Lung (13%) Colon/rectum (13%) Lung (23%) Breast (18%) Lung> breast> genitourinary> osteosarcoma > melanoma > GI. Colon >> stomach > pancreas. Prostate, breast> lung> thyroid, testes. NOTES Lung cancer incidence has dropped in men, but has not changed significantly in women Cancer is the 2nd leading cause of death in the United States (heart disease is lst) NOTES 50% of brain tumors are from metastases. Typically multiple well-circumscribed tumors at gray/white matter junction. Liver and lung are the most common sites of metastasis after the regional lymph nodes. Bone metastasis>> primary bone tumors. Whole-body bone scan shows tumor predilection for axial skeleton. Lung = lytic. Prostate = blastic. Breast= lytic and blastic. HIGH-YIELD PRINCIPLES IN Pharmacology "Take me, I am the drug; take me, I am hallucinogenic." - Salvador Dal i "I was under medication when I made the decision not to bum the tapes." -Richard Nixon "I wondher why ye can always read a doctor's bill an' ye niver can read his fntrscription." - Finley Peter Dunne "Once you get locked into a serious drug collection, the tendency is to push it as far as you can." -Hunter S. Thompson Preparation for questions on pharmacology is straightforward. Memorizing all the key drugs and their characteristics (e.g., mechanisms, clinical use, and important side effects) is high yield. Focus on understanding the prototype drugs in each class. Avoid memorizing obscure derivatives. Learn the "classic" and distinguishing toxicities of the major drugs. Specific drug dosages or trade names are generally not testable. Reviewing associated biochemistry, physiology, and microbiology can be useful while studying pharmacology. There is a strong emphasis on ANS, CNS, antimicrobial, and cardiovascular agents as well as on NSAIDs. Much of the material is clinically relevant. Newer drugs on the market are also fair game. 2 2 6 SECTION II PHARMACOLOGY 􀂃 PHARMACOLOGY-PHARMACOKINETICS & PHARMACODYNAMICS 􀂄 PHARMACOLOGY-PHARMACOKINETICS & PHARMACODYNAMICS Enzyme kinetics Michaelis-Menten kinetics lineweaver-Burk plot Enzyme inhibition [ S] = concentration of substrate; V = velocity. 1 􀀬\ 1 [S] 1 TSi Resemble substrate Overcome by t [S] Bind active site Effect on V max Effect on Km Pharmacodynamics Kill is inversely related to the affinity of the enzyme for its substrate. vlllax is directly proportional to the enzyme concentration. Most enzymatic reactions follow a hyperbolic curve (follow Michaelis-Menten kinetics); however, enzymatic reactions that follow cooperative kinetics (i.e., hemoglobin) have a sigmoid curve. t y-intercept, ! vlllax· The further to the right the x-intercept, the greater the Kill and the lower the affinity. Competitive inhibitors cross each other competitively, whereas noncompetitive inhibitors do not. COMPETITIVE NONCOMPETITIVE INHIBITORS INHIBITORS Yes No Yes No Yes No Unchanged Unchanged ! potency ! efficacy I PHARMACOLOGY 􀂂 PHARMACOLOGY-PHARMACOKINETICS & PHARMACODYNAMICS SECTION II 2 2 7 Pharmacokinetics Bioavailability (F) Volume of distribution (Vd) Half-life (t112) Clearance (CL) Dosage calculations Fraction of administered drug that reaches systemic circulation unchanged. For an I V dose, F = 100%. Orally: F typically <100 class="" data-blogger-escaped---------------------="" data-blogger-escaped-----="" data-blogger-escaped----="" data-blogger-escaped---="" data-blogger-escaped--="" data-blogger-escaped--i="" data-blogger-escaped-.....-="" data-blogger-escaped-......--="" data-blogger-escaped-....="" data-blogger-escaped-0.1="" data-blogger-escaped-0:::="" data-blogger-escaped-0="" data-blogger-escaped-0c="" data-blogger-escaped-0e="" data-blogger-escaped-1.0="" data-blogger-escaped-1.i="" data-blogger-escaped-1000="" data-blogger-escaped-100="" data-blogger-escaped-10="" data-blogger-escaped-12.5="" data-blogger-escaped-125="" data-blogger-escaped-13.="" data-blogger-escaped-14.="" data-blogger-escaped-1997:="" data-blogger-escaped-1998:="" data-blogger-escaped-1="" data-blogger-escaped-2.5="" data-blogger-escaped-2007:="" data-blogger-escaped-2008:="" data-blogger-escaped-229="" data-blogger-escaped-230="" data-blogger-escaped-232="" data-blogger-escaped-233="" data-blogger-escaped-23="" data-blogger-escaped-25="" data-blogger-escaped-2="" data-blogger-escaped-2nd="" data-blogger-escaped-3="" data-blogger-escaped-4-5="" data-blogger-escaped-42.="" data-blogger-escaped-4="" data-blogger-escaped-5.="" data-blogger-escaped-50="" data-blogger-escaped-5="" data-blogger-escaped-5th="" data-blogger-escaped-6.25="" data-blogger-escaped-6="" data-blogger-escaped-76.="" data-blogger-escaped-7th="" data-blogger-escaped-8="" data-blogger-escaped-8th="" data-blogger-escaped-:-4="" data-blogger-escaped-:="" data-blogger-escaped-:j="" data-blogger-escaped-_="" data-blogger-escaped-__="" data-blogger-escaped-a-methyldopa="" data-blogger-escaped-a-receptors.="" data-blogger-escaped-a.="" data-blogger-escaped-a1-mediated="" data-blogger-escaped-a1="" data-blogger-escaped-a2-autoreceptors="" data-blogger-escaped-a2="" data-blogger-escaped-a="" data-blogger-escaped-absorbed="" data-blogger-escaped-absorption="" data-blogger-escaped-accommodation="" data-blogger-escaped-acetylation="" data-blogger-escaped-acetylators="" data-blogger-escaped-acetylcholine.="" data-blogger-escaped-ach.="" data-blogger-escaped-ach="" data-blogger-escaped-ache.="" data-blogger-escaped-ache="" data-blogger-escaped-acid="" data-blogger-escaped-acidic="" data-blogger-escaped-acids="" data-blogger-escaped-act="" data-blogger-escaped-acting="" data-blogger-escaped-action="" data-blogger-escaped-activate="" data-blogger-escaped-activates="" data-blogger-escaped-activation="" data-blogger-escaped-active="" data-blogger-escaped-activity.="" data-blogger-escaped-acts="" data-blogger-escaped-acute="" data-blogger-escaped-adapted="" data-blogger-escaped-adenylyl="" data-blogger-escaped-adrenal="" data-blogger-escaped-affinity="" data-blogger-escaped-agents="" data-blogger-escaped-aggregation="" data-blogger-escaped-agonist="" data-blogger-escaped-agonists.="" data-blogger-escaped-agonists="" data-blogger-escaped-airway="" data-blogger-escaped-aj.="" data-blogger-escaped-aj="" data-blogger-escaped-al.="" data-blogger-escaped-albuterol="" data-blogger-escaped-alkaloids="" data-blogger-escaped-all="" data-blogger-escaped-alone="" data-blogger-escaped-altered="" data-blogger-escaped-alzheimer="" data-blogger-escaped-ammonium="" data-blogger-escaped-amount="" data-blogger-escaped-amphetamine="" data-blogger-escaped-amphetamines.="" data-blogger-escaped-an="" data-blogger-escaped-analgesic="" data-blogger-escaped-anaphylaxis="" data-blogger-escaped-and="" data-blogger-escaped-anesthesia="" data-blogger-escaped-angiotensin="" data-blogger-escaped-angle-closure="" data-blogger-escaped-angle="" data-blogger-escaped-antagonist.="" data-blogger-escaped-antagonist="" data-blogger-escaped-antagonists="" data-blogger-escaped-antibiotics="" data-blogger-escaped-anticholinergic="" data-blogger-escaped-anticholinesterases="" data-blogger-escaped-antidote-atropine="" data-blogger-escaped-antihistamines="" data-blogger-escaped-antihypertensive="" data-blogger-escaped-antilipicl="" data-blogger-escaped-appleton="" data-blogger-escaped-applications.="" data-blogger-escaped-applications="" data-blogger-escaped-aqueous="" data-blogger-escaped-are="" data-blogger-escaped-ark="" data-blogger-escaped-arrows="" data-blogger-escaped-arterial="" data-blogger-escaped-as="" data-blogger-escaped-aspirin.="" data-blogger-escaped-aspirin="" data-blogger-escaped-asthma="" data-blogger-escaped-at="" data-blogger-escaped-ati="" data-blogger-escaped-atp="" data-blogger-escaped-atria="" data-blogger-escaped-atropine="" data-blogger-escaped-attention="" data-blogger-escaped-atura="" data-blogger-escaped-aumazenil="" data-blogger-escaped-autonomic="" data-blogger-escaped-b="" data-blogger-escaped-barrier="" data-blogger-escaped-bases="" data-blogger-escaped-basic="" data-blogger-escaped-bat="" data-blogger-escaped-be="" data-blogger-escaped-because="" data-blogger-escaped-beet="" data-blogger-escaped-benz="" data-blogger-escaped-benztropine="" data-blogger-escaped-bethanechol="" data-blogger-escaped-bg.="" data-blogger-escaped-bg="" data-blogger-escaped-bicarbonate.="" data-blogger-escaped-binding="" data-blogger-escaped-bladder.="" data-blogger-escaped-bladder="" data-blogger-escaped-blind="" data-blogger-escaped-blockade="" data-blogger-escaped-blockers="" data-blogger-escaped-blocks="" data-blogger-escaped-blood-brain="" data-blogger-escaped-blood="" data-blogger-escaped-board="" data-blogger-escaped-body="" data-blogger-escaped-bone="" data-blogger-escaped-boord="" data-blogger-escaped-botulinum="" data-blogger-escaped-bound="" data-blogger-escaped-bowel="" data-blogger-escaped-bowels="" data-blogger-escaped-braclyarrhythmias="" data-blogger-escaped-bradycardia.="" data-blogger-escaped-bradycardia="" data-blogger-escaped-brain="" data-blogger-escaped-breathe="" data-blogger-escaped-bronchial="" data-blogger-escaped-bronchioles="" data-blogger-escaped-bronchoconstriction="" data-blogger-escaped-bronchodilation="" data-blogger-escaped-bronchospasm="" data-blogger-escaped-buprenorphine="" data-blogger-escaped-but="" data-blogger-escaped-by="" data-blogger-escaped-c="" data-blogger-escaped-call="" data-blogger-escaped-camp------="" data-blogger-escaped-can="" data-blogger-escaped-cancer="" data-blogger-escaped-cannot="" data-blogger-escaped-capacity-limited="" data-blogger-escaped-carbachol="" data-blogger-escaped-carbon="" data-blogger-escaped-cardiac="" data-blogger-escaped-catecholamines="" data-blogger-escaped-cause="" data-blogger-escaped-causes="" data-blogger-escaped-cells="" data-blogger-escaped-central="" data-blogger-escaped-certain="" data-blogger-escaped-challenge="" data-blogger-escaped-change="" data-blogger-escaped-channels="" data-blogger-escaped-charged="" data-blogger-escaped-chemotherapeutic="" data-blogger-escaped-chloride.="" data-blogger-escaped-cholesterol="" data-blogger-escaped-cholinergic="" data-blogger-escaped-cholinesterase="" data-blogger-escaped-cholinomimetic="" data-blogger-escaped-chronotropic="" data-blogger-escaped-ciliary="" data-blogger-escaped-circles="" data-blogger-escaped-cl="" data-blogger-escaped-classes="" data-blogger-escaped-clearance="" data-blogger-escaped-cleared="" data-blogger-escaped-clinical="" data-blogger-escaped-clonidine="" data-blogger-escaped-close.="" data-blogger-escaped-close="" data-blogger-escaped-closed-angle="" data-blogger-escaped-closing="" data-blogger-escaped-clown="" data-blogger-escaped-clue="" data-blogger-escaped-cns="" data-blogger-escaped-cocaine="" data-blogger-escaped-collecting="" data-blogger-escaped-competitive="" data-blogger-escaped-components="" data-blogger-escaped-concentration.="" data-blogger-escaped-concentration="" data-blogger-escaped-concentrations="" data-blogger-escaped-conjugation="" data-blogger-escaped-constant="" data-blogger-escaped-constipation="" data-blogger-escaped-contractility="" data-blogger-escaped-contraction="" data-blogger-escaped-contractions="" data-blogger-escaped-contracts="" data-blogger-escaped-control="" data-blogger-escaped-cop="" data-blogger-escaped-copd="" data-blogger-escaped-copy="" data-blogger-escaped-cord="" data-blogger-escaped-cp="" data-blogger-escaped-cr="" data-blogger-escaped-crosses="" data-blogger-escaped-cry="" data-blogger-escaped-ct:="" data-blogger-escaped-curve="" data-blogger-escaped-cyclase="" data-blogger-escaped-cycloplegia="" data-blogger-escaped-cystitis="" data-blogger-escaped-cytochrome="" data-blogger-escaped-d50.="" data-blogger-escaped-d50="" data-blogger-escaped-d="" data-blogger-escaped-dag="" data-blogger-escaped-dapted="" data-blogger-escaped-de="" data-blogger-escaped-decongestant="" data-blogger-escaped-decongestants.="" data-blogger-escaped-decongestion="" data-blogger-escaped-decreases="" data-blogger-escaped-defects="" data-blogger-escaped-deficit="" data-blogger-escaped-depends="" data-blogger-escaped-diagnosis="" data-blogger-escaped-diarrhea="" data-blogger-escaped-diastolic="" data-blogger-escaped-diazepam="" data-blogger-escaped-different="" data-blogger-escaped-digoxin="" data-blogger-escaped-dilation="" data-blogger-escaped-dilator="" data-blogger-escaped-direct="" data-blogger-escaped-directly="" data-blogger-escaped-disease-="" data-blogger-escaped-disease="" data-blogger-escaped-disorder="" data-blogger-escaped-disorientation="" data-blogger-escaped-distribution="" data-blogger-escaped-dl="" data-blogger-escaped-dobutamine="" data-blogger-escaped-does="" data-blogger-escaped-donepezil="" data-blogger-escaped-dopamine="" data-blogger-escaped-dose="" data-blogger-escaped-drool="" data-blogger-escaped-drooling="" data-blogger-escaped-drug="" data-blogger-escaped-drugs-phenytoin="" data-blogger-escaped-drugs.="" data-blogger-escaped-drugs="" data-blogger-escaped-dry="" data-blogger-escaped-dso="" data-blogger-escaped-du="" data-blogger-escaped-due="" data-blogger-escaped-dumbbelss.="" data-blogger-escaped-during="" data-blogger-escaped-e.g.="" data-blogger-escaped-e="" data-blogger-escaped-ecf="" data-blogger-escaped-ed.="" data-blogger-escaped-edrophonium="" data-blogger-escaped-edso="" data-blogger-escaped-effect.="" data-blogger-escaped-effect="" data-blogger-escaped-effective="" data-blogger-escaped-effects:="" data-blogger-escaped-effects="" data-blogger-escaped-efficacy.="" data-blogger-escaped-efficacy="" data-blogger-escaped-el="" data-blogger-escaped-elderly="" data-blogger-escaped-eliminated="" data-blogger-escaped-elimination.="" data-blogger-escaped-elimination="" data-blogger-escaped-ell="" data-blogger-escaped-ending="" data-blogger-escaped-endogenous="" data-blogger-escaped-enteric="" data-blogger-escaped-environments.="" data-blogger-escaped-ephedrine="" data-blogger-escaped-epinephrine="" data-blogger-escaped-ero-ord="" data-blogger-escaped-especially="" data-blogger-escaped-et="" data-blogger-escaped-ethanol="" data-blogger-escaped-ethany="" data-blogger-escaped-exacerbation="" data-blogger-escaped-examination="" data-blogger-escaped-example:="" data-blogger-escaped-example="" data-blogger-escaped-examples:="" data-blogger-escaped-examples="" data-blogger-escaped-excitation="" data-blogger-escaped-excreted="" data-blogger-escaped-exocrine="" data-blogger-escaped-exponentially="" data-blogger-escaped-extreme="" data-blogger-escaped-extremely="" data-blogger-escaped-eye="" data-blogger-escaped-f.="" data-blogger-escaped-f="" data-blogger-escaped-failure="" data-blogger-escaped-farmers.="" data-blogger-escaped-fibers.="" data-blogger-escaped-figure="" data-blogger-escaped-first-order="" data-blogger-escaped-first-pass="" data-blogger-escaped-first.="" data-blogger-escaped-fluid="" data-blogger-escaped-flushed="" data-blogger-escaped-for="" data-blogger-escaped-forms="" data-blogger-escaped-found="" data-blogger-escaped-fraction="" data-blogger-escaped-frequency="" data-blogger-escaped-from="" data-blogger-escaped-full="" data-blogger-escaped-function.="" data-blogger-escaped-functions="" data-blogger-escaped-g-protein-coupled="" data-blogger-escaped-g-protein-linked="" data-blogger-escaped-g-protein="" data-blogger-escaped-g="" data-blogger-escaped-gaba="" data-blogger-escaped-ganglia="" data-blogger-escaped-gardener="" data-blogger-escaped-gas="" data-blogger-escaped-gastric="" data-blogger-escaped-gastrointestinal="" data-blogger-escaped-general="" data-blogger-escaped-genitourinary="" data-blogger-escaped-geriatric="" data-blogger-escaped-gets="" data-blogger-escaped-give="" data-blogger-escaped-given="" data-blogger-escaped-giving="" data-blogger-escaped-gland="" data-blogger-escaped-glands="" data-blogger-escaped-glaucoma="" data-blogger-escaped-glycopyrrolate="" data-blogger-escaped-gq="" data-blogger-escaped-gravis.="" data-blogger-escaped-gravis="" data-blogger-escaped-greater="" data-blogger-escaped-gut="" data-blogger-escaped-h20="" data-blogger-escaped-h="" data-blogger-escaped-half-lives="" data-blogger-escaped-hare="" data-blogger-escaped-has="" data-blogger-escaped-hatter="" data-blogger-escaped-have="" data-blogger-escaped-heart="" data-blogger-escaped-hepatic="" data-blogger-escaped-high-efficacy="" data-blogger-escaped-high="" data-blogger-escaped-higher="" data-blogger-escaped-highly="" data-blogger-escaped-histamine="" data-blogger-escaped-hl="" data-blogger-escaped-homatropine="" data-blogger-escaped-hot="" data-blogger-escaped-however="" data-blogger-escaped-humor="" data-blogger-escaped-hydrolysis="" data-blogger-escaped-hydrophilic="" data-blogger-escaped-hyperplasia="" data-blogger-escaped-hypertension="" data-blogger-escaped-hyperthermia="" data-blogger-escaped-hypotension="" data-blogger-escaped-i-i="" data-blogger-escaped-i.e.="" data-blogger-escaped-i="" data-blogger-escaped-if="" data-blogger-escaped-ii="" data-blogger-escaped-ileus="" data-blogger-escaped-image="" data-blogger-escaped-impaired="" data-blogger-escaped-in="" data-blogger-escaped-inactive="" data-blogger-escaped-include="" data-blogger-escaped-incomplete="" data-blogger-escaped-incontinence="" data-blogger-escaped-increase="" data-blogger-escaped-increasing="" data-blogger-escaped-independent="" data-blogger-escaped-index="L" data-blogger-escaped-indirect="" data-blogger-escaped-infants="" data-blogger-escaped-infused="" data-blogger-escaped-infusion="" data-blogger-escaped-inhaled.="" data-blogger-escaped-inhibit="" data-blogger-escaped-inhibitor="" data-blogger-escaped-innervated="" data-blogger-escaped-inotropic="" data-blogger-escaped-insecticides="" data-blogger-escaped-insulin="" data-blogger-escaped-interval="" data-blogger-escaped-intestinal="" data-blogger-escaped-intoxication="" data-blogger-escaped-intraocular="" data-blogger-escaped-ionized="" data-blogger-escaped-ip3="" data-blogger-escaped-irreversibly="" data-blogger-escaped-is="" data-blogger-escaped-ischemia="" data-blogger-escaped-isoproterenol="" data-blogger-escaped-iss="" data-blogger-escaped-itself="" data-blogger-escaped-jimson="" data-blogger-escaped-junction="" data-blogger-escaped-k="" data-blogger-escaped-katzung="" data-blogger-escaped-kick="" data-blogger-escaped-kidney="" data-blogger-escaped-kidneys="" data-blogger-escaped-kinase="" data-blogger-escaped-kiss="" data-blogger-escaped-l="" data-blogger-escaped-lacrimal="" data-blogger-escaped-lacrimation="" data-blogger-escaped-lange="" data-blogger-escaped-large="" data-blogger-escaped-lead="" data-blogger-escaped-less="" data-blogger-escaped-lethal="" data-blogger-escaped-ligand-gated="" data-blogger-escaped-light-chain="" data-blogger-escaped-like="" data-blogger-escaped-linearly="" data-blogger-escaped-lipid="" data-blogger-escaped-lipids="" data-blogger-escaped-lipolysis="" data-blogger-escaped-lipophilic="" data-blogger-escaped-lithium="" data-blogger-escaped-little="" data-blogger-escaped-liver="" data-blogger-escaped-lnd="" data-blogger-escaped-loading="" data-blogger-escaped-local="" data-blogger-escaped-log="" data-blogger-escaped-long-term="" data-blogger-escaped-long="" data-blogger-escaped-lose="" data-blogger-escaped-loth="" data-blogger-escaped-low-dependent="" data-blogger-escaped-low="" data-blogger-escaped-lpratropium="" data-blogger-escaped-lucuronidation="" data-blogger-escaped-m1="" data-blogger-escaped-m2="" data-blogger-escaped-m3="" data-blogger-escaped-m4="" data-blogger-escaped-m5.="" data-blogger-escaped-m="" data-blogger-escaped-mad="" data-blogger-escaped-mage="" data-blogger-escaped-maintain="" data-blogger-escaped-maintenance="" data-blogger-escaped-major="" data-blogger-escaped-maximal="" data-blogger-escaped-may="" data-blogger-escaped-maybe="" data-blogger-escaped-mbbelss.="" data-blogger-escaped-mcgraw-hill="" data-blogger-escaped-me="" data-blogger-escaped-mean="" data-blogger-escaped-measure="" data-blogger-escaped-measurement="" data-blogger-escaped-median="" data-blogger-escaped-mediated="" data-blogger-escaped-medications="" data-blogger-escaped-medium="" data-blogger-escaped-medulla="" data-blogger-escaped-men="" data-blogger-escaped-messengers="" data-blogger-escaped-metabolism.="" data-blogger-escaped-metabolism="" data-blogger-escaped-metabolites="" data-blogger-escaped-metaproterenol="" data-blogger-escaped-methacholine="" data-blogger-escaped-methotrexate="" data-blogger-escaped-mild="" data-blogger-escaped-minimum="" data-blogger-escaped-miosis="" data-blogger-escaped-ml="" data-blogger-escaped-mm="" data-blogger-escaped-modulated="" data-blogger-escaped-modulates="" data-blogger-escaped-molecules="" data-blogger-escaped-mooth="" data-blogger-escaped-morphine="" data-blogger-escaped-motility="" data-blogger-escaped-motion="" data-blogger-escaped-motor="" data-blogger-escaped-mouth="" data-blogger-escaped-mucus="" data-blogger-escaped-muscarinic="" data-blogger-escaped-muscle="" data-blogger-escaped-my="" data-blogger-escaped-myasthenia="" data-blogger-escaped-mydriasis="" data-blogger-escaped-mydriatic="" data-blogger-escaped-myosin="" data-blogger-escaped-n="" data-blogger-escaped-na="" data-blogger-escaped-narcolepsy="" data-blogger-escaped-nasal="" data-blogger-escaped-ne="" data-blogger-escaped-needed="" data-blogger-escaped-neo="" data-blogger-escaped-neostigmine="" data-blogger-escaped-nerve="" data-blogger-escaped-nervous="" data-blogger-escaped-neurogenic="" data-blogger-escaped-neuromuscular="" data-blogger-escaped-neurotransmitter="" data-blogger-escaped-neutral="" data-blogger-escaped-never="" data-blogger-escaped-new="" data-blogger-escaped-nicotinic="" data-blogger-escaped-nn="" data-blogger-escaped-no="" data-blogger-escaped-noncompetitive="" data-blogger-escaped-noradrenergic="" data-blogger-escaped-norepinephrine="" data-blogger-escaped-not="" data-blogger-escaped-note:="" data-blogger-escaped-note="" data-blogger-escaped-obesity="" data-blogger-escaped-ocular="" data-blogger-escaped-of="" data-blogger-escaped-often="" data-blogger-escaped-on="" data-blogger-escaped-oottslh="" data-blogger-escaped-open-angle="" data-blogger-escaped-open="" data-blogger-escaped-ophthalmic="" data-blogger-escaped-opioid="" data-blogger-escaped-or="" data-blogger-escaped-oral:="" data-blogger-escaped-organ="" data-blogger-escaped-organophosphates="" data-blogger-escaped-other="" data-blogger-escaped-ou="" data-blogger-escaped-outaow="" data-blogger-escaped-overcome="" data-blogger-escaped-overdose.="" data-blogger-escaped-overdose="" data-blogger-escaped-oxidation="" data-blogger-escaped-oxybutynin="" data-blogger-escaped-p-450="" data-blogger-escaped-page.="" data-blogger-escaped-pain="" data-blogger-escaped-parasympathetic="" data-blogger-escaped-parathion="" data-blogger-escaped-parenteral:="" data-blogger-escaped-parkinson="" data-blogger-escaped-part="" data-blogger-escaped-partial="" data-blogger-escaped-patients.="" data-blogger-escaped-patients="" data-blogger-escaped-pea.="" data-blogger-escaped-pea="" data-blogger-escaped-penetrate="" data-blogger-escaped-penetration.="" data-blogger-escaped-peptic="" data-blogger-escaped-per="" data-blogger-escaped-perfusion="" data-blogger-escaped-peripheral="" data-blogger-escaped-peristalsis="" data-blogger-escaped-permeability="" data-blogger-escaped-permission="" data-blogger-escaped-ph="" data-blogger-escaped-pharmacodynamics="" data-blogger-escaped-pharmacology-autonomic="" data-blogger-escaped-pharmacology-pharmacokinetics="" data-blogger-escaped-pharmacology:="" data-blogger-escaped-pharmacology="" data-blogger-escaped-phase="" data-blogger-escaped-phenobarbital="" data-blogger-escaped-phenoxybenzamine="" data-blogger-escaped-phenylephrine="" data-blogger-escaped-phospholipase="" data-blogger-escaped-physostigmine="" data-blogger-escaped-phyxes="" data-blogger-escaped-pilocarpine="" data-blogger-escaped-pilow.="" data-blogger-escaped-pip2="" data-blogger-escaped-plant="" data-blogger-escaped-plasma="" data-blogger-escaped-platelet="" data-blogger-escaped-plus="" data-blogger-escaped-pointes="" data-blogger-escaped-poisoning="" data-blogger-escaped-polar="" data-blogger-escaped-postoperative="" data-blogger-escaped-potency="" data-blogger-escaped-potent="" data-blogger-escaped-pralicloxime="" data-blogger-escaped-pray="" data-blogger-escaped-premature="" data-blogger-escaped-preoperative="" data-blogger-escaped-pressure="" data-blogger-escaped-pressures="" data-blogger-escaped-presynaptic="" data-blogger-escaped-prevents="" data-blogger-escaped-previous="" data-blogger-escaped-primarily="" data-blogger-escaped-procedures="" data-blogger-escaped-produce.="" data-blogger-escaped-produce="" data-blogger-escaped-production="" data-blogger-escaped-property="" data-blogger-escaped-proportional="" data-blogger-escaped-prostatic="" data-blogger-escaped-protein-bound="" data-blogger-escaped-protein="" data-blogger-escaped-pruritus="" data-blogger-escaped-pulse="" data-blogger-escaped-pupil="" data-blogger-escaped-pupillary="" data-blogger-escaped-pyridostigmine="" data-blogger-escaped-q="" data-blogger-escaped-qinky="" data-blogger-escaped-qiq="" data-blogger-escaped-ql="" data-blogger-escaped-qt="" data-blogger-escaped-quickly.="" data-blogger-escaped-r.="" data-blogger-escaped-range="" data-blogger-escaped-rapid="" data-blogger-escaped-rate="" data-blogger-escaped-rcoo-="" data-blogger-escaped-rcooh="" data-blogger-escaped-re="" data-blogger-escaped-reabsorbed.="" data-blogger-escaped-reabsorption="" data-blogger-escaped-reach="" data-blogger-escaped-receptor.="" data-blogger-escaped-receptor="" data-blogger-escaped-receptors.="" data-blogger-escaped-receptors="" data-blogger-escaped-red="" data-blogger-escaped-reduce="" data-blogger-escaped-reduced="" data-blogger-escaped-reduces="" data-blogger-escaped-reduction="" data-blogger-escaped-reflex="" data-blogger-escaped-regardless="" data-blogger-escaped-regenerates="" data-blogger-escaped-relates="" data-blogger-escaped-relaxation="" data-blogger-escaped-relaxes="" data-blogger-escaped-release="" data-blogger-escaped-releases="" data-blogger-escaped-relief="" data-blogger-escaped-remaining="" data-blogger-escaped-renal="" data-blogger-escaped-renally="" data-blogger-escaped-renin="" data-blogger-escaped-represent="" data-blogger-escaped-reproduced="" data-blogger-escaped-required="" data-blogger-escaped-resistant="" data-blogger-escaped-respiratory="" data-blogger-escaped-result="" data-blogger-escaped-resulting="" data-blogger-escaped-retention="" data-blogger-escaped-reuptake="" data-blogger-escaped-reversal="" data-blogger-escaped-review="" data-blogger-escaped-rhinitis="" data-blogger-escaped-rid="" data-blogger-escaped-right-="" data-blogger-escaped-ritodrine="" data-blogger-escaped-rmediated="" data-blogger-escaped-rni-13="" data-blogger-escaped-rni-i2="" data-blogger-escaped-rotating="" data-blogger-escaped-round="" data-blogger-escaped-s.="" data-blogger-escaped-s="" data-blogger-escaped-safer="" data-blogger-escaped-safety.="" data-blogger-escaped-saliva="" data-blogger-escaped-salivation.="" data-blogger-escaped-salmeterol="" data-blogger-escaped-same="" data-blogger-escaped-scale="" data-blogger-escaped-scopolamine="" data-blogger-escaped-secretion="" data-blogger-escaped-secretions="" data-blogger-escaped-section="" data-blogger-escaped-sectionii="" data-blogger-escaped-see="" data-blogger-escaped-seen="" data-blogger-escaped-sex="" data-blogger-escaped-shaped="" data-blogger-escaped-shifts="" data-blogger-escaped-shock="" data-blogger-escaped-short="" data-blogger-escaped-sick="" data-blogger-escaped-sickness="" data-blogger-escaped-side="" data-blogger-escaped-siq="" data-blogger-escaped-site="" data-blogger-escaped-size.="" data-blogger-escaped-skeletal="" data-blogger-escaped-skin="" data-blogger-escaped-slightly="" data-blogger-escaped-slow="" data-blogger-escaped-small="" data-blogger-escaped-smooth="" data-blogger-escaped-soluble="" data-blogger-escaped-somatic="" data-blogger-escaped-soon="" data-blogger-escaped-spasms="" data-blogger-escaped-species="" data-blogger-escaped-sphincter="" data-blogger-escaped-spinal="" data-blogger-escaped-sqs="" data-blogger-escaped-stamford="" data-blogger-escaped-state.="" data-blogger-escaped-state="" data-blogger-escaped-steady="" data-blogger-escaped-still="" data-blogger-escaped-stimulates="" data-blogger-escaped-stimulator="" data-blogger-escaped-stomach="" data-blogger-escaped-stored="" data-blogger-escaped-strength.="" data-blogger-escaped-stress="" data-blogger-escaped-substances.="" data-blogger-escaped-substrate.="" data-blogger-escaped-substrate="" data-blogger-escaped-subtypes.="" data-blogger-escaped-subtypes:="" data-blogger-escaped-such="" data-blogger-escaped-sulfation="" data-blogger-escaped-super="" data-blogger-escaped-susceptible="" data-blogger-escaped-suspected="" data-blogger-escaped-sweat="" data-blogger-escaped-sweating="" data-blogger-escaped-sympathetic="" data-blogger-escaped-sympathomimetics="" data-blogger-escaped-sympathoplegics="" data-blogger-escaped-system="" data-blogger-escaped-systems="" data-blogger-escaped-systolic="" data-blogger-escaped-t112="" data-blogger-escaped-t5="" data-blogger-escaped-t="" data-blogger-escaped-tachycardia="" data-blogger-escaped-takes="" data-blogger-escaped-tears="" data-blogger-escaped-temperature="" data-blogger-escaped-terbutaline="" data-blogger-escaped-terminal="" data-blogger-escaped-terminals.="" data-blogger-escaped-terminals="" data-blogger-escaped-test="" data-blogger-escaped-testing="" data-blogger-escaped-than="" data-blogger-escaped-that="" data-blogger-escaped-the="" data-blogger-escaped-theophylline="" data-blogger-escaped-theoretical="" data-blogger-escaped-therapeutic="" data-blogger-escaped-through="" data-blogger-escaped-ti="" data-blogger-escaped-tile:="" data-blogger-escaped-till="" data-blogger-escaped-time.="" data-blogger-escaped-time="" data-blogger-escaped-tiotropium="" data-blogger-escaped-tissue="" data-blogger-escaped-tissues="" data-blogger-escaped-to="" data-blogger-escaped-tocolysis="" data-blogger-escaped-tone="" data-blogger-escaped-torsacle="" data-blogger-escaped-total="" data-blogger-escaped-toxic="" data-blogger-escaped-toxicity="" data-blogger-escaped-toxin="" data-blogger-escaped-transmitter="" data-blogger-escaped-transporters.="" data-blogger-escaped-trapped="" data-blogger-escaped-treat="" data-blogger-escaped-trevor="" data-blogger-escaped-tropicamide="" data-blogger-escaped-tubules="" data-blogger-escaped-types="" data-blogger-escaped-u="" data-blogger-escaped-ulcer="" data-blogger-escaped-ulcers="" data-blogger-escaped-unchanged.="" data-blogger-escaped-unit="" data-blogger-escaped-units="" data-blogger-escaped-unopposed="" data-blogger-escaped-urgency="" data-blogger-escaped-urinary="" data-blogger-escaped-urination="" data-blogger-escaped-urine="" data-blogger-escaped-use="" data-blogger-escaped-used="" data-blogger-escaped-usually="" data-blogger-escaped-uterine="" data-blogger-escaped-v2="" data-blogger-escaped-v="" data-blogger-escaped-values.="" data-blogger-escaped-values="" data-blogger-escaped-variable="" data-blogger-escaped-vascular="" data-blogger-escaped-vasculature="" data-blogger-escaped-vasoconstriction="" data-blogger-escaped-vasoconstrictor="" data-blogger-escaped-vasodilation="" data-blogger-escaped-vasopressin="" data-blogger-escaped-vel="" data-blogger-escaped-very="" data-blogger-escaped-vesamicol="" data-blogger-escaped-vl="" data-blogger-escaped-volume="" data-blogger-escaped-voluntary="" data-blogger-escaped-vs.="" data-blogger-escaped-w="" data-blogger-escaped-want="" data-blogger-escaped-warfarin.="" data-blogger-escaped-watch="" data-blogger-escaped-water-soluble="" data-blogger-escaped-weak="" data-blogger-escaped-weed="" data-blogger-escaped-when="" data-blogger-escaped-who="" data-blogger-escaped-window="" data-blogger-escaped-with="" data-blogger-escaped-worsen="" data-blogger-escaped-x="" data-blogger-escaped-xe="" data-blogger-escaped-y="" data-blogger-escaped-yield="" data-blogger-escaped-yields="" data-blogger-escaped-york:="" data-blogger-escaped-you="" data-blogger-escaped-your="" data-blogger-escaped-z="" data-blogger-escaped-zero-order="">􀁿) 􀁿I 􀁹 ::J (/) (/) 􀁹 c. "0 0 as0 Mean Diastolic Q) 􀁽 -- --- -- - 􀁾 􀀃 Q) I ' Pulse Isoproterenol (􀁿 > a) ! - 􀀺 􀀏 -------- -- (Reflex bradycardia) f - -- -- 150 100 50 100 50 (Adapted, with permission, from Katzung BG, Trevor AJ. Pharmacology: Examination & Board Review, 5th ed. Stamford, 0: Appleton & Lange, 1998: 72.) Centrally acting aragonists, ! central sympathetic outflow Application: hypertension, especially with renal disease (no decrease in blood flow to kidney) PHARMACOLOGY 􀂃 PHARMACOLOGY-AUTONOMIC DRUGS SECTION II 23 7 a-blockers DRUG Nonselective Phenoxybenzamine (irreversible) Phentolamine (reversible) APPLICATIONS Pheochromocytoma (use phenoxybenzamine before removing tumor, since high levels of released catecholamines w ill not be able to overcome blockage) Give to patients on MAO inhibitors who eat tyramine-conta ining foods 􀁼 selective (-osin ending) Prazosin, terazosin, Hypertension, urinary retention in BPI-I doxazosin, tamsulosin Cl:z selective Mirtazapine Depression TOXICITY Orthostatic hypotension, reAex tachycard ia 1st-close orthostatic hypotension, d izziness, headache Sedation, t serum cholesterol, t appetite a-blockade of epinephrine vs. phenylephrine Before a. blockade Epi (large dose) 􀀂􀁸 j c. "0 0 0 OJ 􀁸 ::J (/) (/) 􀁸 c. "0 0 0 OJ '------------- Net pressor effect Phenylephrine '------------- Net pressor effect After a. blockade Epi (large dose) -L ____ _ '--------Suppression of pressor effect (Adapted, with permission, from Katzung BG, Trevor AJ. Pharmacology: Examination & Board Review, 5th ed. Stamford, a: Appleton & Lange, 1998: 80.) Shown above are the effects of an a-blocker (e.g., phentolamine) on blood pressure responses to epinephr ine and phenylephrine. The epinephrine response exhibits reversal of the mean blood pressure change, from a net increase (the a response) to a net decrease (the 􀀿2 response). The response to phenylephr ine is suppressed but not reversed because phenylephr ine is a "pure" a-agonist w ithout 􀀿 action. 23 8 SECTION II 􀁒-blockers APPLICATION Angina pectoris Ml SVT (metoprolol, esmolol) Hypertension CHF Glaucoma (timolol) TOXICITY SELECTIVITY PHARMACOLOGY 􀂂 PHARMACOLOGY-A U TONOMIC DRUGS Acebutolol, betaxolol, esmolol, atenolol, metoprolol, propranolol, timolol, pindolol, labetalol. EFFECTS 􀁊 heart rate and contractility, resulting in 􀁊 02 consumption 􀀿-blockers 􀁊 mortality 􀁊 AV conduction velocity (class II antiarrhythmic) 􀁊 cardiac output, 􀁊 renin secretion (clue to 􀀿1-receptor blockade on JGA cells) Slows progression of chronic failure 􀁊 secretion of aqueous humor Impotence, exacerbation of asthma, cardiovascular adverse effects (bradycardia, AV block, CHF), CNS adverse effects (seizures, sedation, sleep alterations); use with caution in diabetics 􀀿1-selective antagonists ( 􀀿1 > 􀀿2)- Acebutolol (partial agonist), Betaxolol, Esmolol (short acting), Atenolol, Metoprolol Nonselective antagonists ( 􀀿1 = 􀅕) Propranolol, Timolol, Naclolol, and Pinclolol Nonselective (vasodilatory) a- and 􀀿-antagonists-carveclilol, labetalol Partial 􀀿-Agonists- Pindolol, Acebutolol A BEA M of 􀀿1-blockers. Advantageous in patients with comorbicl pulmonary disease. Please Try Not 􀅖eing Picky. PAPA. PHARMACOLOGY 􀂂 PHARMACOLOGY-TOXICITIES AN D SI DE EFFECTS SECTION II 239 􀂂 PHARMACOLOGY-TOXICITIES AN D SI DE EFFECTS Specific antidotes TOXIN Acetaminophen Salicylates Amphetamines (basic) Acetylcholinesterase inhibitors, organophosphates Antimuscarinic, anticholinergic agents 􀀿-blockers Digitalis Iron Lead Mercury, arsenic, gold Copper, arsenic, gold Cyanide Methemoglobin Carbon monoxide Methanol, ethylene glycol (antifreeze) Opioids Benzodiazepines TCAs Heparin Warfarin t PA, streptokinase, urokinase Theophylline ANTIDOTE/TREATMENT N-acetylcysteine (replenishes glutathione) NaHC03 (alkalinize urine), dialysis N H4Cl (acidify urine) Atropine, pralidoxime Physostigmine salicylate, control hyperthermia Glucagon Normalize K+, Lidocaine, Anti-dig Fab fragments, Mg2+ (KLAM) Deferoxamine, deferasirox CaEDTA, dimercaprol, succimer, penicillamine Dimercaprol ( BAL), succimer Penicillamine Nitrite + thiosulfate, hydroxocobalamin Methylene blue, vitamin C 10 0 % 02, hyperbaric 02 Fomepizole >ethanol, dialysis Naloxone/naltrexone Flumazenil NaHC03 (plasma alkalinization) Protamine Vitamin K, fresh frozen plasma Aminocaproic acid 􀀿-blocker 2 40 SECTION II Drug readions DRUG REACTION BY SYSTEM Cardiovascular Coronary vasospasm Cutaneous flushing Dilated cardiomyopathy Torsades de pointes Hematologic Agranulocytosis Aplastic anemia Direct Coombspositive hemolytic anemia PHARMACOLOGY 􀂃 PHARMACOLOGY-TOXICITIES AND SI DE EFFECTS CAUSAl AGENTS Cocaine, sumatriptan, ergot alkaloids Vancomycin, Adenosine, Niacin, Ca2+ channel VANC blockers Doxorubicin (Adriamycin), daunorubicin Class III (sotalol) and class lA (quinidine) antiarrhythmics Clozapine, Carbamazepine, Colchicine, Propylthiouracil, Methimazole, Dapsone Chloramphenicol, benzene, NSAIDs, propylthiouracil, methimazole Methyldopa, penicillin Agranulocytosis Could Certainly Cause Pretty Major Damage Gray baby syndrome Chloramphenicol Hemolysis in G6PDdeficient patients Megaloblastic anemia Thrombotic complications Respiratory Cough Pulmonary fibrosis Gl Acute cholestatic hepatitis, jaundice Focal to massive hepatic necrosis Isoniazid (IN H), Sulfonamides, Primaquine, Aspirin, Ibuprofen, Nitrofurantoin Phenytoin, Methotrexate, Sulfa drugs OC Ps (e.g., estrogens) ACE inhibitors BLeomycin, Amiodarone, Busulfan Erythromycin Halothane, Amanita phalloides, Valproic acid, Acetaminophen Hepatitis IN H Pseudomembranous Clindamycin, ampicillin colitis Reproductive/endocrine Adrenocortical insufficiency Gynecomastia Hot flashes Hyperglycemia Hypothyroidism Glucocorticoid withdrawal (HPA suppression) Spironolactone, Digitalis, Cimetidine, chronic Alcohol use, estrogens, Ketoconazole Tamoxifen, clomiphene Niacin, tacrolimus, protease inhibitors, HCTZ, corticosteroids Lithium, amiodarone, sulfonamides Hemolysis IS PAIN Having a blast with PMS Note: ARBs like losartan-no cough It's hard to BLAB when you have pulmonary fibrosis Liver "HAVAc" Some Drugs Create Awkward Knockers PHARMACOLOGY 􀂃 PHARMACOLOGY-TOXICITIES AND SIDE EFFECTS SECTION II 2 4 1 Drug reactions (continued) DRUG REACTION BY SYSTEM CAUSAL AGENTS Musculoskeletal/connective tissue Fat redistribution Gingival hyperplasia Gout Myopathies Osteoporosis Photosensitivity Rash (Stevens- Johnson syndrome) SLE-Iike syndrome Teeth (kids) Tendonitis, tendon rupture, and cartilage damage Renai/GU Glucocorticoids, protease inhibitors Phenytoin, verapamil Furosemide, thiazides, niacin, cyclosporine Fibrates, Niacin, Colchicine, Hyclroxychloroquine, Interferon-a, Penicillamine, Statins, Glucocorticoids Corticosteroids, heparin Sulfonamides, Amiodarone, Tetracycline Penicillin, Ethosuximide, Carbamazepine, Sulfa drugs, Lamotrigine, Allopurinol, Phenytoin, Phenobarbital Hydralazine, INH, Procainamicle, Phenytoin Tetracyclines Fluoroquinolones Diabetes insipidus Lithium, demeclocycline Fanconi's syndrome Expired tetracycline Hemorrhagic cystitis Cyclophosphamide, ifosfamide (prevent by coaclministering with mesna) Interstitial nephritis Methicillin, NSAIDs, furosemide SIADH Carbamazepine, cyclophosphamide Neurologic Cinchonism Parkinson-like syndrome Seizures Tardive dyskinesia Multiorgan Antimuscarinic Disulfiram-like reaction Nephrotoxicity/ ototoxicity Quinidine, quinine Antipsychotics, reserpine, metoclopramicle Isoniazid, Bupropion, lmipenem/cilastatin, Tramadol, EnAurane, Metoclopramide Antipsychotics Atropine, TCAs, H1-blockers, neuroleptics Metronidazole, certain cephalosporins, procarbazine, 1st-generation sulfonylureas Aminoglycosides, vancomycin, loop diuretics, cisplatin Fish N CHIPS Give you myopathies SAT for a photo Bad rash after a PEC SLAPP It's not HIPP to have lupus With seizures, I BITE My tongue 2 4 2 SECTION II P-450 interactions Sulfa drugs PHARMACOLOGY 􀂃 PHARMACOLOGY-TOXICITIES AND SIDE EFFECTS Inducers (+) Modafinil Barbiturates St. John's wort Pheny toin Rifampin Griseofulvin Carbamazepine Chronic a lcohol use Mom ma Barb Steals Phen-phen and Refuses Greasy Carbs Chronica lly. Inhibitors (-) Macrolides Amiodarone Grapefruit juice Is oniazid Cimetidine Ritonavir Acute alcohol abuse Ciproflox acin Ketoconazole Sulfonamides G emfibrozil Q uinidine MAGIC RACKS in GQ. Probenecid, Furosemide, Acetazolamide, P opular FACTSSS Celecoxib, T hiazides, Sulfona mide antibiotics, Sulfasalazine, Sulfonylureas Patients with sulfa allergies may develop fever, urinary tract infection, pruritic rash, StevensJohnson syndrome, hemolytic anemia, thrombocytopenia, agr􀅔nulocytosis, and urticaria (hives). Symptoms range from mild to life-threatening. PHARMACOLOGY 􀁻 PHARMACOLOGY-MISCELLANEOUS 􀁺 PHARMACOLOGY-MISCEL LANEOUS Drug name ENDING CATEGORY EXAMPLE Antimicrobial -azole Antifungal Ketoconazole -cillin Penicillin Methicillin -cycline Antibiotic, protein synthesis inhibitor Tetracycline -navir Protease inhibitor Saquinavir CNS -triptan 5-HT18110 agonists (migraine) Sumatriptan -ane Inhalational general anesthetic Halothane -caine Local anesthetic Lidocaine -operidol Butyrophenone (neuroleptic) Haloperidol -azine Phenothiazine (neuroleptic, antiemetic) Chlorpromazine -barbital Barbiturate Phenobarbital -zolam Benzocliazepine Alprazolam -azepam Benzodiazepine Diazepam -etine SSRI Fluoxetine -ipramine TCA Imipramine -triptyline T CA Amitriptyline Autonomic -olol 􀀿-antagonist Propranolol -terol 􀀿ragonist Albuterol -zosin a1-antagonist Prazosin Cardiovascular -ox in Cardiac glycoside (inotropic agent) Digoxin -pril ACE inhibitor Captopril -afil Erectile dysfunction Sildenafil Other -trap in Pituitary hormone Somatotropin -tidine I-12 antagonist Ci me tid ine SECTION II 2 4 3 2 44 SECTION II 􀂃 NOTES PHARMACOLOGY SECTION Ill High-Yield Organ Systems "Symptoms, then, are in reality nothing but the cry from SHf{ering organs." -Jean-Martin Charcot "Man is an intelligence in servitude to his organs." -Aldous Huxley 2 4 6 SECTION Ill HIGH-YIELD ORGAN SYSTEMS 􀁑 APPROACHING THE ORGAN SYSTEMS In this section, we have divided the High-Yield Facts into the major Organ Systems. Within each Organ System are several subsections, including Embryology, Anatomy, Physiology, Pathology, and Pharmacology. As you progress through each Organ System, refer back to information in the previous subsections to organize these basic science subsections into a "vertical" framework for learning. Below is some general advice for studying the organ systems by these subsections. Embryology For 2013, we have shifted Embryology into the Organ Systems section. Relevant embryology is tied to each organ system subsection. Embryology tends to correspond well with the relevant Anatomy, especially with regard to congenital malformations. Anatomy Several topics fall under this heading, including gross anatomy, histology, and neuroanatomy. Do not memorize all the small details; however, do not ignore anatomy altogether. Review what you have already learned and what you wish you had learned. Many questions require two steps. The first step is to identify a structure on anatomic cross section, electron micrograph, or photomicrograph. The second step may require an understanding of the clinical significance of the structure. Wl1en studying, stress clinically important material. For example, be familiar with gross anatomy related to specific diseases (e.g., Pancoast tumor, Horner's syndrome), traumatic injuries (e.g., fractures, sensory and motor nerve deficits), procedures (e.g., lumbar puncture), and common surgeries (e.g., cholecystectomy). There are also many questions on the exam involving x-rays, CT scans, and neuro MRI scans. Many students suggest browsing through a general radiology atlas, pathology atlas, and histology atlas. Focus on learning basic anatomy at key levels in the body (e.g., sagittal brain MRI; axial CT of the midthorax, abdomen, and pelvis). Basic neuroanatomy (especially pathways, blood supply, and functional anatomy) also has good yield. Use this as an opportunity to learn associated neuropathology and neurophysiology. Physiology The portion of the examination dealing with physiology is broad and concept oriented and thus does not lend itself as well to fact-based review. Diagrams are often the best study aids, especially given the increasing number of questions requiring the interpretation of diagrams. Learn to apply basic physiologic relationships in a variety of ways (e.g., the Fick equation, clearance equations). You are seldom asked to perform complex HIGH·YIELD ORGAN SYSTEMS calculations. Hormones are the focus of many questions, so learn their sites of production and action as well as their regulatory mechanisms. A large portion of the physiology tested on the USMLE Step 1 is now clinically relevant and involves understanding physiologic changes associated with pathologic processes (e.g., changes in pulmonary function with COP D). Thus, it is worthwhile to review the physiologic changes that are found with common pathologies of the major organ systems (e.g., heart, lungs, kidneys, GI tract) and endocrine glands. Pathology Questions dealing with this discipline are difficult to prepare for because of the sheer volume of material involved. Review the basic principles and hallmark characteristics of the key diseases. Given the increasingly clinical orientation of Step 1, it is no longer sufficient to know only the "buzz word" associations of certain diseases (e.g., cafe-au-lait macules and neurofibromatosis); you must also know the clinical descriptions of these findings. Given the clinical slant of the USMLE Step 1, it is also important to review the classic presenting signs and symptoms of diseases as well as their associated laboratory findings. Delve into the signs, symptoms, and pathophysiology of major diseases that have a high prevalence in the United States (e.g., alcoholism, diabetes, hypertension, heart failure, ischemic heart disease, infectious disease). Be prepared to think one step beyond the simple diagnosis to treatment or complications. The examination includes a number of color photomicrographs and photographs of gross specimens that are presented in the setting of a brief clinical history. However, read the question and the choices carefully before looking at the illustration, because the history will help you identify the pathologic process. Flip through an illustrated pathology textbook, color atlases, and appropriate Web sites in order to look at the pictures in the clays before the exam. Pay attention to potential clues such as age, sex, ethnicity, occupation, recent activities and exposures, and specialized lab tests. Pharmacology Preparation for questions on pharmacology is straightforward. Memorizing all the key drugs and their characteristics (e.g., mechanisms, clinical use, and important side effects) is high yield. Focus on understanding the prototype drugs in each class. Avoid memorizing obscure derivatives. Learn the "classic" and distinguishing toxicities of the major drugs. Do not bother with drug dosages or trade names. Reviewing associated biochemistry, physiology, and microbiology can be useful while studying pharmacology. There is a strong emphasis on ANS, CNS, antimicrobial, and cardiovascular agents as well as on NSAI Ds. Much of the material is clinically relevant. ewer drugs on the market are also fair game. SECTION Ill 2 4 7 2 4 8 SECTION Ill 􀁑 NOTES HICiH·YIELD ORGAN SYSTEMS HIGH-YIELD SYSTEMS Cardiovascular "As for me, except for an occasional heart attack, I feel as young as I ever did." - Robert Bench ley "Hearts will never be practical until they are made unbreakable." -The Wi zard of Oz "As the arteries grow hard, the heart grows soft." - H . L. Mencken "Nobody has ever measured, not even poets, how much the heart can hold." -Zelda Fitzgerald "Only from the heart can you touch the sky." - Ru m i 2 50 SECT I O N I l l CA R D I O VASC U L A R 􀀻 C A R D I OVAS C U L A R-E M B R YO LOGY 􀀻 C A R D I OVASC U L A R -E M B R YO LOGY Heart embryology Truncus arteriosus EMBRYO N I C STRUCTURE Truncus arteriosus (TA) Bulbus cord is Prim itive ventricle Prim itive atria Left horn of sinus venosus ( SV) Right horn of SV Right common cardinal vein and right anterior cardinal vei n G IVES RISE TO Ascending aorta and pulmonary trunk Smooth parts (outAow tract) of left and right ventricles Trabecul ated left and right ventricles Trabecu Ia ted left and right atria Coronary sinus Smooth part of right atrium svc Neural crest migration -+ truncal and bulbar ridges that spiral and fuse to form the aorticopul monary (AP) septu m -+ ascending aorta and pulmonary trunk. Pathology- transposition of great vessels (failure to spiral), tetralogy of Fallot (skewed AP septum development) , persistent TA (partial AP septum development) . Interventricular septum development 0 M uscu Ia r ----T->T""'+ ventricular septum Membranous ventricular septum 0 Muscular ventricular septum forms. Opening is called interventricular foramen . f) AP septum rotates and fuses with muscular ventricular septum to form membranous interventricular septum , closing interventricular foramen . E) Growth of endocardial cushions separates atria from ventricles and contributes to both atrial separation and membranous portion of the interventricular septum . Pathology- improper neural crest migration into theTA c a n result in transposition o f t h e great arteries or a persistent TA. Membranous septal defect causes an i n itial left-to-right shunt, wh ich later reverses to a right-to-left shunt clue to the onset of pul monary hypertension (Eisenmenger's syndrome) . CA RDIOVASC ULAR 􀀻 CARD IOVASCULA R-EMBRYOLOGY SECT I O N I l l 2 5 1 Interatrial septum development Fetal erythropoiesis Foramen secundum Dorsal Septum Foramen endocardial primum secundum -l\=􀂾= 􀁊#i;􀁉septum cushion Foramen primum primum Foramen Degenerating 0 secundum septum primum Septum Foramen Foramen 4#􀃀1􀃁::;:;::rr--Valve of primum ovale (closed) ovale (open) 0 Foramen pri mum narrows as septum primum grows toward endocardial cushions. E) Perforations in septum primum form foramen secundum (foramen primum d i sappears) . €) Foramen secundum maintains right-to-left shunt as septu m secundum begins to grow. 0 Septum secundum contains a permanent open i n g (foramen ovale). 0 Foramen secundum enlarges and upper part of septum pri m u m degenerates. 0 Rem a i n ing portion of septu m primum forms valve of foramen ovale. 7. ( Not shown) S eptum secundum and septum primum fuse to form the atrial septum. 8 . ( Not shown) Foramen ovale usually closes soon after birth because of t LA pressure. foramen ovale Pathology- patent foramen ovale, caused by fa ilure of the septu m primum and septum secundum to fuse after bi rth. Fetal erythropoiesis occurs i n : • Yol k sac ( 3- 1 0 wk) • Liver (6 wk-birth) • Spleen ( 1 5 -30 wk) • B one marrow (22 wk to adult) Young Liver Synthesizes Blood. Fetal hemoglobin = a2rz. Adult hemoglobin = a2􀂿2. Cellularity (%) .-.-.--.-.���----� 100 80 60 40 20 10 20 30 40 Fetal weeks Birth 2 52 SECT I O N I l l C A R D I OVASC U L A R 􀀻 C A R D I OVASC U L A R -E M B R YOLOGY fetal circulation 0 Ductus venosus Inferior vena cava arteries To placenta '--- From placenta Fetal-postnatal derivatives Umbilical vein Umb ilical arteries Ductus arteriosus Ductus venosus Foramen ovale AllaNtois Notochord Ligamentum teres hepatis MediaL u mbilical l i gaments Ligamentum arteriosum Ligamentum venosum Fossa ovalis Urachus-mediaN umbilical l igament Nucleus pulposus of intervertebral elise Blood in umbilical vei n has a P02 of"' 30 m m H g a n d is"' 8 0 % saturated with 02. Umbil ical arteries have low 02 saturation. 3 important shunts : 0 Blood entering the fetus through the umb i l ical vei n is concluctecl via the ductus venosus into the IVC to bypass the hepatic c i rculation 0 Most oxygenated blood reachi n g the heart via the I VC is d iverted through the foramen ovale and pumped out the aorta to the head and body E) Deoxygenated blood entering the RA from the SVC enters the RV, is expelled into the pulmonary artery, and then passes through the ductus arteriosus i nto the descending aorta. At birth, infant takes a breat h ; ! resistance in pul monary vasculature causes t left atrial pressur e vs. right atrial pressur e ; foramen ovale closes (now called fossa oval is); t i n 02 leacls to ! in prostaglandins, causing closure of ductus arteriosus . I ndomethaci n helps close PDA. Prostaglandins E1 and E2 keep PDA open. Conta ined i n falciform l i gament. The urachus i s the part of the allantoic duct between the bladder and the umbilicus. Urachal cyst or sinus is a remnant. CA RDIOVA SCU L A R 􀀻 CARDIOVASC ULAR- ANAT O MY SECT I O N I l l 2 53 􀀺 CARDIOVAS C ULA R-ANATOMY Coronary artery anatomy Right coronary artery SA and AV nodes a re usually suppl ied by RCA . R i ght-dominant circulation = 8 5 % Left circumflex coronary = PO ar i ses from RCA. artery (LCX)-supplies lateral and posterior walls of left ventricle __ Left anterior descending Posterior descending/interventricular artery (PD)-supplies posterior '13 of interventricular septum and posterior walls of ventricles artery (LAD)-supplies anterior 2/3 of interventricular septum, anterior papillary muscle, and anterior surface of left ventricle Left marginal artery Left-dom inant c i rculation = 8 % = PO arises fro m LCX. Codominant c i rculation = 7% = PO arises from both LCX and RCA. C oronary a rtery occlusion most commonly occurs in the LAD. C oronary arteries fill duri n g diastole. The most posterior part of the heart i s the left atrium ; enlargement can cause dysphagia (due to compression of the esophagus) or hoarseness ( clue to compression of the left recurrent laryngeal nerve, a branch of the vagus) . Transesophageal echocardi ography is useful for d i agnosing left atrial enlargement, aortic d i ssection , and thoracic aortic aneurysm. 􀀺 C A R D I OVASC U L A R - P H YS I O LOGY Cardiac output C O = stroke volume ( SV) x heart rate ( H R ) . Fick principle : C O = rate of 02 consumption arterial 02 content - venous 02 content Mean arterial = (cardiac) x (total peripheral) pressure ( MAP) output resistance MAP =% d i astol ic pressure+ X systolic pressure. Pulse pressure = s ystolic pressure - d iastol ic pressure. Pulse pressure ex: stroke volume. SV = C O = E DV - ESV H R D ur i n g the early stages o f exercise, C O i s maintained b y t H R and t S V. D u ring the late stages of exercise, C O is m a i nta ined by t H R only ( SV plateaus) . If H R is too high, d i astol ic fi l l i n g is i ncomplete and C O 􀂺 (e.g., ventricular tachycard ia) . Cardiac output variables Preload and afterload Starling curve Ejection fraction (EF) CARDIOVASCULAR • CAR D I OVASC U L AR- PHYS IOLOGY S troke Volume affected by C ontractil ity, A fterload, and P reload . f SV when f preload, ! afterload , or f contractil ity. C ontractility (and SV) f with : • Catecholamines (f activity of Ca2+ pump in sarcoplasmic reticulum) • f i ntracellular Ca2+ • ! extracel lular Na+ U activity of Na+/Ca2+ exchanger) • Digitalis ( blocks Na+fK+ pump --+ f intracellular Na+ --+ ! Na+/Ca2+ exchanger activity --+ f intracel lular Ca2+) Contractil ity (and SV) ! with: • 􀁺1 -bl ockade ( ! cAMP) Heart failur e (systol ic dysfunction) • Acidosis • Hypoxia /hypercapnea ( ! Po7 /f Pco7) • Non-dihydropyridine Ca2+ 􀂽han nel - blockers Preload =ventricular EDV. Afterload = mean arterial pressure (proportional to peripheral resistance) . VE nodilators (e.g., n itroglycerin) ! prE load. VAsodilators (e.g., hydrA la zine) ! Afterload (a rterial) . Q) E ::J 0 > Q) .OS: e iii 0 0 0 Sympathetic nerve impulses Ventricular EDV (preload) EF = SV = E DV- E SV E DV EDV EF is an index of ventricular contractility. EF is normally;?: 5 5 % . S V CAP. SV f i n anxiety, exercise, and pregnancy. A failing heart has ! SV. Myocard ial 02 demand is f by: • f afterload (oc arterial pressure) • f contractil ity • f heart rate • f heart size (f wall tension) Preload f with : Exercise (slightly) . • f blood volume (e.g., overtransfusion) . • Excitement (f sympathetic activity) . Force of contraction is proportional to endd iastol ic length of cardiac muscle fiber (preload) . f contractil ity with sympathetic stimulation, catecholam ines, d igox i n . ! contractil ity w i t h l o s s of myocard ium ( M I ) , 􀁺 -blockers, calcium channel blockers. E F ! in systol ic heart fa i lure. Resistance. pressure. flow Cardiac and vascular fundion curves CA R D I O VASC U L A R 􀀻 C A R D I OVASC U L A R - P H YS I O LOGY SECT ION I l l 2 55 􀄊p = Q x R Similar to Ohm's law: 􀄊V = IR Resistance Pressure grad ient d rives flow from h igh pressure to low pressure. = driving pressure (􀄊P) = 811 (viscosity) x length flow (Q) 1t r Total resistance of vessels in series = Rl + R2 + R3 . . . l /Total resistance of vessel s in parallel = l / R1 + l /R2 + l /R3 . . . Viscosity depends mostly on hematocrit. Viscosity t i n : • Polycythemia • Hyperpro teinemic states (e.g., multiple myeloma) • Hereditary spherocytosis Viscosity ! i n anemia. ---------, Resistance is d i rectly proportional to viscosity and vessel length and inversely proportional to the rad i u s to the 4th power. Arterioles account for most of total peripheral resistance --+ regulate capillary flow. '@.- - ------------ (+) I not ropy E 􀂼 􀂽 ::l / \ co "§ I \ \ (/) ::l 0 c Ql > 0 0 0 ----, I ' I '../ I , I ' I I I I I I I I I I I 0 ,.."..::....-------􀂩---+0==---'--------;􀂪 Right atrial pressure or EDV 0 Operating point of heart (cardiac output and venous return are equal) f) ,J. TPR, e.g., exercise, AV shunt E) i TPR, e.g., hemorrhage before compensation can occur 0 As in heart failure, narcotic overdose 0 X-intercept of venous return curve = mean systemic filling pressure 256 SECT I O N I l l C A R D I O VASC U L A R 􀀻 C A R D I OVASC U L A R- P H YS I OLOGY Cardiac cycle I Contractility I sv !EF 140 IESV 120 100 -en I E 80 E. (1) (1)􀁈 60 Q: 40 20 ESV 120 Oi 100 I E 80 .s 􀂻 60 :::> (/) (/) 40 􀂻 c... 20 0 s 0 0.1 Stroke +---volume E) (EDV-ESV) Mitral valve opens (h0 Volume Systole c 0 u (!) "(j) 0.2 0.3 0.4 Time (sec) Mitral I Afterload I Aortic pressure j sv !ESV valve closes􀂼 Cl .!: EDV pressure I Mitral valve opens - - I ---- 1 Heart sounds Jugular venous pulse ECG p 0.5 0.6 0.7 0.8 Phases-left ventricl e : 0 Isovolumetric contraction - period between mitral valve closure and aortic valve open ing; period of h ighest 02 consumption €} Systol ic ejection - period between aortic valve open ing and closing E) Isovolumetric relaxation - period between aortic valve closing and m itral valve openmg 0 Rapid fi l l i n g- period just after m i tral valve open ing 0 Reduced fi l l i n g- period just before m itral valve closure Sounds : S l - m itral and tricuspid valve closure. Loudest at m itral area. S2 - aortic and pulmonary valve closure. Loudest at left sternal border. S 3 - i n early diastole dur i n g rapid ventricular filling phase. Associated with t filling pressures (e.g., m itral regur g i tation, C H F) and more common in dilated ventricles (but normal i n children and pregnant women) . S 4 ( "atrial kick " ) - i n late diastole . H igh atrial pressure. Associated with ventricular hypertrophy. Left atrium must push against stiff LV wal l . Jugular venous pulse (JVP) : a wave - atrial contraction . c wave - RV contraction (closed tricuspid valve bulging i nto atrium) . x descent-atrial relaxation and downward d i splacement of closed tricuspi d valve during ventricular contraction. v wave - t right atrial pressure due to fi l l i n g against closed tricuspid valve . y descent-blood fl o w from RA t o R V. CARDIOVASC U LAR 􀀺 CARDIOV AS CULA R-PHYSIOLOGY Splitting Normal splitting Inspiration ..... drop in intrathoracic pressure Ex piration --+ t venous retu rn to the RV ..... increased RV stroke volume --+ t RV ejection time --+ delayed ln spi ration closure of pulmonic valve. ! pulmonary impedance (t capacity of the pulmonary circulation) also occurs during inspiration, wh ich contributes to delayed closure of pulmonic valve. Wide splitting Seen in conditions that delay RV emptying Expiration (pulmonic stenosis, right bundle branch block). Delay in RV emptying causes delayed Inspiration pulmonic sound (regardless of breath). An exaggerat ion of normal spl itting. Fixed splitting Se en in ASD. ASD --+ left-to -right shunt --+ t RA Ex piration and RV volumes --+ t flow through pulmonic valve such that, regardless of breath, pulmonic Inspi ration closure is greatly delayed. Paradoxical splitting Seen in conditions that delay LV emptying Expiration (aortic stenosis, left bundle branch block). Normal order of valve closure is reversed so Inspiration that PZ sound occurs before delayed AZ sound. Therefore on inspiration, PZ closes later and moves closer to AZ, thereby "paradoxical ly" eliminating the spl it. SECTION Ill 2 57 I II Sl AZ PZ I I I I I I Sl AZ PZ I I I I I I Sl AZ PZ I I I I I I Sl PZ AZ I II - ' 2 58 SECT I O N I l l CARDIOVASCULAR 􀀻 CARDIOVASC ULAR- PHYS I OLOGY Auscultation of the heart Where to listen: APT M Aortic area: Systolic murmur • Aortic stenosis Diastolic murmur • Aortic regurgitation • Pulmonic regurgitation Systolic murmur • Hypertrophic cardiomyopathy Pulmonic area: Systolic ejection murmur • Pulmonic stenosis • Flow murmur (e.g., atrial septal defect', patent ductus arteriosus') Tricuspid area: Pansystolic murmur • Tricuspid regurgitation • Ventricular septal defect Diastolic murmur • Tricuspid stenosis @ • Atrial septal defect' 􀁇􀁇M itral area: Systolic murmur • Mitral regurgitation Diastolic murmur • Mitral stenosis 'ASD commonly presents with a pulmonary flow murmur li flow through pulmonary valve) and a diastolic rumble (i flow across tricuspid); blood flow across the actual ASD does not cause a murmur because there is no pressure gradient. The murmur later progresses to a louder diastolic murmur of pulmonic regurgitation from dilatation of the pulmonary artery. 'The continuous, machine-like murmur of PDA is best appreciated in the left infraclavicular region. BEDSIDE MANEUVER Inspiration Expiration Hand grip (t systemic vascular resistance) Valsalva ( 􀂺 venous return) Rapid squatting ( t venous return, t preload , t afterload with prolonged squatting) EFFECT t inte nsity of right heart sounds t intensity of left heart sounds t i ntensity of MR, AR, VSD, MVP murm ur s 􀂺 intensity of A S , hypertroph ic cardiomyopathy murmur s 􀂺 intensity o f most murm ur s t intensity of MVP, hypertroph ic card iomyopathy murmurs 􀂺 i ntensity of MVP, hypertroph ic card iomyopathy murmurs Systolic heart sounds include aortic/pulmon ic stenosis, mitral /tricuspid regurgitation , ve ntricular septal defect. Diastol ic heart sounds i nclude aortic/pul monic regurgitation, mitral/tricuspid stenosis. Heart murmurs Systolic Mitral/tricuspid regurgitation (MR/TR) 51 52 􀀗 Aortic stenosis (AS) 51 EC 52 1􀀛1 VSD 51 52 􀀖 Mitral valve prolapse ( MV P) 51 MC 52 I 􀀘 Diastolic Aortic regurgitation (AR) 51 52 I 􀀙u Mitral stenosis (MS) 51 52 OS I I 􀀚 Continuous PDA 51 52 􀀕 CARDIOVASCULAR 􀀹 CARDIOVASCULAR-PHYSIOLOGY Holosystol ic, high-pitched " blowi ng murmur." SECTION Ill 2 59 M itra l -loudest at apex and radiates toward axilla. E n hanced by maneuvers that t TPR (e.g., squatting, hand grip) or LA return (e.g., expiration) . MR is often due to ischemic heart disease, mitral valve prol apse, or LV d ilation. Tricuspid- loudest at tricuspid a rea and radiates to right sternal border. E nhanced by maneuvers that t RA return (e.g., inspiration) . TR can be caused by RV d ilation . Rheumatic fever and infective endocard itis can cause either M R or T R . Crescendo-decrescendo systol ic ejection murmu r followi n g e jection cl ick (EC ; due to abrupt halting of valve leaflets) . LV >> aortic pressure during systole. Radiates to carotids/heart base. "Pulsus parvus et tardus" - pulses are weak with a del ayed peak. Can lead to Syncope, Angina, and Dyspnea on exertion ( SAD) . Often due to age-related calcific aortic stenosis or bicuspid aortic valve. Holosystol ic, harsh-sounding murmur. Loudest at tricuspid area, accentuated with hand grip maneuver due to i ncreased afterload. Late systol ic crescendo murmur with midsystolic cl ick ( M C ; due to sudden tensing of chordae tendineae) . Most frequent valvular lesion. Best heard over apex. Loudest at S2. Usually benign. Can predispose to i n fective endocarditis. Can be caused by myxomatous degeneration , rheumatic fever, or chordae rupture. Enhanced by maneuvers that ! venous return (e.g., stand ing or Valsalva) . Immed iate high-pitched " blowing" d iastolic decrescendo murmur. Wide pulse pressure when chroni c ; can present with bound i n g pulses and head bobbing. Often due to aortic root d ilation, bicuspid aortic valve, endocard itis, or rheumatic fever. t murmur during hand grip. Vasodilators ! i ntensity of mur mur. Follows opening snap (OS ; due to abrupt halt i n leaflet motion i n diastole , after rapid open ing due to fusion at leaflet tips). Del ayed rumbli n g late d iastolic murmur. LA >> LV pressure during diastole. Often occurs zo to rheumatic fever. Chronic MS can result in LA d i lation . Enhanced by maneuvers that t LA return (e.g., expi ration ) . Conti nuous mach i ne-l ike murmur. Loudest at S 2 . Often d u e t o congenital rubella or prematurity. Best heard at left i n fraclavicular area. 2 60 SECT I O N I l l Ventricular adion potential -85 mV CARDIOVASCU LAR 􀀻 CARDIOVASCULAR-P HYSIOLOGY Also occurs in bundle of H i s and Purkinje fibers. Phase 0 = rapid upstroke - voltage-gated Na+ channels open. Phase 1 = i n itial repolarization -inactivation of voltage-gated Na+ channels. Voltage-gated K+ channels begin to open . Phase 2 = plateau - C a2+ influx th rough voltage-gated Ca2+ channels balances K+ efflux. C aZ+ influx triggers Ca2+ release from sarcoplasmic reticulum and myocyte contraction . Phase 3 = rapid repolarization - massive K+ efflux clue to open ing of voltage-gated slow K+ channels and closure of voltage-gated Ca2+ channels. Phase 4 = resting potentia l - h igh K+ permeabil ity through K+ channels. Effective refractory period (ERP) Na+ 3 Na+ I n contrast to skeletal muscle : • Cardiac muscle AP has a plateau , wh ich is clue to Ca2+ influx and K+ efflux; myocyte contraction occurs clue to Ca2+ -induced Ca2+ release from the sarcoplasmic reticulum. • Cardiac nodal cells spontaneously depolarize during d iastole resulting in automaticity clue to Ir channels ( " funny current" channels responsible for a slow, m i xed Na+fK+ i nward current) . K+ Channel currents K+ Ca2+ Pump Exchanger • Cardiac myocytes a re electrically coupled to each other by gap j u nctions. Pacemaker adion potential "Leak" currents Occurs in the SA and AV nodes. Key differences from the ventricular action potential i nclude : Phase 0 =upstroke - opening of voltage-gated Ca2+ channels. Fast voltage-gated Na+ channels are permanently inactivated because of the less negative resting voltage of these cells. Results in a slow conduction velocity that is used by the AV node to prolong transmission from the atria to ventricles. Phase 2 = plateau is absent. Phase 3 = inactivation of the Ca2+ channels and t activation of K+ channels -+ t K+ efflux. Phase 4 = slow d iastolic depolarization - membrane potential spontaneously clepolarizes as Na+ conductance t (If different from INa in phase 0 of ventricular action potential ) . Accounts for automaticity of SA and AV nodes. The slope of phase 4 in the SA node determ ines heart rate. ACh /aclenosine l the rate of d iastol ic depolarization and l heart rate, wh ile catechol a m i nes t depolarization and t heart rate. Sympathetic stimulation t the chance that Ir channels a re open and thus t H R . 0 .l!l -20 􀀈 -40 􀀸 -60 -80 100 msec Eledrocardiogram Superior vena cava Sinoatrial node Bundle of His Right bundle branch CA RDIOVASCU LAR 􀀷 CARDIOVASCU L AR-PHYSIOLOGY SECT I O N I l l 2 6 1 P wave -atrial depolarization. Atrial repolarization is masked by QRS complex. PR i nterval - conduction delay through AV node (normally < 200 msec) . QRS complex-ventricular depolarization (normally < 1 20 msec ) . QT i nterva l - mechanical contraction o f the ventricles. T wave -ventricular repolarization. T-wave i nversion may ind icate recent MT. ST segment- isoelectric, ventricles depolarized. U wave - caused by hypokalemia, bradycardia. Speed of conduction - Pu rkinje > atri a > ventricles > AV node. Pacemakers - SA > AV > bundle of H i s / Purk i n j e /ventricles. Conduction pathway- SA node -+ atria ..... AV node ..... common bundle -+ bundle branches --+ Purk i n j e fibers ..... ventricles. SA node "pacemaker" i nherent dominance with slow phase of upstroke . AV node - 10 0 -msec delay- atrioventricular delay; allows t i me for ventricular fi l l i ng. 1.0 > 0.5 .s Cii 'E (]) 􀂻 -0.5 p 0 􀂺 QRS complex R s 0.2 ST segment 􀂺 QT interval 0.4 Time (s) T lsoelectric line 􀂨 0.6 Purkinje system Torsades de pointes Left posterior fascicle Ventricular tachycardia, characterized by shifting si nusoidal waveforms on E C G , can progress to ventricular fibri llation . Anyth ing that prolongs the QT i nterval can predispose to torsades de pointes. Treatment includes magnesium sulfate. Congen ital long QT syndromes are most often due to defects in cardiac sodium or potassium channels. Can present with severe congenital sensorineural deafness (Jervell and Lange-Nielsen syndrome). 2 6 2 SECT I O N I l l ECG tracings CA R D I O VASC U L A R 􀀻 C A R D I OVAS C U L A R- P H YS I O LOGY Atrial fibrillation Chaotic and erratic basel ine (irregularly i rregular) with no discrete P waves in between irregularly spaced QRS complexes. Can result in atrial stasis and lead to stroke. Treatment includes rate control , anticoagulation, and possible cardioversion. Atrial flutter A rapid succession of identical, back-to-back atrial depolarization waves . The identical appearance accounts for the "sawtooth " appearance of the flutter waves. Pharmacologic conversion to sinus rhythm : class lA, IC, or III antiarrhythm ics. Rate control : 􀁺 -blocker or calcium channel blocker. Ventricular fibrillation A completely erratic rhythm with no identifiable waves. Fatal a rrhythm i a without im med iate AV block 1st degree 2nd degree Mobitz type I (Wenckebach) C PR and defibri llation . The PR i nterval is prolonged (> 200 msec). Asymptomatic. Progressive lengthening of the PR interval until a beat i s " dropped" (a P wave not fol lowed by a QRS complex) . Usually asymptomatic. Progressive increase i n P R length before dropped beat ;; \ ECG tracings (continued) Mobitz type II 3rd degree (complete) Atrial natriuretic peptide CA R D I O VASC U L A R 􀀷 C A R D I OVASC U L A R - P H YS I O LOGY SECT I O N I l l 2 63 Dropped beats that are not preceded by a change in the length of the PR interval (as i n type 1). These abrupt, nonconducted P waves result in a pathologic condition. It is often fou n d as 2 : 1 block, where there are 2 or more P waves to l QRS response . M ay progress to 3rd-degree block. Often treated with pacemaker. A No QRS lnllowlog P wa,., oocmal PR '""""''' 1'--􀂹-./\--- The atria and ventricles beat independently of each other. Both P waves and QRS complexes are present, although the P waves bear no relation to the QRS complexes. The atrial rate i s faster than the ventricular rate. Usually treated with pacemaker. Lyme d i sease can result in 3rd-degree heart block. P wave on ST-T compix ANP is released from atrial myocytes in response to t blood volume and atrial pressure. Causes generalized vascular relaxation and ! Na+ reabsorption at the medullary collecting tubule. C onstricts efferent renal arterioles and dilates afferent arterioles (cGMP mediate d ) , promoting d iuresis and contributing to the "escape from aldosterone" mechan i s m . 2 64 SECT I O N I l l I C A R D I O VASC U L A R 􀀷 C A R D I OVASC U L A R - P H YS I O LOGY Baroreceptors and chemoreceptors Carotid sinus (baroreceptor) Carotid body chemoreceptor Receptors: • Aortic arch transm its via vagus nerve to solitary nucleus of medulla (responds only to t BP) . • Carotid sinus transm its via glossopharyngeal nerve to sol itary nucleus of medulla (responds to 􀂆 and t in BP) . Baroreceptors: • Hypotension - 􀂆 arterial pressure - 􀂆 stretch - 􀂆 afferent baroreceptor firing -+ t efferent sympathetic firing and 􀂆 efferent parasympathetic sti mulation -+ vasoconstriction, t HR, t contractility, t B P. I mportant in the response to severe hemorrhage. • Carotid massage - t pressure on carotid a rtery -+ t stretch -+ t afferent baroreceptor firing -+ 􀂆 H R . • Contributes to Cushing reaction (triad o f hypertension, bradycard ia, and respiratory depression) t i ntracra n ial pressure constricts arterioles -+ cerebral ischemia and reflex sympathetic increase i n perfusion pressur e ( hypertension) -+ t stretch -+ reflex baroreceptor i nduced-bradycardia. Chemoreceptors: • Periphera l - carotid and aortic bodies are stimulated by 􀂆 Po2 (< 60 mmHg), t Pco2 , and 􀂆 pH of blood. • Centra l - are stimulated by changes i n pH and Pco2 of bra i n i nterstitial fluid, which in turn are influenced by arterial C02 . D o not d irectly respond to Po2 . Circulation through organs Lung Organ with largest blood flow ( 1 00% of cardiac output) . Liver Kidney Heart Normal pressures Largest share of systemic cardiac output. H ighest blood flow per gram of tissue. Largest arteriovenous 02 difference because 02 extraction is- 8 0 % . Therefore t 02 demand is met by t coronary blood flow, not by t extraction of 02 . <12 data-blogger-escaped-a="" data-blogger-escaped-approximation="" data-blogger-escaped-atrial="" data-blogger-escaped-capilla="" data-blogger-escaped-good="" data-blogger-escaped-i="" data-blogger-escaped-in="" data-blogger-escaped-is="" data-blogger-escaped-itral="" data-blogger-escaped-left="" data-blogger-escaped-m="" data-blogger-escaped-mmhg="" data-blogger-escaped-n="" data-blogger-escaped-of="" data-blogger-escaped-pcwp-="" data-blogger-escaped-pcwp="" data-blogger-escaped-pressure.="" data-blogger-escaped-pressure="" data-blogger-escaped-pulmonary="" data-blogger-escaped-ry="" data-blogger-escaped-stenosis="" data-blogger-escaped-wedge=""> LV diastol ic pressure. Measured with pulmonary artery catheter ( Swan-Ganz catheter) . Autoregulation ORGAN Heart Brain Kidneys Lungs Skeletal muscle Skin Capillary fluid exchange Capillary CARDIOVASCU LAR 􀀺 C A RDIOVAS CU LAR- PATHOLOGY SECT I O N I l l 2 6 5 How blood flow to an organ remains constant over a wide range of perfusion pressures. FACTORS DETERM I N I N G AUTOREGU LATION Local metabol ites (vasodilatory)-C02 , adenosine, NO Local metabolites (vasodilatory) -C02 (pH) Myogenic and tubuloglomerular fe edback Hypoxia causes vasoconstriction Local metabol ites-lactate, adenosine, K+ Sympathetic stimulation most important mechan ism - temperature control Note : the pulmonary vasculature is u n ique in that hypoxia causes vasoconstriction so that only well-ventilated areas a re perfused. In other organs, hypoxia causes vasodilation. Starl ing forces determine fluid movement through capillary membranes : • Pc =capillary pressure - pushes fluid out of capillary • Pi= i nterstitial fluid pressur e - pushes fluid into capillary • 1tc =plasma colloid osmotic pressur e - pulls fluid into capi llary • 1ti = i nterstitial fluid colloid osmotic pressur e - pulls fluid out of capillary Thus, net filtration pressure= Pnet = [(Pc- P)- (7tc - 7t)] . Kr =filtration constant (capillary permeabi l ity) . Jv =n et fluid flow= (Kr) (Pnet). Edema- excess fluid outflow into interstitium commonly caused by: • t capi llary pressure (t Pc; heart failure) • 􀂆 plasma proteins (! 1tc; nephrotic syndrome, 1 iver fa ilure) • t capillary permeability (t Kr; toxins, infections, burns) • t i nterstiti al fluid colloid osmotic pressu re (t 1ti; lymphatic blockage) 􀀺 C A R D I OVASC U L A R- PAT H OLOGY Congenital heart disease Right-to-left shunts (early cyanosis)" blue babies" Left-to-right shunts (late cyanosis)" blue kids" Tetralogy of Fallot (most common cause of early cyanosis) Transposition of great vessels Persistent Truncus a rteriosus -failure of truncus arteriosus to divide into pulmonary trunk and aorta ; most patients have accompanying VSD Tricuspid atresi a - characterized by absence of tricuspid valve and hypoplastic RV; requires both ASD and VSD for viabil ity Total anomalous pulmonary venous return (TAPVR) - pul monary veins drain into right heart c i rculation ( SVC , coronary sinus, etc . ) ; associated with ASD a n d sometimes PDA to allow for right-to-left shunting to maintain C O VSD ( m o s t common congenital cardiac anomaly) ASD (loud Sl ; wide, fixed spl it S2 ) PDA (close with i ndomethacin) The 5 T's: Tetralogy Tra nsposition Truncus Tricuspid TAPVR Frequency: VSD > ASD > PDA 2 6 6 SECT I O N I l l Eisenmenger's syndrome Tetralogy of Fallot D-transposition of great vessels Coarctation of the aorta I CA R D I O VASC U L A R 􀀷 C A R D I OVASC U L A R - PAT H OLOGY Uncorrected VSD, ASD, or PDA causes compensatory pulmonary vascular hypertrophy, wh ich results in progressive pulmonary hypertension. As pulmonary resistance t, the shunt reverses from leftto- right to right-to-left, which causes late cyanosis, clubbing, and polycythem ia. Tetralogy of Fallot is caused by anterosuperior d isplacement of the infundibular septum. 0 Pul monary infundibular stenosis (most important determi nant for prognosis) @RVH 􀈫Overriding aorta (overrides the VSD) avso Early cyanosis ( " tet spells") caused by a rightto- left shunt across the VSD. Isolated VSDs usually flow left to right (acyanotic) . In tetralogy, pulmonary stenosis forces right-to left (cyanotic) flow and causes RVH (on x-ray, boot-shaped heart) . Aorta leaves R V (anterior) and pulmonary trunk leaves LV (posterior) -+ separation of systemic and pulmonary circulations. Not compatible with l i fe unless a shunt is present to allow ade quate mixing of blood (e.g., VSD, PDA, or patent foramen ovale) . Due to failure of the aorticopulmonary septu m to spiral. Without surgical correction, most infants die with i n the first few months of l i fe . Can result in aortic regurgitation. Infantile type-aortic stenosis proximal to i n sertion of ductus arteriosus (preductal) . Associated with Tu rner syndrome. Adult type- stenosis is d istal to ligamentum arteriosum (postductal) . Associated with notching of the ribs (due to collateral circulation), hypertension in upper extrem ities, weak pulses in lower extremities. PROVe . Older patients h istorically learned t o squat to rel ieve cyanotic symptoms. S quattin g reduced blood flow to the legs, t peripheral vascular resistance ( P VR), and thus ! the cyanotic right-to-left shunt across the VSD. Preferred treatment is early, primary surgical correction . Right ventricle Ventricular septum Infantile : in close to the heart. Left ventricle Check femoral pulses on physical exa m . Adult: d istal t o ductus . M o s t commonly associated w ith bicuspid aortic valve . Patent dudus arteriosus Aorta Ductus arteriosus (patent) Pulmonary artery Congenital cardiac defed associations Hypertension RISK FACTORS FEATURES PREDISPOSES TO Hyperlipidemia signs Atheromas Xanthomas Tendinous xanthoma Corneal arcus Arteriosclerosis Monckeberg Arteriolosclerosis Atherosclerosis CA RDIOVASCULAR 􀀷 CARDIOVASC ULAR-PATHOLOGY SECT I O N I l l 2 67 I n fetal period, shunt is right to left (normal) . I n neonatal period, lung resistance 􀂆 and shunt becomes left to right with subse quent RVI-1 and/or LVH and fa ilur e (abnormal) . Associated with a continuous, "machine-l ike" murmur. Patency is maintained by PGE synthesis and low 02 tension . Uncorrected PDA can eventually result in late cyanosis in the lower extrem ities (differential cyanosis) . DISORDER 2 2q l l syndromes Down syndrome C ongenital rubella Turner syndrome Marfan's syndrome I n fant of diabetic mother Defined as BP 􀅑 140/90 mm Hg. Endomethacin ( indomethacin) ends patency of PDA ; PGE k EEps it open (may be necessary to susta i n l i fe in conditions such as transposition of the great vessels) . PDA is normal i n utero and normally closes only after bi rth. DEFECT Truncus arteriosus, tetral ogy of Fallot ASD, VSD, AV septal defect (endocard i a l c u s h i o n defect) Septal defects, PDA, pulmonary a rtery stenosis Coarctation of aorta (preductal) Aortic insufficiency and d i ssection (late compl ication) Transposition of great vessels t age, obesity, diabetes, smoking, genetics, black > white > Asian . 9 0 % o f hypertension is 1 ° (essential) and related to t C O or t T P R ; rem a i n i n g 1 0 % mostly 2 ° to renal d isease. Mal ignant hypertension is severe (> 1 80 1 1 2 0 mm Hg) and rapidly progressing. Atherosclerosis, left ventricular hypertrophy, stroke, C H F, renal fa ilure, reti nopathy, and aortic d issection. Pla ques i n blood vessel walls. Pla ques or nodules composed of l ipid-laden histiocytes i n the skin, especially the eyel ids (xanthelasma) . Lipid deposit in tendon, especially Achilles. Lipid deposit in cornea, nonspecific (arcus sen ilis) . Calcification in the media of the arteries, especially rad ial or u l n a r. Usually ben i g n ; "pipestem" arteries. Does not obstruct blood flow; intima not involve d . Two types : hyaline (thickening of small arteries i n essential hypertension or d iabetes mell itus) a n d hyperplastic ("onion skinning" in mal ignant hypertension ) . Fibrous pla ques a n d atheromas form i n intima o f arteries. 2 6 8 SECT I O N I l l Atherosclerosis RISK FACTORS PROGRESSION COMPLICATIONS LOCATION SYMPTOMS Aortic aneurysms Abdominal aortic aneurysm Thoracic aortic aneurysm Aortic dissection CARDIOVASCU LAR 􀀷 CAR DIOVASC ULAR- PAT HOLOGY D isease of elastic arteries and large- and medium-sized muscular arteries. Modifiable : smoking, hypertension, hyperl ipidemia, diabetes. Non-modifiabl e : age, gender (t i n m e n a n d postmenopausal women ) , and positive fam i ly history. Inflammation i mportant in pathogenesis. Endothelial cell dysfunction - macrophage and LDL accumul ation - foam cell formation -+ fatty streaks - smooth muscle cell migration ( involves PDGF and FGF), proliferation, and extracel lular matrix deposition - fibrous pla que - complex atheromas rJ. Aneurysms, ischem ia, infarcts, peripheral vascular d isease, thrombus, embol i. Abdom inal aorta > coronary artery > popliteal artery > carotid artery. Angina, claudication, but can be asymptomatic. Local ized pathologic dilation of blood vessel. I Atherosclerosis. Atherosclerotic plaque 1n the LAD coronary a rtery. Note the cholesterol crystals (arrow) 13 Associated with atherosclerosis. Occurs more fre quently in hypertensive male smokers > 5 0 years of age. Associated with hypertension, cystic medial necrosis (Marfan's syndrome) and h istorically 3° syph i l is. Longitud inal i ntraluminal tear forming a false lumen rJ. Associated with hypertension, bicuspid aortic valve, cystic medial necrosis, and inherited connective tissue disorders (e.g., Marfan's syndrome) . Presents with tearing chest pain radiating to the back. CXR shows mediastinal widening. The false lumen can be l i m ited to the ascending aorta, propagate from the ascending aorta, or propagate from the descending aorta. Can result in pericard ia! tamponade, aortic rupture, and death. Aortic dissection (CT). Note 1ntralummal tear form 1ng a "flap" that separates the true and false lum1na 1n the descend1ng aorta (arrow). C CARDIOVASCULAR 􀀺 CARDIOVAS CULAR- PAT HOLOGY SECT I O N I l l 269 Ischemic heart disease manifestations Angina Coronary steal syndrome Myocardial infarction Sudden cardiac death Chronic ischemic heart disease CAD narrowing > 7 5 % ; no myocyte necrosis : • Sta ble - mostly 2 ° to atherosclerosis; ST depression on E C G (retrosternal chest p a i n with exertion) • Prinzmeta l 's va riant- occurs at rest 2 ° to corona ry artery spas m ; ST elevation on ECG • U n stable/crescendo -thrombosis with incomplete coronary a rtery occlusion ; ST depression on ECG (worsen ing chest pain at rest or with m i n i mal exertion) Vasod ilator may aggravate ischemia by shunting blood from a rea of critical stenosis to an area of h i gher perfusion. Most often acute thrombosis clue to coronary artery atherosclerosis with complete occlusion of coronary artery and myocyte necrosis ; ECG in itially shows ST depression progressi ng to ST elevation with continued ischemia and transmural necrosi s . Death from cardiac causes with i n l h o u r of onset of symptoms, m o s t commonly due t o a lethal arrhythm i a (e.g., ventricular fibrillation ) . Associated w ith CAD (up to 70% of cases) . Progressive onset of C H F over many years clue to chronic ische m i c myocard i a l damage. 2 7 0 SECTION Ill Evolution of Ml TIME 0-4 hr 4-1 2 hr 12-24 hr 1-3 days 3-14 days 2 weeks to several months CAR DIOVASCULAR 􀀷 CARDIO VASCULAR-PAT HOLOGY Coronary artery occlusion: LAD > RCA > circumflex. Symptoms: diaphoresis, nausea, vomiting, severe retrosternal pain, pain in left arm and/or jaw, shortness of breath, fatigue. GROSS None Infarct liGHT MICROSCOPE one Early coagulative necrosis, edema, hemorrhage, wavy fibers. - - Dark mottling; Contraction bands from pale with tetrazolium stain Hyperemia Hyperemic border; central yellow-brown softe ningmaximally yellow and soft by 1 0 days '.1-M.-- Recanalized artery Gray-white reperfusion injury. Release of necrotic cell content into bl ood. Beginning of neutrophil migrat ion. Extensive coagulative necrosis. Tissue surrounding infarct shows acute inflammation . Neutrophil migration . - - Macrophage infiltration fo llowed by granulation tissue at the margins. - - - Contracted scar complete. RISK Arrhythmia, CHF exacerbation, cardiogen ic shock Arrhythmia Arrhythmia Fibrinous pericarditis Free wall rupture leading to tamponade, papillary muscle rupture, ventricular aneurys m, inte rventricular septal rupture due to macrophages that have degraded important structural components Dressler's syndrome Diagnosis of M l Types of infarcts ECG diagnosis of M l Ml complications CARDIOVASCULAR 􀀻 CARDIOVAS C ULA R-PATHOLOGY SECT I O N I l l 2 7 1 I n the first 6 hours, ECG is the gold standard. Cardiac troponin I rises after 4 hours and is elevated for 7-1 0 days ; more specific than other protein markers . C K-MB is predom i nantly found in myocardium but can also be released from skeletal muscle. Usefu l i n d iagnosing reinfarction following acute MI because levels return to normal after 48 hours. ECG changes can include ST elevation (transmural infa rct) , ST depression (subendocard ial infa rct) , and pathologic Q waves (transmural infarct) . Transmural i nfarcts t necrosis Affects entire wal l ST elevation o n ECG, Q waves I N FARCT lOCATION Anterior wall ( LAD) Anteroseptal ( LAD) Anterolateral ( LCX) Lateral wall ( LCX) I n ferior wall ( RCA) Subendocardial i nfarcts Due to ischemic necrosis of < 5 0 % of ventricle wall Subendocard ium especially vulnerable to ischem ia ST depression on E C G lEADS WITH Q WAVES V l -V4 V l -V2 V4-V6 I , aVL II, I I I , aVF Cardiac arrhyth m i a - i mportant cause of death before reachi n g hospita l ; common i n fi rst few days LV failure and pulmonary edema. Cardiogenic shock (large infarct- h igh risk of mortal ity) . Ventricular free wall rupture -+ cardiac tamponade ; papillary muscle rupture -+ severe mitral regurgitation ; and i nterventricular septum rupture - VSD. Ventricular aneurysm formation - ! CO, risk of arrhythmia, embolus fro m mural thrombus ; greatest risk approximately l week post-M I . Postinfarction fibrinous pericarditis-friction rub ( l -3 days post-M I ) . D ressler's syndrome - autoimmune phenomenon resulting i n fibrinous pericarditis (several weeks post-M I ) . 272 SECT I O N I l l Cardiomyopathies Dilated (congestive) cardiomyopathy Hypertrophic cardiomyopathy Restrictive/ obliterative cardiomyopathy C A R D I OVASC U L A R 􀀷 C A R D I OVASC U l A R -PAT H O lOG Y Most common cardiomyopathy (90% of cases ) . Often id iopathic (up to 5 0 % of cases may be famil ial). Other etiologies include chron ic Alcohol abuse, wet Beriberi , Coxsackie B virus myocard itis, chron ic C ocaine use, C hagas' d isease, Doxorubicin toxicity, hemochromatosis, and peripartum cardiomyopathy. Findings : S 3, d i lated heart on ultrasound, balloon appearance on chest x-ray. Treatment: Na+ restriction, ACE inh ibitors, d iuretics, d igoxin, heart transplant. Hypertrophied i nterventricular septum is " too close" to m itral valve leaflet, leading to outflow tract obstruction r.J. 60-70 % of cases are fam i l ial, autosomal dom inant (commonly a 􀁺-myosin heavy cha i n mutation). Associated with Friedreich 's ataxia. Disoriented, tangled, hypertrophied myocardial fibers. Cause of sudden death in young athletes. Findings: normal-sized heart, S4, apical impulses, systolic murmur. Treatment: 􀁺-blocker or non-d i hydropyridine calcium channel blocker (e.g., verapamil). Major causes include sarcoidosis, amyloidosis, postrad iation fibrosis, endocardial fibroelastosis (th ick fibroelastic tissue in endocardium of young children), Loftier's syndrome (endomyocardial fibrosis with a prom inent eosinoph ilic i n filtrate), and hemochromatosis (dilated cardiomyopathy can also occur) . Systolic dysfu nction ensues. Eccentric hypertrophy (sarcomeres added in series) . ABCCCD. Diastol ic dysfunction ensues. Asymmetric concentric hypertrophy (sarcomeres added i n parallel ) . Proxim ity o f hypertrophied interventricular septum to m itral leaflet obstru cts outflow tract, resulting i n systolic murmur and syncopal episodes. Diastol ic dysfunction ensues. CHF ABNORMALITY Cardiac dilation Dyspnea on exertion Left heart failure Pulmonary edema, paroxysmal nocturnal dyspnea Orthopnea (shortness of breath when supine) Right heart failure Hepatomegaly (nutmeg liver) Perip heral edema Jugular venous distention CA R D I O VASC U L A R 􀀺 C A R D I OVASC U L A R - PAT H O L O GY SECT I O N I l l 273 A clin ical syndrome that occurs in patients with an inherited or acqu i red abnormal ity of cardiac structure or function, which is characterized by a constellation of c l i n ical symptoms (dyspnea, fatigue) and signs (edema, rales) . Right heart fa ilure most often results from left heart fa ilure. I solate d right heart failure is usually clue to cor pulmonale. AC E inh ibitors, 􀁺 -blockers (except in acute decompensated I-I F ) , angiotensin receptor antagon ists, and spironolactone reduce mortal ity. Thiazide or loop d iuretics are used mainly for symptomatic rel ief. Hydralazine with nitrate therapy improves both symptoms and mortal ity i n select patients. CAUSE Greater ventricular end-diastol ic volume. Fa ilur e of cardiac output to t during exercise. t pulmonary venous pressure --+ pulmonary venous d istention and transudation of fluid. Presence of hemosiderin-laden macrophages ( " heart fa ilure" cells) in the lungs. t venous return i n supine position exacerbates pul monary vascular congestion . t central venous pressure --+ t resistance to portal flow. Rarely, leads to "cardiac cirrhosis." t venous pressure --+ fluid transudation . t venous pressure. Pulmonary edema I Pulmonary venous ! Cardiac output r congestiOn t__J 1 1 i Renin· Peripheral edema ! RV output angiotensin· aldosterone i Syslemic venous i Ren􀀔l Na\ - pressure +----- and H20 .__ ___J ! reabsorption i Preload, i cardiac i LV +----- i Sympathetic output (compensation) contractility activity 2 7 4 SECTION Ill Baderial endocarditis Rheumatic fever CARDIOVASCULAR 􀀷 CARDIOVASC ULAR-PA THOLOGY Fever (most common symptom), Roth 's spots (round white spots on retina surrounded by hemorrhage), Osler's nodes (tender ra ised lesions on fin ger or toe pads), new murmur, Janeway lesions (smal l, painless, erythematous lesions on palm or sole), anemia, spl inter hemorrhages rzJ on nail bed. Multiple blood cultures necessary fo r diagnosis. • Acute -S. aureus (high virulence). Large vegetations on previously normal valves [I) . Rapid onset. • Subacute- viriclans streptococci (low virulence). Smaller vegetations on congenitally abnormal or diseased va lves. Sequela of dental procedures. More insidious onset. Endocarditis may also be non bacterial zo to malignancy, hypercoagulable state, or lupus (marantic/th rombotic endocarditis). S. hovis is present in colon cancer, S. epidermidis on prosthetic valves. A consequence of pharyngeal infection with group A 􀁺-hemolytic streptococci. Early deaths cl ue to myocard itis. Late sequelae include rheumatic heart disease, wh ich affects heart valves - mit ral > aortic >> tricuspid (highpressure valves affected most) . Early lesion is mitral valve regurgitation ; late lesion is mitral stenosis. Associated with Aschoff bodies (granuloma with giant cells) r.J, Anitschkow's cells (activated histiocytes), elevated ASO titers. Immune mediated (type II hypersensitivity) ; not a direct effect of bacteria. Antibodies to M protein. Mitral valve is most fre quently involve d. Tric u spid valve endocarditis is associate d with IV drug abuse (don't tri drugs) . Associated with S. aureus, Pseudomonas, and Candida. Complications: chordae rupture, glomerulonephritis, suppurative pericarditis, emboli. Bacteria FROM JANE: Fever Roth 's spots Os le r's nodes M urmur J aneway lesions A n e mia Nail-bed hemorrhage Emboli FEVERSS: Fever Er ythe ma marginatum Valvular damage (vegetation and fib rosis) E SR t Reel-hot joints (migratory polyarthri tis ) Subcutan eous nodules St. Vitus' dance (Syclenha m's chorea)

You can download it from the link below for free:

First-Aid-Usmle-Step-1-2013.pdf