PASS Step 1 Course Book.pdf

P A SS P rogram C ourse N otes J an 2022 Acknowledgments I would like to acknowledge my parents, who instilled a strong desire in me to be excellent in life. I thank them for their love, their guidance, and their belief in me. I also owe much thanks to Dr. J.J. Shah, a pediatric cardiologist at S...

P A SS P rogram C ourse N otes J an 2022 Acknowledgments I would like to acknowledge my parents, who instilled a strong desire in me to be excellent in life. I thank them for their love, their guidance, and their belief in me. I also owe much thanks to Dr. J.J. Shah, a pediatric cardiologist at Saint Francis Medical Center in Peoria, Illinois for being the one person who ignited this fire by showing me “how to understand” medicine rather than memorize it. I owe so much to my wife, Vickie, who has stood by me when I had nothing and who has been there beside me through all of the ups and the downs. I also want to thank the countless students who have believed in me by attending the PASS Program®. I learn from them as they learn from me. And most importantly, I give all praise and thanks to God. For He is the one who guided me here and has blessed me with everything and everyone I need to be successful. —Francis Chukuemeka Ihejirika Developing a passion. I have always enjoyed educating myself as well as others. This passion was inspired at an early age for me. For both of my parents were educators. And they instilled in me the drive to achieve the highest level of education that I wanted. I had a goal. And I realized at eight years of age that I wanted to be a physician. However, my journey involved much academic struggle, as it does for countless other students like me. After sacrificing free time, social life and holidays in order to devote as much time as possible to studying, I made only average grades, most of the time either barely passing or barely failing. Like most students in medical school, I was memorizing information rather than understanding it. My four years of medical school was one academic struggle after another. But, I survived! And, I graduated! The academic struggles followed me into my Internal Medicine/ Pediatrics Residency. I was called before the residency chairman, put on academic probation and given a three month remediation program. All of this sounds bad, I know. However, it was during the remediation program that I met the person who would forever change more than just my medical career. In fact, he changed my entire life as well. His name is Dr. J. J. Shah; and he is a pediatric cardiologist at St. Francis Medical Center in Peoria, Illinois. Through his teaching, I began to understand what a concept was. And I suddenly realized that one concept could explain a thousand details. I realized that it is far more important for a physician to understand one concept than to memorize a thousand details. I could not believe that this one man could inspire my brain to suddenly think in a way that it had not done; to understand more in a shorter time than I ever had; and to suddenly be able to integrate knowledge in a clinically meaningful way. I was now able to understand complex issues, even ones that I had not read about yet, simply by breaking it down into its basic concepts. I had discovered a power that I never knew that I had! It is this same power that I now try tenaciously to help each student who attends the PASS Program to discover for him or herself. With this clearer understanding of medical knowledge, my medical career became fun; I regained my confidence and self-esteem; and I made the commitment to teach other students what I had learned. My pledge to each student in the PASS Program is that we will do everything we can to help you prepare for your exam, for your career, and for your future. I believe in your dream to one day become an excellent physician. We look forward to working with you and making you our next success story. Dr. Francis Ihejirika, M.D., Director of Pass Program TABLE OF CONTENTS LIST OF FIGURES........................................................................................................ A CHAPTER 1 LOW ENERGY STATE ............................................................................ 1 CHAPTER 2 VITAMINS.............................................................................................. 19 CHAPTER 3 BIOCHEMISTRY ................................................................................... 41 CHAPTER 4 PROTEIN STRUCTURE/PROTEIN FUNCTION ................................... 67 CHAPTER 5 ENZYMES ............................................................................................ 129 CHAPTER 6 ANABOLIC PATHWAYS .................................................................... 142 CHAPTER 7 ANEMIAS ............................................................................................. 197 CHAPTER 8 CLOTTING CYCLE & BLEADING DISORDERS............................... 210 CHAPTER 9 CATABOLIC PATHWAYS .................................................................. 223 CHAPTER 10 CANCER ............................................................................................. 261 CHAPTER 11 BEHAVIORAL SCIENCE & PSYCHIATRY ..................................... 294 CHAPTER 12 CELLULAR PHYSIOLOGY ............................................................... 335 CHAPTER 13 MEMBRANE PHYSIOLOGY & SECOND MESSENGER................. 360 CHAPTER 14 ELECTORLYTE PHYSIOLOGY & EKG PHYSIOLOGY ................. 379 CHAPTER 15 NEUROMUSCULAR PHYSIOLOGY ................................................ 402 CHAPTER 16 VASCULAR PHYSIOLOGY .............................................................. 442 CHAPTER 17 ENDOCRINE PHYSIOLOGY & PATHOLOGY ................................ 474 CHAPTER 18 GI PHYSIOLOGY & PATHOLOGY .................................................. 515 CHAPTER 19 RENAL PHYSIOLOGY & PATHOLOGY .......................................... 566 CHAPTER 20 PEDIATRICS DEVELOPMENT ......................................................... 618 CHAPTER 21 SURGERY PRINCIPLES & TRAUMA .............................................. 634 CHAPTER 22 BIOSTATISTICS ................................................................................ 648 CHAPTER 23 CARDIAC PHYSIOLOGY & PATHOLOGY ..................................... 658 CHAPTER 24 PULMONARY PHYSIOLOGY & PATHOLOGY .............................. 676 CHAPTER 25 ANTIBIOTICS .................................................................................... 706 CHAPTER 26 NEUROPHYSIOLOGY & PATHOLOGY .......................................... 722 CHAPTER 27 REPRODUCTIVE PHYSIOLOGY & PATHLOGY ............................ 748 CHAPTER 28 LEUKOCYTOSIS/LEUKEMIA/MYELODYSPLASIA, ETC. ............ 769 CHAPTER 29 IMMUNOLOGY IMMUNODEFICIENCY ......................................... 797 CHAPTER 30 NORMAL FLORA .............................................................................. 820 CHAPTER 31 GRAM POSITIVES............................................................................. 824 CHAPTER 32 GRAM NEGATIVES .......................................................................... 830 CHAPTER 33 ATYPICALS ....................................................................................... 842 CHAPTER 34 FUNGI................................................................................................. 845 CHAPTER 35 PARASITES AND PROTOZOA ......................................................... 847 CHAPTER 36 MYCOB., SPIRO. & RICKETTSIA .................................................... 849 CHAPTER 37 VIRUSES ............................................................................................ 856 INDEX ............................................................................................................................ I LIST OF FIGURES FIGURE PAGE Chapter 1: The Low Energy State Figure 1.1 Epithelial Cells (Skin, Hair, and Nail) .............................................................. 1 Figure 1.2 Small Intestine................................................................................................ 2 Figure 1.3 Respiratory Epithelium ................................................................................... 3 Figure 1.4 Proximal Convoluted Tubule .......................................................................... 4 Figure 1.5 Blood Vessel Surface ..................................................................................... 5 Figure 1.6 Bladder Wall ................................................................................................... 5 Figure 1.7 Uterine Wall.................................................................................................... 6 Figure 1.8 Breast Tissue ................................................................................................. 7 Figure 1.9 Sperm............................................................................................................. 7 Figure 1.10 Bone Marrow ................................................................................................ 9 Figure 1.11 Brain Cells .................................................................................................. 10 Figure 1.12 Muscle Cells ............................................................................................... 11 Figure 1.13 Sodium/Potassium Pump ........................................................................... 13 Figure 1.14 Lobar Pneumonia Chest X-ray ................................................................... 14 Figure 1.15 Dilated Heart X-ray..................................................................................... 17 Chapter 2: Vitamins, Minerals, and Trace Elements Figure 2.1 Free Radicals Penetrating the Membrane.................................................... 20 Figure 2.2 Sodium-Calcium Gradient ............................................................................ 21 Figure 2.3 CT Dilated Brain Ventricles .......................................................................... 22 Figure 2.4 Papilledema ................................................................................................. 23 Figure 2.5 MRI of Temporal Lobe.................................................................................. 24 Figure 2.6 MRI Mamillary Bodies .................................................................................. 24 Figure 2.7 Angular Cheilosis ......................................................................................... 25 Figure 2.8 Patient with Gout .......................................................................................... 26 Figure 2.9 Megaloblastic Cells ...................................................................................... 29 Figure 2.10 Hyper segmented Neutrophils .................................................................... 29 Figure 2.11 Scurvy ........................................................................................................ 30 Figure 2.12 Patient with Rickets .................................................................................... 31 Figure 2.13 Clotting Cycle ............................................................................................. 33 Figure 2.13 Clotting Cycle ............................................................................................. 33 Figure 2.14 Electron Transport Chain ........................................................................... 37 Figure 2.15 Patient with Wilson’s Disease .................................................................... 38 Figure 2.16 Autosomal Recessive Inheritance .............................................................. 39 Figure 2.17 Autosomal Dominant Inheritance ............................................................... 39 Figure 2.18 Menke’s Kinky Hair Syndrome ................................................................... 39 Chapter 3: Amino Acids Figure 3.1 Amino Acid Structure ................................................................................... 43 Figure 3.2 Amino Acid Dissociation ............................................................................... 46 Figure 3.3 Acid-Base Dissociation................................................................................. 48 Figure 3.4 Isoelectric Point Migration ............................................................................ 54 A Figure 3.5 Titration Curve.............................................................................................. 55 Figure 3.6 Titration Curve.............................................................................................. 56 Figure 3.7 Albinism........................................................................................................ 65 Figure 3.8 Vitiligo........................................................................................................... 65 Figure 3.9 Tyrosine Catabolism .................................................................................... 66 Chapter 4: Protein Structure and Function Figure 4.1 Primary Amino Acid...................................................................................... 68 Figure 4.2 Gel Electrophoresis ...................................................................................... 70 Figure 4.3 The 4 Levels of Protein Structure ................................................................. 74 Figure 4.4 Zero-order vs. First Order............................................................................. 75 Figure 4.5 Michaelis-Menten Graph .............................................................................. 83 Figure 4.6 Lineweaver- Burk Graph .............................................................................. 85 Figure 4.7 Hemoglobin-Oxygen Dissociation ................................................................ 86 Figure 4.8 Hemoglobins (HbA, HbA2, HbF) .................................................................. 90 Figure 4.9 Collagen Synthesis ...................................................................................... 92 Figure 4.10-4.12 Collagen Synthesis Cont. ................................................... 110,117,119 Chapter 5: Enzymes Figure 5.1 Enzyme Reaction ....................................................................................... 129 Figure 5.2 Enzyme Binding Sites ................................................................................ 130 Figure 5.3 Gibbs Free Energy Equation ...................................................................... 132 Figure 5.4 General Redox Reaction ............................................................................ 134 Figure 5.5 Electron Transport Chain ........................................................................... 135 Chapter 6: Anabolic Pathways Figure 6.1 Glycogen Synthesis, Steps 1-8 .................................................................. 146 Figure 6.2 Glycogen Synthesis, Steps 9-12 ................................................................ 147 Figure 6.3 Pentose Pathway ....................................................................................... 148 Figure 6.4 Transketolase and Transaldolase Activity .................................................. 151 Figure 6.5 Amino Acid Synthesis................................................................................. 152 Figure 6.6 Fatty Acid Synthesis................................................................................... 155 Figure 6.7 Citrate Shuttle ............................................................................................ 156 Figure 6.8 Fatty Acid Synthesis................................................................................... 156 Figure 6.9 Arachidonic Acid Pathway .......................................................................... 158 Figure 6.10 Triglyceride Synthesis .............................................................................. 165 Figure 6.11 Triglyceride Transport .............................................................................. 166 Figure 6.12 Sphingolipid Synthesis ............................................................................. 168 Figure 6.13 Cholesterol Synthesis............................................................................... 170 Figure 6.14 Lipid Transport ......................................................................................... 172 Figure 6.15 Urea Cycle ............................................................................................... 175 Figure 6.16 Purine De Novo Synthesis ....................................................................... 181 Figure 6.17 Purine Salvage Pathway .......................................................................... 182 Figure 6.18 Pyrimidine Synthesis ................................................................................ 186 Figure 6.19 Ribonucleotide Reductase ....................................................................... 187 Figure 6.20 Cellular Cycle ........................................................................................... 189 B Chapter 7: Anemias Figure 7.1 Anemia Classification based on Reticulocyte Count .................................. 200 Figure 7.2 Anemia Classification based on MCV ........................................................ 205 Chapter 8: The Clotting System Figure 8.1 Coagulation Cascade ................................................................................. 222 Chapter 9: Catabolic Pathways Figure 9.1 Glycolysis, Steps 1-2.................................................................................. 225 Figure 9.2 Glycolysis, Alternative Pathway ................................................................. 226 Figure 9.3 Glycolysis, Steps 3-5.................................................................................. 227 Figure 9.4 Glycolysis, Step 6....................................................................................... 228 Figure 9.5 Glycolysis, Steps 7-10................................................................................ 228 Figure 9.6 2,3 DPG ..................................................................................................... 230 Figure 9.7 Gluconeogenesis ....................................................................................... 231 Figure 9.8 Glycolysis Summary................................................................................... 232 Figure 9.9 Galactose Metabolism, Steps 1-5 .............................................................. 233 Figure 9.10 Fructose Metabolism ................................................................................ 235 Figure 9.11 5 Fates of Pyruvate .................................................................................. 236 Figure 9.12 Anaerobic Product-Lactate ....................................................................... 236 Figure 9.13 Anaerobic Function-Alanine ..................................................................... 237 Figure 9.14 Fermentative Function-Alcohol................................................................. 238 Figure 9.15 Alcohol Metabolism .................................................................................. 238 Figure 9.16 Anapleurotic Function-OAA ...................................................................... 240 Figure 9.17 Aerobic Function-AcCoA .......................................................................... 241 Figure 9.18 PLAN F, Cofactors of Pyruvate Dehydrogenase ...................................... 241 Figure 9.19 Krebs Cycle .............................................................................................. 243 Figure 9.20 Malate-Aspartate Shuttle .......................................................................... 244 Figure 9.21 G3P Shuttle .............................................................................................. 245 Figure 9.22 Carnitine Shuttle, Step 7 .......................................................................... 248 Figure 9.23 Odd Chain FA Catabolism........................................................................ 249 Figure 9.24 Ketogenesis ............................................................................................. 249 Figure 9.25 Glycogen Breakdown ............................................................................... 250 Figure 10.1 Neoplasia ................................................................................................. 262 Figure 10.2 Hairy Cell Leukemia ................................................................................. 271 Figure 10.3 Bone Structure ......................................................................................... 289 Chapter 12: Cellular Physiology Figure 12.1 Cell Structure ........................................................................................... 335 Figure 12.2 Coarctation of Aorta ................................................................................. 342 Figure 12.3 Formation of Atrial Septum....................................................................... 345 Figure 12.4 Cell Cycle ................................................................................................. 348 C Chapter 13: Membrane Physiology Figure 13.1 Cell Membrane ......................................................................................... 360 Figure 13.2 Electrolyte Movement ............................................................................... 371 Figure 13.3 cAMP........................................................................................................ 374 Figure 13.4 IP3-DAG ................................................................................................... 376 Chapter 14: Electrolyte Physiology Figure 14.1 Membrane Potentials ............................................................................... 380 Figure 14.2 Sodium Channels ..................................................................................... 382 Figure 14.3 Action Potential ........................................................................................ 383 Figure 14.4 Electrical Conduction System of the Heart ............................................... 389 Figure 14.5 Na+/Ca2+ Exchanger............................................................................... 401 Chapter 15: Neuromuscular Physiology Figure 15.1 Neuromuscular Precursor/Pathways Making Neurotransmitters .............. 408 Figure 15.2 Excitation-Contraction Coupling ............................................................... 416 Figure 15.3 Sarcomere................................................................................................ 426 Figure 15.4 Length/Tension ........................................................................................ 428 Figure 15.5 Frank-Starling Curve ................................................................................ 431 Chapter 16: Vascular Physiology Figure 16.1: Resistance in Series & Parallel ............................................................... 451 Figure 16.2: Neurological Control of Blood Pressure .................................................. 460 Chapter 17: Endocrinology Figure 17.1 Calcium and Phosphate Homeostasis ..................................................... 494 Figure 17.2 Vitamin D Synthesis ................................................................................. 498 Figure 17.3 Hypothalamic-Pituitary Axis...................................................................... 501 Chapter 18: Gastrointestinal Physiology Figure 18.1 Abdominal Aorta....................................................................................... 518 Figure 18.2 Stomach Blood Supply ............................................................................. 518 Figure 18.3 Esophageal Disorders .............................................................................. 529 Figure 18.4 Gastric Physiology ................................................................................... 533 Figure 18.5 Hepato-biliary ........................................................................................... 546 Figure 18.6 Bilirubin Metabolism ................................................................................. 546 Figure 18.7 Gallstones ................................................................................................ 551 Chapter 19: Renal Physiology and Pathology Figure 19.1 Nephron Structure .................................................................................... 571 Figure 19.2 Ureter Anatomy ........................................................................................ 582 Figure 19.3 Posterior Urethral Valves ......................................................................... 583 Figure 19.4 Benign Prostate Hypertrophy ................................................................... 585 Figure 19.5 Bladder Anatomy...................................................................................... 586 Figure 19.6 Urethral Anatomy ..................................................................................... 589 Figure 19.7 Nephron-Arteriole ..................................................................................... 592 D Figure 19.8 Renal Filtration and Secretion .................................................................. 594 Figure 19.9 Proximal Convoluted Tubule .................................................................... 602 Figure 19.10 Loop of Henle ......................................................................................... 605 Figure 19.11 Distal Convoluted Tubule ....................................................................... 609 Figure 19.12 Collecting Duct ....................................................................................... 610 Chapter 22: Biostatistics Figure 22.1: 2 x 2 Table .............................................................................................. 651 Figure 22.2: Precision/Reliability vs Accuracy/Validity ................................................ 653 Figure 22.3: Bell-shaped Curve................................................................................... 655 Figure 22.4: Positive and Negative Correlation ........................................................... 656 Figure 22.5: PPV and NPV.......................................................................................... 657 Chapter 23: Cardiac Physiology Figure 23.1 Heart Sounds ........................................................................................... 659 Figure 23.2 Cardiac Pressures.................................................................................... 664 Figure 23.3 Oxygen Saturation of Cardiac Chambers ................................................. 665 Figure 23.4 Filtration Forces Equation ........................................................................ 669 Figure 23.5 Pressure-Volume Loop............................................................................. 671 Figure 23.6 Pressure-Volume Loop............................................................................. 672 Figure 23.7 Pressure-Volume Loop............................................................................. 672 Figure 23.8 Normal LA, LV, Aortic Pressures.............................................................. 673 Figure 23.9 High LA Pressure ..................................................................................... 673 Figure 23.10 High LV Pressure ................................................................................... 673 Figure 23.11 Atrial Action potential.............................................................................. 674 Figure 23.12 Ventricular Action Potential .................................................................... 674 Figure 23.13 EKG........................................................................................................ 674 Chapter 24: Pulmonary Physiology Figure 24.1 Lung Anatomy .......................................................................................... 682 Figure 24.2 Pneumocytes ........................................................................................... 685 Figure 24.3 Compliance .............................................................................................. 691 Figure 24.4 Compliance of lung, chest wall and combined lung and chest wall .......... 692 Figure 24.5 Fibrosis vs Emphysema ........................................................................... 692 Figure 24.6 Lung Volumes .......................................................................................... 693 Figure 24.7 FEV1/FVC ...................................................................................................... Figure 24.8 Intratho-racic Pressure Changes.............................................................. 694 Figure 24.9 Pulmonary Circulation .............................................................................. 696 Figure 24.10 Flow-Volume Loops................................................................................ 698 Figure 24.11 Chemoreceptors..................................................................................... 704 Chapter 25: Antibiotics Figure 25.1 Transformation ......................................................................................... 706 Figure 25.2 Transduction ............................................................................................ 708 Figure 25.3 Conjugation .............................................................................................. 709 E Chapter 26: Neurophysiology Figure 26.1 Dermatomes............................................................................................. 724 Figure 26.2 CSF Flow ................................................................................................. 727 Figure 26.3 Coup vs. Countrecoup.............................................................................. 729 Figure 26.4 Embryology of the Brain ........................................................................... 729 Figure 26.5 Myopia...................................................................................................... 730 Figure 26.6 Visual Field Defects ................................................................................. 731 Figure 26.7 Brain ......................................................................................................... 736 Figure 26.8 Corticospinal Tract ................................................................................... 738 Figure 26.9 Dorsal Column Medical ............................................................................ 739 Figure 26.10 Spinothalamic Tract................................................................................ 740 Figure 26.11 Spinocerebellar Tract ............................................................................. 741 Figure 26.12 Facial Nerve Palsy ................................................................................. 743 Figure 26.13 Circle of Willis......................................................................................... 744 Chapter 27: Reproductive Physiology and Pathology Figure 27.1 Phases of the Menstrual Cycle................................................................. 751 Figure 27.2 Stages of Oogenesis ................................................................................ 752 Figure 27.3 Hormonal Peaks during the Menstrual Cycle ........................................... 753 Figure 27.4 Follicular/Proliferative Phase (Days 1-10) ................................................ 754 Figure 27.5 Ovulation Phase (Days 10-14) ................................................................. 756 Figure 27.6 Luteal/Secretory Phase (Days 14-28) ...................................................... 758 Figure 27.7 Stages of Spermatogenesis ..................................................................... 760 Figure 27.8 Stages of Sexual Response ..................................................................... 761 Figure 27.9 Male Reproductive Anatomy .................................................................... 762 Chapter 28: Lymphocytes, Leukocytes, and Granulocytes Figure 28.1 Killing Catalase Positive Organisms ......................................................... 779 Figure 28.2 Primary and Secondary Exposure to Allergens ........................................ 781 Figure 28.3 Vaccination Schedule............................................................................... 789 Figure 28.4 Anti-body Structure .................................................................................. 790 Chapter 29: Immunology Figure 29.1 HIV in Host Cell ........................................................................................ 808 Figure 29.2 HIV Pharmacology ................................................................................... 809 Figure 29.3 HIV Diagnosis .......................................................................................... 810 Figure 29.4 Complement System ................................................................................ 814 Figure 29.5 ABO Blood Type ...................................................................................... 815 Chapter 31: Gram Positive Figure 31.1 Gram Positive Flow Chart ........................................................................ 825 Figure 31.2 Corynebacterium Diphtheria..................................................................... 827 Chapter 37: Viruses Figure 37.1 Hepatitis ................................................................................................... 859 Figure 37.2 Hepatitis Graph ........................................................................................ 859 F Chapter One: The Low Energy State The Most Important Concept in Medicine The low energy state is the most powerful concept in medicine. It is based on a fusion of biochemistry and physiology. Once you understand those 2 topics, you can pretty much figure out anything they are going to ask you in any field of medicine. Your body spends so much time everyday creating and expending energy. The question is, why is it doing that? Because every cell in your body needs energy. If your body runs out of energy, every cell in your body will eventually die. Who will run out of energy first? The cells that use the most energy, the rapidly dividing cells. They need lots of nucleotides (the building blocks of DNA) which costs a lot of energy in the form of ATP. Because they use the most energy, they will die first if your body runs out of it. Chapter Sections: I. II. III. IV. V. Rapidly Dividing Cell Lines and Low Energy Less Rapidly Dividing Cells and Low Energy State Consequences of Low Energy Inside the Cell How to Create a Disease or Syndrome Complications of the Low Energy State Rapidly Dividing Cell Lines and Low Energy Figure 1.1 Epithelial Cells (Skin, Hair, and Nail) 1 Low Energy State Skin • • Hair • Epithelial cells no longer have ATP for collagen synthesis or DNA repair Dry, flaky, and itchy Epithelial cells no longer have ATP for replacement. Hair cannot grow and will become dry, brittle, and eventually fall out • Dry, brittle and falls out Nails and Cuticles • Epidermal skin under nail stops making new cells • Dry and brittle GI tract • Mucosal epithelium no longer has ATP for active transport of nutrients • Malabsorption- Causes nausea, vomiting and diarrhea Figure 1.2 Small Intestine 2 Low Energy State Respiratory tract • Cilia on respiratory epithelium no longer has ATP needed for motion • Cilia usually moves mucus — containing particles, pathogens, and dead cells — from distal airways up to trachea, which induces cough reflex • Without cilia function, mucus blocks airway, causing ventilation problem • Particles, pathogens, and dead cells get trapped, causing respiratory infections like bronchitis and pneumonia Figure 1.3 Respiratory Epithelium Renal • Ductal epithelium of proximal convoluted tubule (PCT) no longer has ATP needed for active transport Decreased reabsorption and secretion in PCT affects concentration of solutes and water in blood and urine 3 Low Energy State Figure 1.4 Proximal Convoluted Tubule • • PCT reabsorbs 70-80% of everything from urine filtrate If cells of PCT are non-functional due to lack of energy: o Blood concentration of solutes usually secreted into the urine will increase o Blood concentration of solutes usually reabsorbed from the urine will decrease Definitions Reabsorption: Move things from the urine back into the blood Secretion: Moving things from the blood out to the urine for excretion in the kidney 4 Low Energy State Figure 1.5 Blood Vessel Surface Figure 1.6 Bladder Wall 5 Low Energy State Uterus • • • Endometrial cells do not have enough ATP to replicate every month Results in secondary amenorrhea Without endometrial replication, there is no source of nourishment for fertilized eggs that try to implant in uterine wall, resulting in sterility Figure 1.7 Uterine Wall 6 Low Energy State Breast • • Ductal epithelium will atrophy Tissue becomes fibrous and dense Figure 1.8 Breast Tissue Figure 1.9 Sperm 7 Low Energy State Testicles • • Decreased function of epithelium of the seminiferous tubules Sperm count will be low, causing sterility Endothelium • • • • • • Technically, not a rapidly dividing cell under normal circumstances, however, becomes so when injured Injured cells become inflamed, leading to inflammation of the blood vessel wall or vasculitis Vasculitis causes tears in platelets and red blood cells (RBCs), creating schistocytes Ripped RBCs are taken out of the system, RBC count drops Ripped platelets are taken out of the system, platelet count drops If there are not enough platelets, the patient will start bleeding from skin and mucosal surfaces, causing petechiae, purpura and ecchymoses, along with GI, GU and respiratory tract bleeding Stem cells • • • Underneath all epithelium is a layer of pluri-potent stem cells In a low-energy state, stem cells are in overdrive replacing the loss rapidly dividing cells Stem cells become low energy themselves REMEMBER 3 reasons your body needs stem cells to replicate: 1. Apoptosis- scheduled cell death. Every day we lose cells that must be replaced. 2. Necrosis- unscheduled cellular death. They die by accident. 3. Mutation– When live cells have a mutation, as in cancer. This is how a low-energy state with faulty stem cells can predispose a person to cancer. Bone marrow • • Without ATP, hematopoietic stem cells cannot differentiate into other cell lines including RBCs, white blood cells and platelets Lack of these cells cause anemia, leukopenia, and thrombocytopenia, respectively 8 Low Energy State • When a toxin or drug attacks rapidly dividing cells, the most damage is done in the bone marrow because it contains the most cell lines Figure 1.10 Bone Marrow REMEMBER Cells can be classified according to how much they divide: Labile cells — Are constantly dividing. Examples: see list of rapidly dividing cells on this page Stable cells — Only divide when necessary. Examples: functional tissue of liver, pancreas; endothelial cells, fibroblasts, and smooth muscle cells Permanent cells — Cannot divide. Example: neurons, cardiac myocytes, skeletal myocytes 9 Low Energy State Less Rapidly Dividing Cells and Low Energy State Brain • • • In resting state, brain uses 60% of body’s glucose, mostly to maintain the Na+-K+ membrane potential needed for nerve-impulse transmission Lack of energy produces lethargy, somnolence, sedation, mental dullness, depression, slow thinking and then death When a brain does not have enough global energy– a child becomes mentally disabled, and an adult becomes demented Figure 1.11 Brain Cells Muscle • • • • Skeletal muscle-> generalized weakness Smooth muscle of blood vessels, GI and urinary tracts-> hypotension, impotence, constipation, and urinary retention Diaphragm-> shortness of breath Heart-> weak contractions, causing decreased contractility, decreased pulse, decreased ejection fraction, etc. leading to heart failure 10 Low Energy State Figure 1.12 Muscle Cells Consequences of Low Energy Inside the Cell Low energy is just another way of saying low ATP Definitions ATP: Adenosine triphosphate; made in mitochondria via oxidative phosphorylation, which uses an electrochemical proton gradient created across inner mitochondrial membrane to transfer electrons to oxygen How ATP is used in the cell: o Used to drive chemical reactions by creating new bonds, copy DNA and build proteins 11 Low Energy State o Used to move something  Myosin uses ATP to contract muscle fibers  A working muscle cell uses about 10 million molecules of ATP every second  Motor proteins — such as dynein and kinesin — use ATP to move along microtubules with their cargo o Used to transport solutes across a membrane as in active transport o Active transport is when a substance is transported across a cell membrane from an area of low concentration to an area of high concentration using energy, usually ATP  Examples of movement across a membrane: • Axonal transport • Moving substances from the neuron's cell body though the axon’s cytoplasm and releasing it into the synapse • Endocytosis • Form of active transport where the cell engulfs substances that are external to it and pulls them inside • Depolarization • Relies on the movement of ions across the membrane • Absorption by enterocytes in GI tract o Transport of substances — such as glucose, amino acids, and lipids  from intestinal lumen into cell Movement across a membrane requires 3 things: o ATP o Calcium o Microtubules REMEMBER Membrane movement means such things as: • • • Axonal transport Endocytosis Absorption in the GI tract “Primary active transport” is anything with an ATPase in it o Every protein with “ATPase” in it must have ATP to work  ATPases are integral membrane proteins that use active transport 12 Low Energy State o Examples: Ca2+ATPase transfers calcium after a muscle has contracted; H+/K+ATPase, also called gastric proton pump, acidifies the contents of the stomach o The most important one is Na+/K+ATPase (also called the sodium- potassium pump)  Found in all cells  Maintains cell-membrane potential  Transports Na+ out of the cell and K+ into the cell  If ATPase is nonfunctional, Na+ trapped inside and Cl- then H2O will follow, leading to cell swelling  Cell swelling is the first visible sign of cell injury Figure 1.13 Sodium/Potassium Pump 13 Low Energy State How to Create a Disease or Syndrome Disease vs. Syndrome • • A disease involves one organ A syndrome involves more than one organ. It may also be the progression of a disease. What two common symptoms of the low-energy state will bother a patient enough to visit the doctor? 1. 2. Weakness • The patient is too weak to go to work and therefore cannot make money Shortness of breath • Scares people: they think they may die Signs: what you can see on the patient • • • Tachypnea (breathing rate increased) Dyspnea (having trouble breathing) These are the most common signs of the low energy state Symptoms: what you hear the patient complain of • • • Weakness Shortness of breath These are the most common symptoms What infections will tell you that a patient is in a low-energy state? 1. 2. Pulmonary infections • Because the patient cannot move the cilia to clean out the lung Urinary tract infections • Because the patient cannot contract their bladder to empty urine and expel microbes REMEMBER How do we figure out the presentation of a disease? We must ask: What will bother a patient enough for them to see the doctor? Whatever they complain of is the presentation of the disease. Figure 1.14 Lobar Pneumonia Chest X-ray What is a complication? 14 Low Energy State • A disease will begin in one tissue or organ. However, when it affects another tissue or organ, the second tissue involvement becomes a complication. Example: heart disease is the primary disease. If the skin becomes dry because of decreased perfusion to the skin, that becomes a complication. • REMEMBER To help organize how we look at medicine, we can use a concept to create a pattern: Example: • Concept: low energy state • Pattern: Our bodies protect our organs from the top-down; they sacrifice our organs from the bottom-up In this way, one concept can be applied to many diseases. So, instead of memorizing disease mechanisms one by one, we can identify a unifying pattern. MANAGEMENT Why has the urinalysis become protocol? When a disease gets out of hand — meaning it starts to cause complications — the body will protect organs in a specific order: Brain-> Heart-> Kidney (we look at urinalysis because the kidney is the first organ to be sacrificed) When a disease starts to cause complications, the body will sacrifice organs in a specific order: Kidney-> Heart-> Brain If a patient presents with low-energy symptoms, what organ do I want to check first? • • Kidney, because it is sacrificed first o Example: In preeclampsia, what organ will go first? The kidney How do I check it? o Urinalysis-> Therefore urinalysis is done on every patient If tests show the kidney is not functioning correctly, what organ should I test? • The heart because it will be sacrificed next In an embryo, what organs develop first? • The brain, then the heart, then the kidney If something goes wrong and an embryo is malformed, what organ gets sacrificed in most genetic diseases? • The kidney-> Therefore renal problems are part of almost every pediatric syndrome 15 Low Energy State Complications of the Low Energy State • • • • • • • • • • • • • • • Dry skin Hair dry and brittle Nails brittle Bone marrow suppressed 1. red cells (anemia) 2. white cells (leukocytopenia) 3. platelets (thrombocytopenia) Endothelium atrophic Endometrium atrophic Breasts atrophic Sperm count low GI nausea, vomiting and diarrhea Renal—PCT shuts down Bladder atrophic, leading to UTI’s Respiratory tract weak cough, leading to infections Germ cells unable to replicate, leading to skin, GI, and bone marrow cancers CNS MR (children) and dementia (adults) CV heart failure due to loss of contractility REMEMBER Cancer in the low energy state: • • • The skin will be the first place to develop cancer because it is exposed to sunlight radiation. The second-place cancer will develop is the GI tract because we inhale radioactive substances out of the air, half goes through the trachea, half goes in the GI tract. We also eat radioactivity in foods. The third-place cancer will develop is the bone marrow where all toxins must circulate. What is the most common cause of death in a patient with low energy? Heart failure • • Because all the individual cardiac structures must have energy for the heart to operate as one machine o Parts of the brain can go without energy and can still operate Heart failure is most common cause of death in all patients 16 Low Energy State Figure 1.15 Dilated Heart X-ray Make the Clinical Connection: Connect the Disease to the Low Energy State Example 1: Diabetes Mellitus (a problem with insulin) In Type 1 DM, the islet cells are not working; In Type 2 DM, the receptor is not working • • • • • What do we need insulin for? To push glucose into the cells. What do the cells need glucose for? To create energy, thus it is a problem of a low- energy state Keeping the low-energy state concept in mind, can you answer the following: o What is the most common presenting symptoms of diabetes? o What are the most common signs of diabetes? o What infections do diabetics get? What are other complications might diabetics have? o Hair? Skin? Nails? GI tract? Bone marrow? Breast size? Endothelium Endometrium? Etc. Apply the entire concept! Example 2: Crohn’s disease (inflammation of the bowel) • Therefore, they cannot absorb, so they get malabsorption of nutrients. What does your body do with nutrients? Create energy. Now connect it to the low energy state. 17 Low Energy State REMEMBER The Cortisol Effect • • • When taking a test or answering a question in class, any amount of performance anxiety can induce the cortisol effect. The brain interprets performance anxiety as fear, putting the body into fight-or- flight mode. As the sympathetic system engages, epinephrine and a small amount of cortisol are released, blocking long-term memory. This means you can no longer access the information you need to answer the question. There is a 15-20 second lag time until the cortisol response takes hold. So, you have that short amount of time to access the information you need to answer the question. If you pause for too long before answering, your brain will lose access to the information, and you will start guessing at the answer or draw a blank. Putting It All Together • • • The low-energy state is a factor in 98% of illnesses Whenever in doubt, use the low energy state concept as a starting point Stop guessing on questions! 18 Chapter Two: Vitamins, Minerals, and Trace Elements The Beginning Chapter Sections: I. II. III. Vitamins Minerals Trace Elements Vitamins, minerals, and trace elements play the biggest role in enzymes. What is the role of enzymes? To help you create energy (through all the pathways). If the vitamin, mineral or trace element is missing, it will lead to a low energy state. Vitamins Vitamin A • Cofactor for parathyroid hormone function o Stimulates osteoclastic activity (calcium increases, phosphorus decreases) o Whenever PTH is involved, serum calcium and phosphorus will go in opposite directions o Calcium and the hormone always go in the same direction (except in pseudo) o If the calcium and phosphorus go in the same direction, the problem is a vitamin D issue • Used for cerebrospinal fluid (CSF) production • Used for epithelial cell maturation (anywhere) o Especially hair, skin, and eyes o Most unique function is night vision • A mild antioxidant Clinical Correlation Vitamin A is used for the maturity of cells: 1. 2. 3. 4. Measles (regenerate epithelium of lung) Cancer (T15/17) Infections that destroy cells Burn patients 19 Vitamins, Minerals, and Trace Elements The Beginning Antioxidants • • • • • • Eat up free radicals (made of oxygen, high energy molecules) Free radicals pierce the cell membrane, then the nuclear membrane and then through the DNA Cells then have only 2 choices: die or mutate If they mutate, they will cause cancer Therefore, free radicals cause cells to die or mutate Ex: cancer after radiation therapy due to free radical production Figure 2.1 Free Radicals Penetrating the Membrane 20 Vitamins, Minerals, and Trace Elements The Beginning PP Clue What is the most common cause of free radical formation? • • Infections, of which viruses are the most common Neutrophils are the cells that make free radicals, via the enzyme NADPH oxidase Vitamin A excess • Hyperparathyroidism o Calcium will go up, phosphorus will go down o Moans, groans, bones, and stones  Moans and groans are from pancreatitis, the most common severe abdominal pain  When calcium deposits into the pancreas (saponification), it will irritate the fat that is right behind the pancreas; this in turn will irritate the pancreas, causing pancreatitis o When calcium flows into the cell (concentration gradient), it is called metastatic calcification, which can also cause pancreatitis o Bones are going to hurt because the PTH is destroying the bones o Stones can be caused by the excess calcium, causing gallstones, kidney stones or calcification all throughout the body (metastatic calcification) Figure 2.2 Sodium-Calcium Gradient • Pseudotumor cerebri o Most common cause is obesity; #2 is vitamin A toxicity 21 Vitamins, Minerals, and Trace Elements The Beginning o Vitamins A, D, E, and K get stuck in the adipose tissue. One day, it lets go of it and it floods the serum. o Sign: papilledema (evidence of high intracranial pressure) o Symptom: headache o Evaluation: CT scan (shows enlarged ventricles) o Treatment: d/c vitamin A; serial LPs (see box) o Main complication: blindness o This is the only cause of increased intracranial pressure (ICP) where you do not have to worry about herniation Figure 2.3 CT Dilated Brain Ventricles Management: Headache with Papilledema- (Vitamin A Excess) If you suspect high intracranial pressure: Step 1: Rule out the worst it could be • • Mass (i.e., cancer) How? CT scan (Non-contrast first, in case it is a bleed. This way, the contrast will not leak out all over the brain and cause more damage.) Step 2: What is the next worse thing it could be? • • Infection (i.e. Meningitis) How? Lumbar puncture If dilated ventricles (+), next step will be treatment of Pseudotumor Cerebri • • • • Discontinue vitamin A Acute: serial lumbar punctures Remove ≤ 30 cc/24 hrs. until the papilledema is gone Chronic: Weight loss, carbonic anhydrase inhibitors (acetazolamide) in the meantime or mannitol, which decreases ICP acutely 22 Vitamins, Minerals, and Trace Elements The Beginning Figure 2.4 Papilledema Clinical Correlation Why remove less than 30 ccs of CSF/24 hrs.? CSF is continuous with plasma? Avoid osmotic shifts which may lead to damage of the pons. Vitamin B1: Thiamine • • • Necessary for four important enzymes: 1. Pyruvate dehydrogenase 2. Alpha-ketoglutarate dehydrogenase 3. Branched chain amino acid dehydrogenase 4. Transketolase All use thiamine pyrophosphate (TPP) The heart needs all 3 dehydrogenases; brain uses transketolase Thiamine deficiency • Wernicke’s encephalopathy (signs of increased ICP) o Wernicke’s is in the posterior Temporal Lobe; responsible for receiving Spoken or written language 23 Vitamins, Minerals, and Trace Elements The Beginning Figure 2.5 MRI of Temporal Lobe • • Wernicke’s Aphasia o Receptive aphasia Wernicke-Korsakoff Syndrome o Mamillary bodies now also involved o Confabulation (start making things up) o Unable to move short term memory into long term memory Figure 2.6 MRI Mamillary Bodies • Beriberi (heart has given out; massive dilation) o Dry beriberi (until you have heart failure) o Wet beriberi (when there is fluid in the lungs, massive ventricular dilatation) 24 Vitamins, Minerals, and Trace Elements The Beginning Test-Taking Strategy: The next step in management is a loaded question for Boards 2 (it is a multi-level question). First you must figure out what it is the patient has. Then you must figure out the pathophysiology of what they have. Then, ask yourself, what is the worst it could be, i.e. What is going to kill the patient first? Rule this out first! Figure 2.7 Angular Cheilosis Vitamin B2: Riboflavin • • Used in cofactors (like FAD) Best source is milk Riboflavin deficiency • • Sunlight breaks riboflavin down Angular cheilosis Vitamin B3: Niacin • • Necessary for cofactors (NAD, NADH, NADP, NADPH) Needed by o Pyruvate dehydrogenase o Alpha-ketoglutarate dehydrogenase o Branched chain amino acid dehydrogenase Niacin Deficiency • • Pellagra: 4 D’s o Diarrhea, dermatitis, dementia, and death Hartnup’s Disease o Presents just like pellagra o Defective renal transport of tryptophan, causing tryptophan to leak into urine o Tryptophan is needed to make niacin 25 Vitamins, Minerals, and Trace Elements The Beginning Make the Connection Carcinoid syndrome • • • Another disease that uses up tryptophan. Tryptophan is needed to make serotonin or niacin Serotonin gets excreted out rapidly, using up a lot of tryptophan. Clinical Correlation Niacin • • Blocks VLDL production in the liver, therefore treating hypertriglyceridemia (probucol also) Increases HDL better than any other drug on the market (45%) BUT has side effects: 1. Flushing and itching due to release of prostaglandins, which stimulate mast cells to degranulate and release histamine, causing itching and flushing from vasodilation Prevention: aspirin or any NSAID Treatment: antihistamines 2. Blocks insulin receptors, leading to insulin resistance 3. Competes with uric acid, causing gout Figure 2.8 Patient with Gout 26 Vitamins, Minerals, and Trace Elements The Beginning Management: Gout Acute gout • • • Most effective treatment: colchicine o Blocks microtubules, therefore blocking all rapidly dividing cells (because microtubules are needed for mitosis) o Causes bone marrow suppression and renal failure Current treatment: indomethacin o Reversibly inhibits COX 1 and 2 In case of renal failure, locally inject with an IV steroid (because colchicine and indomethacin are renally excreted) Chronic/Recurrent gout • • Allopurinol—blocks xanthine oxidase Rasburicase— a recombinant of urate oxidase (or uricase) that metabolizes uric acid • Probenecid—increases excretion of uric acid by blocking the reabsorption of uric acid Vitamin B4: Lipoic Acid • • Needed by o Pyruvate dehydrogenase o Alpha-ketoglutarate dehydrogenase o Branched chain amino acid dehydrogenase No deficiency state Vitamin B5: Pantothenic Acid • • Needed by o Pyruvate dehydrogenase o Alpha ketoglutarate dehydrogenase o Branched chain amino acid dehydrogenase o Coenzyme A No deficiency states Vitamin B6: Pyridoxine • • Needed to make heme Needed by all transaminases 27 Vitamins, Minerals, and Trace Elements The Beginning • • INH pulls pyridoxine out of the body Forms the cofactor pyridoxal phosphate Pyridoxine deficiency • Neuropathy Management: Chronic Neuropathy/Pain • • • Drug of choice is amitriptyline (TCA) o Blocks reuptake of catecholamine (so levels increase) If heart disease, drug of choice is gabapentin If shooting/stabbing neuropathy/pain, drug of choice is carbamazepine (ex: syphilis) Vitamin B9: Folate • Lasts for 24 hours • The first vitamin to run out whenever you have rapidly dividing cells • Used to make tetrahydrofolate (THF) from which you make nucleotides (Thymidine) PP Clue When are cells most rapidly dividing? 1. 2. 3. 4. Pregnancy 0-2 years of age 4-7 years of age Puberty Folate deficiency • • Megaloblastic anemia Hyper segmented neutrophils o Cytoplasm divided; nucleus did not divide but tried to, forming many segments 28 Vitamins, Minerals, and Trace Elements The Beginning Figure 2.9 Megaloblastic Cells • • Figure 2.10 Hyper segmented Neutrophils Neural tube defects in fetuses Most common cause: overcooked vegetables Clinical Correlation The order in which groups over cook their food: 1. 2. 3. 4. Black Hispanics White Asians Who has the highest life expectancy: 1. 2. 3. 4. Asians Whites Hispanics Blacks Vitamin B12: Cyanocobalamin • Lasts for 6-9 months in the liver (acts like a fat-soluble vitamin, even though it is water- soluble) • Needed by two enzymes: o Homocysteine methyltransferase  Like with B9, it is needed to make THF o Methyl malonyl-CoA mutase • Needed to recycle odd-numbered carbon fatty acids o Ex: cholesterol is a 27-C FA used to make myelin • Used to make tetrahydrofolate 29 Vitamins, Minerals, and Trace Elements The Beginning • B12 is also used in treatment of cyanide poisoning Vitamin B12 Deficiency • • • • • Deficiency occurs after 3 to 4 years Megaloblastic anemia Hyper segmented neutrophils Neuropathy, especially involving the dorsal column