USMLE STEP 1 PLATINUM NOTES

USMLE STEP 1 PLATINUM NOTES The Complete Preparatory Guide Second Edition Ashfaq UI Hassan MBBS MS Consultant Anatomy SKIMS Medical College Bemina, Srinagar, Jammu and Kashmir, India The Health Sciences Publisher New Delhi | London | Panama | Philadelphia Jaypee Brothers Medical Publishers (P) Ltd Headquarters Jaypee Brothers Medical Publishers (P) Ltd. 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 Email: jaypee@jaypeebrothers.com Overseas Offices J.P. Medical Ltd. 83, Victoria Street, London SW1H 0HW (UK) Phone: +44-20 3170 8910 Fax: +44-(0)20 3008 6180 Email: info@jpmedpub.com Jaypee-Highlights Medical Publishers Inc. 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Inquiries for bulk sales may be solicited at: jaypee@jaypeebrothers.com USMLE Step 1 Platinum Notes First Edition: 2013 Second Edition: 2016 ISBN: 978-93-5250-171-7 Printed at Contributors Ashfaq UI Hassan MBBS MS Consultant–Anatomy SKIMS Medical College Bemina, Srinagar, Jammu and Kashmir, India Prof. Showkat A Zargar MD DM (Gastroenterology) Director and Principal Sher-i-Kashmir Institute of Medical Sciences (SKIMS) Srinagar, Jammu and Kashmir, India Prof. Naseer Mir MS (Orthopedics) Professor and Head – Orthopedics Sher-i-Kashmir Institute of Medical Sciences (SKIMS) Srinagar, Jammu and Kashmir, India Dr Sheikh Manzoor Ahamed MD (Dermatology) Associate Professor and Head–Dermatology Sher-i-Kashmir Institute of Medical Sciences (SKIMS) Srinagar, Jammu and Kashmir, India Preface to the Second Edition I am extremely obliged to the Almighty Allah and no words would be enough to express my thanks to his holiness for guiding me. This book USMLE Step 1 Platinum Notes consists of complete revision material for the preparation of the USMLE examinations with important latest questions asked in these examinations and most of the students do not fare well with these questions, thus significantly lowering their scores. The book is for complete revision with special focus on the most common and most important cases asked. It covers special and important topics which are most frequently asked by the examiners. The prime focus for the students to go through the most important points and recapitulating these at the end is important for any examination and special focus for the same has been given for their benefit. Like the other series of books for the USMLE examinations being authored by me, which have had a tremendous success, I hope this effort of mine again would be helpful for the students throughout the world in their pursuit of academic excellence along with the important fact of getting a very good score in the examinations. I hope the book proves to be useful for our students to the fullest. I would encourage any aspiring student to join me for his/her contribution. Ashfaq Ul Hassan ashhassan@rediffmail.com Preface to the First Edition It gives me a great pleasure to introduce Platinum Notes for USMLE Step 1 and Step 2. A need was felt by most of the students for a comprehensive book for USMLE for preparing extensively and simultaneously getting a very good score. My efforts are directed to benefit the students to the maximum. For a student preparing, revising, forgetting and consulting different books is a part of the game. In this journey some students tend to get nervous and anxious and I thought of putting all my best efforts into one book which would make the preparation simpler, interesting, more lucid and palatable. High yield points, important topics, clinical correlations, in-depth focus on subjects, easy retention and quick revision are the points on which I have focused taking into account the latest trends of the examinations. The matter in the book is highly concentrated, needs multiple revisions and deep concentration for retention. The book has been framed to simulate the study pattern of USMLE examinations to its best. The questions in the text and after every subject are almost similar to the questions put in the actual USMLE examination which gives a student a good chance to understand the standard of USMLE as well as to prepare for the examinations in a better way. I feel that the students would be benefitted through my effort and a feedback from the students would be highly appreciated at ashhassan@rediffmail.com I wish you good luck for your academic pursuits. Ashfaq Ul Hassan ashhassan@rediffmail.com Acknowledgments No words would be enough to express my regards to Prof. Showkat A Zargar, Director, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India for his constant encouragement. I am also thankful to my father Prof. Ghulam Hassan for his constant encouragement in all my academic pursuits and guiding me throughout the process of the completion of this book. I convey my sincere thanks to Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India for their efforts and suggestions, especially Shri Jitendar P Vij (Group Chairman), Ms Chetna Vohra (Associate Director), and Ms Payal Bharti (Project Manager) for helping me through my idea. Abbreviations 1° Primary bid Twice a day 2° Secondary BMR Basal metabolic rate # Fracture BP Blood pressure ACE Angiotensin converting enzyme BPH Benign prostatic hypertrophy ACE-I Angiotensin converting enzyme inhibitor BUN Blood urea nitrogen ACTH Adrenocorticotropic hormone B/L Bilateral ACh Acetylcholine BM Bone marrow, basement membrane Adr Adrenaline b/n or b/w Between AD Autosomal dominant C/S Culture and sensitivity ADH Anti-diuretic hormone Ca Calcium AF Atrial fibrillation CABG Coronary artery bypass graft AFB Acid-fast bacilli CAD Coronary artery disease AFP Alpha-fetoprotein CCF Congestive cardiac failure A.k.a Also known as CT Computerized tomography ALL Acute lymphocytic leukemia CHF Congestive heart failure AML Acute myelogenous leukemia CHO Carbohydrate ANA Antinuclear antibody CML Chronic myelogenous leukemia ANS Autonomic nervous system CMV Cytomegalovirus AP Anteroposterior CN Cranial nerves AR Autosomal recessive CNS Central nervous system ARDS Acute respiratory distress syndrome CO Cardiac output ARF Acute renal failure C/O Complaining of AS Aortic stenosis COLD Chronic obstructive lung disease ATP Adenosine triphosphate COPD Chronic obstructive pulmonary disease ASD Atrial septal defect CPK Creatine phosphokinase AV Atrioventricular CRF Chronic renal failure A/E All except CRP C-reactive protein Acc/ to According to CSF Cerebrospinal fluid Ad/E, ad/e Adverse effects CVA Cerebrovascular accident A/W or a/w Associated with CVP Central venous pressure BBB Bundle branch block CVS Cardiovascular system 2+ xii USMLE Step 1 Platinum Notes CXR Chest X-ray FTT Failure to thrive Ca Carcinoma/Cancer FVC Forced vital capacity C/c Complication FA Fatty acid CT Chemotherapy FFA Free fatty acid C/I Contraindication GFR Glomerular filtration rate CI/f Clinical features GH Growth hormone CTD Connective tissue disease GIT Gastrointestinal tract Cont./L Contralateral GTT Glucose tolerance test Cx Cervix GU Genitourinary D and C Dilation and curettage HAV Hepatitis A virus DI Diabetes insipidus HCG Human chorionic gonadotropin DIC Disseminated intravascular coagulopathy HDL High density lipoprotein DIP Distal interphalangeal joint Hb Hemoglobin DKA Diabetic ketoacidosis HIV Human immunodeficiency virus dL Deciliter HLA Histocompatibility locus antigen DM Diabetes mellitus H/O History of DTR Deep tendon reflexes HR Heart rate DVT Deep venous thrombosis HSV Herpes simplex virus d/to Due to HTN Hypertension D/g Diagnosis HS Hereditary spherocytosis DOC Drug of choice HCC Hepato cellular carcinoma Ds, d/s Disease, disease HD Hodgkin’s disease DM Diabetes mellitus I and D Incision and drainage ECG Electrocardiogram IDDM Insulin dependent diabetes mellitus ECT Electroconvulsive therapy Ig Immunoglobulin ECHO Echocardiography IM Intramuscular EMG Electromyogram INR International normalized ratio EOM Extraocular muscles ITP Idiopathic thrombocytopenic purpura ESR Erythrocyte sedimentation rate IV Intravenous ERCP Endoscopic retrograde cholangioPancreatography IVP Intravenous pyelogram IVU Intravenous urogram EUA Examination under anesthesia ICT Intracranial tension FBS Fasting blood sugar IOC Investigation of choice FEV Forced expiratory volume ILD Interstitial lung disease FFP Fresh frozen plasma IOT Intraocular tension FRC Functional residual capacity Ipsi/L Ipsilateral Abbreviations xiii JVP Jugular venous pressure PT Prothrombin time, or physical therapy K + Potassium PTCA K/as Known as Percutaenous transluminal coronary angioplasty LAE Left atrial enlargement PTH Parathyroid hormone LBBB Left bundle branch block PTT Partial thromboplastin time LDH Lactate dehydrogenase P/g Prognosis LMN Lower motor neuron Px Prophylaxis LE Lupus erythematosus PBC Primary bilary cirrhosis LP Lumbar puncture RA Rheumatoid arthritis LV Left ventricle RBBB Right bundle branch block LVH Left ventricular hypertrophy RBC Red blood cell LN Lymph node RIA Radioimmunoassay MAO Monoamine oxidase RNA Ribonucleic acid MEN Multiple endocrine neoplasia RTA Renal tubular acidosis MI Myocardial infarction or mitral insufficiency RVH Right ventricular hypertrophy Rx Treatment mL Milliliter R, or T/t Treatment MMR Measles, mumps, rubella RT Radiotherapy MRI Magnetic resonance imaging SBE Subacute bacterial endocarditis MRSA Methicillin resistant staph aureus SGOT Serum glutamic-oxaloacetic transaminase MG Myasthenia gravis SGPT Serum glutamic-pyruvic transaminase Mc or MC Most common SIADH MN Malnutrition Syndrome of inappropriate antidiuretic hormone M/m Management SLE Systemic lupus erythematous Ms, m/s Muscle SCLC Small cell lung carcinoma Na Sodium SM Smooth muscle NIDDM Non-insulin dependent diabetes mellitus Supf. Superficial NSAID Non-steroidal anti-inflammatory drugs SqCC Squamous cell carcinoma n.or nv Nerve TIBC Total iron binding capacity NHL Non-Hodgkin’s lymphoma tid Three times a day OCG Oral cholecystogram TSH Thyroid stimulating hormone PA Posteroanterior TT Thrombin time PDA Patent ductus arteriosus TTP Thrombotic thrombocytopenic purpura PMN Polymorphonuclear leukocyte (neutrophil) TURP Transurethral resection of prostate TOC Treatment of choice Patient profile UC Ulcerative colitis PP xiv USMLE Step 1 Platinum Notes UMN Upper motor neuron V/s Vessel URI Upper respiratory infection Vs Versus (= against) US, U/S Ultrasound WBC White blood cell UTI Urinary tract infection WPW Wolff-Parkinson-White UVA Ultraviolet A light WG Wegner’s granulomatosis U/L Unilateral WT Wilm’s tumor VF Ventricular fibrillation XLR X linked recessive VDRL Venereal disease research laboratory Yr Year (test for syphilis) Zn Zinc V/Q Ventrilation-perfusion ZES Zollinger Ellison Syndrome VT Ventricular tachycardia — Reaction block by, inhibited by vWD von Willebrand’s virus ~ Denotes heading VZV Varicella zoster virus ! Increase Contents 1. Anatomy 1 2. Physiology 115 3. Biochemistry 183 4. Microbiology 237 5. Pathology 333 6. Pharmacology 451 7. Biostatistics 549 ANATOMY Anatomy 1 EMBRYOGENESIS Important Events and Their Time Sequence: (Days) •• Implantation occurs at •• 6 days •• Uteroplacental circulation establishes at •• 11–12 days •• Primitive streak appears on •• Formed from: ectoderm •• 13–15th day •• Angiogenesis •• 15th day •• Closure of anterior neuropore •• 24 days •• Embryo develops by •• 8 week •• Fetus is •• > 8 weeks Common Signaling Pathways Used during Development The differentiation of many different cell types is regulated through a relatively restricted set of molecular signaling pathways: •• Morphogens: These are diffusible molecules that specify which cell type will be generated at a specific anatomic location and direct the migration of cells and their processes to their final destination •• These Include –– Retinoic acid –– Transforming growth factor bone morphogenetic proteins (BMPs) and –– The hedgehog and the Wnt family proteins •• Notch/Delta: This pathway often specifies which cell fate precursor cells will adopt •• Transcription factors: This set of evolutionarily conserved proteins activates or represses downstream genes that are essential for many different cellular processes. Many transcription factors are members of the homeobox or helix-loop-helix (HLH) families. Their activity can be regulated by all of the other pathways described in this chapter •• Receptor tyrosine kinases (RTKs): Many growth factors signal by binding to and activating membrane-bound RTKs. These kinases are essential for the regulation of cellular proliferation, apoptosis and migration as well as processes such as the growth of new blood vessels and axonal processes in the nervous system. Fetal Landmarks (Weeks) •• Within 1 week •• Implantation •• Within 2 week •• Bilaminar disk •• Within 3 week •• Trilaminar disk Gastrulation •• Within 3 week •• Primitive streak begins to form •• Notochord forms •• Within 3–8 week •• Organogenesis •• Teratogen susceptibility maximum •• Week 10 •• Genitalia with male and female characters 4 USMLE Step 1 Platinum Notes Stem Cells (USMLE Favorite) Stem cells must be able to: •• Divide to produce sufficient cells •• Differentiate into the cell types needed •• Survive after transplant •• Mesh into the surrounding tissues •• Function properly for long enough to extend the recipient’s life or to improve it significantly •• Avoid harming the recipient Karyotyping In 1961 an international meeting was held at the University of Colorado Medical School in Denver, Colorado to standardize the format for a normal human karyotype. The format that evolved is known as the ‘Denver System.’ Each chromosome has its own individuality as shown by its size, shape, and position of its kinetochore. Using the ‘Denver System,’ the chromosomes are put into similar groups designated by letters. Then numbers are used to subdivide the chromosomes within the groups designated by numbers based on the position of the kinetochore and the length of the chromatids. The homologous chromosomes are paired based on their banding. X Chromosome belongs to group C Y Chromosome belongs to group G Group A Ch 1, 2, 3 Group B Ch 4, 5 Group C Ch 6, 7, 8, 9, 10, 11, 12, X Group D Ch 13, 14, 15 Group E Ch 16, 17, 18 Group F Ch 19, 20 Group G Ch 21, 22, Y Important Embryological Structures: High Yield Points for USMLE Meckel’s Diverticulum This true diverticulum is a remnant of the vitelline duct and often contains ectopic gastric mucosa which can cause bleeding and perforation. The Ductus Venosus It is a shunt that bypasses the liver and carries blood from the umbilical vein directly to the IVC. Its remnant is the ligamentum venosum. The Ductus Arteriosus It is a shunt that bypasses the lungs to carry blood from the pulmonary artery to the aortic arch. Its remnant is the ligamentum arteriosum. The Urachus –– Becomes the Median umbilical ligament –– The 2 umbilical arteries becomes the Medial umbilical ligaments –– Urachal fistula from persistent allantois The Vitelline Duct •• It is a connection with the yolk stalk and bowel, but normally obliterates during week 7 of development. Anatomy Fetal Structure Adult Remnant •• Right and left umbilical artery •• Medial umbilical ligament •• Left umbilical vein •• Ligamentum teres •• Ductus venosus •• Ligamentum venosum •• Foramen ovale •• Fossa ovalis •• Ductus arteriosus •• Ligamentum arteriosum Embryology of Umbilical Cord: (USMLE Favorite ) •• Connects fetus and placenta •• It is rich in Wharton’s jelly •• Has Two arteries and one vein •• Rt umbilical vein disappears, left is left •• In case of single artery only, congenital anomalies should be excluded •• Umbilical arteries carry deoxygenated blood •• Umbilical arteries do not possess internal elastic lamina •• Vas vasorum are absent in cases of umbilical vessels Female Gametogenesis •• Oogonia are derived from yolk sac •• Germ cells are derived from yolk sac •• Polar bodies are formed during oogenesis •• Polar bodies are extruded 24 hours prior to ovulation Male Gametogenesis •• Spermatogenesis occurs at temperature lower than body temperature •• Y chromosome is ACROCENTRIC •• In absence of Y chromosome ovaries develop •• Sperms are stored in epididymis •• Length of mature human sperm is 50–60 microns Chromosomal Configuration of Important Cells in Gonads Number of Chromosomes in Cells During Gametogenesis •• Primordial germ cell, oogonia, spermatogonia •• 46, 2N •• Primary oocyte, primary spermatocyte •• 46, 4N •• Secondary oocyte, secondary spermatocyte •• 23, 2N •• Oocyte, spermatid, sperm •• 23, 1N Placentation: (USMLE Favorite) Abnormalities of Placenta •• Biscoidal placenta: Placenta has two disks •• Lobed placenta: Placenta divides into lobes •• Diffuse placenta: Chorionic villi persist all around the blastocys. •• Placenta succenturiate: Small part of placenta separated from the rest 5 6 USMLE Step 1 Platinum Notes –– Fenestrated: Placenta has hole in center –– Circumvallate: Edge of placenta covered by circular fold of deciduous According to umbilical cord attachment: –– Marginal: Marginal as well as battledore placenta refers to placenta with cord attached to margins –– Furcate: Blood vessels divide before reaching the placenta –– Velemantous insertion: Blood vessels are attached to amnion where they ramify before reaching the placenta •• Oligohydramnios: Low level of amniotic fluid (< 400 ml) in renal agenesis •• Polyhydramnios: High level of amniotic fluid (>2000 ml) •• In the fourth intrauterine month the fetus begins to swallow amniotic fluid (25 to 40% of the volume) and absorbs the fluid from the upper gastrointestinal tract •• The fluid is urinated back out into the amniotic pool by the fetal kidneys and a functioning bladder. Although there are maternal causes of polyhydramnios (cardiac failure, renal failure, other causes of fluid retention) and some idiopathic cases, many instances are related to the presence of fetal anomalies. These include: •• Central nervous system problems such as anencephaly, which prevents normal swallowing, and any high alimentary tract obstruction that blocks the passage of the amniotic fluid and prevents its absorption such as: –– Esophageal atresia –– Pyloric atresia –– Duodenal atresia –– Maternal diabetes •• Amniotic band syndrome: When bands of amniotic membrane encircle and constrict parts of fetus causing limb amputations and Craniofacial anomalies USMLE Case Scenario Polyhydramnios is not seen in one of the following conditions: 1. Esophageal atresia 2. Duodenal atresia 3. Pyloric atresia 4. Hirschsprung’s disease 5. Congenital diaphragmatic hernia Ans. 4. Hirschsprung’s disease Derivatives of Germ Layers: (USMLE Favorite) Derivatives of Ectoderm •• •• •• •• •• •• Skin and most of appendages Lens of eye Epithelial linning of Lower half of anal canal Epithelial lining of external auditory meatus Epithelial lining of distal part of male urethra Adenohypophysis Derivatives of Mesoderm •• •• •• •• Musculoskeletal system Cardiovascular system Kidney, ureter Trigone of bladder (mesonephric duct absorption) Anatomy •• •• •• •• •• •• •• Posterior wall of female urethra Posterior wall of prostatic part of male urethra Reproductive tract except labia majora, minora and major part of prostate Mesothelium of pleural, pericardial and peritoneal cavities Dentine of teeth Cornea, sclera, choroid, ciliary body and iris of eye Somites from paraxial mesoderm Derivatives of Endoderm •• •• •• •• •• Epithelial lining of GIT Epithelial lining of Biliary tract Epithelial lining of Respiratory tract Epithelial lining of vagina Epithelial lining of auditory tube, middle ear Development of Lungs •• •• •• •• Glandular stage Cannalicular stage Terminal sac stage Alveolar stage 5–17 weeks 16–25 weeks 24 Weeks–birth Birth-8 years Respiration not possible Respiratory bronchioles and terminal sacs form Type I and II Pneumocytes present Respiratory bronchioles, terminal sacs, alveolar duct, alveoli↑ Embryology of Heart: (USMLE Favorite) Embryonic Structure Adult Structure •• Truncus arteriosus •• Aorta •• Pulmonary trunk •• Bulbus cordis •• Smooth part of R ventricle •• Smooth part of L ventricle Development of heart 7 8 USMLE Step 1 Platinum Notes •• Primitive ventricle •• Rough part of R ventricle •• Rough part of L ventricle •• Primitive atrium •• Rough part of R ventricle •• Rough part of Latrium •• Sinus venosus •• Smooth part of Ratrium •• Coronary sinus (Lt horn of sinus venosus) •• Oblique vein of left atrium Embryology of Thoracic Vessels Embryonic Structure Adult Structure •• Aortic arch 1 •• Aortic arch 2 •• Aortic arch 3 •• Common carotid artery •• Internal carotid artery (proximal part) •• Aortic arch 4 •• Rt. Subclavian artery (proximal part) •• Part of aortic arch •• Persistence leads to double aortic arch •• Aortic arch 5 •• Regresses •• Aortic arch 6 •• Pulmonary artery •• Ductus arteriosus Remember •• Ventral mesogastrium Lesser omentum, hepatoduodenal, hepatogastric, falciform, coronary and triangular ligament of liver •• Dorsal mesogastrium Greater omentum, mesentry of small intestine, mesoappendix, sigmoid mesocolon, transverse mesocolon Embryology of Urinary Tract: (USMLE Favorite) Embryo Adult structure •• Ureteric Bud •• Collecting duct •• Major/Minor Calyx •• Renal pelvis •• Ureter •• Epithelium of ureter from mesonephros •• Metanephric Mesoderm •• Renal glomerulus •• Bowmans capsule •• PCT •• DCT •• Loop of Henle •• Connecting tubule Anatomy Embryology of Genital Tract Gonads Ovary Testis •• Paramesonephric duct or Mullerian duct •• •• •• •• •• Appendix testis •• Mesonephric ‘duct’ or Wollfian duct Appendix vesiculosa Duct of Garnier Epididymis ductus deferens Seminal vesicles Ejaculatory ducts Appendix epididymis •• Mesonephric ‘tubules’ Epoophoron Paroophoron Efferent ductules Paradidymis •• Phallus Clitoris Glans penis •• Urethral folds Labia minora •• Genital swellings Labia majora Uterine tubes Uterus Cervix Hydatid of morgagni Scrotum USMLE Favorite Embryonic Structure •• •• •• •• Genital ridge Genital swelling Genital fold Genital tubercle Female Male Ovary L majora L minora Clitoris Testis Scrotum Ventral aspect of penis Glans penis Testicular Descent •• Iliac fossa 3rd month •• Deep inguinal ring 7th month •• Pass through inguinal canal 7th month •• At superficial inguinal ring 8th month •• Enter scrotum 9th month Derivatives of Neural Crest •• Neurons of spinal posterior nerve root ganglia •• Neurons of sensory ganglia •• Neurons of autonomic ganglia (sympathetic ganglia) •• Schwann cells •• Melanocytes •• Piamater and arachnoid matter •• Mesenchyme of dental papillae •• Cartilage cells of branchial arches •• Chromaffin tissue 9 10 USMLE Step 1 Platinum Notes Defective Migration of Neural Crest Cells Results in •• •• •• •• •• Albinism Melanoma Hirschsprungs disease Oropharyngeal teratoma Neurocristopathies (Cleft Lip, Cleft palate, Digeorges syndrome, Waarden burgs syndrome, Charge syndrome Tumors of Neural Crest Origin •• •• •• •• •• Neuroblastoma Pheochromacytoma Carcinoid tumor Neurofibromatosis Medullary carcinoma thyroid USMLE Case Scenario A newborn boy does not pass meconium until 45 hours after his birth. Several weeks later his well educated mother complains that he has not been passing stool regularly. Anorectal manometry reveals increased internal anal sphincter pressure on rectal distention with a balloon. The patient’s disorder maybe attributed to distention with a balloon. The patient’s disorder maybe attributed to: 1. Defective recanalization of the colon 2. Failure of neural crest cells to migrate 3. Herniation of abdominal contents into the umbilical cord 4. Persistence of the proximal end of the yolk stalk 5. Persistence of processus vaginalis 6. Failure of gastrulation Ans. 2. Failure of neural crest cells to migrate Pharyngeal Apparatus (USMLE Favorite) •• Pharyngeal Arches are derived from Mesoderm •• Pharyngeal clefts are derived from Ectoderm •• Pharyngeal Pouches are derived from Endoderm Five pharyngeal arches Anatomy Pharyngeal Arch 1 Derivatives •• Meckels Cartilage: –– Mandible –– Malleus –– Incus –– Sphenomandibular ligament •• Muscles: Muscles of mastication (Medial pterygoid and lateral pterygoid, masseter, temporalis) •• Two Tensors (Tensor tympani, tensor palati) •• Mylohyoid, anterior belly of digastrics Pharyngeal Arch 2 Derivatives (Word S) •• Reicherts Cartilage: –– Stapes –– Styloid process –– Smaller cornu of Hyoid Bone –– Superior surface of Hyoid Bone –– Stylohyoid ligament •• Muscles of facial expression, Stapedius, Stylohyoid, Posterior Belly of Digastric •• Platysma Pharyngeal Arch 3 Derivatives •• Greater cornu of Hyoid Bone •• Stylopharyngeus muscle Think of Stylopharyngeus when thinking about Glossopharyngeal Nerve Pharyngeal arch 4 and 6 Derivatives •• Cartilages of larynx •• Intrinsic muscles of larynx and pharynx PHARYNGEAL ARCH 5 DOES NOT CONTRIBUTE TO DEVELOPMENT Nerve Supply of Pharyngeal arches is: My Father gave me Some Rupees •• •• •• •• •• Mandibular nerve Ist arch Facial nerve 2nd arch Glossopharyngeal nerve 3rd arch Superior laryngeal nerve 4th arch Reccurent laryngeal nerve 6th arch Treacher-Collins syndrome/Mandibulofacial dysostosis •• Abnormal formation of pharyngeal arch •• Faulty migration of neural crest cells 11 12 USMLE Step 1 Platinum Notes Patients are mostly characterized by the following abnormalities •• Hypoplasia of the facial bones: An underdeveloped mandibular and zygomatic bone leading to a small and malformed jaw •• Ear anomalies: Consist small, rotated or even absent ears with or without bilateral stenosis or atresia of the external auditory canals •• Eye problems: Varying from colobomata of the lower eyelids and aplasia of lid lashes to short, downslanting palpebral fissures and missing eyelashes. Vision loss can occur and is associated with strabismus, refractive errors, and anisometropia •• Cleft palate •• Airway problems: Which are often results of mandibular hypoplasia •• Dental anomalies: Consist in tooth agenesis, enamel disformaties and malplacement of the maxillary first molars. Less Frequent Defects •• Nasal deformity •• High-arched palate •• Coloboma of the upper lid •• Ocular hypertelorism •• Choanal atresia •• Macrostomia •• Preauricular hair displacement Pharyngeal Pouch Adult Structure •• Pharyngeal Pouch 1 •• Epithelial linning of Auditory tube/Middle ear •• Pharyngeal Pouch 2 •• Palatine tonsil •• Pharyngeal Pouch 3 •• Inferior parathyroid and Thymus •• Pharyngeal Pouch 4 •• Superior parathyroid and Ultimobranchial body •• Para follicular cells are derived from ultimobranchial body Pharyngeal Cleft/Groove Adult Structure •• 1 •• External linning of External auditory meatus •• 2, 3, 4 •• Obliterated Cleft Lip and Cleft Palate: (USMLE Favorite) Cleft Lip: •• Failure of Fusion of Maxillary and Medial Nasal Process •• Usually associated with cleft palate. (Commonest) •• Midline cleft lip is due to failure of fusion of two medial nasal processes •• Cleft Palate: Failure of fusion of lateral palatine process, nasal septum and median palatine process (occasional) Cleft Lip and Cleft Palate (Detailed Overview) Unilateral cleft lip. Also called Harelip •• Failure of fusion of medial nasal process with maxillary process Midline defect of upper lip •• Defect in development of lowermost part of frontonasal process Midline defect of lower lip •• Defective fusion of mandibular processes Anatomy Microstomia •• Excessive fusion of maxillary and mandibular processes Macrostomia •• Inadequate fusion of maxillary and mandibular processes Oblique facial cleft •• Non fusion of maxillary and lateral nasal process Tongue Development •• 1st pharyngeal arch forms ant 2/3 •• 3 rd and 4 th arch forms post 1/3 •• Muscles of tongue develop from occipital myotomes •• Muscles of tongue are both smooth and skeletal muscles •• Muscles of tongue are supplied by hypoglossal nerve •• Safety muscle of tongue is genioglossus Genioglossus •• •• •• •• Tip of tongue drains to submental lymph nodes Posterior 1/3 of tongue is supplied by glossopharyngeal nerve Pain of cancer base of tongue is also reffered to ear through glossopharyngeal nerve Circumvallate pappilae of tongue are supplied by glossopharyngeal nerve Development of tongue 13 14 USMLE Step 1 Platinum Notes General Features of Tongue •• •• •• •• •• •• •• •• •• Anterior 2/3 of tongue develops from lingual swellings and tuberculum impar Anterior 2/3 of tongue is supplied by chorda tympani (FACIAL) (taste) Anterior 2/3 of tongue is supplied by lingual nerve (general) Anterior 2/3 of tongue drains into submandibular lymph nodes Posterior 1/3 of tongue develops from hypobranchial eminence Posterior 1/3 of tongue is supplied by glossopharyngeal nerve (taste) Posterior 1/3 of tongue is supplied by glossopharyngeal nerve (general) Posterior 1/3 of tongue drains into jugulo omohyoid lymph nodes Tip drains into submental lymph nodes Tonsil: (USMLE Favorite) •• •• •• •• •• •• •• Has nonkeratinized squamous epithelium It is an endodermal structure Rests on superior constrictor muscle of pharynx Vagus supplies tonsil Main nerve supply is the glossopharyngeal nerve Lymph drains into jugulo digastric nodes Arterial supply: –– Ascending palatine –– Descending palatine and –– Ascending pharyngeal artery supply tonsils Diaphragm Development •• •• •• •• Septum transversum Pleuroperitoneal folds Body wall Dorsal mesentry of esophagus Development of Intra-abdominal Organs Frequently Asked Spleen It is unique in respect to its development within the gut. While most of the gut viscera are endodermally derived (with the exception of the neural-crest derived suprarenal gland), the spleen is derived from mesenchymal tissue. Specifically, the spleen forms within, and from, the dorsal mesentery. Pancreas The pancreas develops between the layers of the mesentery from dorsal and ventral pancreatic buds of endodermal cells, which arise from the caudal or dorsal part of the foregut. Most of the pancreas is derived from the dorsal pancreatic bud. The larger dorsal pancreatic bud appears first and develops a slight distance cranial to the ventral bud. The liver, gallbladder and the biliary duct system arise as a ventral outgrowth (hepatic diverticulum) from the caudal foregut in the 4th week •• This hepatic diverticulum extends into septum transversum, a mass of splanchnic mesoderm between the developing heart and the midgut •• The septum transversum forms the ventral mesentery in this region. This double-layered membrane gives rise to the lesser omentum and the falciform ligament •• The superior layers of the coronary and left triangular ligaments meet and continue as a ventral mesentery attached to the ventrosuperior aspect of the liver Gallbladder arises from pars cystica (from the hepatic bud) Anatomy 15 Embryology of Nervous System •• The nervous system develops from the neural plate which appears at the beginning of the third week as thickening of the ectoderm •• Its lateral edges soon elevate to form the neural folds •• With further development, the neural folds continue to elevate, and form a tube known as neural tube •• The neural tube has an enlarged cranial part that forms the brain, and a narrow caudal part that becomes the spinal cord •• The wall of the neural tube at first has a single layer of cells. They multiply and form three layers- ependymal, mantle and marginal layer Neural tube closure begins at cephalic end The mantle layer divides into a •• Ventral part, the basal lamina and •• Dorsal part, the alar lamina, separated by a groove, the sulcus limitans Alar plate gives rise to sensory areas of the spinal cord and the sensory nuclei Basal plate forms the motor areas of the spinal cord and motor nuclei The cerebellum and its nuclei develop from the dorsal parts of the alar plate Inferior olivary and Substantia nigra are sensory nuclei and thus derived from the alar plate Hypoglossal is a motor nuclei and develops from the basal plate The Wall of the Spinal Cord Neuroepithelial Layer Mantle Layer Marginal Layer •• These cells extend over the •• Once the neural tube closes, •• entire thickness of the wall and neuroepithelial cells begin to give rise form a thick PSEUDOSTRATIFIED to another cell type. EPITHELIUM The outermost layer of the spinal cord, the marginal layer, contains nerve fibers emerging from neuroblasts in the mantle layer. •• Junctional complexes at the •• These cells are characterized by •• lumen connect them a large round nucleus with pale nucleoplasm and a dark- staining nucleolus. These are primitive nerve cells, or NEUROBLASTS. As a result of myelination of nerve fibers, this layer takes on a white appearance and therefore is called the white matter of the spinal cord. •• After closure of neural tube, •• they divide rapidly, producing more and more neuroepithelial cells They form the mantle layer, a zone around the neuroepithelial layer. The mantle layer later forms the gray matter of the spinal cord. Remember Forebrain (Prosencephalon) Telencephalon Cerebral hemispheres Diencephalon Thalamus Hypothalamus Posterior Pituitary Pineal body No division Tectum Metancephalon Cerebellum Pons Myelencephalon Medulla No division Spinal cord Midbrain (Mesencephalon) Hindbrain (Rhombencephalon) Remainder of neural tube 16 USMLE Step 1 Platinum Notes Development of brain 3rd ventricle develops from diencephalon 4th ventricle develops from rhombencephalon Myelination •• Myelin is formed in the central nervous system by oligodendrocytes •• There are no myelinated fibers in the CNS before the end of the fifth fetal month •• There is no myelination of the forebrain until the seventh fetal month. Most myelination in the telencephalon occurs in the third trimester and postnatally •• The first neurones to acquire myelin sheaths are the olfactory, optic and acoustic cortical areas and the motor cortex (pyramidal cells) •• The last to be myelinated are the projection commissure and association neurons of the cerebral hemispheres •• Myelination is a critical process for the development of the brain because it enhances the speed of neural communication. It occurs most rapidly during the first 2 years of life, but continues until early adulthood In CNS Myelin is produced by Oligodendrocyte A single oligodendrocyte myelinates as many as 20 or 30 different CNS axonal segments, each over a length of 1 mm or less Oligodendrocyte membrane extensions wrap around the axons in a concentric fashion to form the myelin sheath. Myelin proteins include proteolipid protein, myelin basic protein, myelin-associated glycoprotein, and a number of less abundant proteins detectable by electrophoretic separation Active myelin synthesis starts in utero and continues for the first 2 years of life; slower synthesis continues during childhood and adolescence. High Yield USMLE Points Lately Asked Developmental Anomalies of Lungs •• Lobe of Azygos Vein: This lobe appears especially in the right lung in approximately 1% of people. It develops when the apical bronchus grows superiorly, medial to the arch of the azygos vein and produces a linear marking on a radiograph of the lungs •• Sequestration of lung: Lung tissue getting trapped in the core of a lobe is called as intralobar sequestration. Lung tissue completely separated from tracheobronchial tree replacing complete lobe is lobar sequestration •• Potters Syndrome: It is pulmonary Hypoplasia with renal agenesis. Anatomy 17 Developmental Anomalies of Thyroid •• Thyroglossal Duct Cysts and Sinus: Normally, the thyroglossal duct atrophies and disappears, but a remnant of it may persist and form a cyst in the tongue or in the anterior part of the neck, usually just inferior to the hyoid bone. •• Most thyroglossal duct cysts are observed by the age of 5 years. The swelling produced by a thyroglossal duct cyst usually develops as a painless, progressively enlarging, movable mass. The cyst may contain some thyroid tissue. •• After infection of a cyst, a perforation of the skin occurs, forming a thyroglossal duct sinus that usually opens in the median plane of the neck, anterior to the laryngeal cartilages. •• Ectopic Thyroid Gland: An ectopic thyroid gland is usually located along the course of the thyroglossal duct. Lingual thyroid tissue is the most common of ectopic thyroid tissues. Other sites: –– Larynx –– Trachea –– Esophagus –– Pericardium –– Pleura –– Ovaries Struma Ovary: •• It is a rare ovarian tumor defined by the presence of thyroid tissue •• Most commonly, they occur as part of a teratoma, but may occasionally be encountered with serous or mucinous cystadenomas •• Benign strumosis is a rare version of mature thyroid tissue implants throughout the peritoneal cavity Teratoma (ovary) •• A 10-year-old girl with round 1 cm mass in midline of neck moving with •• Throglossal duct cyst movement of tongue •• A 15-year-old girl with round 1 cm on side of neck beneath and in front of •• Branchial cyst sternocleidomastoid. •• A 6-year-old with fluid filled translucent mass in supraclavicular area •• Cystic hygroma Developmental Anomalies of Tongue Ankyloglossia: The lingual frenulum normally connects the inferior surface of the tongue to the floor of the mouth. Sometimes the frenulum is short and extends to the tip of the tongue. This interferes with its free protrusion and may make breastfeeding difficult. A short frenulum usually stretches with time, making surgical correction of the anomaly unnecessary. Macroglossia: An excessively large tongue is not common. Amyloidosis is associated with Macroglossia •• Microglossia: An abnormally small tongue is extremely rare and is usually associated with micrognathia (underdeveloped mandible and recession of the chin) and limb defects (Hanhart’s syndrome) •• Bifid Tongue •• Fissured tongue 18 USMLE Step 1 Platinum Notes Developmental Anomalies of Larynx •• Laryngeal Atresia: This anomaly results from failure of recanalization of the larynx, which causes obstruction of the upper fetal airway. Distal to the region of atresia (blockage) or stenosis (narrowing), the airways become dilated, the lungs are enlarged and echogenic •• Laryngeal web: Results from incomplete recanalization of the larynx during the 10th week. A membranous web forms at the level of the vocal folds, partially obstructing the airway •• Laryngoptosis: Larynx is situated lower down in neck •• Laryngeocele: Excessive enlargement of saccule of larynx. Developmental Anomalies of Trachea •• Tracheoesophageal Fistula: –– A fistula between the trachea and esophagus –– Most affected infants are males –– In more than 85% of cases, the tracheoesophageal fistula (TEF) is associated with esophageal atresia –– A TEF results from incomplete division of the cranial part of the foregut into respiratory and esophageal parts during the fourth week –– Incomplete fusion of the tracheoesophageal folds results in a defective tracheoesophageal septum and a TEF between the trachea and esophagus Polyhydramnios is often associated with esophageal atresia. The excess amniotic fluid develops because fluid cannot pass to the stomach and intestines for absorption and subsequent transfer through the placenta to the mother’s blood Developmental Anomalies of Cardiovascular System •• Ectopia cordis: Non union of sternal plates exposing the heart to surface •• Dextrocardia: If the heart tube bends to the left instead of to the right, the heart is displaced to the right and there is transposition — the heart and its vessels are reversed left to right as in a mirror image. Dextrocardia is the most frequent positional abnormality of the heart. In isolated dextrocardia, the abnormal position of the heart is not accompanied by displacement of other viscera •• Maybe associated with Situs Inversus/ Kartageners Syndrome/Immotile Cilia Syndrome •• Atrial Septal Defects: An atrial septal defect (ASD) is a common congenital heart anomaly and occurs more frequently in females than in males. The most common form of ASD is patent oval foramen. A small isolated patent oval foramen is of no hemodynamic significance; however, if there are other defects (e.g. pulmonary stenosis or atresia), blood is shunted through the oval foramen into the left atrium and produces cyanosis. •• Ventricular Septal Defects: VSDs are the most common type of CHD, accounting for approximately 25% of defects. VSDs occur more frequently in males than in females. VSDs may occur in any part of the IV septum but membranous VSD is the most common type frequently, small VSDs close spontaneously. Most people with a large VSD have massive left-to-right shunting of blood. Muscular VSD is a less common type of defect and may appear anywhere in the muscular part of the interventricular septum. Sometimes there are multiple small defects, producing what is sometimes called the ‘Swiss cheese’ VSD. •• Cor biloculare: Two chambered heart •• Cor Triloculare: Three chambered heart •• L. Cor triloculare biatriatum: (Two atria, one ventricle): Absence of the IV septum-single ventricle or common ventricle-resulting from failure of the IV septum to form is extremely rare and results in a three-chambered heart (L. cor triloculare biatriatum). •• Transposition of the Great Arteries: TGA is the most common cause of cyanotic heart disease in newborn infants. TGA is often associated with other cardiac anomalies (e.g. ASD and VSD). In typical cases, the aorta lies anterior and to the right of the pulmonary trunk and arises from the morphologic right ventricle, whereas the pulmonary trunk arises from the morphologic left ventricle. The aorticopulmonary septum fails to pursue a spiral course during partitioning of the bulbus cordis and TA This defect is thought to result from failure of the conus arteriosus to develop normally during incorporation of the bulbus cordis into the ventricles Recent studies suggest that defective migration of neural crest cells may also be involved. Anatomy 19 •• Tetralogy of Fallot: This classic group of four cardiac defects –– Pulmonary stenosis (Obstruction of right ventricular outflow) –– VSD –– Dextroposition of aorta (Overriding or straddling aorta) –– Right ventricular hypertrophy •• Coarctation of the Aorta: Aortic coarctation (constriction) occurs in approximately 10% of children and an adult with CHDs. Coarctation is characterized by an aortic constriction of varying length. Most coarctations occur distal to the origin of the left subclavian artery at the entrance of the DA (juxtaductal coarctation). The classification into preductal and postductal coarctations is commonly used. Coarctation of the aorta occurs twice as often in males as in females and is associated with a bicuspid aortic valve in 70% of cases. Developmental Anomalies of Lymphatic System •• Cystic hygroma: Large swellings usually appear in the inferolateral part of the neck and consist of large single or multilocular, fluid-filled cavities. Hygromas maybe present at birth, but they often enlarge and become evident during infancy. Most hygromas appear to be derived from abnormal transformation of the jugular lymph sacs –– Represents lymphatic venous anastamotic failure –– Located usually in the neck at lower in posterior triangle –– Brilliantly translucent Developmental Anomalies of GIT •• Esophageal Atresia: Esophageal atresia is associated with tracheoesophageal fistula in more than 85% of cases. Atresia may occur as a separate anomaly, but this is less common. Esophageal atresia results from deviation of the tracheoesophageal septum in a posterior direction as a result there is incomplete separation of the esophagus from the laryngotracheal tube. A fetus with esophageal atresia is unable to swallow amniotic fluid; consequently, this fluid cannot pass to the intestine for absorption and transfer through the placenta to the maternal blood for disposal. This results in polyhydramnios Tracheoesophageal fistula •• Esophageal Stenosis: Narrowing of the lumen of the esophagus can be anywhere along the esophagus, but it usually occurs in its distal third, either as a web or as a long segment of esophagus with a thread like lumen. Stenosis usually results from incomplete recanalization of the esophagus. •• Short Esophagus (Congenital Hiatal Hernia): Initially the esophagus is very short. Its failure to elongate sufficiently as the neck and thorax develop results in displacement of part of the stomach superiorly through the esophageal hiatus into the thoraxcongenital hiatal hernia. Most hiatal hernias occur long after birth, usually in middle-aged people. 20 USMLE Step 1 Platinum Notes •• Dysphagia Lusoria: Abberant vessels compressing esophagus leading to dysphagia. Usually Abnormal right subclavian artery is implicated. •• Duodenal Atresia: Complete occlusion of the lumen of the duodenum. If recanalization of the lumen fails to occur a short segment of the duodenum is occluded. The blockage occurs nearly always at the junction of the bile and pancreatic ducts (hepatopancreatic ampulla) but occasionally involves the horizontal (third) part of the duodenum. •• In infants with duodenal atresia, vomiting begins a few hours after birth. The vomitus almost always contains bile; duodenal atresia may occur as an isolated anomaly, but other congenital anomalies are often associated with it, e.g. anular pancreas cardiovascular abnormalities, anorectal anomalies, and malrotation. Importantly, approximately one third of affected infants have Down syndrome and an additional 20% are premature. Duodenal atresia is associated with bilious emesis (vomiting of bile) because the blockage occurs distal to the opening of the bile duct. Polyhydramnios also occurs because duodenal atresia prevents normal intestinal absorption of swallowed amniotic fluid. The diagnosis of duodenal atresia is suggested by the presence of a ‘double bubble‘ sign on plain radiographs or ultrasound scans. This appearance is caused by a distended, gas-filled stomach and proximal duodenum. •• Riedels Lobe: A tongue like extension of right lobe of liver. •• Phrygian cap: Fundus of the gallbladder folded upon itself giving rise to an appearance of cap worn by people of an ancient Asian community of Phrygia. •• Moynihans Hump: Normally the arterial supply of gallbladder is from cystic artery which is a branch of Right hepatic artery. Sometimes an accessory cystic artery is also seen to arise from either Gastroduodenal or right hepatic artery The Right hepatic artery takes a tortuous course called ‘caterpillar turn’ or ‘Moynihans hump.’ This can be a source of profuse bleeding. •• Intrahepatic gallbladder is one of the ectopic locations of the gallbladder. The gallbladder is usually intrahepatic during its embryologic period and becomes extrahepatic later on in its development. In adults approximately 60% of intrahepatic gallbladders are associated with gallstones •• Double and Triple gallbladders have been reported, the latter being extremely rare. Double gallbladders may share a common cystic duct and be completely separated, or they maybe divided by a septum. When they do not share a common outlet, the cystic ducts of double or triple gallbladders open separately into the common bile duct or, less commonly, into the right hepatic duct •• Choledochal Cyst: Choledochal cysts are congenital cystic dilatations of the extrahepatic and/or intrahepatic biliary tree. They are rare. Originally, they were described as cystic dilatations of the extrahepatic duct system. Subsequently this classification was extended to include the frequent association with cystic dilatation of the duct system within the liver, a condition described in 1958 and now known as Caroli’s disease. •• Extrahepatic Biliary Atresia: This is the most serious anomaly of the extrahepatic biliary system and occurs in one in 10,000 to 15,000 live births •• The most common form of extrahepatic biliary atresia is obliteration of the bile ducts at or superior to the porta hepatis •• Biliary atresia could result from a failure of the remodeling process at the hepatic hilum or from infections or immunologic reactions during late fetal development •• Jaundice occurs soon after birth and stools are acholic (clay colored). •• Accessory Pancreatic Tissue: Accessory pancreatic tissue is most often located in –– The wall of the stomach –– Wall of duodenum –– In an ileal diverticulum a/Meckel diverticulum •• Anular Pancreas: –– May cause duodenal obstruction –– The ring like or anular part of the pancreas consists of a thin, flat band of pancreatic tissue surrounding the descending or second part of the duodenum. –– An anular pancreas may cause obstruction of the duodenum either shortly after birth or later. Infants present with symptoms of complete or partial bowel obstruction. An anular pancreas maybe associated with –– Down syndrome –– Intestinal atresia –– Imperforate anus –– Pancreatitis –– Malrotation Anatomy 21 •• Congenital Omphalocele: This anomaly is a persistence of the herniation of abdominal contents into the proximal part of the umbilical cord. Herniation of intestines and herniation of liver and intestines occurs •• Infants with these large omphaloceles often suffer from pulmonary and thoracic hypoplasia and a delayed closure is a better clinical decision. The covering of the omphalocele is by amnion and peritoneum. •• Umbilical Hernia: When the intestines return to the abdominal cavity during the 10th week and then herniate through an imperfectly closed umbilicus, an umbilical hernia forms. This common type of hernia is different from an omphalocele. In an umbilical hernia, the protruding mass (usually the greater omentum and part of the small intestine) is covered by subcutaneous tissue and skin. The defect through which the hernia occurs is in the linea alba. The hernia protrudes during crying, straining, or coughing and can be easily reduced through the fibrous ring at the umbilicus. Surgery is not usually performed unless the hernia persists to the age of 3 to 5 years. •• Gastroschisis: This anomaly is a relatively uncommon congenital abdominal wall defect. Gastroschisis results from a defect lateral to the median plane of the anterior abdominal wall. The linear defect permits extrusion of the abdominal viscera without involving the umbilical cord. The viscera protrude into the amniotic cavity and are bathed by amniotic fluid. Anomalies of the Midgut •• Nonrotation occurs when the intestine does not rotate as it re-enters the abdomen. As a result, the caudal limb of the midgut loop returns to the abdomen first and the small intestines lie on the right side of the abdomen and the entire large intestine is on the left and the cecum lies just inferior to the pylorus of the stomach. The cecum is fixed to the posterolateral abdominal wall by peritoneal bands that pass over the duodenum. These bands and the volvulus (twisting) of the intestines cause duodenal obstruction. When midgut volvulus occurs, the superior mesenteric artery maybe obstructed, resulting in infarction and gangrene of the intestine supplied by it. Infants with intestinal malrotation are prone to volvulus and present with bilious emesis. •• Reversed Rotation: In very unusual cases, the midgut loop rotates in a clockwise rather than a counterclockwise direction. As a result, the duodenum lies anterior to the superior mesenteric artery rather than posterior to it, and the transverse colon lies posterior instead of anterior to it. In these infants, the transverse colon maybe obstructed by pressure from the superior mesenteric artery. Development of gut •• Congenital Megacolon or Hirschsprung Disease: Infants with congenital megacolon or Hirschsprung’s disease lack autonomic ganglion cells in the myenteric plexus distal to the dilated segment of colon (Hirschsprung’s disease is the congenital absence of enteric neurons in the submucosal and myenteric plexuses, due to an arrest of the embryonic caudal migration of the enteric neurons along the gut. The aganglionic segment remains contracted, dilating the proximal normal bowel The severity of symptoms and the age at diagnosis are related to the length of the aganglionic segment. Involvement of the rectum or additional parts of the colon results in constipation or obstipation in infancy, requiring emergent resection of the a ganglionic bowel and a pull-through anastomosis to the anus.) 22 USMLE Step 1 Platinum Notes •• Imperforate Anus and Anorectal Anomalies: Imperforate anus occurs approximately once in every 5000 newborn infants and is more common in males. Most anorectal anomalies result from abnormal development of the urorectal septum, resulting in incomplete separation of the cloaca into urogenital and anorectal portions. There is normally a temporary communication between the rectum and anal canal dorsally from the bladder and urethra ventrally but it closes when the urorectal septum fuses with the cloacal membrane. •• Anal Agenesis, with or without a Fistula: The anal canal may end blindly or there maybe an ectopic anus or an anoperineal fistula that opens into the perineum. The abnormal canal may, however, open into the vagina in females or the urethra in males. •• Anal Stenosis: The anus is in the normal position, but the anus and anal canal are narrow. This anomaly is probably caused by a slight dorsal deviation of the urorectal septum as it grows caudally to fuse with the cloacal membrane. As a result, the anal canal and anal membrane are small. USMLE Case Scenario Embryologically, The Gut rotates and the rotation occurs in a way that: 1. The large intestine rotates in a clockwise manner around the axis of the celiac trunk 2. The large intestine rotates in a clockwise manner around the axis of the superior mesenteric artery 3. The large intestine rotates in a clockwise manner around the axis of the inferior mesenteric artery 4. The large intestine rotates in a counterclockwise manner around the axis of the celiac trunk 5. The large intestine rotates in a counterclockwise manner around the axis of the superior mesenteric artery 6. The large intestine rotates in a counterclockwise manner around the axis of the inferior mesenteric artery Ans. 5. The large intestine rotates in a counterclockwise manner around the axis of the superior mesenteric artery Derivatives of fore, mid and hindgut Developmental Anomalies of Urinary Tract •• Horseshoe Kidney: In 0. 2% of the populations, the poles of the kidneys are fused; usually the inferior poles fuse. The large U-shaped kidney usually lies in the hypogastrium, anterior to the inferior lumbar vertebrae. Normal Persons with Turner’s syndrome have horseshoe kidneys. •• Ectopic Ureter: An ectopic ureter does not enter the urinary bladder. In males, ectopic ureters usually open into the neck of the bladder or into the prostatic part of the urethra, but they may enter the ductus deferens, prostatic utricle, or seminal gland. In females, ectopic ureters may open into the –– Bladder neck –– Urethra –– Vagina –– Vestibule of the vagina Anatomy 23 •• An ectopic ureter: Results when the ureter is not incorporated into the trigone in the posterior part of the urinary bladder. Instead it is carried caudally with the mesonephric duct and is incorporated into the middle pelvic portion of the vesical part of the urogenital sinus. Cystic Kidney Diseases •• In autosomal recessive polycystic kidney disease, diagnosed at birth or in utero by ultrasonography, both kidneys contain many hundreds of small cysts which result in renal insufficiency. •• Multicystic dysplastic kidney disease results from dysmorphology during development of the renal system. The outcome for children with multicystic dysplastic kidney disease is generally good because the disease is unilateral in 75% of the cases. In multicystic dysplastic kidney disease, fewer cysts are seen than in autosomal recessive polycystic kidney disease and they range in size from a few millimeters to many centimeters in the same kidney. •• Congenital Adrenal Hyperplasia (CAH): An abnormal increase in the cells of the suprarenal cortex results in excessive androgen production during the fetal period. In females, this usually causes masculinization of the external genitalia. Affected male infants have normal external genitalia, and the syndrome may go undetected in early infancy. Later in childhood in both sexes, androgen excess leads to rapid growth and accelerated skeletal maturation. CAH is a group of autosomal recessive disorders that result in virilization of female fetuses. Developmental Anomalies of Genital System •• Mesonephric Duct Remnants in Males The cranial end of the mesonephric duct may persist as an appendix of the epididymis, which is usually attached to the head of the epididymis Caudal to the efferent ductules, some mesonephric tubules may persist as a small body, the paradidymis. It forms –– Epididymis –– Ductus deferens –– Seminal vesicles –– Ejaculatory ducts –– Appendix epididymis •• Mesonephric Duct Remnants in Females The cranial end of the mesonephric duct may persist as an appendix vesiculosa. A few blind tubules and a duct, the epoophoron, correspond to the efferent ductules and duct of the epididymis in the male. The epoophoron may persist in the mesovarium between the ovary and uterine tube. Closer to the uterus, some rudimentary tubules may persist as the paroophoron. Parts of the mesonephric duct, corresponding to the ductus deferens and ejaculatory duct, may persist as Gartner’s duct cysts between the layers of the broad ligament along the lateral wall of the uterus and in the wall of the vagina. •• Paramesonephric Duct Remnants in Males The cranial end of the paramesonephric duct may persist as a vesicular appendix of the testis, which is attached to the superior pole of the testis The prostatic utricle, a small saclike structure that opens into the prostatic urethra, is homologous to the vagina. •• Paramesonephric Duct Remnants in Females •• Part of the cranial end of the paramesonephric duct that does not contribute to the infundibulum of the uterine tube may persist as a vesicular appendage it forms –– Uterus –– Cervix –– Uterine tubes –– Hydatid of morgagni 24 USMLE Step 1 Platinum Notes Appendages around testis •• Cryptorchidism or Undescended Testes –– The term cryptorchidism (Greek cryptos = hidden, orchis = testis) should be reserved for impalpable, usually abdominal, testes –– There is a higher incidence of undescended testes in premature than in full-term babies –– Two-thirds of undescended testes in newborn infants will descend, usually by 6 weeks in term and 3 months in preterm babies –– There is an increased incidence of cryptorchidism in anencephalics and other cerebral anomalies. •• Ectopic Testes: After traversing the inguinal canal, the testis may deviate from its usual path of descent and lodge in various abnormal locations –– Interstitial (external to aponeurosis of external oblique muscle) –– In the proximal part of the medial thigh –– Dorsal to the Penis –– On the opposite side (crossed ectopia) –– Exstrophy of the bladder results from a rare ventral body wall defect through which the posterior wall of the urinary bladder protrudes onto the abdominal wall. Epispadias is a common associated anomaly in males; the urethra opens on the dorsum of the penis. Developmental Anomalies of CNS •• Spina Bifida: The original defect lies in the vertebrae when their laminae fail to cover the spinal cord dorsally. Spina bifida maybe simple or complicated. Complicated Spina bifida is associated with involvement of the cord and its membranes •• Rarely do the two halves of the vertebral body fail to fuse and the spinal cord protrudes anteriorly through the gap. This rarity is called as anterior spina bifida •• Spina bifida occulta: Here the spinal cord is normal. The defect is not manifest externally and usually a tuft of hair is present on the skin over the affected area •• Meningocele: The Arachnoid and the Piamater covering the spinal cord protrude through the opening of the bifid spine and form a cystic swelling •• Meningomyelocele: Here the spinal cord along with its meninges and the spinal nerves are seen to protrude. It is a more serious condition owing to development of infection of the cord itself •• This condition is associated with displacement of medulla and a part of cerebellum which cause obstruction of the foramen magnum producing hydrocephalus. An association of hydrocephalus and Meningomyelocele is called Arnold Chiari malformation •• Syringomyelia: Once the central canal of the spinal cord is distended with excessive fluid it is called Syringomyelia •• Myelomalacia: Abnormal softening of spinal cord. Usually seen after trauma to spinal cord Anatomy 25 Syringomyelia •• In Syringomyelia there is softening of the spinal cord and the central canal becomes very wide at lesion in this position will interrupt the pain and temperature fibers which pass in front of the central canal as they cross from one side to another •• Syringomyelia usually occurs in the lower cervical and the upper thoracic regions of the spinal cord and the loss of pain and temperature •• Only the fibers of the pain and temperature which pass in front of the central canal are injured: the lateral spinothalamic tracts ‘themselves’ remain normal and there is no loss of pain and temperature in the lower limbs •• Touch can be felt in the area of the skin in which pain and temperature are lost: this condition in which pain and temperature is lost while touch is nearly normal called Dissociated sensory loss. USMLE Case Scenario Which of the following embryonic structures gives rise to the adrenal cortex? 1. Ectoderm 2. Endoderm 3. Mesoderm 4. Mesonephros Ans. 3. Mesoderm Types of Neurons Based on Poles Unipolar Neurons They have only one pole Both Axon and Dendrons arise by a common stem. Present in •• Fetal life •• Posterior root ganglion •• Sensory nucleus of the fifth cranial nerve Bipolar Neurons They have two poles Axon and Dendron lie at opposite poles Present in •• •• •• •• Cochlear ganglion of the eight nerves Vestibular ganglion of the eight nerves Retina Olfactory nerve Multipolar Neurons They have multiple poles The Axon and all other Dendrons form multiple poles Present in •• The spinal cord •• Cerebral cortex •• Cortex of cerebellum 26 USMLE Step 1 Platinum Notes Important Changes in Phases of Cell Cycle •• •• •• •• •• •• •• Leptotene: Chromosomes become visible Zygotene: Pairing of chromosomes Pachytene: Tetrad formation, crossing over, chiasmata formation Diplotene: Chromosomes break Metaphase: Spindle formation Anaphase: Chromosomes move from equator to poles Telophase: Chromosomes move completely to opposite sides Sex Chromatin or Barr body Of the two X-chromosomes in a Female only one is functionally active. The other (Inactive) X-chromosome forms a mass of heterochromatin that lies just under the nuclear membrane. This mass of heterochromatin can be identified in suitable preparations and can be useful in determining whether a particular tissue belongs to a male or a female. Because of this association with sex this mass of heterochromatin is called the SEX CHROMATING. It is also called a BARR-BODY after the name of the scientist who first discovered it. Sex chromatin •• In NEURONS it forms a rounded mass lying very close to the nucleolus and is therefore called a NUCLEOLAR SATELLITE. •• In NEUTROPHIL LEUCOCYTES it may appear as an isolated round mass attached to the rest of the nucleus by a narrow band, thus resembling the appearance of a DRUM-STICK. Rarely, some individuals may have more than two X-chromosomes. In these cases only one X-chromosome is active (and hence euchromatic) while others are represented by masses of heterochromatin. •• In normal females XX •• There is one barr body •• In normal males XY •• There is no barr body •• In Turners Syndrome XO •• There is no barr body •• In males with Klienfilters syndrome XXY •• There is one barr body •• In super female XXX •• There are two barr bodies •• The number of Barr bodies is (X-1) Cell Division The number of chromosomes found in somatic cells is constant and is termed the diploid (2n) number. Each gamete, however, has only half the diploid number and is said to be haploid (n). In order to maintain this regularity, two types of cell division occur: mitosis, which is the cell division occurring in somatic tissues during growth and repair, and meiosis, which is the specialized form of cell division occurring when gametes form. Mitosis The function of mitosis is to distribute and maintain the continuity of the genetic material in every cell of the body. This process consists of a number of different phases, which results in an equal distribution of the chromosomes to the two daughter cells. The cell cycle has four stages: mitosis (M), gap1 (G1), synthesis (S), and gap2 (G2). The G1 phase follows mitosis, during which RNA and protein synthesis occurs. S is the period during which DNA replication takes place and the DNA content of the cell doubles, and G2 is the period during which energy requirements for cell division are built-up and any repair of errors in DNA synthesis takes place. Anatomy 27 Meiosis This process occurs only during the formation of the gametes and results in four daughter cells, each with the haploid number of chromosomes. In males each primary spermatocyte forms four functional spermatids that develop into sperm, while in females each oocyte forms only one ovum, the remaining products of meiosis being nonfunctional polar bodies. Lyonization In females, the sex chromosomes are identical in size and are genetically homologous chromosomes (as in the case of autosomes); however, in the normal diploid interphase cell, one of the X’s forms a condensed heterochromatic body called the Barr body. These condensations, together with evidence from coat color pattern in mice, led Lyon to hypothesize X-inactivation. She Stated –– In each somatic cell there is inactivation of all but one of the X-chromosomes; –– This process occurs early in development and is random with respect to maternally or paternally derived X-chromosomes in different cells; and –– Once a particular X is inactive, it is inactive in all daughter cells. Important Points about Skin •• •• •• •• 1. 2. 3. 4. The Skin has stratified squamous epithelium Classically epidermis has four layers Normal turn over of epidermis is 4 weeks Skin doubling time is 4 weeks Stratum Germinativium composed of stratum Basale and Stratum Spinosum Stratum Granulosum (Granular cell layer) Stratum Lucidum (Clear cell layer) Stratum Corneum (horny cell layer) 1. Stratum Germinativium is also called as Malphigian layer composed of (a) Basal cell layer (b) Prickle cell layer (stratum spinosum) The Basal cell layer is composed of single layer of columnar cells resting on a clear wavy basement membrane From the basal borders of these cells Cytoplasmic processes extend anchoring the epidermis to dermis Melanocytes are present here. –– Acantholytic cells are present here –– Dermatophytes are present here –– It is underdeveloped in VLBW infants The prickle cell layer (stratum spinosum) consists of 4–6 layers of cells which are polygonal and connected together by tonofilaments giving them a prickly appearance. 2. Stratum Granulosum –– Consists of 3–4 layers of flattened cells rich in keratohyaline granules –– The keratohyaline granules eventually fill much of the cell, and it is these granules which give the cells of the stratum Granulosum its granular appearance –– The keratohyaline granules contain a protein called filaggrin, the function of which appears to be to bind the tonofibrils together, converting them into keratin 3. Stratum Lucidum –– Consists of few layers of dead, non nucleated cells without cell boundaries –– These cells are rich in Eleidin granules 4. Stratum Corneum –– It is the most superficial layer of epidermis –– It is made of flat, dead cornified cells which have horny scales –– They are continuously shed from the surface and replaced by newer cells 28 USMLE Step 1 Platinum Notes •• The Dermis is formed of CT present beneath the epidermis. It is made of two layers continuous with each other •• The Papillary layer or the loose connective tissue layer •• The Reticular layer or the deeper layer The Hypodermis is continuous with the dermis. It is formed of loose CT rich in blood vessels, loose CT, nerve endings. Cells in Skin are ‘Langerhans Cells’ •• Are located primarily in the stratum spinosum •• They function in the immune system as antigen presenting cells •• They stain selectively with gold chloride and contain numerous rod like or racket-shaped Cytoplasmic granules (Birbeck’s granules) ‘Merkel Cells’ •• Are located in the stratum basale •• They contain granules which contain catecholamines •• The base of a Merkel cell makes contact with the expanded terminal disk of a nerve fiber, forming a special receptor which functions as a mechanoreceptor (detection of touch) ‘Dendritic Cells’ •• Are found throughout the epidermis •• They are antigen presenting cells EPITHELIUM Simple Squamous Epithelium •• Alveoli of lungs •• Mesothelium of pleura, peritoneum and pericardium •• Endothelium of heart and blood vessels Simple Cuboidal Epithelium •• Lining of the thyroid follicles •• Germinal epithelium of ovary •• Anterior surface of lens of eye Simple Columnar Epithelium •• The lining of stomach •• Intestines •• Gallbladder Simple Columnar Ciliated •• Fallopian tubes and the uterus •• Central canal of spinal cord •• Osseous part of eustachian tube Anatomy 29 Pseudostratified Columnar (Pseudo: False, Stratified: Layered) It is a simple type of columnar cells resting on a clear wavy basement membrane. The cells are crowded over each other and appear multilayered. The nuclei are arranged at different levels, some situated basal and others centrally as a result of which a false impression of multilayered cells is created. However, most of the cells reach the basement membrane. The cells maybe ciliated or nonciliated With cilia •• Nasal cavity, nasal air sinuses, nasopharynx, larynx, trachea and bronchi •• Eustachian tube in its cartilaginous parts Without cilia •• Vas deferens •• Part of male urethra Stratified Squamous Epithelium The surface of the cells maybe keratinized (Protective function) as in case of •• Epidermis of skin •• External ear •• External nose The surface of the cells maybe without keratin called Nonkeratinized as in case of •• Esophagus •• Tongue •• True vocal cords •• Cornea •• Tonsil Stratified Columnar Epithelium •• Conjunctival fornicies •• Penile part of male urethra •• Anorectal junction Transitional Epithelium •• •• •• •• It is a type of epithelium composed of multiple cell layers They have extra reserve of cell membrane The top cell layers are broader The intermediate cell layers are polyhedral without intercellular bridges separated by mucus like substance. The cells can undergo transition in relaxed and contracted state. In the relaxed state the number of layers is 6–8 while as in the contracted state it is 2–3 layers •• The basal cell layers are cuboidal. It is present in •• •• •• •• •• Calyces Ureter Urinary bladder UV junction Male urethra 30 USMLE Step 1 Platinum Notes Salivary Glands Gland Duct Type of Gland Duct opening •• Parotid •• Stensens duct •• Serous Vestibule of mouth opposite second upper molar •• S u b m a n d i - •• Whartons duct bular •• Mixed but predominantly serous On the floor of mouth on summit of sublingual papilla at the side of frenulum of tongue •• Sublingual •• Mixed but predominantly mucus On the floor of mouth on summit of sublingual papilla •• Bartholins duct Structures within Parotid Gland •• External carotid artery •• Retromandibular vein •• Facial nerve Questions Frequenly asked from Histology of Liver •• Classic Hepatic Lobule: This model is based on the direction of blood flow. In sections, liver substructure exhibits a pattern of interlocking hexagons; each of these is a classic lobule. Whereas lobules in pigs are defined by a sheath of connective tissue, there is less connective tissue in humans and the lobule boundaries are indistinct. The central vein at its center and the alternating hepatocyte plates and sinusoids that lie between them. •• Portal Canal/triad: One triad occupies a potential space (portal space) at each of the 6 corners of the lobule. Each triad contains 3 main elements surrounded by connective tissue: a portal venule (a branch of the portal vein), a hepatic arteriole (a branch of the hepatic artery) and a bile ductule (a tributary of the larger bile ducts). A lymphatic vessel may also be seen. In the portal canal blood vessels and bile ductules are separated by a space called as Space of Mall •• Portallobule: This model is based mainly on the direction of bile flow, which is opposite to that of blood. From this perspective, the liver parenchyma is divided into interlocking triangles, each of which has a portal triad at the center and a central vein at each of its 3 comers •• Hepatic lobule: It is the structural unit of liver. It has a central vein. A single vein marks the center of each lobule. This vessel is easily distinguished from those in the portal triad by its larger opening and lack of a connective tissue investment. –– Kuffercells are Reticuloendothelial cells of liver –– Itto cells are fat storing cells in liver –– 'Space of Dissie’ and ‘Space of Mall’ are seen in Liver Important Histological Features: (USMLE Favorite) •• Hassals corpuscles •• Thymus •• Corpora amaylacea •• Prostate •• Corpora atretica •• Ovary •• Germinal center •• Lymph node •• Corpora aranacea •• Pineal gland •• Herring bodies •• Pituitary gland •• Cords of Billiroth •• Spleen Cells of Stomach The Mucus neck cells •• Called so as they are present in the necks of glands •• They secrete mucin which serves as a protective layer against HCL Anatomy 31 •• They appear pale because of dissolved mucin •• They are low columnar with basal flat nuclei The Chief cells (The Peptic cells or the Zymogen cells) •• Called as chief because they line the main part of the body of the gland •• They are low columnar with basal round nuclei •• They secrete pepsinogen Oxyntic Cells (Parietal Cells) •• They are scattered in between peptic cells •• They are highly acidophilic •• Intrinsic factor of Castle is secreted by parietal cells •• They secrete HCL •• They contain secretory canaliculi and are rounded The Argentaffin Cells •• They are chromaffin positive and stain positive with Silver salts •• They also contain acidophilic granules and are oval in shape Cells of Intestine Simple Columnar Cells •• Line the villi and crypts •• Have free brush border due to presence of microvilli to increase surface area Goblet Cells •• Are also present in the villi and crypts •• They are unicellular glands •• They are flask shaped •• They secrete mucin Paneth Cells •• Are acidophilic •• Secrete intestinal enzymes •• Rich in Rough ER Argentaffin cells •• These are cells with silver staining properties •• They secrete serotonin Diffuse Lymphatic Tissue, Isolated Lymphatic Nodules The diffuse lymphatic tissue is a collection of lymphatic tissue in: •• Alimentary tract •• Respiratory tract •• Genitourinary tract The lymphoid tissue is deposited randomly in the subepithelial layers and placed strategically so as to detect and destroy the pathogenic agents instantaneously and effectively. Located in adventitia Functioning in close collaboration is other set of localized concretions of lymphocytes in the form of follicles and nodules such as: •• Pharyngeal tonsils •• Palatine tonsils •• Lingual tonsils •• Peyers patches in the small intestine especially in the ileum •• Lymphoid follicles in appendix/abdominal tonsil 32 USMLE Step 1 Platinum Notes In the alimentary canal the diffuse and the local lymphatic systems combine synergistically to form the GUT ASSOCIATED LYMPHOID TISSUE (GALT). The main function of this system is to act along with the main lymphatic organs. Remember frequently asked Terms in USMLE Eponyms Description Bowman’s capsule Glomerular capsule of the kidney seen on histology slides Bowman’s membrane Layer in the cornea below epithelium seen on histology slides Brunner’s glands Glands in the duodenum seen on histology slides Bundle of His Atrioventricular bundle Cords of Billroth Splenic cords of the spleen seen on histology slides Crypts of Lieberkuhn Epithelial glands in the small intestine seen on histology slides Descemet’s membrane Limiting layer of the cornea seen on histology slides Ducts of Bellini Papillary duct of the kidney seen on histology slides Ducts of Luschka Small ducts found in the connective tissue between the gallbladder and the liver Golgi aparatus Intracellular organelle Golgi tendon organ Sensory nerve ending embedded in a tendon for proprioception Graafian follicle Tertiary follicle of an ovary seen on a histology slide Haversian canal Central canal of an osteon of bone seen on a histology slide Haversian system Osteon of bone seen on a histology slide Islets of Langerhans Pancreatic islets of the pancreas seen on histology slides Leydig cells Interstitial cells of the testis Loop of Henle U shaped loop in the nephron of the kidney Krause end bulbs Cylindrical/oval sensory receptor Malpighian corpuscle Renal corpuscle of the kidney seen on histology slides Meissner’s corpuscle Mechanoreceptor Meissner ‘s plexus Submucosal plexus Merkel’s disk Tactile receptor Moll’s gland Glands of the conjunctiva Nissl bodies Rough endoplasmic reticulum of a neuron Node of Ranvier Area between two Schwann cells covering nerve fibers with axon which is not covered by myelin Organ of Corti Small organ of sound transduction; spiral organ Pacinian corpuscle Lamellar corpuscle Peyer’s patches Aggregates of lymphatic tissue in the ileum seen on histology slides Purkinje fibers Part of the conducting system of the heart Renal columns of Bertin Renal columns seen on histology slides Ruffini’s corpuscle Sensory receptor Space of Disse Perisinosoidal space of the liver seen on histology slides Volkmann’s canals Perforating canals of bone Wharton’s jelly Mucous connective tissue seen in umbilical cord Anatomy HIGH YIELD CLINICAL ANATOMY Upper Limb Brachial Plexus •• C5 and C6 roots join to form the upper trunk •• C7 root alone forms the middle trunk •• C8 and T1 roots join to form the lower trunk Each trunk divides into an anterior and posterior division: •• All the posterior divisions join to form the posterior cord •• The upper two anterior divisions join to form the lateral cord •• The lowest anterior division alone forms the medial cord Branches of the Brachial Plexus Branches from the roots •• Nerve to serratus anterior (C5,C6,C7) •• Dorsal scapular nerve (C5) •• Muscular branches to the 3 scalene muscles Branches from the trunks •• Suprascapular nerve (C5,C6) •• Subclavius nerve (C5,C6) Branches from the cords Medial cord •• Medial head of median nerve (C8, T1) •• Medial pectoral (C8, T1) •• Ulnar nerve (C8, T1) •• Median cutaneous nerve of forearm (C8, T1) •• Medial cutaneous nerve of arm (T1) Lateral cord •• Lateral pectoral (C5, C6, C7) •• Lateral head of median (C5, C6, C7) •• Musculocutaneous (C5, C6, C7) Posterior cord •• •• •• •• •• Radial (C5, C6, C7, C8, T1) Axillary (C5, C6) Nerve to latissimus dorsi (C6, C7, C8) Subscapular Upper (C5, C6) Subscapular lower Upper trunk deformity is called •• Erbs palsy or policemans •• Waiters tip •• Porter tip deformity Lower trunk deformity is called Klumpkes palsy 33 34 USMLE Step 1 Platinum Notes Questions frequently asked from Nerves of Upper Limb Ulnar nerve ‘Musicians Nerve’ •• Ulnar nerve supplies medial 1/3 of palm. (Hypothenar area) •• Ulnar nerve in hand supplies: –– 3, 4 Lumbricals –– Palmar and dorsal interosei –– Adductor pollicis –– Hypothenar muscles •• Ulnar nerve in hand supplies flexor carpi ulnaris and medial half of flexor digitorum profundus Lesion of ulnar nerve causes: –– Weakness of ulnar deviation –– Weakness of wrist flexion –– Adductor pollicis paralysis with loss of thumb adduction In Ulnar Nerve Palsy there is •• Positive card test •• Positive book test/Froment sign •• Positive Egawas test •• Ulnar claw hand Median nerve: ‘Laborers nerve’, Eye of hand •• Does not supply arm •• Supplies all flexors except flexor carpi ulnaris and medial half of flexor digitorum profundus in forearm •• Supplies thenar eminence –– Lumbrical 1 and 2 –– Opponens pollicis –– Abductor pollicis brevis –– Flexor pollicis brevis in hand. (LOAF) Implicated in: Lunate dislocation •• Ape thumb deformity •• Carpal tunnel syndrome •• Pointing index •• Pen test is positive in median nerve injury •• Loss of opposition and abduction of thumb Carpal Tunnel Syndrome Affects the median nerve. Patients often note a tingling, a loss of sensation, or diminished sensation in the digits. There is also often a loss of coordination and strength in the thumb, because the median nerve also sends fibers to the abductor pollicis brevis, flexor pollicis brevis, and the opponens pollicis. A final function of the median nerve distal to the carpal tunnel is control of the first and second lumbricals which function to flex digits two and three at the metacarpophalangeal joints and extend interphalangeal joints of the same digits. Anatomy 35 Radial Nerve Supplies: •• Extensor compartment of arm, forearm •• Triceps •• Anconeus and extensors of forearm. Extension of MCP joint •• Injury to RN Causes –– Wrist drop –– Saturday night palsy/crutch palsy •• Commonly injured in Radial groove USMLE Case Scenario A 43-year-old man suffered an injury in his left upper limb. His radial nerve was injured. The radial nerve is at greatest risk for injury with: 1. Fracture of the surgical neck of the humerus 2. Fracture of the shaft of the humerus 3. Supracondylar fracture of the humerus 4. Olecranon fractures Ans. 2. Fracture of the shaft of the humerus Remember The radial nerve lies in proximity to the humerus as it courses laterally at the junction of the middle and distal thirds of the shaft of the humerus. Therefore, it is at greatest risk of injury in shaft fractures. Common Questions in Surgical Anatomy (Hot Questions) •• In ‘supracondylar fracture’ of humerus triangular relationship of three bony prominences is not disturbed. In elbow dislocation it is disturbed •• The ‘shoulder joint’ is the most commonly dislocated major joint in the body •• MC dislocation is inferior •• In subacromial bursitis, person feels pain when arm is abducted. ‘Dawbarns sign’ is seen in subacromial bursitis •• PIN (Posterior interosseous nerve) is a branch of radial nerve. No wrist drop is seen in injury to PIN •• If posterior medial aspect of elbow is banged against a hard object, it mat cause temporary ulnar nerve damage. This may result in painful tingling sensations along ulnar aspect of forearm and hand. Because of these sensations, this area of elbow is called ‘Funny bone/Crazy bone’ •• Eye of hand: median nerve. Enables the individual to feelthinness and texture of cloth •• Pronator syndrome: compression of Median nerve between two heads of pronator teres •• Infection of pulp spaces is Felon/Whitlow REMEMBER USMLE Favorite Important Nerves Involved in •• •• •• •• •• •• •• Wrist drop Foot drop Meralgia parasthetica Winging of scapula Erbs Palsy Klumpkes palsy Sluders neuralgia •• •• •• •• •• •• •• Radial nerve palsy Common peroneal nerve palsy Lateral cutaneous nerve of thigh Long thoracic nerve of bell Upper trunk of brachial plexus Lower trunk of brachial plexus Middle turbinate pressing anterior ethmoidal nerve 36 USMLE Step 1 Platinum Notes The Axillary Nerve •• The Axillary nerve is a branch of the posterior cord of the brachial plexus It is particularly susceptible to the injury in shoulder dislocations that displace the humeral head or in fracture of the surgical neck of the humerus A poorly placed crutch (Crutch Palsy) may also damage this nerve causing paralysis of the Teres minor and Deltoid muscles •• Arm abduction is impaired and there is associated loss of sensation over the lower half of the deltoid •• When the head of the humerus dislocates from the glenohumeral joint, it exits inferiorly, where the joint capsule is the weakest. Immediately inferior to the glenohumeral joint, the axillary nerve exits from the axilla by passing through the quadrangular space. At this location, the downward movement of the head of the humerus can stretch the axillary nerve. The axillary nerve innervates the deltoid muscle after leaving the axilla. •• The Lower Subscapular nerve innervates the Teres major, which is responsible for adducting and medially rotating the arm, it is a branch of the posterior chord (C5 C6) of the brachial plexus. •• The Suprascapular nerve innervates the Supraspinatus and Infraspinatus muscle that are responsible for abduction and lateral rotation of the arm. The nerve is derivated from the C5 and C6 nerve roots In shoulder abduction: Humerus elevates Clavicle rotates Lateral rotation of scapula occurs along with acromioclavicular joint movement. •• The Throacodorsal nerve innervates the latissimus dorsi muscle that is responsible from adduction and extension of the arm. The nerve arises from the posterior chord (C5, C6, C7) of the brachial plexus •• Musculocutaneous nerve supplies (BBC) biceps, bracialis and corocabrachialis. •• Brachioradialis is supplied by radial nerve. Effects caused by Injuries of Important Nerves of Upper Limb •• Musculocutaneous nerve Muscles of anterior compartment of arm •• Median nerve Muscles of anterior compartment of forearm Supplies Biceps, corocabrachialis, brachialis •• Injury causes loss of elbow flexion and weakness in supination. Injury to median nerve at wrist causes: •• Ape thumb deformity •• Pen test for abductor pollicis brevis •• Inability to count on fingers with thumb •• Axillary nerve Deltoid and teres minor Injury causes •• Loss of abduction of shoulder •• Rounded contour of shoulder is lost •• Sensory loss over lower half of deltoid •• Radial nerve Posterior muscles of arm and forearm Injury causes •• Saturday night palsy •• Crutch palsy •• Wrist drop Fracture surgical neck of humerus dislocation of shoulder Fracture of humeral shaft Anatomy 37 USMLE Case Scenario Deltoid is a thick muscle. It arises from the anterior border and superior surface of the lateral third of the clavicle. Which of the following nerves innervates the deltoid? 1. Radial 2. Musculocutaneous 3. Ulnar 4. Anterior interosseous c nerve 5. Cranial nerve XI 6. Subscapular 7. Axillary Ans. 7. Axillary Nerve Action of Various Muscles of Upper Limb •• Flexors of forearm: Biceps, brachialis, brachioradialis •• Extensors of arm: Triceps, Anconeus •• Muscles attached to greater tubercle: Supraspinatus, infraspinatus, teres minor •• Muscles attached to lesser tubercle: subscapularis •• Muscles attached to coracoid process: biceps, short head of biceps –– Abductors of shoulder joint: Deltoid, serratus anterior, trapezius –– Adductors of shoulder joint: pectoralis major, lattismus dorsi Cleidocranial Dysostosis •• Defective intramembranous ossification •• Agenesis of clavicle and deformity of skull cap Four Rotator Cuff Muscles are Supraspinatus Infraspinatus Teres minor Subscapularis Remember: Clinical Anatomy (USMLE Favorite) •• •• •• •• •• •• •• •• •• Frozen shoulder Dropped shoulder Chronic supraspinatus tendinitis Tennis elbow Golfers elbow Base pitchers elbow De quevarians disease Trigger finger Mallet finger •• •• •• •• •• •• •• •• •• Is adhesive capsulitis or periarthritis Paralysis of trapezius Is painful arc syndrome Is lateral epicondylitis Is medial epicondylitis Is damage to soft tissues/bones around elbow Is tenosynovitis of Extensor pollicis brevis and abductor pollicis longus Is thickening of tendon sheaths at metacarpophalyngeal joint Is avulsion of extensor tendon of distal interphalangeal joint 38 USMLE Step 1 Platinum Notes The ‘Anatomical Snuffbox’ •• Triangular depression formed on the posterolateral side of the wrist and metacarpal I by the extensor tendons passing into the thumb •• Historically, ground tobacco (snuff ) was placed in this depression before being inhaled into the nose •• The base of the triangle is at the wrist and the apex is directed into the thumb. The impression is most apparent when the thumb is extended: •• The lateral border is formed by the tendons of the abductor pollicis longus and extensor pollicis brevis; •• The medial border is formed by the tendon of the extensor pollicis longus; •• The floor of the impression is formed by the scaphoid and trapezium and distal ends of the tendons of the extensor carpi radialis longus and extensor carpi radialis brevis. Structures inside: Remember essentially: •• The radial artery passes obliquely through the anatomical snuffbox •• Terminal parts of the superficial branch of the radial nerve pass subcutaneously over the snuffbox •• Origin of the cephalic vein from the dorsal venous arch of the hand Volkmans Ischemic Contracture (Features) (P) •• •• •• •• •• Pallor Pain (Most important sign) Paralysis Parasthesias Pulselessness Median nerve mostly involved with Deformity: Flexion of wrist, Extension of Fingers at MCP, Flexion at IP and Pronation of forearm. Flexor digitorum profundus and Flexor Pollicis Longus are muscles damaged. Dupuytrens contracture Progressive, Painless, Puckeringor fibrosis of skin of Palmar Fascia with flexion of MCP joints of ring and little fingers Colles Fracture •• Fall on outstretched hands, Common in elderly women •• Distal fragment displaced dorsally, Angulated dorsally, supinated and is also called as ‘Dinner Fork’ Deformity De Quervain syndrome Also known as washerwoman’s sprain or mother’s wrist is a tendinosis of the sheath or tunnel that surrounds two tendons that control movement of the thumb. (Extensor pollicis brevis and abductor pollicis longus muscles). De Quervain is potentially more common in women; the speculative rationale for this is that women have a greater styloid process angle of the radius. Symptoms are pain, tenderness, and swelling over the thumb side of the wrist, and difficulty gripping. Finkelstein’s test is used to diagnose de Quervain syndrome in people who have wrist pain. Scaphoid Fracture Scaphoid is one of the Carpal bones which undergo fracture commonly as well as avascular necrosis. Avascular necrosis of ‘proximal’ fragment is seen Injury occurs by fall on outstretched hands. MC site of injury is ‘Waist’ Tenderness in ‘Anatomical snuff box’ maybe seen. Best Radiological view is Oblique view In absence of Radiological findings, suspect scaphoid fracture. Most common site is between proximal 1/3 and distal 2/3. Anatomy 39 Action of Various Muscles of Lower Limb Hip joint •• Medial rotator of thigh: Gracilis •• Lateral rotators of femur are: Obturator internus, Obturator externus Sartorius, Pyriformis Superior gemellus, inferior gemellus •• Abductors of the hip include the gluteus medius and gluteus maximus •• Adductors of the hip include the adductors longus, brevis and magnus •• Extensors of hip include gluteus maximus •• Internal (medial) rotators of the hip include gluteus medius, minimus, Tensor facia lata •• Lateral rotators: quadriceps femoris (rectus femoris, vastus lateralis, medialis and intermedius) •• Iliopsoas is flexor of hip Remember: •• Tensor fascia lata is extensor of knee, Abductor and medial rotator of hip. (Imp) TEAM •• Ilio tibial tract is flexor, external rotator, abductor of hip. (Imp) Knee Joint •• Extensor of knee: quadriceps femoris •• Flexion of knee: long head of biceps femoris. Semimembranosus, semitendonosus, ischial head of adductor magnus •• Medial rotation: Semimembranosus, semitendonosus, popliteus •• Lateral rotation: biceps femoris Important Points: (USMLE Favorite) •• Meralgia Parasthetica Lateral cutaneous nerve of thigh •• Anterior Tarsal Tunnel Syndrome: Deep peroneal nerve •• Tarsal Tunnel syndrome: Tibial nerve •• Joggers Foot: Medial plantar nerve •• Hip Pointer: Iliac Crest •• Tennis Leg: Gastrocnemius Soleus strain Hip Joint •• •• •• •• Ileo femoral ligament is ligament of Bigelow It is the strongest ligament It prevents hyperextension of hip Pain of hip is referred to knee joint Knee •• •• •• •• •• Coronary ligament is present between menisci and tibial condyle There is other Coronary ligament in liver Posterior dislocation of Femur is prevented by anterior cruciate ligament Posterior cruciate ligament prevents posterior dislocation of Tibia Ligament of Humphery and Wrisberg are anterior and posterior meniscofemoral ligaments 40 USMLE Step 1 Platinum Notes MENISCAL TEAR •• Medial meniscus is 20 times more prone to injury than lateral meniscus. The medial meniscus is firmly adherent to the deep part of tibial collateral ligament. In forceful strains (adduction and lateral rotation of the femur over the tibia with the foot firmly placed on the ground) the medial meniscus gets torn. It is because: •• The medial collateral ligament does not allow the meniscus to move away from under the femoral condyle •• It gets compressed crushed between femoral and tibial condyles that are moving with great force •• Part of torn cartilage may get displaced. This small piece floats in the joint cavity. It may get lodged between femoral and tibial condyles causing locking of knee joint in flexed position Arterial Supply of Hip Joint •• •• •• •• •• Obturator artery Medial circumflex artery Lateral circumflex artery Superior gluteal artery Inferior gluteal artery In Fracture Neck of femur, Blood supply is from these vessels. USMLE Case Scenario A 88-year-old osteoporotic female who was a chronic smoker stumbled and fell. The right leg is shortened and externally rotated with marked loss of range of movements at hip joint The most likely cause is: Fracture Neck of femur Nerve Supply of Hip Joint •• •• •• •• Femoral nerve through nerve to rectus femoris Anterior division of obturator nerve Nerve to quadrates femoris Superior gluteal nerve Arterial Supply of Knee Joint •• •• •• •• •• Genicular branches of popliteal artery Genicular branches of femoral artery Genicular branches of lateral circumflex femoral artery Branches of anterior tibial artery Branches of posterior tibial artery Nerve Supply of Knee Joint •• Femoral nerve through nerve to vasti •• Posterior division of obturator nerve •• Sciatic nerve through tibial and common peroneal nerves Nerves Related to Lower Limb Compartments: (USMLE Favorite) •• •• •• •• Adductor compartment of thigh: Obturator nerve Flexor compartment of thigh: Femoral nerve Posterior compartment of thigh (hamstrings); tibial part of sciatic nerve Gluteal region: superior and inferior gluteal nerves Anatomy 41 •• Anterior compartment of leg: Deep peroneal nerve •• Lateral compartment of leg: Superficial peroneal nerve •• Posterior compartment of leg: Tibial nerve Nerves of Lower Limb •• Femoral nerve (posterior division of L2, L3, L4) Anterior compartment of high •• Obturator nerve (anterior division of L2, L3, L4) Medial compartment of thigh •• Tibial nerve Posterior compartment of thigh Posterior compartment of leg •• Common peroneal nerve Short head of biceps femoris •• Superficial peroneal nerve Lateral compartment of leg Injury causes loss of eversion of foot •• Deep peroneal nerve Anterior compartment of leg Injury causes foot drop Superior gluteal nerve (Very Important) Gluteus minimus, gluteus medius, tensor fascia lata NOT Gluteus maximus. Injury Causes loss of abduction of limb Impairment of gait Patient cannot keep pelvis level when standing on one leg. Tredlenburgs sign + Inferior gluteal nerve Gluteus maximus. Injury causes: Weakened hip flexion Difficulty rising from sitting position. •• Q angle: Quadriceps angle is formed by line of pull of quadriceps femoris muscle and that of ligamentum patellae as they intersect at center of patella. more pronunced in females •• Genu valgum (knock knee) angle < 165° •• Genu varum (bow legs) angle > 180° The Common Peroneal Nerve Branches into the superficial and deep peroneal nerves, which supply the muscles of the anterior compartment of the leg and cutaneous areas of the distal anterior leg, dorsum of the foot, and most of the digit The Tibial Nerve Supplies all the muscles in the posterior compartment of the leg (e.g. tibialis posterior, flexor digitorum longus, gastrocnemius, and soleus) Movements at Different Joints •• Ankle: Dorsiflexion, Plantar flexion •• Subtalar joint: Inversion, eversion •• Mid tarsal joint: Forefoot adduction and abduction Muscles Involved in Various Movements •• Plantar flexion Gastrocnemius, soleus •• Dorsiflexion Tibialis anterior •• Inversion Tibialis anterior, tibialis posterior •• Eversion Peroneus longus, peroneus brevis 42 USMLE Step 1 Platinum Notes Common Peroneal Nerve •• It is related to the neck of fibula and winds around it •• It is the smaller terminal branch of Sciatic nerve •• It pierces peroneus longus •• It divides into superficial and deep peroneal nerves and supplies the anterior and lateral compartments of leg •• Injury to CPN produces foot drop •• It is subcutaneous •• It is the most common nerve in lower limb to get injured Ankle Joint Dorsiflexion •• •• •• •• Tibialis anterior Extensor digitorum longus Extensor hallucis longus Peroneus tertius Plantar flexion •• •• •• •• •• •• Gastrocneimus Soleus Plantaris Tibialis posterior Flexor hallucis longus Flexor digitorum longus Inversion •• Tibialis posterior •• Flexor hallucis longus •• Flexor digitorum longus Eversion •• Peroneus longus •• Peroneus brevis •• Peroneus tertius Reflexes •• Biceps C5, C6 •• Supinator C5, C6 •• Pronator C5, C6 •• Triceps C6, C7 •• Cremaster L1, L2 •• Knee L2, L3, L4 •• Plantar L5 S1 •• Ankle S1, S2 •• Anal, Bulbocavernous S3, S4 Important Points about Anatomy of Breast •• The protuberant part of the human breast is generally described as overlying the 2nd to the 6th ribs, and extending from the lateral border of the sternum to the anterior axillary line. Actually, a thin layer of mammary tissue extends considerably farther from the clavicle above to the 7th or 8th ribs below, and from the midline to the edge of latissimus dorsi posteriorly. •• The Axillary tail of Spence in the breast is of considerable surgical importance. In some normal cases it is palpable, and in a few it can be seen premenstrually or during lactation. A well-developed axillary tail is sometimes mistaken for a mass of enlarged lymph nodes or a lipoma. Anatomy 43 Axillary tail •• The lobule is the basic structural unit of the mammary gland. The number and size of the lobules vary enormously: they are most numerous in young women. From 10 to over 100 lobules empty via ductules into a lactiferous duct of which there are from 15 to 20. Each lactiferous duct is lined by a spiral arrangement of contractile myoepithelial cells and is provided with a terminal ampulla — a reservoir for milk or abnormal discharges. •• The ligaments of Cooper are hollow conical projections of fibrous tissue filled with breast tissue, the apices of the cones being attached firmly to the superficial fascia and thereby to the skin overlying the breast. These ligaments account for the dimpling of the skin overlying a carcinoma. •• The areola contains involuntary muscle arranged in concentric rings as well as radially in the subcutaneous tissue. The areolar epithelium contains numerous sweat glands and sebaceous glands, the latter of which enlarge during pregnancy and serve to lubricate the nipple during lactation (Montgomery’s tubercles). •• The nipple is covered by thick skin with corrugations. Near its apex lie the orifices of the lactiferous ducts. The nipple contains smooth muscle fibers arranged concentrically and longitudinally; thus is an erectile structure which points outwards. Lymphatics of the breast drain predominantly into the axillary and internal mammary lymph nodes. The axillary nodes receive approximately 75 percent of the drainage and are arranged in the following groups. Blood Supply is via •• Internal thoracic artery •• Intercostal artery •• Lateral thoracic artery Lymph nodes of Breast •• Lateral, along the axillary vein •• Anterior, along the lateral thoracic vessels •• Posterior, along the subscapular vessels •• Central embedded in fat in the center of the axilla •• Interpectoral, a few nodes lying between the pectoralis major and minor muscles •• Apical, which lie above the level of the pectoralis minor tendon in continuity with the lateral nodes and receive the efferents of all the other groups The apical nodes are also in continuity with the supraclavicular nodes and drain into the subclavian lymph trunk which enters the great veins directly or via the thoracic duct or jugular trunk. The sentinal node is that lymph node designated as the first axillary node draining the breast. The internal mammary nodes are fewer in number and lie along the internal mammary vessels deep to the plane of the costal cartilages Mondor’s disease is thrombophlebitis of the superficial veins of the breast and anterior chest wall (although it has also been encountered in the arm). Familial breast cancer Recent developments in molecular genetics and the identification of a number of breast cancer predisposition genes (BRCA1, BRCA2 and TPS3). These women have a risk of developing breast cancer two to 10 times above baseline. 44 USMLE Step 1 Platinum Notes Lymph nodes below Pectoralis Minor Level 1 Lymph nodes behind Pectoralis Minor Level 2 Lymph nodes above Pectoralis Minor Level 3 The principal nodes which drain the breast are: Axillary Group of Lymph nodes About 70 -75% of lymph from breast drains into Axillary group of Lymph nodes, 20% into internal mammary group of Lymph nodes and 5% into posterior intercostal group of lymph nodes •• Among the Axillary Group Chief is the Anterior group •• Rotters nodes are interpectoral nodes •• Absence of sternal head of pectoralis major: Polands syndrome •• •• •• •• •• Openings of Diaphragm: (USMLE Favorite) •• Vena caval opening: –– Thoracic 8 level –– Inferior vena cava –– Rt phrenic nerve •• Esophageal opening: –– Thoracic 10 level –– Esophagus –– Vagus nerves –– Esophageal branch of it gastric artery •• Aortic opening: –– Thoracic 12 level –– Aorta –– Thoracic duct –– Azygous vein CONTENTS OF IMPORTANT STRUCTURES Contents of Spermatic Cord: (USMLE Favorite) •• •• •• •• •• •• •• The ducts deferens Testicular and cremastric arteries Artery of vas The pampiniform plexus of veins Lymph vessels from testis Genital branch of Genitofemoral nerve Remains of processus vaginalis Contents of Rectus Sheath: (USMLE Favorite) •• •• •• •• Rectus abdominis and pyramidalis muscle Superior epigastric artery and inferior epigastric artery Superior epigastric vein and inferior epigastric vein Lower five intercostal nerves and subcostal nerve Contents of Broad Ligament: (USMLE Favorite) •• •• •• •• •• •• Uterine tube Round ligament of uterus, ligament of ovary Uterine vessels, ovarian diseases Uterovaginal, ovarian nerve plexus Epoophoron, Paroophoron Lymph vessels, lymph nodes Anatomy Contents of Ischiorectal Fossa: (USMLE Favorite) •• •• •• •• Perianal space Ischiorectal space Lunate fascia Pudendal canal Contents of Adductor Canal are: (USMLE Favorite) •• Femoral artery •• Saphanous nerve •• Nerve to vastus medialis •• •• •• •• •• •• •• •• •• •• •• •• •• Esophageal opening lies in muscular part of diaphragm Vena caval lies in central tendon of diaphragm Aortic opening is not a true opening but an osseo aponeurotic opening Greater and lesser splanchnic nerves pierces each crus of diaphragm Lt crus is also pierced by hemi azygous vein Sympathetic chain passes behind medial arcuate ligament Subcostal nerves vessels pass behind lateral arcuate ligament Superior epigastric vessels and lymphatics pass through Foramen of Morgagni (Larrys space) Musculophrenic vessels pierce the diaphragm Hernia does not occur through vena caval opening Bochaldeks hernia occurs through posterolateral part of diaphragm Morgagni hernia occurs anteriorly on right usually Remember Accessory phrenic nerve is commonly a branch from the nerve to subclavius Sites of Esophageal Constrictions Distance from Incisor Landmark •• 6 inches Pharyngoesophageal junction •• 9 inches Aortic arch crossing •• 11 inches Left bronchus •• 15 inches Pierces diaphragm Esophagus •• •• •• •• •• Length 25 cm Commences at lower end of cricoid Has squamous epithelium Toughest layer is muscularis No serosa THORAX Heart •• Right coronary artery arises from anterior aortic cusp •• Left coronary arises from posterior aortic cusp •• Posterior interventricular artery determines coronary dominance 45 46 USMLE Step 1 Platinum Notes •• In case it arises from right coronary artery, right dominance •• In case it arises from left coronary, left dominance •• Right Coronary artery mostly supplies SA node, AV node, AV bundle •• The SA node is usually supplied by Right coronary artery and Right Vagus •• The AV node is usually supplied by Right coronary artery and Left vagus •• Sympathetic innervation is by T2-T6 •• Maximum (90%) of venous drainage of Heart goes to Coronary Sinus •• In fetal life left sided svc drains into coronary sinus •• Great Cardiac Vein follows Anterior Interventricular artery •• Middle Cardiac Vein follows Posterior Interventricular artery •• Small Cardiac Vein follows Rt Marginal artery •• Inferior surface of heart is formed by Rt and Lt ventricle •• Base of heart is formed by Rt and Lt atrium •• Part of heart lying close to esophagus: Lt atrium Structures Present In: Musculi pectinati: Atria of heart Trabeculae cornea: Rt ventricle of heart Moderator band/Septomarginal trabeculae: right ventricle Coronary sinus, SVC, IVC: open in Right atrium SA node is located in: Rt Atrium Whole of conducting system is mostly supplied by rt coronary artery except Right bundle branch (supplied by left coronary artery) •• Holmes heart: single ventricle •• •• •• •• •• •• Coronary Sinus It is the largest venous channel of the heart about 3 cms. It located in left posterior coronary sulcus It is a remnant of left horn of sinus venosus = while the right horn gets incorporated into right atrium It opens into the right atrium of the heart through an orifice of coronary sinus and has a valve called the Thebesian valve. It receives: –– Great cardiac vein –– Middle cardiac vein –– Small cardiac vein –– Right marginal vein –– Oblique vein of left atrium –– Right marginal vein Thoracic Duct •• •• •• •• •• •• •• Also called as Pecquets duct Beaded in appearance 18 inches in length It is the largest lymphatic pathway in body The duct commences in the abdomen as an elongated lymph sac of the cisterna chylli is: Thoracic duct Begins from cisterna chyli at the level of T12 vertebrae Injury to thoracic duct by trauma leads to chylothorax Anatomy 47 LUNGS Bronchopulmonary Segment •• •• •• •• Vascular segment Independent Bronchial artery supplies till respiratory bronchiole Largest subdivision of lobe Remember Because the right main bronchus is wider and more vertical than the left, foreign objects are more likely to be aspirated into the right main bronchus. The superior segmental bronchus of the lower lobar bronchus is the only segmental bronchus that exits from the posterior wall of the lobar bronchi. Therefore, if a patient is supine at the time of aspiration, the object is most likely to enter the superior segmental bronchus of the lower lobe. Peculiarities of Blood Supply of Lung •• Smallest functional unit of lung is lobule •• Blood supply of lung tissue proper is by Bronchial arteries •• Bronchial arteries are branches of descending: Thoracic Aorta •• They supply nutrition to bronchial tree and pulmonary tissue up to respiratory bronchiole •• Segments distal to respiratory bronchiole are supplied by branches from pulmonary vessels •• On the right side there is only one BA arising indirectly from descending Thoracic Aorta •• On the Left side there are two BA arising directly from descending Thoracic Aorta •• Bronchial arteries are responsible for Hemoptysis •• Pulmonary arteries carry deoxygenated blood •• Pulmonary veins carry oxygenated blood •• Sequestered segments are supplied by systemic circulation AZYGOS Lobe of Lung •• Azygos means unpaired. Azygos lobe maybe seen on the right lung •• It is seen as a result of developmental anomaly related to lung bud and posterior cardinal vein •• The posterior cardinal vein (future azygos vein) gets embedded in the substance of lung which passes as lung bud below the arch formed by posterior cardinal vein •• The part of lung medial to the vein forms the azygos lobe GEMS ABOUT INTRA-ABDOMINAL ORGANS The Spleen •• It is a hemolymphatic organ: •• The second largest organ of the reticuloendothelial system •• It is located in the posterior left upper quadrant of the abdomen (left hypochondrium) where its relationships to the diaphragm, stomach, pancreas, left kidney, and splenic flexure of the colon are maintained by suspensory ligaments. The splenophrenic, splenorenal, and splenocolic ligaments are usually relatively avascular and their transection allows the spleen to be displaced medially and anteriorly •• The ‘Gastrosplenic ligament’ extends from the greater curvature of the body and fundus of the stomach to the spleen, contains the short gastric arteries and veins •• The ‘Splenorenal’ ligament (Lienorenal) and attached to the spleen at the hilum: Splenic artery and vein, lymphatic structures, and often the tail of the pancreas 48 USMLE Step 1 Platinum Notes •• The arterial supply to the spleen is derived from the celiac artery from both the splenic artery and the short gastric arteries, which usually arise as branches of the gastroepiploic or the splenic arteries •• The splenic vein is formed by a coalescence of polar veins in the splenic hilum and courses with the splenic artery along the dorsal surface of the pancreas to enter the portal system. The Stomach Starts from gastroesophageal junction to the pylorus It is bounded on the left by the spleen and on the right by the liver The blood supply to the stomach is extensive •• Left gastric artery, which supplies the upper lesser curvature of the stomach from celiac trunk •• The right gastric artery branches off the hepatic artery, which originates from the celiac axis; it supplies blood to the distal lesser curvature •• The left gastroepiploic artery is a branch off the short gastric vessels; it comes from the splenic and therefore originally from the celiac axis •• The right gastroepiploic artery branches off the gastroduodenal artery, which comes originally from the hepatic artery and therefore from the celiac axis The venous drainage of the stomach empties in a variety of directions, including venous tributaries along the esophagus, veins that flow with the short gastrics to the splenic vein, and venous drainage that is carried toward the duodenum and toward the portal vein Nerve supply is predominantly by the vagus An anterior (left) and posterior (right) vagus nerve courses with the esophagus until the gastroesophageal junction The ‘criminal’ nerve of Grassi is the first branch of the posterior vagal nerve innervating the greater curvature fundus. At the junction of the fundus and the antrum of the stomach, the vagal nerves branch and innervate the antrum. This vagal branch point is called the crow’s foot The lesser sac is bounded ventrally by the stomach and is an important location during operation, in that it is a frequent space for fluid collection and is an important plane for the exposure of gastric anatomy. Duodenum The duodenum extends from the pylorus about 20 to 30 cm and ends at the ligament of Treitz, which is where the jejunum begins. This is marked by adhesive bands between the duodenal-jejunal junction and the retroperitoneum on the left side of the abdomen •• The duodenum is divided into four anatomic regions: •• The first portion, or the cap or bulb •• The second portion, or the descending duodenum •• The third, or transverse, portion; and the •• Fourth, or ascending, portion Gems about Duodenum The duodenal cap lies just beyond the pylorus. Ninety percent of ulcers occur in the duodenal cap region. The gastroduodenal artery lies directly behind the duodenal cap, and penetrating ulcers into the pancreas initially erode through the gastroduodenal artery, accounting for the massive bleeding that occurs with these ulcers. The second (descending) portion of the duodenum: The ampulla of Vater and the minor papilla both enter into the duodenum in this portion. The second portion of the duodenum is approximately 10 cm in length. The third and fourth portions of the duodenum (transverse and ascending portions) are mostly retroperitoneal. The third portion is attached to the uncinate process and crosses the abdomen and over the aorta. Compression of the junction of the third and fourth portions of the duodenum by the angle of the SMA and the aorta is called the SMA syndrome. Anatomy 49 The fourth portion of the duodenum blends into the jejunum at the ligament of Treitz, which attaches this junction to the retroperitoneum. Mobilization of the ligament of Treitz is necessary in duodenal resections. The ligament is often composed of small strands of striated muscle that eventually extend to the crus of the diaphragm. ‘Kerckring’s folds’ The mucosal surface of the small intestine contains numerous circular mucosal folds called the plicae circulares (valvulae conniventes, or valves of Kerckring) of the duodenum begin just beyond the cap and continue throughout the duodenum. The concentric folds of Kerckring are approximately 1 to 2 mm thick and 2 to 4 mm high. They are taller and more numerous in the distal duodenum and proximal jejunum, becoming shorter and fewer distally. Difference between Small and Large Intestine Small intestine Large intestine •• About 6 -7 meters in length •• About 180 cms in length •• Small diameter •• Larger diameter •• Mucosa has villi and crypts •• Mucosa hascrypts but no villi •• Paneth cells present •• Paneth cells absent •• Less goblet cells •• More goblet cells •• Brunner’s glands in duodenum present •• Peyers patches in ileum present •• Both absent •• Sacculations absent •• Sacculations present •• Appendices epiploicae absent •• Appendices epiploicae present •• Tenia absent •• Tenia present Celiac Trunk •• LEFT GASTRIC ARTERY — Esophageal branch, gastric branch •• COMMON HEPATIC ARTERY — Right hepatic, left hepatic, Gastroduodenal artery→ supraduodenal, right gastroepiploic, superior pancreaticoduodenal artery •• SPLEENIC ARTERY — Short gastric, left gastroepiploic, pancreatic branches Meckel’s Diverticulum •• A Meckel’s diverticulum, a true congenital diverticulum •• It is a vestigial remnant of the omphalomesenteric duct (also called the vitelline duct) and is the most frequent malformation of the gastrointestinal tract •• Meckel’s diverticulum is located in the distal ileum, usually within about 60-100 cm of the ileocecal valve •• It is typically 3-5 cm long, runs antimesenterically and has its own blood supply •• It is a remnant of the connection from the umbilical cord to the small intestine present during embryonic development A Memory Aid is the Rule of 2’s •• 2% (of the population) •• 2 feet (from the ileocecal valve) •• 2 inches (in length) •• 2% are symptomatic •• 2 types of common ectopic tissue (gastric and pancreatic) •• Most common age at clinical presentation is 2 •• Males are 2 times as likely to be affected 50 USMLE Step 1 Platinum Notes Anal canal above Dentate Line Anal Canal Below Dentate Line •• Endodermal •• Ectodermal •• Cuboidal epithelium •• Stratified squamous •• Superior Rectal Artery •• Inferior Rectal Artery •• Superior Rectal Vein •• Inferior Rectal Vein •• Internal Iliac group of lymph nodes •• Superficial inguinal group of lymph nodes •• Pain insensitive •• Pain sensitive The liver •• Lies in the right upper quadrant of the abdomen •• It is the largest gland in the body, it weighs approximately 1500 gm •• The gallbladder lies on the dorsal surface of the liver in a transpyloric plane •• A peritoneal membrane (Glisson’s capsule) covers the liver •• The superior surface of the liver conforms to the undersurface of the right diaphragm. The relations of the inferior surface of the liver are the duodenum, colon, kidney, adrenal gland, esophagus, and stomach. Peritoneum invests the entire liver except for a bare area under the diaphragm on the posterosuperior surface adjacent to the inferior vena cava and hepatic vein. Ligaments of Liver •• The falciform ligament, which attaches the liver to the anterior abdominal wall from the diaphragm to umbilicus and incorporates the ligamentum teres hepaticus •• The anterior and posterior right and left coronary ligaments, which in continuity with the falciform ligament connect the diaphragm to the liver. The lateral aspects of the anterior and posterior leaves of the coronary ligaments fuse to form the right and left triangular ligaments •• The gastrohepatic and hepatoduodenal ligaments, which consist of the anterior layer of lesser omentum and are continuous with the left triangular ligament. The hepatoduodenal ligament contains the hepatic arteries, portal vein, and extrahepatic bile ducts. It forms the anterior boundary of the epiploic foramen of Winslow and the communication between the greater and lesser peritoneal cavities. Four Lobes of the Liver are Commonly Described •• •• •• •• Right Left Quadrate Caudate Portal Vein •• The portal vein provides about three fourths of the liver’s blood supply •• The combination of the superior mesenteric and splenic veins forms the portal vein, behind the neck of the pancreas •• The portal vein then passes superiorly, posterior to the first part of the duodenum at the level of the second lumbar vertebra •• Portal vein is 1 to 3 cm in diameter and 5 to 8 cm in length before dividing into right and left branches at the portal hepatis •• The portal vein usually passes behind the bile duct and hepatic artery in the hepatoduodenal ligament •• The portal trunk divides into left and right hepatic branches in the portal fissure. The left branch of the portal vein is longer •• The portal vein divides into small veins and venules, which finally enter hepatic sinusoids •• The portal vein has no valves Anatomy 51 Portocaval Anastomosis Numerous tributaries of the portal vein connect outside the liver with the systemic venous system. Under normal circumstances these communications have little physiologic significance. However, if portal hypertension develops, these rudimentary portosystemic communications develop into large channels with increased collateral flow. Sites of Portosystemic Anastomoses Include •• The submucosal veins of the proximal stomach and distal esophagus, which can receive blood from the coronary and short gastric veins to drain into the azygous veins (high blood flow through this pathway produces gastric varices, esophageal varices, or both) •• Umbilical and periumbilical veins, recanalized from the obliterated umbilical vein in the ligamentum teres hepaticus, and which may cause caput medusae or the loud Cruveilhier-Baumgarten bruit •• Tributaries of the inferior mesenteric vein, which include the superior hemorrhoidal veins that communicate with the middle and inferior hemorrhoidal veins of the systemic circulation and may cause large hemorrhoids; and •• Other retroperitoneal communications, including connections to the renal and adrenal veins. Sphincter of Oddi The circular smooth muscle fibers in the ampulla of Vater area constitute the sphincter of Oddi, which regulates the flow of bile from the liver into the duodenum The three principal parts of the sphincter of Oddi are: 1. The sphincter of the choledochus (i.e. the circular muscle fibers surrounding the intramural and submucosal bile duct); 2. The pancreatic sphincter, which consists of a muscular septum between the bile and pancreatic ducts; 3. Ampullary sphincter: The ampullary sphincter, the most important component of the sphincter of Oddi, includes a layer of longitudinal muscle fibers that help prevent reflux of intestinal contents into the ampulla Relaxation of the ampullary sphincter may promote reflux into the pancreatic duct. Gallbladder The gallbladder, a pear-shaped (pyriform), distensible appendage of the extrahepatic biliary system Capacity: 30 to 50 ml of bile Parts: It has a fundus, body, and neck The duct of gallbladder cystic duct varies in length and usually contains spiral valves of Heister that regulate bile flow Enlargement of the neck of the gallbladder such as from a stone may form a pouch (Hartmann’s pouch) The triangle bounded by the cystic duct, common hepatic duct, and inferior border of the liver is the Triangle of Calot The gallbladder receives its blood supply from the cystic artery, which originates from the right hepatic artery Venous drainage of the gallbladder enters principally into the portal vein The lymphatics drain into cystic duct nodes near the superior aspect of the cystic duct. (Cystic Lymph node of Lund) The Triangle of Calot It is a surgical landmark used to identify important structures during cholecystectomy, is bounded by the cystic duct, the common hepatic duct, and the inferior border of the liver The right hepatic and cystic arteries are located within it and anomalous structures often pass through it Moynihans Hump: An abnormal bend in the course of the right hepatic artery, throwing it into the configuration of a caterpillar hump, (Moynihan’s hump) invites injury unless it is carefully dissected free 52 USMLE Step 1 Platinum Notes The Pancreas (Pan: All creas Flesh) •• It is a retroperitoneal organ, lying posterior to the stomach and lesser omentum •• It extends from the duodenal C loop to the hilum of the spleen •• The gland has a distinctive yellow/tan/pink color and is multilobulated •• The pancreas is covered by peritoneum anteriorly and posteriorly it lies in proximity to the inferior vena cava, right renal vein, aorta at the level of the first lumbar vertebra, superior mesenteric vessels, and splenic vein. •• The gland is divided into four portions: a. b. c. d. The head (which includes the uncinate process) The neck The body and The tail •• The head of the gland extends to the right of the neck, lying within the confines of the duodenal C loop; it includes the posteroinferior extension arising from the ventral primordium, designated the uncinate process. The uncinate process extends posterior to the superior mesenteric vein, ending at the right margin of the superior mesenteric artery. The body of the pancreas lies immediately to the left of the neck; the tail of the pancreas extends to the left of the body into the splenic hilum. •• The head of the pancreas is intimately associated with the second portion of the duodenum, and these two structures are jointly supplied by two arterial arcades known as the anterior and posterior pancreaticoduodenal arteries. These arteries originate from the superior and inferior pancreaticoduodenal vessels as branches of the celiac axis and superior mesenteric artery, respectively. The distal body and tail of the pancreas are supplied by short branches of the splenic and left gastroepiploic arteries. Within the posterosuperior and posteroinferior aspects of the body of the pancreas lie the superior and inferior pancreatic arteries, respectively. •• Veins draining the pancreatic parenchyma eventually terminate in the portal vein, which arises posterior to the neck of the pancreas at the junction of the splenic and superior mesenteric veins Multiple lymph node groups drain the pancreas •• From the head of the gland, nodes in the pancreaticoduodenal groove communicate with subpyloric, portal, mesocolic, mesenteric, and aortocaval nodes •• Lymphatics in the body and tail of the pancreas drain to retroperitoneal nodes in the splenic hilum or to celiac, aortocaval, mesocolic or mesenteric nodes The Kidneys •• Bean shaped •• Retroperitoneal •• Right kidney is lower than left (but right suprarenal is higher than left.) •• Each kidney is 9 to 15 cm long, 4 to 5 cm wide and approximately 3 cm thick. They are located on each side of the vertebral column between the parietal perineum and the fascia and musculature of the posterior abdominal wall and are embedded in a variable amount of fat and surrounded by a layer of fascia (Gerota’s fascia) •• They lie on the side of the psoas muscle •• They are not parallel, with the upper poles being approximately 2 cm from the midline and the lower poles approximately 3.5 cm from the midline •• Coverings of Kidney (From inside to out) –– Fibrous capsule –– Perinephric fat –– Renal fascia with 2 layers -- Anterior layer of Toldts Fascia -- Posterior layer of fascia of Zuckerkandl –– Pararenal Fat Anatomy 53 Posterior Relations of Kidney •• •• •• •• •• 3 parts of diaphragm: Medial arcuate ligament, Lateral arcuate ligament, Diaphragm 3 muscles: Psoas major, quadrates lumborum, transverses abdominis 3 nerves: Subcostal, iliohypogastric, ilioinguinal nerves Right kidney: 12th rib Left kidney: 11th and 12th rib Ureter •• 25 cm long (PGI) •• Totally retroperitoneal •• It enters true pelvis after crossing iliac vessel Important Points about Ureter •• •• •• •• •• Starts at the hilum Changes its direction at the ischial spine Penetrates the bladder wall without any valve Enters the bladder at the lateral angle of the trigone Enters pelvis in front of bifurcation of common iliac artery The Suprarenals or the Adrenal Glands •• Are bilateral retroperitoneal organs located on the superior medial aspect of the upper pole of each kidney •• Each gland weighs approximately 4 gm. The left adrenal is larger and flatter •• The normal adrenal cortex is bright yellow and thicker than the red-brown medulla. Blood Supply of Suprarenals •• Superior suprarenal artery: branch of inferior phrenic artery •• Middle suprarenal artery: branch of abdominal aorta •• Inferior suprarenal artery: branch of renal artery Venous Drainage The left adrenal vein empties primarily into the left renal vein but may occasionally drain directly to the vena cava Lymphatic plexuses within the subcapsular portion of the adrenal cortex and the adrenal medulla drain to the adjacent para-aortic subdiaphragmatic and renal lymph nodes. Important Anatomical Relations Relations at hilum of kidney (Anterior to Posterior) ‘VAP’ •• Renal vein •• Renal artery •• Renal pelvis Relations at Femoral Triangle (From Medial to Lateral) 'VAN’ •• Femoral vein •• Femoral artery •• Femoral nerve 54 USMLE Step 1 Platinum Notes Intercostal space (From Above Downwards) ‘VAN’ •• Intercostal vein •• Intercostal artery •• Intercostal nerve Cubital Fossa (From Medial to lateral side). ‘MBBR’ •• Median nerve (Medial aspect) •• Brachial artery •• Biceps tendon •• Radial nerve •• Lateral boundary by brachioradialis muscle. MALE REPRODUCTIVE TRACT Testes •• •• •• •• It is male gonad Two oval structures are average 4 to 5 cm in length and 2.5 to 3.5 cm in width in the normal adult male 10–15 gms in weight (Indians average) Testis arises from the genital ridge Covered by •• Tunica vaginalis •• Tunica albugenia •• Tunica vasculosa •• Blood supply is by testicular artery which is a branch of abdominal aorta •• Venous drainage of the testis is through the pampiniform plexus to the spermatic vein, which is usually single and emerges from the upper end of the cord and then follows the internal spermatic artery through the retroperitoneum. On the right the spermatic vein empties into the vena cava below the right renal vein, whereas on the left the spermatic vein empties into the main renal vein. Increased hydrostatic pressure, particularly on the left, may result in dilatation of the pampiniform venous plexus, producing a varicocele •• The lymphatic drainage of the testis is through the spermatic cord and the inguinal canal and then to the common iliac and preaortic and paraortic nodes, with the latter communicating across the midline at the level of the kidneys and also with the mediastinal and supraclavicular chains •• Histologically, there are two principal portions of the testis: The seminiferous tubules, which are responsible along with the Sertoli cells for spermatogenesis, and the interstitial or Leydig cells, which elaborate androgenic hormones, predominantly testosterone Testicular Descent •• Iliac Fossa: 3rd month •• Deep Inguinal Ring: 7th month •• Pass through Inguinal Canal: 7th month •• At Superficial Inguinal ring: 8th month •• Enter Scrotum: 9th month Anatomy 55 Epididymis Are coiled structures each containing a single epididymal tubule 12 to 19 feet long and attached to the posterolateral surface of each testis Remember: From the tails of the epididymi sperm are transmitted into the vasa deferentia, which are direct continuations of the duct of the epididymi passing up the spermatic cord, across the inguinal canal, and then retroperitoneally to the ampulla of the seminal vesicles, with which they conjoin to form an ejaculatory duct on each side. The ejaculatory duct then empties directly into the prostatic urethra. The principal blood supply for the epididymis is from the internal spermatic artery. Venous drainage corresponds to the arterial supply, and the lymphatic drainage of the epididymis parallels that of the testis. The prime function of the epididymis is not only as a conduit for spermatozoa but also for biochemical and functional maturation and ultimate storage. Ductus deferens/Vas Deferens It is 18 inches in length. The vas deferens is an easily discernible structure within the scrotum and spermatic cord because it is a heavily muscled tubular structure Spermatic Cord The spermatic cord, suspending each testis and its attached epididymis, is composed of the vas deferens, the internal spermatic artery, the external spermatic artery, the pampiniform plexus of veins, the lymphatic drainage system of the contents of the scrotum, and the autonomic nerve supply to the testis. In addition, the cord is surrounded by fibers of the cremasteric muscle, which assist by contraction and relaxation in the maintenance of optimal testicular temperature and provide for testicular retraction with sexual excitation or in the primitive fright reaction. Contents of Spermatic Cord •• •• •• •• •• •• •• The ducts deferens Testicular and cremastric arteries Artery of vas The pampiniform plexus of veins Lymph vessels from testis Genital branch of genitofemoral nerve Remains of processus vaginalis Scrotum •• The scrotal sac, consisting of two lateral compartments fused in the midline encloses the testes, epididymi, and terminal portions of the spermatic cords. The dartos, consisting of elastic fibers, connective tissue, and smooth muscle fibers, is attached to the corrugated skin of the scrotum, rich in sebaceous glands, and provides for muscular contraction of the scrotal sac in response to temperature changes or sexual excitation. The principal function of the scrotum is to aid in temperature control of the testes for optimal spermatogenesis, which takes place at temperatures several degrees lower than those in the intra-abdominal cavity •• The blood supply of the scrotum comes from the deep pudendal branches of the femoral artery and branches of the internal pudendal artery •• The lymphatics of the scrotal halves anastomose freely, surround the penis, and drain to the inguinal and femoral nodes. There are no connections between the lymphatics of the scrotum and the testes; the scrotal lymphatics do not accompany the pudendal vessels. Seminal Vesicles •• Are paired, monotubular, convoluted structures lying beneath the base of the bladder and trigone. Posteriorly they are invested by Denonvilliers’ fascia, which separates them from the anterior wall of the rectum •• The two seminal vesicles fuse immediately with the ampullae of the vasa, forming the ejaculatory ducts, which open into the prostatic urethra at the level of the verumontanum. The seminal vesicles secrete a mucoid vehicle for the spermatozoa and also elaborate the body’s only source of fructose, which is used as an essential nutrient for maintenance of spermatozoal viability. 56 USMLE Step 1 Platinum Notes Prostate Gland •• It is a fibromuscular, glandular organ that surrounds the neck of the urinary bladder and the proximal portion of the male urethra. The gland is supported anteriorly by the puboprostatic ligaments, inferiorly by the genitourinary diaphragm (external urinary sphincter), and posteriorly by the rectal wall, which is separated from the prostate by an obliterated pelvic reflection of the peritoneum called Denonvilliers’ fascia. •• The prostate consisting of two portions: an anterior (inner) group of glands intimately associated with the urethra and a posterior (outer) portion of more fibromuscular character •• Arterial supply: The inferior vesical and internal pudendal arteries provide the blood supply to the prostate, entering the gland posterolaterally at the vesical neck •• Venous drainage of the prostate is complex and diffuse, with plexuses over the anterior and lateral portions of the gland that drain into the internal iliac veins •• Intercommunicating lymphatics of the prostate, bladder, seminal vesicles, vasa deferentia, and rectum provide drainage into both the internal and external iliac systems as well as the sacral promontory nodes •• Zones of Prostate: •• These zones have physiologic and surgical significance because Benign enlargement of the prostate (BHP) occurs in the transition or periurethral zone and Malignancy develops in the majority of cases in the Peripheral zone. Urethra 18-20 cms in length with 3 parts •• Prostatic (3 cms semilunar) •• Membranous (2 cms stellate) •• Spongy/penile (15 cms slit shaped) Prostatic part is widest and more dilatable part Contains: •• Veru montanum (urethral crest) •• Colliculus seminalis •• Prostatic sinuses •• Prostatic utricle (analogous to uterus/vagina of females) Cowper’s Glands: (Bulbourethral glands of Cowper) are small, paired glands lying between the layers of the urogenital diaphragm at the junction of the bulbous and membranous portions of the urethra. The ducts of the glands empty distally into the bulbous urethra traversing the corpus spongiosum. The secretions from this gland not only act as a lubricant but may also have factors that aid in seminal fluid coagulation after ejaculation. Penile Tissue •• Organ of copulation and excretion of urine •• It consists of two parallel erectile tissues as the corpora cavernosa, which are situated dorsolaterally, and the corpus spongiosum, which invests the urethra ventrally, terminating distally in the erectile glans penis •• Each corpus cavernosum and the corpus spongiosum are enveloped in fascial sheaths, and all three corpora are surrounded by Buck’s fascia •• The blood supply of the penis is through the dorsal arteries derived from the internal pudendal arteries, which are branches of the internal iliac artery •• The venous drainage is through the dorsal veins, with the superficial dorsal vein emptying into the saphenous vein, and the deep dorsal vein emptying into the prostatic plexus known as the plexus of Santorini •• Penile erection is induced by the engorgement of the erectile tissues of the corpora, principally the corpora cavernosa •• Lymphatic drainage of the penis is abundant. The lymphatics from the shaft of the penis, the corpora cavernosa, and the skin pass through the superficial and deep inguinal nodes, communicating with the iliac nodes. Anatomy 57 •• Lymphatic drainage of the glans penis drains into deep inguinal nodes and rest of the penis drains into superficial inguinal nodes •• The skin of the penis differs considerably from other skin of the body in its paucity of sebaceous glands, its elasticity, and its extensive blood supply. REMEMBER High Yield Points •• •• •• •• •• •• •• •• The bulbourethral glands secrete mucus for lubrication The epididymis concentrates and stores sperm for ejaculation The prostate gland secretes alkaline fluid to neutralize vaginal pH and induces clotting of the semen The seminal vesicles produce fructose, citric acid, prostaglandins, and fibrinogen. These comprise about 60% of the volume of semen The ampulla is the end of the vas deferens The bulbourethral glands secrete mucus for lubrication The epididymis concentrates and stores sperm for ejaculation The prostate gland secretes alkaline fluid to neutralize vaginal pH and induces clotting of the semen The seminal vesicles produce fructose, citric acid, prostaglandins, and fibrinogen. These comprise about 60% of the volume of semen. FEMALE REPRODUCTIVE TRACT The Vagina The vagina is a female copulatory organ. It is a muscular tube lined with stratified squamous epithelium. The adult vagina measures 12 to 13 cm in-depth. In virgin lower end of vagina is closed partially by annular fold of mucus membrane called hymen which gets distorted after intercourse forming rounded elevations called caruncle hymenale. The Cervix •• It is the lower cylindrical portion of the uterus •• The cervix, is a fibromuscular organ covered with stratified squamous epithelium. The walls of cervix show mucosal folds called arbor vitae •• The squamocolumnar junction is the most common site of origin of squamous cell carcinoma •• The endocervical canal is lined by columnar epithelium, and racemose glands, lined with similar epithelium, are found in the fibromuscular stroma. Such glands, if obstructed, may form nabothian cysts on the cervical surface •• The nulliparous cervical os is round. The Uterus The uterus is a hollow, fibromuscular-walled organ between the bladder The normal position of uterus is anteverted and anteflexed Angle of anteversion is 90° Angle of anteflexion is 120° The organ is pear shaped and in nonpregnant women measures approximately 8 cm in length and weighs 30 to 100 gm The fallopian tubes and the cervical canal communicate with the uterine cavity, which is lined by the endometrium The uterine fundus is covered by peritoneum except in the lower anterior portion, where the bladder is contiguous with the lower uterine segment and the peritoneum is reflected, and laterally where the folds of the broad ligament are attached. The uterus is supported by condensations of endopelvic fascia and fibromuscular tissue laterally at the base of the broad ligaments Blood supply of uterus is by uterine artery which is tortuous and branch of anterior division of internal iliac artery lying on the lateral aspect of uterus in the broad ligament. •• •• •• •• •• •• •• 58 USMLE Step 1 Platinum Notes Uterine Prolapse, or Procidentia and Uterine Descensus •• Occurs when the uterus and its adjoining structures herniate through the vaginal canal •• Prolapse is described as first, second, or third degree in severity, the last being protrusion of the entire uterus from the vagina, with the entire vagina everted as a consequence. •• Although congenital weakness of the supporting tissues may occasionally cause uterine prolapse, the most frequent cause is childbirth. The signs of uterine prolapse are protrusion of the cervix or uterus through the introitus. Prolapse is frequently associated with cystocele or rectocele, and these defects may cause presenting symptoms. Symptoms include backache, significant pelvic pressure, and ulceration or bleeding of the prolapsed structures. The Fallopian Tubes Tortous ducts about 10 cms in length: •• Arise from the superior portion of the lateral borders of the uterus, superior to the attachment of the round ligaments, and are patent. The distal ends, the fimbriae, open into the abdominal cavity and the proximal ends open into the uterine cavity. It is divided into interstitial, isthmic, ampullar, and fimbriated portions •• The wall is thin with two muscular layers and an outer layer of peritoneum within the upper borders of the broad ligament. The Ovaries Lie in the ovarian fossa. Ovaries are almond-shaped structure measuring 2 × 3 × 3 cm and is located on the posterior surface of the broad ligament and inferior to the fallopian tube. The ovary has a cortex and a medulla. Germinal epithelium, a single layer of cuboidal cells, covers condensed fibrous tissue called the tunica albuginea. Follicles originate within the ovarian cortex and are composed of the basic embryonic complement; no new follicles are formed after birth Mesovarium is a fold of peritoneum by which ovary is connected to the broad ligament The Arterial blood supply is predominantly by ovarian artery a branch of Abdominal aorta Venous drainage is by Pampiniform plexus. The left ovarian vein empties into the left renal vein; the right ovarian vein empties into the vena cava just inferior to the renal vein. The Adult Inguinal Canal It is approximately 4 cm in length Extends between the internal (deep inguinal) ring and the external (superficial inguinal) ring opening The inguinal canal contains either the spermatic cord or the round ligament of the uterus The inguinal canal is bounded superficially by the external oblique aponeurosis The superior wall is composed of internal oblique muscle, transversus abdominis muscle, and the aponeuroses of these muscles The inferior wall of the inguinal canal is formed by the inguinal ligament and lacunar ligament The posterior wall (floor) of the inguinal canal is formed by the transversalis fascia and the aponeurosis of the transversus abdominis muscle •• Hesselbach’s triangle: The inferior epigastric vessels serve as the superolateral border of Hesselbach’s triangle. The medial border of the triangle is formed by the rectus sheath, and the inguinal ligament serves as its inferior border •• Hernias occurring within Hesselbach’s triangle are considered direct hernias, whereas hernias occurring lateral to the triangle are indirect hernias. •• •• •• •• •• •• •• THE HEAD AND NECK AND CNS The Scalp The SCALP has five layers: •• S – Skin •• C – Connective tissue Anatomy 59 •• A – Aponeurosis -galea aponeurotica •• L – Loose connective tissue •• P – Pericranium The scalp receives a rich vascular supply. This arises from both the external and internal carotid arteries with the vessels lying in the dense connective tissue layer. The anterior part of the scalp is supplied by the supratrochlear and supraorbital arteries, and branches of the internal carotid via the ophthalmic artery The lateral and posterior part of the scalp is supplied by the superficial temporal, posterior auricular and occipital arteries, and branches of the external carotid The sensory nerves run with the arteries and are derived from the trigeminal nerve at the front and sides The posterior aspect is supplied by the greater and lesser occipital nerves with motor supply to the occipitofrontalis muscle by the facial nerve Venous drainage of the face and anterior scalp is via the facial vein. The lateral and posterior aspects are drained by the external jugular vein and the vertebral venous plexus, respectively. The veins of the scalp and face communicate directly with the intracranial venous sinuses via emissary veins, hence infections in the nasal region have the potential to cause cavernous sinus thrombosis Lymph drainage from the scalp is to the preauricular and occipital lymph nodes The loose areolar tissue under the galea aponeurotica is a ‘Dangerous zone for infections‘. Pus can spread freely in this layer and reach the intracranial sinuses through the emissary veins Abscesses and hematomas under the pericranium are limited to the area of one bone because the pericranium is firmly adherent to the sutures between the skull bones Osteomyelitis of the skull is associated with a subperiosteal swelling and edema of the scalp referred to as Port’s puffy tumor Fractures of Facial Skeleton The Le Fort I fracture separates the alveolus and palate from the facial skeleton above The fracture line runs through points of weakness from the pyriform aperture, through the lateral and medial wall of the maxillary sinus running posteriorly to include the lower part of the pterygoid plates The Le Fort II fracture is pyramidal in shape. The fracture involves the orbit, running through the bridge of the nose, and the ethmoids whose cribriform plate maybe fractured, leading to a dural tear and CSF leak. It continues to the medial part of the infraorbital rim, through the infraorbital foramen and through the infraorbital fissure. The orbital floor is always involved The Le Fort III fracture effectively separates the facial skeleton from the base of the skull — The fracture lines run high through the nasal bridge, septum and ethmoids, again with the potential for dural tear and CSF leak, and irregularly through the bones of the orbit to the frontozygomatic suture. The zygomatic arch fractures, and the facial skeleton is separated from the bones above at a high level through the lateral wall of the maxillary sinus and the pterygoid plates. Various Important Areas of Cerebrum •• •• •• •• •• •• Motor area Premotor area Brocas area Sensory area Visual area Werneckies area •• •• •• •• •• •• Precentral gyrus Anterior to motor area Motor speech area (Inferior frontal gyrus) Postcentral gyrus Occipital lobe Superior temporal lobe Important Points about Functional Anatomy of Cerebral Cortex Frontal lobe Primary motor area (concerned with initiation of Precentral cortex voluntary movements and speech) (Post Part) Premotor area Supplementary motor area Area 4 – center for movement Area 4S – suppressor area. Inhibits movements initiated by area 4. Area 6 – concerned with coordination of movements initiated by area 4. Area 8 – frontal eye field. Area 44 and 45 (broca’s area) – motor area for speech. Concerned with coordinated skilled movements. 60 USMLE Step 1 Platinum Notes Prefrontal cortex Silent area or association area (Ant Part) Center for higher functions emotion, learning, memory Area 1 – concerned with sensory perception Area 2 and 3 – integration of these sensations. Spatial recognition. Recognition of intensity, similarities and diff. B/W stimuli Concerned with perception of sensation. Somesthetic area I Parizetal lobe Somesthetic area II Somesthetic association area Synthesis of various sensations perceived by S. Area-I. Stereognosis Primary auditory area Area 41, 42 and wernicke’s area – concerned with perception of auditory impulses, analysis of pitch, determination of intensity and source of sound Superior part of temporal gyrus. Auditopsychic area Area of equilibrium Primary visual area Area 22 – Interpretation of auditory sensation Maintenance of equilibrium Area 17 – Perception of visual impulse Lines of Gernari seen. Area 18 - Interpretation of visual impulses Area 19 - Movements of eye Temporal lobe Occipital lobe Area – 9 to 14, 23, 24, 29 and 32. Center for planned action – Seat of intelligence. Personality of individual Visual association area Occipital eye field Lemniscus Lemniscus, tract and sensation Thalamic nucleus Part of the internal capsule Sensory areas of the cerebral cortex Medial lemniscus (Proprioception and fine touch) Spinal lemniscus (Pain, temperature and crude touch) PLVNT SENSORY RADIATION Trigeminal lemniscus (Pain, temperature, touch and proprioception from the «head», taste) PMVNT In posterior ½ of postlimb of Lower 1/3 of sensory area in internal capsule (IC) post-central gyrus (Face region). Lateral lemniscus (hearing) Medial geniculate body AUDITORY RADIATION [MGB] in sublentiform part of IC Upper 1/3 of sensory area in post-central gyrus (Arm and leg region). Auditory area in Heschl’s gyrus in temporal lobe (area 41 and 42). Internal Capsule Part of internal capsule Types of fibers in it •• Anterior limb •• Fibers from and to the prefrontal area of the cortex •• Genu (MOTOR) •• Corticobulbar fibers •• Sensory fibers from thalamus to brain •• Ant ½ of posterior limb (MOTOR) •• Corticospinal fibers •• Post ½ of posterior limb (SENSORY) •• SENSORY radiation •• (From PLVNT and PMVNT to main sensory area in post central gyrus) •• Retrolentiform part (VISION) •• OPTIC radiation •• (From LGB to visual sensory area 17) •• Sublentiform part (HEARING) •• AUDITORY radiation •• (From MGB to auditory area in temporal lobe) Anatomy 61 Remember: M-M (medial geniculate body/hearing (music) Lateral L-L Lateral geniculate body/light) Arrows show geniculate bodies A small lesion at the level of internal capsule can result in a clinical scenario with widespread manifestations and most of them lethal depending on what part of internal capsule is damaged. The internal capsule maybe damaged by a cerebrovascular lesion mostly by Hemorrhage (rupture of Charcots artery) leading to Hemiplegia on the opposite side of the body. In this type of Hemiplegia motor functions are effected mostly and sensory functions later or not at all because motor fibers lie laterally and the arterial supply is more laterally as a result of which are motor fibers likely to be effected more. Summary of the Lesion in Brown Sequard Syndrome On the «same» side of the lesion •• Pyramidal tract damage results in: UMNL and motor paralysis below the injury (spastic paralysis, hyperactive reflexes, loss of superficial reflexes and Babinski sign) •• Proprioceptive tracts damage (gracile and cuneate) results in: loss of sense of position, sense of passive movement, sense of vibration and touch discrimination below the injury. These are the signs of sensory ataxia. On the «opposite» side of the lesion: •• Lateral spinothalamic tract damage results in: loss of pain and temperature sensation beginning one or two dermatomes below the lesion •• Ventral spinothalamic tract damage results in: little or No change in the sense of simple touch. Remember Midbrain: Usually the fibers of the third (oculomotor) nerve are affected — alternating oculomotor hemiplegia, this means; Hemiplegia on opposite half of the body (UMNL) Signs of oculomotor nerve paralysis on the same side (LMNL) Pons: Usually the fibers of the sixth (abducent) nerve are affected — alternating abducent hemiplegia, this means: Hemiplegia on opposite half of the body (UMNL) Signs of abducent nerve paralysis on the same side (LMN) Medulla: Usually the fibers of the hypoglossal nerve are affected — alternating hypoglossal hemiplegia, this means Hemiplegia on opposite half of the body (UMNL) Signs of hypoglossal nerve paralysis on the same side (LMNL) 62 USMLE Step 1 Platinum Notes Brown sequard syndrome Arterial Territories and Important Points in Blood Supply of Brain •• Left middle cerebral artery: Blockage of this vessel would cause, among other effects, right-sided hemiplegia and sensory deficits mainly of the face and arms, a right visual field defect with inability to gaze to the right, and aphasia. Anatomy 63 •• Right middle cerebral artery: Blockage of this vessel would cause, among other things, left-sided hemiplegia and sensory deficits mainly of the face and arms and left visual field neglect with inability to gaze to the left. In addition, there maybe neglect of the left side. •• Left anterior cerebral artery: This vessel supplies the medial aspects of the left hemisphere. Blockage may cause a weak, numb right leg (and possibly arm symptoms in milder forms). The face is typically spared. •• Right anterior cerebral artery: This vessel supplies the medial aspects of the right hemisphere. Blockage may cause a weak, numb left leg (and possibly arm symptoms in milder forms). The face is typically spared. •• Left posterior cerebral artery: This lesion presents as a right-sided visual field deficit, alexia without agraphia (if the corpus callosum is spared), and possible defects in naming colors. •• Right posterior cerebral artery: This lesion typically presents as a left-sided visual field deficit along with left-sided sensory loss if the thalamus is affected. There may also be left-sided neglect •• Visual cortex is supplied by posterior + middle cerebral artery. •• Left posterior inferior cerebellar artery: This lesion would cause infarction of the lateral medulla and inferior cerebellar surface, causing vertigo with vomiting, dysphagia, and dysarthria. In addition, there would be nystagmus looking toward the left, left–sided Horner’s syndrome, and loss of pinprick sensation on the left side of the face and on the right side of the trunk and extremities. This condition is also known as Wallenberg’s syndrome. Blood supply of brain •• Right posterior inferior cerebellar artery: This lesion would cause infarction of the lateral medulla and inferior cerebellar surface, causing vertigo with vomiting, dysphagia, and dysarthria. In addition, there would be nystagmus looking toward the right, right–sided Horner’s syndrome, and loss of pinprick sensation on the right side of the face and on the left side of the trunk and extremities. This condition is also known as Wallenberg’s syndrome. 64 USMLE Step 1 Platinum Notes MOVEMENT DISORDERS AND THEIR NUCLEI Cranial Nerves: (USMLE Favorite) •• •• •• •• Optic nerve is not only a cranial nerve. It is a tract and direct extension of CNS This nerve is about 4 cm long The optic nerve is enclosed in 3 sheaths covering with meninges It is crossed by ophthalmic artery –– Trigeminal nerve is the largest cranial nerve –– Abducent nerve has the longest course –– Trochlear nerve has the longest intracranial course. Thinnest as well –– Cranial nerve 3 and 4 have their nuclei in midbrain –– Cranial nerve 5, 6, 7, 8 have their nuclei in pons –– Cranial nerve 9, 10, 11, 12 have their nuclei in medulla •• •• •• •• Cranial nerve emerging from dorsal aspect of brain: Trochlear MC nerve involved in intracranial aneurysms: Occulomotor Common nucleus for VII, IX, X nerves is Nucleus Tractus Solitarius. (NTS) Trochlear nerve has the longest intracranial course Summary of Distribution of Cranial Nerves: (USMLE Favorite) No. Nerve Type Function 1. Olfactory Sensory smell 2. Optic Sensory vision 3. Oculomotor Motor To all muscles of the eye except two: (superior oblique and lateral rectus) 4. Trochlear Motor To one eye muscle (superior oblique) 5. Trigeminal Mixed Sensory to mainly sensory with small –– Mouth motor part –– Face –– Ant ½ of scalp 6. Abducent Motor To one eye muscle (lateral rectus) 7. Facial Mixed Motor ———Sensory Parasympathetic (a) (b) (c) (d) Motor to muscles of the face Sensory: taste to anterior 2/3 of tongue Parasym Pathetic to certain glands. 8. Vestibulocochlear Sensory (a) (b) Hearing (cochlear part) Equilibrium (Vestibular part) 9. Glossopharyngeal Mixed Motor ———Sensory Parasympathetic •• Sensory for pharynx and tongue •• Motor to: One muscle of pharynx (stylophar ngeus) •• Parasympathetic to parotid gland 10. Vagus (Including Cranial accessory) Mixed Motor ———Sensory Parasympathetic –– Motor to: Muscles of pharynx, larynx and palate Parasympathetic and sensory to: The structures in the thorax and abdomen 11. Spinal Accessory Motor To two important muscles of the neck: 1. Sternomastoid 2. Trapezius 12 Hypoglossal Motor To all muscles of the tongue (except one) Anatomy 65 Cranial Nerve The First (Olfactory) Nerve Palsy The chief function of the 1st cranial nerve (olfactory nerve) is concerned with the sense of smell. Cells of origin are located in the nasal mucosa. Nerve filaments group and pass through the cranium at cribriform plate and end in olfactory bulb. The olfactory nerve is composed exclusively of somatic afferent fibers. The olfactory nerve branches penetrate through the cribriform plate, and collect in the olfactory bulb and nerve which passes under the frontal lobe to the temporal lobe and other centers EXAMINATION Each nostril is examined separately. One nostril is closed while the patient sniffs with the other. Mild aromatic substances such as orange, coffee, or tobacco should be used as strong irritant smells stimulate the sensory endings of the fifth nerve. The result of affection will be loss of smell or anosmia. The Third (Oculomotor) Nerve Palsy It supplies all extraocular muscles except the superior oblique and the lateral rectus Complete paralysis results in: •• External ophthalmoplegia: In a complete lesion inability to move the eye upward, inward and downward •• External Squint: The eye is deviated laterally and downwards due to the unopposed action of the lateral rectus and superior oblique •• Diplopia: A person sees double •• Ptosis: Drooping of the upper eyelids due to paralysis of levator palpabrea superioris •• Dilated nonreactive pupil due to paralysis of the sphincter pupillae. The pupil also shows no reaction to light (direct or consensual), or to accommodation. The Fourth (Trochlear) Nerve Palsy •• There is weakness or paralysis of the superior oblique muscle which normally moves the eye downwards and inwards •• Result: Defective depression of the adducted eye. The patient is unable to look at his shoulder •• Symptom presentation: DIPLOPIA (double vision), when looking downwards, e.g. when reading or descending the stairs. The head may tilt to the opposite side to minimize the diplopia. The Sixth (Abducent) Nerve Palsy The sixth nerve supplies the lateral rectus which normally rotates the eye laterally. Its paralysis causes: •• Internal Squint: The eyeball is turned inwards due to unopposed adduction of the medial rectus •• Diplopia, which is maximum on looking outwards. The Fifth (Trigeminal) Nerve Palsy The sensory fibers are divided into three divisions: 1. Ophthalmic Division 2. Maxillary Division 3. Mandibular Division Sensation Sensation is tested in the distribution of the 3 divisions of the nerve. Routinely, it is sufficient to test the sensation at three Sites: on the forehead, the cheek and over the lower jaw, together with anterior two-thirds of the tongue Motor Functions A. Masseters And Temporalis: •• Any wasting of the temporalis •• The degree of contraction of the temporalis and masseter by palpation while asking the patient to bite hard. 66 USMLE Step 1 Platinum Notes The Seventh (Facial) Nerve Palsy Weakness in the facial muscles may result from: •• Upper motor neuron lesion: Here only the muscles of the lower part of face are affected. The eye closure is normal This is because the muscles of the lower part (unlike those of the lower part) are activated through the upper motor neuron fibers of both sides Spontaneous emotional expression is unaffected •• Lower motor neuron lesion: All the muscles of the face (upper and lower) are affected on the same side Facial nerve passes through parotid gland but does not supply it Facial nerve supplies submandibular and lacrimal glands Arterial supply to facial nerve: ascending pharyngeal artery. Facial Nerve has: •• The longest intraosseous course •• It is the Mc paralyzed cranial nerve Muscles supplied by facial nerve: •• Platysma •• Stylohyoid •• Muscles of facial expression •• Buccinator •• Stapedius •• Posterior belly of digastric •• Submandibular, Lacrimal, nasal gland •• Supplies gustatory sensation to soft palate •• Kindly never forget that despite the fact that facial nerve traverses the substance of parotid but does not supply it. (keeps it high and dry) Facial nerve is related to •• Pterygopalatine ganglion •• Geniculate ganglion submandibular ganglion Submandibular The Eight (Vestibulocochlear) Nerve Palsy The eighth nerve consists of two parts which have different functions Cochlear and vestibular nerves •• The cochlear part is concerned with hearing. An affection results is tinnitus and deafness •• The vestibular part is concerned with equilibrium. Its affection may result in vertigo. The Ninth (Glossopharyngeal) Nerve Palsy Paralysis of Glossopharyngeal nerve causes: •• Anesthesia of the pharynx •• Loss of taste on the posterior third of the tongue Glossopharyngeal nerve is involved in: •• Jugular foramen syndrome: Involving IX, X, XI cranial nerves •• Collet Sicard Syndrome: Involving IX, X, XI, XII cranial nerves (Extracranially) •• Villaret Synrome: Lesion in retropharyngeal space involving IX, X, XI, XII cranial nerves Anatomy 67 The Tenth (Vagus) Nerve Palsy Paralysis of vagus nerve causes: Ipsilateral paralysis of the palate, Ipsilateral paralysis of the pharynx and Ipsilateral paralysis of the larynx with anesthesia of the larynx on the affected side Remember: The Recurrent Laryngeal nerve arises from vagus. On the Right side it winds around the subclavian artery and on the Left side it winds around the aortic arch behind ligamentum arteriosum. The Eleventh (Accessory) Nerve Palsy As a Result of damage to the Accessory nerve Sternomastoids Unilateral Apparent wasting The muscle does not stand out on testing Bilateral Wasting of the neck which appears like that of a chicken Falling of head backwards Trapezius Unilateral paralysis •• Drooping of the shoulder when arm is hanging •• Weak movements on testing Supplies all palatal muscles except Tensor palate Spasmodic torticollis is due to central irritation of this nerve (cranial part) The Twelfth (Hypoglossal) Nerve Palsy •• Lesion of one hypoglossal nerve results in deviation of the tongue ‘towards the paralyzed side’. If you ask the patient to protrude his tongue the muscles of the same side of the lesion become paralyzed and begin to atrophy (lower motor neuron lesion) •• Safety muscle of tongue is geniglossus supplied by hypoglossal nerve. GEMS NEVER TO BE FORGOTTEN The Pituitary Gland Also known as Hypophysis cerebri. Pineal is Epiphysis cerebri The average adult pituitary measures 11 × 15 × 5 mm The gland is oval, bilaterally symmetrical, and brownish red The pituitary is approximately 20% larger in females than in males and it enlarges about in females during pregnancy It lies within the sella turcica (Turkish saddle) This fossa is bordered anteriorly, posteriorly, and inferiorly by the sphenoid bone and laterally by the cavernous sinus The floor of the sella forms the roof of the sphenoidal sinus The diaphragma sellae, a thick reflection of dura mater, covers the roof of the sella and closely encircles the pituitary stalk in 50% of individuals The arterial supply to the hypothalamic-pituitary region is complex and arises from three sources a. The inferior hypophyseal artery, a branch of the carotid artery, supplies the posterior pituitary. b. The superior hypophyseal arteries branch from the circle of Willis to supply the median eminence c. The middle hypophyseal arteries are of variable origin and supply the pituitary stalk Capillary portions of the superior hypophyseal arteries drain from the hypothalamus, the median eminence, and the superior portions of the pituitary stalk. These vessels drain into the hypophyseal portal system, which forms a secondary venous plexus in the anterior pituitary and ultimately empties into the cavernous sinus. This portal venous system constitutes the principal blood supply to the anterior pituitary and serves as the medium through which releasing hormones from the hypothalamus reach the pituitary. 68 USMLE Step 1 Platinum Notes The pituitary has dual embryonic origin The Anterior pituitary arises from embryonic ectoderm (Rathke’s pouch) and includes the pars distalis, pars intermedia (vestigial in humans), and pars tuberalis The Posterior pituitary of the gland arises from the diencephalon and includes the neural stalk, infundibulum, and posterior lobe Embryonic defects in invagination and obliteration of the pharyngeal extent of Rathke’s pouch may lead to craniopharyngiomas or hormonally active ectopic pituitary adenomas. Cavernous Sinus •• •• •• •• Paralysis of 3, 4, 6 cranial nerves indicates lesion of cavernous sinus Occulomotor, trochlear and ophthalmic nerves lie in lateral wall of cavernous sinus Abducent nerve is a direct content of cavernous sinus Infections from dangerous area of face can spread to cavernous sinus Remember The pituitary gland is located in the pituitary fossa within the skull. The floor of this fossa is formed by the sella turcica. The lateral walls of the fossa are formed by the cavernous sinuses. The abducens nerve passes through the cavernous sinus along with the internal carotid artery. As the tumor expands laterally, the first nerve that will be encountered is the abducens nerve, producing lateral rectus palsy. Sympathetic and Parasympathetic Systems Organ Sympathetic Parasympathetic Pupil Dilates Constricts Lacrimal and salivary glands Stops secretion Produces secretion Heart Accelerates Slows Bronchioles Dilates Constricts Alimentary canal Dilates Contracts Urinary bladder Dilates Contracts Penis Causes erection [For this reason the pelvic nerve was called the nervus erigens]. Limbic System •• •• •• •• •• •• Subcallosal Gyri Cingulate Gyri Hippocampal formation comprising of Hippocampal Gyrus, Parahippocampal Gyrus and Dentate gyrus Amygdaloidal nucleus Mammillary bodies Anterior thalamic nucleus Briefly Functions of the Limbic System can be summarized by Five Fs •• •• •• •• •• Feeding Flight Feeling Fighting and Fun {sex} Anatomy 69 SKULL FORAMINA AND CONTENTS (USMLE FAVORITE) What Passes through What Foramen Contents •• Optic canal •• Optic (II) Nerve and ophthalmic artery •• Superior orbital fissure •• III, IV, VI and ophthalmic division of V cranial nerves, sympathetic nerves and ophthalmic veins •• Stylomastoid foramen •• VII cranial nerve •• Foramen Rotundum •• Maxillary division of V •• Foramen ovale •• Mandibular division of V and accessory meningeal artery •• Foramen spinosum •• Middle meningeal artery, meningeal branch of the mandibular nerve •• Foramen magnum •• Accessory (XI) nerve, vertebral and spinal arteries. NOT SPINAL CORD •• Foramen lacerum •• Internal carotid artery, lesser petrosal •• Nerve (branch of IX), greater petrosal •• Nerve (branch of VII), deep petrosal •• Jugular foramen •• Inferior petrosal sinus (anterior part) •• Internal jugular vein and IX, X, XI cranial nerves •• Hypoglossal foramen •• XII cranial nerve, meningeal branch of ascending pharyngeal artery •• Internal auditory meatus •• Dorello’s canal •• VII and VIII cranial nerves, labyrinthine (internal auditory) artery •• Abducent nerve. Cerebrospinal Fluid (CSF) •• Clear fluid •• Colorless fluid •• Choroid Plexus (formed by) •• Chloride content ↑ •• Cells minimal •• Cushions the brain •• •• •• •• •• •• •• •• •• •• Circulus arteriosus (branches) supply choroids plexus CSF is principally secreted by choroid plexus Choroid plexus is absent in anterior horn of lateral ventricle Total volume of CSF 150 ml Normal adult CSF pressure: 6 —12 mm Hg pH of CSF is: 7.33 Epidural space is devoid of CSF Rate of CSF absorption is the main factor controlling CSF Pressure Persistent leakage can cause headache No neutrophils in normal state seen ARTERIAL TERITORIES IN HEAD AND NECK AND CLINICAL CORRELATION (USMLE Favorite) * Occlusion of the vertebral artery may cause Medial Medullary Syndrome which is characterized by: •• Paralysis or atrophy of tongue on the side of lesion (XII nerve involvement) •• Paralysis of arm and leg on opposite side •• Impaired tactile and proprioceptive sense on opposite side. (Involvement of pyramidal tract and medial lemniscus) 70 USMLE Step 1 Platinum Notes * The posterior inferior cerebellar artery: –– It is the largest and main branch of the vertebral artery –– It has a tortuous S-shaped course. Immediately after it arises from the vertebral artery, it runs backwards around the lower end of the olive passing through the rootless of the hypoglossal nerve, it then turns round the inferior cerebellar peduncle and finally divides into two terminal branches which supply: (a) the inferior vermis (b) the posterior part of the inferior surface of the cerebellum. •• Impaired pain and temperature sense on opposite side –– Nystagmus (involvement of vestibular nucleus) –– Dysphagia (involvement of nucleus ambigus) –– Nystagmus (involvement of cerebellum) –– Horner’s syndrome (involvement of sympathetic pathway) Occlusion of the Anterior Spinal Artery May Cause •• •• •• •• Loss of motor function below the level of the lesion (due to damage to the corticospinal tracts) Loss of pain and temperature Sensation below the level of the lesion (due to damage to the spinothalamic tracts) Weakness of limbs (due to damage of the anterior grey horns in the cervical or lumbar regions of the cord) Loss of bowel and bladder control (due to damage of the descending autonomic tracts) Occlusion of the Posterior Spinal Artery May Cause Loss of position sense, vibration sense and light touch due to damage of the posterior white columns Larynx Larynx has three paired and three unpaired cartilages Extends from C3-C6 Anatomic basis of stridor is in larynx The larynx serves as the sounding source for speech. A fundamental tone is produced by the movement of the vocal cords, which is brought about by the flow of exhaled air past lightly approximated vocal cords •• The internal laryngeal nerve is sensory to larynx above vocal cords •• The recurrent laryngeal nerve is sensory to larynx below vocal cords •• All muscles of larynx except cricothyroid are supplied by recurrent laryngeal nerve •• Cricothyroid supplied by External laryngeal nerve Muscles of Larynx and their Action Abductor of vocal cords: Posterior Cricoarytenoid Adductor of vocal cords: •• Lateral cricoarytenoid •• Transverse arytenoids •• Cricothyroid •• Thyroarytenoid Tensor of vocal cords: Cricothyroid Relaxor of vocal cords: •• Thyroarytenoids •• Vocalis Anatomy 71 Muscles Acting at Temporomandibular Joint •• •• •• •• •• •• Depression: Lateral Pterygoid Elevation: Temporalis, Massetter, Medial Pterygoid Protrusion: Pterygoids Retraction: Posterior fibers of Temporalis Lateral movements: Pterygoids Buccinator: Nota muscle of mastication In Simple Terms •• •• •• •• •• The backward movement step is accomplished by the posterior fibers of the temporalis muscle The digastric helps to depress the lower jaw during chewing The lateral pterygoid helps to move the lower jaw forward during chewing The medial pterygoid helps to elevate the lower jaw during chewing The mylohyoid helps to depress the lower jaw during chewing Ansa Cervicalis Ansa cervicalis is a thin nerve loop that lies in the anterior wall of carotid sheath Superior root is a continuation of descending branch of hypoglossal (XII) Cranial nerve. Superior root supplies Superior belly of omohyoid. Its fibers are derived from first cervical nerve Inferior root is derived from spinal nerves C2 and C3 Loop of Ansa supplies: •• Inferior belly of omohyoid •• Sternothyroid •• Sternohyoid Dangerous Areas: (USMLE Favorite) •• Dangerous area of face: Lowerpart of nose and upper lip •• Dangerous area of scalp: Loose areolar tissue layer of scalp •• Dangerous zone of eye: Ciliary body Commonest Sites •• •• •• •• •• Commonest site of BHP: Periurethral zone Commonest site of cancer prostate: peripheral zone Commonest site of varicocele: Left side Commonest position of appendix: Retrocecal Commonest site of internal hemorrhoids: 3, 7 and 11 O’clock Superficial Cutaneous Reflexes Center – spinal segment involved Reflex Stimulus Response Scapular Irritation of skin at the interscapular space Contraction of scapular muscles and C5 to T1 drawing in of scapula Upper abdominal Stroking the abdominal wall below the Ipsilateral contraction of abdominal T6 to T9 costal margin muscle and movement of umbilicus towards the site of stroke 72 USMLE Step 1 Platinum Notes Lower abdominal Stroking the abdominal wall at umbilical Ipsilateral contraction of abdominal T10 to T12 and iliac level muscle and movement of umbilicus towards the site of stroke Cremasteric Stroking the skin at upper and inner aspect Elevation of testicles of thigh L1, L2 Gluteal Stroking the skin over glutei Contraction of glutei L4 to S1, S2 Plantar Stroking the sole Plantar flexion and adduction of toes L5 to S2 Bulbocavernous Stroking the dorsum of glans penis Contraction of bulbocavernous S3, S4 Anal Stroking the perianal region Contraction of anal sphincter S4, S5 Functions of Limbic System •• Emotion •• Memory •• Higher functions –– Consolidation of long-term memory occurs in hippocampus –– Processing of short term memory to long term occurs in hippocampus –– Amygdala is the window of limbic system –– Damage to amygdala causes Kluver Bluck syndrome –– Reward center is in medial forebrain bundle. Herniations •• Uncal or transtentorial herniation. The herniated uncus will compress the oculomotor nerve, the posterior cerebral artery, and the brainstem. The pathophysiologic consequences include oculomotor paralysis (manifesting with fixed and dilated pupil on the same side), ipsilateral infarction of the occipital lobe, and hemorrhages within the midbrain and pons. The latter may result in respiratory paralysis and death •• Cerebellar tonsillar herniation refers to downward displacement of the cerebellar tonsils through the foramen of magnum. This results from space-occupying lesions in the infratentorial compartment, such as bleeding and tumors. It leads to compression of the medulla and death by cardiorespiratory arrest •• Subfalcine (cingulate) herniation describes the lateral displacement of the cingulate gyrus beneath the falx cerebri. This event is caused by space-occupying masses in the cerebral hemisphere. It leads to compression of the anterior cerebral artery and infarction of dependent cerebral territories (mostly the medial portion of the frontal and parietal lobes) •• Reverse cerebellar herniation is a rare form of herniation due to midbrain lesions (again, hemorrhages and tumors) that push the midbrain upward through the incisura of the tentorium •• Transcalvarial herniation may develop in open (i.e. accompanied by calvarial bone fractures) head injuries if brain parenchyma is displaced outside the cranial cavity through a calvarial defect •• Split brain syndrome: Disconnection syndrome of cerebral cortex resulting from transection or congenital absence of cerebral cortex. Types of Fibers in CNS Association fibers: Connecting different areas of same cerebral hemisphere •• Superior longitudinal fasiculus •• Inferior longitudinal fasiculus •• Cingulum •• Uncinate fasiculus Anatomy 73 Projection fibers: Connecting cerebral cortex to other parts of CNS •• Corticospinal tract •• Internal capsule Commisural fibers: connecting corresponding parts of two cerebral hemispheres •• Corpus callosum •• Anterior commisure •• Posterior commisure •• Hippocampal commisure •• Habenular commisure •• Hypothalmic commisure Clinical observation Effects Upper motor neuron Lower motor neuron lesion Muscle tone Hypertonic Hypotonic Paralysis Spastic type of paralysis Flaccid type of paralysis Wastage of muscle No wastage Present Superficial reflexes Lost Lost Plantar reflex Abnormal – babinski’s sign Absent Deep reflexes Exaggerated Lost Clonus Present Lost Anatomy of Eye: (USMLE Favorite) •• The ‘Extroter’ of Eye ball is Inferior Oblique and Inferior Rectus •• The ‘Introter’ of Eye ball is Superior Oblique and Superior Rectus. •• Action of Superior oblique is Abduction, Intorsion and depression •• Dilator Pupillae dilates pupil and is supplied by Sympathetics •• Sphincter Pupillae constricts pupil and is supplied by Parasympathetics •• LR6S04 –– Lateral rectus is supplied by 6th Cranial Nerve (Abducent) –– Superior oblique is supplied by 4th Cranial Nerve (Trochlear) –– Rest other ocular muscles are supplied by 3rd Cranial Nerve (Occulomotor) –– Muscle attached to posterior tarsal margin: Mullers muscle –– Ligament of Lockwood is found in Orbit. Structures passing through ‘Superior Orbital Fissure’ are Live Free To See No Insult at All •• Lacrimal Nerve •• Frontal Nerve •• Trochlear Nerve •• Superior Ophthalmic Vein •• Nasociliary Nerve •• Inferior Ophthlamic Vein •• Abducent Nerve 74 USMLE Step 1 Platinum Notes Structures Passing Through ‘Inferior Orbital Fissure’ are •• •• •• •• Maxillary nerve Zygomatic nerve Infraorbital vessels Orbital branch of pterygoplatine ganglion Lesions and Effects of (Visual Pathway) •• •• •• •• •• •• •• Central scotoma ~ macula Ipsilateral blindness ~ optic nerve Bitemporal hemianopia ~ optic chiasm Homonymous hemianopia ~ optic tract Upper homonymous quadrantanopia ~ temporal optic radiations Lower homonymous quadrantanopia ~ parietal optic radiations Also, cortical lesions produce defects similar to those of the optic radiations, but may spare the macula. Spinal Cord •• •• •• •• •• •• •• Spinal cord in adults ends at L1- L2 Spinal cord in infant sends at L3 Thoracic and sacral curves are concave anteriorly Subarachnoid space/Subdural space ends at S2 Dural sheath ends at S2 Filum terminale and piamater extend up to tip of coccyx Number of spinal nerve pairs: 31. Cauda Equina Syndrome It is a serious neurologic condition in which there is acute loss of function of the lumbar plexus, neurologic elements (nerve roots) of the spinal canal below the conus of the spinal cord After the conus, the canal contains a mass of nerves (the cauda equina or ‘horse-tail’) that branches off the lower end of the spinal cord and contains the nerve roots from L1-5 and S1-5. The nerve roots from L4-S4 join in the sacral plexus which affects the sciatic nerve, which travels caudally (toward the feet) End of spinal cord Anatomy 75 Vertebrae and Corresponding Spinal Level •• Cervical region C1-C7 Add1 •• Upper Thoracic Lesion T1 –T6 Add 2 •• Lower Thoracic Lesion T7-T9 Add 3 •• T 10 Corresponds to L1-L2 •• T12-L1 Corresponds to L5-S1 Ascending Tracts of Spinal Cord Situation Tract Function Anterior white funiculus Anterior spinothalamic tract ‘Crude‘ touch sensation Lateral spinothalamic tract Pain and temperature sensation Ventral spinocerebellar tract Subconscious kinesthetic sensations Dorsal spinocerebellar tract Subconscious kinesthetic sensations Spinotectal tract Concerned with spinovisual reflex Fasiculus dorsolateralis Pain and temperature sensations Spinoreticular tract Conciousness and awareness Spino olivary tract Proprioception Spinovestibular tract Proprioception Fasciculus gracilis Tactile sensation Fasciculus cuneatus Tactile localization Tactile discrimination ‘Vibratory’ sensation ‘Conscious kinesthetic sensation’ ‘Stereognosis’ Lateral white funiculus Posterior white funiculus Descending Tracts of Spinal Cord Situation Tract Function Pyramidal tracts Anterior corticospinal tract •• Control voluntary, skilled movements Lateral corticospinal tract •• Forms upper motor neurons Medial longitudinal fasciculus •• Coordination of reflex ocular movement •• Integration of movements of eyes and neck Extra Pyramidal tracts Anterior vestibulospinal tract •• Maintenance of muscle tone and posture Lateral vestibulospinal tract •• Maintenance of position of head and body during acceleration Reticulospinal tract •• Coordination of voluntary and reflex movements •• Control of muscle tone •• Control of respiration and blood vessels Tectospinal tract •• Control of movement of head in response to visual and auditory impulses Rubrospinal tract •• Facilitatory influence on flexor muscle tone Olivospinal tract •• Control of movements due to proprioception 76 USMLE Step 1 Platinum Notes Important Stains used in Histology •• Hand E Stain (Hematoxylin and Eosin): Hematoxylin, a natural dye product, acts as a basic dye that stains blue or black. Nuclear heterochromatin stains blue and the cytoplasm of cells rich in ribonucleoprotein also stains blue •• The aniline dye, Eosin, is an acid dye that stains cytoplasm, muscle, and connective tissues various shades of pink and orange. This difference in staining intensity is useful in differentiating one tissue from another •• Vital Stain: Such as Neutral red, Trypan blue are used for staining living cells such as Reticuloendothelial cells •• Metachromatic Stains are used for staining mast cells with Toluidine blue. The stains react with granules of mast cells (metachromasia) to give a new color to the cells •• Periodic Acid-Schiff Method (PAS): Principally used to demonstrate structures rich in carbohydrate macromolecules such as glycogen, glycoprotein, and proteoglycans found in ground substance of connective tissues, basement membranes and mucus •• Phosphotungstic Acid Hematoxylin (PTAH): This is an ideal stain for the demonstration of striated muscle fibers and mitochondria, which stain blue •• Silver Stains: Certain tissue components called Argyrophilic have a natural affinity for silver salts. Reticular fibers and the granules in diffuse endocrine cells are argyrophilic •• Sudan Stains: Sudan dyes are used to stain lipids. The Sudan dyes, e.g. Sudan IV, dissolve in droplets containing triglycerides and color them intensely. Important Points about Vessels: (USMLE Favorite) •• •• •• •• •• Umbilical arteries carry venous blood Pulmonary vasculature also follows reverse pattern Coronary arteries have three elastic lamina: Internal, middle and external Umbilical arteries have no elastic lamina The arteries of lower limb have more developed muscular tissue than those of upperlimb IMPORTANT POINTS ABOUT SKULL BONES Skull Scaphocephaly Boat shaped skull due to premature union of saggital suture Acrocephaly/Oxycephaly Pointed skull due to premature union of coronal suture Plagiocephaly Twisted skull due to assymetrical union of sutures Trigonocephaly Triangular prominence of forehead due to premature fusion of metopic suture Brachycephaly Short and broad skull Seen in Cleidocranial dysostosis Seen in Downs Syndrome Seen in Achondroplasia Dolicocephaly Long and thin skull Seen in Marfans syndrome Anencephaly Vault of skull not developed resulting in the absence of a major portion of the brain, skull, and scalp Pneumatic Bones: (USMLE Favorite) •• Contain air spaces. Usually present in skull •• Make the skull light in weight •• Act as air conditioners –– Maxilla –– Sphenoid –– Ethmoid –– Mastoid Bones Anatomy Sesamoid Bones •• Patella •• Pisiform •• Fabella Bones Ossified at Birth •• Lower end of femur •• Upper end of tibia •• Calcaneum Important Points about Muscles •• Anti rape muscle/muscle virgineous: Gracilis •• Cheating muscle: Superior oblique of eye •• Safety muscle of tongue: Genioglossus •• Tailors muscle: Sartorius •• Thermostat of testis cremaster •• Bladder muscles in whorls detrusor Hybrid/Composite Muscles •• •• •• •• •• Adductor magnus Biceps Femoris Pectineus Digastric Flexor digitorum superficialis Digastric Muscles •• Digastric: Anterior belly, posterior belly •• Omohyoid: Superior belly, inferior belly •• Occipitofrontalis: Occipital belly, frontal belly •• Gastrocnemius: Lateral head, medial head •• Ligament of Treitz: Skeletal part, smooth part Important Lymph Nodes (USMLE Favorite) •• Glans Penis and clitoris •• Cloquets node •• Rest of Penis •• Superficial inguinal node •• •• •• •• •• •• •• •• Labium majus Testis Ovaries Palatine tonsil Superficial inguinal node Preaortic/Para aortic nodes Preaortic/Para aortic nodes Jugulo digastric nodes •• Tip of Tongue •• Submental nodes •• Anal canal above pectinate line •• Internal iliac nodes •• Anal canal below pectinate line •• Superficial inguinal nodes •• Delphic nodes •• Pretracheal •• Spongiform urethra •• Deep inguinal nodes 77 78 USMLE Step 1 Platinum Notes •• Lymph node of lund: cystic lymph node of gallbladder •• Cloquets node/Rossenmullers node •• Mucocutaneous lymph node syndrome •• Sister mary josephs node •• Virchows node •• Rotter’s lymph nodes are small interpectoral lymph nodes located between the pectoralis major and pectoralis minor muscles. They receive lymphatic fluid from the muscles and the mammary gland, and deliver lymphatic fluid to the axillary lymphatic plexus. Thoracic duct •• •• •• •• Thoracic duct starts as continuation of cisterna chylii Crosses from right to left at four level Passes through aortic opening of diaphragm The right lymphatic duct drains the right arm, the right side of the chest, and the right side of the head. The thoracic duct drains the rest of the body. Both the right lymphatic duct and the thoracic duct dump into the large venous channels at the base of the neck. Occlusion of this drainage cans produce intractable edema in sites feeding these ducts. Primary lymphoid organs are Thymus and Bone marrow Lymphatics are absent in •• •• •• •• •• •• •• •• Epidermis Eye Cornea Lens Articular cartilage Placenta Bone marrow Glottis Eponym Nerves: (USMLE Favorite) •• Arnolds nerve/Aldermans nerve auricular branch of vagus •• Nerve of Bell long thoracic nerve •• •• •• •• •• •• Buffer nerve carotid sinus and vagal fibers from aortic arch Saphenous nerve longest/largest cutaneous branch of femoral nerve Herrings nerve branch of glossopharyngeal nerve to carotid sinus Exners nerve from pharyngeal plexus to cricothyroid membrane Vidian nerve Greater pertrosal + deep pertrosal nerve (N of Pterygoid canal) Nerve of Wrisberg: (2 nerves) Nervus intermedius (branch of Facial nerve), medial cutaneous nerve of forearm Freys syndrome/Baillargers Syndrome Due to abnormal and inappropriate regeneration Auriculotemporal branch of trigeminal nerve there is rednesss, sweating especially on cheeks while eating, talking (gustatory sweating) Important Points about Veins •• •• •• •• •• Great cerebral vein of Galen is formed by union of internal cerebral veins Great cerebral vein of Galendrains into straight sinus Facial vein communicates to cavernous sinus via: Superior ophthalmic vein, inferior ophthalmic vein, deep facial vein Long saphenous vein is the largest and longest superficial vein of lower limb formed on medial side of dorsal venous arch Injury to great saphenous vein corresponds to area of femoral nerve distribution. Anatomy 79 •• The portal vein begins at the level of the second lumbar vertebra and is formed from the convergence of the superior mesenteric and splenic veins. It is 3. 8 cm long and lies anterior to the inferior vena cava and posterior to the neck of the pancreas. It lies obliquely to the right and ascends behind the first part of the duodenum, the common bile duct and gastroduodenal artery. At this point it is directly anterior to the inferior vena cava. It enters the right border of the lesser omentum, and ascends anterior to the epiploic foramen to reach the right end of the porta hepatis. It then divides into right and left main branches which accompany the corresponding branches of the hepatic artery into the liver •• Portal vein is formed behind the neck of pancreas by union of superior mesentric and spleenic vein •• Normal pressure is 5–10 mm Hg •• Portal venous system is valveless. •• •• •• •• Left suprarenal drains into left renal vein Left testicular vein drains into left renal vein Left ovarian vein drains into left renal vein Batesons vertebral venous plexus is valveless Varicose Veins Are dilated, tortuous veins and are very common; they may either give no symptoms or cause aching and discomfort in the legs. Varices are recognized as tortuous dilated veins in the leg, a varicose vein is one which permits reverse flow through its faulty valves. Occasionally complications of varicose veins may develop. These include: •• Thrombosis: Which is referred to as superficial thrombophlebitis •• Sometimes thrombosis extends into the deep venous system to cause Deep vein thrombosis, although this is infrequent •• Hemorrhage: Can occur when large superficial varices are damaged •• The most serious problem is venous ulceration which complicates varicose veins. Excepts in Anatomy •• All muscles are mesodermal in origin except muscles of Iris (Sphincter pupillae and dilator pupillae) which are ectodermal •• All Pharyngeal arches persist except fifth which disappears •• All intrinsic muscles of Larynx are supplied by recurrent laryngeal nerve except cricothyroid which is supplied by external laryngeal nerve •• All major salivary gland are supplied by facial nerve except Parotid gland (Although passes through the substance of parotid) •• All divisions of Trigeminal nerve except Mandibular division lie in lateral wall of Cavernous sinus •• All muscles of pharynx are supplied by pharyngeal plexus except stylopharyngeus which is supplied by Glossopharyngeal nerve. •• All muscles of soft palate are supplied by pharyngeal plexus except tensor palate which is supplied by Nerve to medial pterygoid •• All muscles of tongue are supplied by hypoglossal nerve except palatoglossus which is supplied by pharyngeal plexus. Important Vessels and Source of Bleeding: (USMLE Favorite ) •• •• •• •• •• •• •• Hemoptysis: Bronchial artery Duodenal ulcer: Gastroduodenal artery Gastric ulcer: Left Gastric artery SDH: Bridging veins EDH: Middle meningeal artery Tonsillectomy: Paratonsillar vein Menstruation: Spiral arteries Duodenal ulcer: The duodenal cap lies just beyond the pylorus. Externally, the cap has attachments to the hepatoduodenal ligament in the pancreatic head. Most of the ulcers occur in the duodenal cap region. The gastroduodenal artery lies directly behind the duodenal cap, and penetrating ulcers into the pancreas initially erode through the gastroduodenal artery, accounting for the massive bleeding that occurs with these ulcers Extradural hemorrhage: Usually follows arterial hemorrhage between the skull and the dura. Most frequently, acute epidural hematomas occur in the temporal or temporoparietal region as a consequence of hemorrhage from one of the branches of the middle meningeal artery. 80 USMLE Step 1 Platinum Notes Eponym Ducts •• Parotid duct: Stensons duct •• Submandibular duct: Whartons duct •• Pancreatic duct: Wirsungs duct •• Accessory pancreatic duct: Santoniris duct •• Gartners duct: Remanant of Mesonephric duct (WOLLFIAN) •• Thoracic duct: Pecquet duct Important Membranes in Body: (USMLE Favorite) •• Huxles Membrane Inner layer of cells of root sheath of hair •• Henles Membrane Outer layer of cells of root sheath of hair •• Bowmans Membrane 'Anterior’ limiting membrane of Cornea •• Decemet’s Membrane ‘Posterior’ limiting membrane of Cornea •• Bruchs Membrane Pigment membrane in Retina •• Elschings Membrane Astroglial membrane covering Optic Disk •• Heusers Membrane Exocelomic Membrane •• Sharpnells Membrane Pars Flaccida of the tympanic membrane Important Cells in Histology (USMLE Favorite) •• Bergmann Cells •• Glial cells of Cerebellum •• Gitter Cells •• Microglia •• Interstitial Cells of Cajal •• Nerve cells of superficial layers of cerebral cortex •• Supporting Cells of Claudius •• Cells in floor of Cochlear canal of inner ear •• Dieters Cells •• Outer hair cells of organ of Corti •• Hensens Cells •• Supporting cells in organ of Corti external to Dieters cells •• Houfbauers Cells •• Ellipsoidal cells in chorionic villi of placenta •• JG Cells •• Smooth muscle cells of afferent arteriole. (kidney) •• Ito Cells •• Stellate cells in liver •• Langerhans Cells •• Antigen presenting epithelial dendritic cells •• Langhans Cells •• Cytotrophoblastic cells of chorionic villi •• Basket Cells •• Myoepithelial cells in salivary/mammary/sweat glands •• Gitter Cells •• Microglia of brain •• Basket Cells of Cerebellum •• Neurons of molecular layer of Cerebellum •• Merkel Cells •• Sensory nerve endings •• Muller’s Cells •• Neuroglial cells in Retina •• Hilus Cells •• Rare cells found in Medulla of Ovary at Hilum of Ovary •• Lacis Cells •• Extra glomerular Mesengial Cells outside Glomerulus •• Peg Cells •• Secretory cells in mucosa of uterine tube •• Glomus Cells •• Present in Carotid Bodies Anatomy 81 ‘Abnormal’ cells Reed Sternberg cell These cells characteristically are neoplastic giant cells with a bilobed mirror-image nucleus that may have large (‘owl-eyes’) nucleoli surrounded by a clear halo. Most commonly, these cells are associated with Hodgkin’s disease. The Langhans cell It is a giant cell with peripherally arranged nuclei found in granulomas The LE cell It is a degenerating neutrophil seen in lupus erythematosus in in vitro preparations The Mott cell It is a ‘constipated’ plasma cell filled with immunoglobulins, producing a grape-cluster appearance to the cell. Mott cells are seen in multiple myeloma and some parasitic infestations The Touton giant cell Has distributed nuclei and is found in tumors other than Hodgkin’s lymphoma Diaphragms of Body (USMLE Favorite) •• Diaphragm of oral cavity: Mylohyoid •• Diaphragm of Superior thoracic aperture: Sibsons Fascia Sibsons fascia •• Pelvic diaphragm: Levator ani and coccygeus •• Urogenital diaphragm: Deep transverse perinea and sphincter urethrae, perineal mermbrane •• Diaphragm sella: Fold of duramater overlying pituitary fossa •• Iris diaphragm: In eye Eponym Fascias (USMLE Favorite) •• Toldts fascia •• Anterior renal fascia •• Zuckerland fascia •• Posterior renal fascia •• Bucks fascia •• Deep fascia of penis •• Denonvillers fascia •• Fascia separating rectum from prostate •• Waldeyers fascia •• Fascia separating rectum from coccyx 82 USMLE Step 1 Platinum Notes •• Campers fascia •• Fatty layer of superficial fascia •• Scarpas fascia •• Deep membranous layer of Superficial fascia •• Fascia Colli •• Investing layer of deep cervical fascia of neck •• Fascia transversalis •• Forms anterior wall of femoral sheath •• Fascia iliaca •• Forms posterior wall of femoral sheath •• Pelvic fascia •• Forms hypogastric sheath USMLE Case Scenario The Fascial layer separating the rectum from the coccyx is: 1. Waldeyers Fascia 2. Fascia Coli 3. Denonveliers Fascia 4. Gerota’s Fascia 5. Cruveilhier’s Fascia 6. Camper’s Fascia 7. Colles’ Fascia 8. Scarpa’s Fascia Ans. 1. Waldeyers Fascia Bursitis Bursitis is inflammation of a bursa, which is a thin-walled sac lined with synovial tissue The function of the bursa is to facilitate movement of tendons and muscles over bony prominences: •• Subacromial bursitis (subdeltoid bursitis) is the most common form of bursitis. Trochanteric bursitis involves the bursa around the insertion of the gluteus medius onto the greater trochanter of the femur. •• Olecranon bursitis occurs over the posterior elbow, and when the area is acutely inflamed, infection should be excluded by aspirating and culturing fluid from the bursa. Achilles bursitis involves the bursa located above the insertion of the tendon to the calcaneus and results from overuse and wearing tight shoes. •• Retrocalcaneal bursitis involves the bursa that is located between the calcaneus and posterior surface of the Achilles tendon. •• Ischial bursitis (weaver’s bottom) affects the bursa separating the gluteus medius from the ischial tuberosity and develops from prolonged sitting and pivoting on hard surfaces. •• Iliopsoas bursitis affects the bursa that lies between the iliopsoas muscle and hip joint and is lateral to the femoral vessels. •• Anserine bursitis is an inflammation of the sartorius bursa located over the medial side of the tibia just below the knee and under the conjoint tendon and is manifested by pain on climbing stairs. •• Prepatellarbursitis (housemaid’s knee) occurs in the bursa situated between the patella and overlying skin and is caused by kneeling on hard surfaces. Treatment of bursitis consists of prevention of the aggravating situation, rest of the involved part, administration of a nonsteroidal anti-inflammatory drug (NSAID), or local glucocorticoid injection. Bursitis of Knee Joint •• Housemaid’s knee is the result of inflammation of Prepatellar bursa •• Miners beat knee is the result of inflammation of Prepatellar bursa •• Clergymans knee is the result of inflammation of subcutaneous infrapatellar bursa Important Nutrient Arteries •• Nutrient artery of clavicle •• Suprascapular artery •• Nutrient artery of humerus •• Profunda brachii artery Anatomy 83 •• Nutrient artery of femur •• Second perforating artery. Sometimes by first and third perforating arteries •• Nutrient artery of tibia. Largestin body •• Posterior tibial artery •• Nutrient artery of fibula •• Peroneal artery Axis Arteries Axis artery of upper limb: seventh cervical intersemental artery persisting as: •• Axillary •• Brachial •• Anterior interosseous artery and •• Deep palmar arch Axis artery of lower limb: fifth lumbar intersemental artery persisting as: •• Inferior gluteal artery •• Companion artery of sciatic nerve •• Popliteal artery •• Peroneal artery and •• Plantar arch Important Vessels (USMLE Favorite) The Marginal artery of Drummond is also known as the Marginal artery of the colon. The anastomoses of the terminal branches of the ileocolic, right colic and middle colic arteries of the continuous arterial circle or arcade along the inner border of the colon known as the marginal artery of Drummond. Components •• Ileocolic artery - colic branch •• Right colic artery – ascending and descending branches •• Middle colic artery – right and left branches •• Left colic artery – ascending and descending branches •• Sigmoid arteries – unnamed terminal branches –– From this marginal artery, straight vessels (known as vasa recta) pass to the colon –– The marginal artery is an important connection between the SMA and IMA, and provides collateral flow in the event of occlusion or significant stenosis. The junction of the SMA and IMA territories is at the: -- Superior mesentric artery (SMA), and of the left colic and sigmoid branches of the IMA, form a splenic flexure. Anastomoses here are often weak or absent, hence the marginal artery at this point (known as Griffiths’ point) is often focally small or discontinuous. For this reason, the splenic flexure is a watershed area prone to ischemia and infarction -- One of the commonest area of colonic ischemia is called Sudeck’s point. Charcots Artery Charcots Artery: lenticulostriate arteries which arise at the commencement of the middle cerebral artery supply blood to part of the basal ganglia and posterior limb of the internal capsule. The lenticulostriate perforators are end arteries. The name of these arteries is derived from some of the structures it supplies: the lenticular nucleus and the striatum. Heubner’s Artery Heubner’s artery: A branch of anterior Cerebral artery, supplies the anteromedial part of the head of the caudate and anteroinferior internal capsule Its vascular territory is the anteromedial section of the caudate nucleus and the anteroinferior section of the internal capsule. 84 USMLE Step 1 Platinum Notes Artery of Adamkiewicz Artery of Adamkiewicz: Arteria Radicularis Magna, Great radicular artery of Adamkiewicz. Provides the major blood supply to the lumbar and sacral cord. When damaged or obstructed, it can result in anterior spinal artery syndrome, with loss of urinary and fecal continence and impaired motor function of the legs; sensory function is often preserved to a degree. It is important to identify the location of the artery when treating a thoracic aortic aneurysm or a thoracoabdominal aortic aneurysm. The Dorsalis Pedis Artery •• The dorsalis pedis artery is the continuation of the anterior tibial artery after the artery anterior tibial artery crosses the ankle to reach the dorsum of the foot •• Its pulse is the most distal palpable pulse in the lower limb and therefore is useful for evaluating the arterial supply to the limb •• On the dorsum of the foot, the pulse maybe felt as the artery passes over the navicular bone between the extensor hallucis longus tendon and the extensor digitorum longus tendon. Batson’s Vertebral Venous Plexus Batson’s vertebral venous plexus: The valveless vertebral venous veins that communicate with the prostatic venous plexus and explain the readiness with which carcinoma of the prostate spreads to the pelvic bones and vertebrae. Tortuous Arteries •• Facial artery •• Splenic artery •• Uterine artery •• Vaginal artery •• Ophthalmic artery •• Lingual artery •• PICA (Post Inferior Cerebellar Artery) USMLE Case Scenario A 66-year-old male patient from Florida complains of loss of pain and temperature sensation over the left side body ipsilateral dysphagia, hoarseness, and diminished gag reflex with vertigo and diplopia of two months duration. Most likely tortuous vessel affected is: 1. AICA 2. PICA 3. Common carotid 4. Internal carotid 5. Arch of aorta Ans. 2. PICA: The condition itself is Lateral Medullary (Wallenburgs Syndrome) End Arteries •• •• •• •• Central artery of retina Central branches of cerebral artery Coronary artery Segmental branches of renal/splenic artery Important Arteries and Their Branches: (USMLE Favorite) Axillary Artery •• It is continuation of subclavian artery •• Pectoralis minor divides it into three Branches Anatomy Ist part: –– Superior thoracic artery 2nd part: –– Thoracoacromial artery –– Lateral thoracic artery 3rd part: –– Subscapular artery –– Anterior circumflex humeral artery –– Posterior circumflex humeral artery Internal Carotid Artery No Branches in Neck •• Caroticotympanic •• Pterygoid •• •• •• •• •• •• •• Cavernous branch to trigeminal ganglion Superior and inferior hypophyseal Ophthalmic Anterior cerebral Middle cerebral Posterior communicating Anterior choridal External Carotid Artery •• •• •• •• •• •• •• •• Superior thyroid Lingual Facial Occipital Posterior auricular Ascending pharyngeal Maxillary Superficial temporal Subclavian Artery •• •• •• •• Vertebral artery Internal thoracic artery Thyrocervical trunk (Inferior thyroid, suprascapular, superficial cervical) Costocervical trunk (Superior intercostal, Deep cervical) Vertebral Artery •• •• •• •• •• •• •• Spinal Muscular Meningeal Anterior spinal Posterior spinal Posterior inferior cerebellar Medullary 85 86 USMLE Step 1 Platinum Notes Basilar Artery •• •• •• •• •• •• Formed by Union of Two Vertebral Arteries: Posterior cerebral arteries Superior cerebellar Pontine Labyrinthine Anteroinferior cerebellar Internal Iliac Artery •• It is smaller terminal branch of common iliac artery •• It is about one and half inches long (3–3.5 cn) •• It begins in front of sacroiliac joint •• It divides into ant and post Divisions at upper margin of greater sciatic notch Branches from Anterior Division: (Six in males and seven in females.) •• Superior vesical artery •• Inf vesical •• Obturator •• Middle rectal •• Inf Gluteal •• Internal pudendal •• In females, inferior vesical is replaced by vaginal artery •• Uterine artery is the 7th branch in females Branches from Posterior Division •• Superior gluteal •• IIio lumbar •• Lateral sacral Questions asked in USMLE Examinations •• Inferior thyroid artery is a branch of: Thyrocervical trunk •• Ascending pharyngeal artery is a branch of external carotid artery •• Internal pudendal artery in females is a branch of internal iliac artery •• Left gastroepiploic artery is a branch of splenic artery •• Splenic artery is a branch of celiac trunk •• Uterine artery is a branch of internal iliac artery •• Cystic artery is a branch of right hepatic artery •• Cilio retinal artery is a branch of choridal artery •• Middle meningeal artery is a branch of maxillary artery •• Anterior spinal artery is a branch of vertebral artery •• Ophthalmic artery is a branch of internal carotid artery Structures Pasing between/Piercing •• Structure passing between two heads of gastrocnemius: Sural nerve •• Structure passing between two heads of lateral pterygoid: Maxillary artery •• Structure passing between pronator teres: Median nerve Anatomy 87 •• Structure passing between two plains of fibers of supinator: Posterior interosseous nerve •• Structure passing through tarsal tunnel: Posterior tibial nerve •• Structure passing through choroid fissure of eye: Hyaloids artery •• Structure passing through foramen of Vesalius: Emissary vein •• Structure passing through carotid sheath: Internal carotid/common carotid artery, internal jugular vein, vagus nerve. External carotid is External to sheath •• Structure piercing corocabrachialis: Musculocutaneous nerve •• Structure piercing clavipectoral fascia (encloses subclavius): Lateral pectoral nerve, thoracoacromial vesses Cephalic vein •• Structure piercing thyrohyoid membrane: Internal laryngeal nerve Important Structures ‘Accompanying’ (USMLE Favorite) •• Axillary nerve accompanies posterior humeral circumflex artery •• Radial nerve accompanies profunda brachii vessels •• Short saphenous vein accompanies sural nerve •• Great saphenous vein accompanies saphenous nerve •• Superior thyroid vessels accompany external laryngeal nerve •• Superior laryngeal vessels accompany internal laryngeal nerve •• Inferior laryngeal vessels accompany recurrent laryngeal nerve 88 USMLE Step 1 Platinum Notes USMLE Case Scenario Stroking the skin of the medial side of the thigh evokes a reflex contraction of the muscle, the cremasteric reflex, which is most, pronounced in children. It may represent a protective reflex, and the cremaster may also have a role in testicular thermoregulation. Cremaster consists of loosely arranged muscle fasciculi lying along the spermatic cord. It is variable in thickness and is thickest in young men. It may form an incomplete coating around the cord, known as the cremasteric fascia, which extends around the testis but lies within the external spermatic fascia. Cremaster is innervated by: 1. The terminal branches of the subcostal nerve 2. The terminal branches of the iliohypogastric nerve 3. The terminal branches of the ilioinguinal nerve 4. The genital branch of the genitofemoral nerve 5. The femoral branch of the genitofemoral nerve Ans. 4. The genital branch of the genitofemoral nerve USMLE Case Scenario A 45-year-old man is evaluated by a neurologist because of a gait disorder. When the physician passively moves the patient’s right great toe upward or downward, the patient cannot accurately report the direction of motion. This finding can best be explained by a lesion of which of the following structures? 1. Right fasciculus cuneatus 2. Right fasciculus gracilis 3. Right lateral lemniscus 4. Right medial lemniscus Ans: 2. Right fasciculus gracilis USMLE Case Scenario As part of a complete neurological examination, a medical student takes a cotton-tipped applicator and touches the patient’s left eye with a thin wisp of cotton as the patient looks to the right. The patient closes both of his eyelids in response. Which of the following cranial nerves is responsible for the motor limb of this reflex? 1. Abducens 2. Facial 3. Optic 4. Trigeminal Ans. 2. Facial USMLE Case Scenario The Epithelium of the Bronchi contains: 1. Simple ciliated columnar cells, basal cells, and goblet cells 2. Simple ciliated columnar cells, basal cells, but not goblet cells 3. Non ciliated columnar cells, basal cells, and goblet cells 4. Stratified ciliated columnar cells, basal cells, and goblet cells Ans. 4. Stratified ciliated columnar cells, basal cells, and goblet cells USMLE Case Scenario The Dandy-Walker malformation is a developmental abnormality in which: 1. In which the roof of the third ventricle fails to perforate with concomitant hyperplasia of the cerebellar vermis 2. In which the roof of the fourth ventricle fails to perforate with concomitant hyperplasia of the cerebellar vermis 3. In which the roof of the third ventricle fails to perforate with concomitant hypoplasia of the cerebellar vermis 4. In which the roof of the fourth ventricle fails to perforate with concomitant hypoplasia of the cerebellar vermis Ans. 4. In which the roof of the fourth ventricle fails to perforate with concomitant hypoplasia of the cerebellar vermis. Anatomy 89 The Dandy-Walker malformation is a developmental abnormality in which the roof of the fourth ventricle fails to perforate to form the foramen of Magendie. The resultant cystic dilatation of the fourth ventricle expands the posterior fossa, elevating the tentorium and causing hydrocephalus because of obstruction of the aqueduct of Sylvius, with concomitant hypoplasia of the cerebellar vermis. USMLE Case Scenario The kidneys and ureter arise from: 1. The pronephros and a diverticulum from the wolffian duct 2. The mesonephros and a diverticulum from the wolffian duct 3. The metanephros and a diverticulum from the wolffian duct 4. The pronephros and a diverticulum from the gartners duct 5. The mesonephros and a diverticulum from the gartners duct 6. The metanephros and a diverticulum from the gartners duct Ans. 2. The mesonephros and a diverticulum from the wolffian duct. USMLE Case Scenario From its origin, the uterine artery crosses the ureter anteriorly in the broad ligament before branching at the level of the uterus. One major branch ascends the uterus tortuously within the broad ligament until it reaches the region of the ovarian hilum where it anastomoses with branches of the ovarian artery. The uterine artery arises as a branch of: 1. The anterior division of the internal iliac artery 2. The anterior division of the external iliac artery 3. The posterior division of the internal iliac artery 4. The posterior division of the external iliac artery 5. The common iliac artery Ans. 1. The anterior division of the internal iliac artery USMLE Case Scenario A 34-year-old patient arrives in the emergency room after having suffered severe head trauma in a accident. Radiographic studies of the head reveal a basilar skull fracture in the region of the foramen ovale. Which of the following nerve passes through this foramen: 1. Maxillary 2. Mandibular 3. Ophthalmic 4. Occulomotor Ans. 2. Mandibular 90 USMLE Step 1 Platinum Notes USMLE Case Scenario A Lecturer in Florida is demonstrating a thick fibrous band that runs on the visceral surface of the liver. It is attached on one end to the inferior vena cava and on the other end to the left branch of the portal vein. In the Adult the structure corresponds to: 1. Ductus venosus 2. Ligamentum teres 3. Ligamentum venosum 4. Umbilical arteries 5. Ligamentum arteriosum 6. Ligamentum nucha 7. Ligament of Treitz Ans. 3. Ligamentum venosum USMLE Case Scenario A Lecturer in Florida is demonstrating a fibrous band that runs on the visceral surface of the liver. It is attached on one end to the inferior vena cava and on the other end to the left branch of the portal vein. In the embryo structure corresponds to: 1. Ductus venosus 2. Ligamentum teres 3. Ligamentum venosum 4. Umbilical arteries Ans. 1. Ductus venosus USMLE Case Scenario A 66-year-old driver suffers a stroke while driving on highway. He has a history of hypertension, is a heavy smoker, and drinks beer every weekend A right upper motor neuron paralysis of the facial nerve is noted; the other cranial nerves are normal. He has a hemiplegia on the right side, with equal paralysis of the arm and leg. His lesion most likely involves the: 1. Left internal capsule 2. Left midbrain 3. Left pons 4. Left medulla Ans. 1. Left internal capsule Remember: The anterior limb of the internal capsule conveys frontopontine fibers, the genu conducts corticobulbar fibers, and the posterior limb of the internal capsule conveys corticospinal fibers to the contralateral arm and leg. Hemorrhage of the left internal capsule results in right-sided dense hemiplegia in which paralysis of the arm and leg are of the same intensity. USMLE Case Scenario A structure is caused by failure of obliteration of the vitellointestinal duct. It is classically located in the distal ileum within 30 cm of the ileocecal valve, and the structure is a true diverticulum. The anatomist is talking about: 1. Ligament of Trietz 2. Meckel’s diverticulum 3. Appendicis epiploicae 4. Sacculations Ans. 2. Meckel’s diverticulum USMLE Case Scenario A newborn boy does not pass meconium until 48 hours after his birth. Several weeks later his mother complains that he has not been passing stool regularly. Anorectal manometry reveals increased internal anal sphincter pressure on rectal distention with a balloon. The patient’s disorder maybe attributed to distention with a balloon. The patient’s disorder maybe attributed to: 1. Defective recanalization of the colon Anatomy 91 2. Failure of neural crest cells to migrate 3. Herniation of abdominal contents into the umbilical cord 4. Persistence of the proximal end of the yolk stalk Ans. 2. Failure of neural crest cells to migrate USMLE Case Scenario The vagina is a muscular tube lined with: 1. Non stratified squamous epithelium that is histologically similar to the mucosa of the cervix and vulva 2. Stratified squamous epithelium that is histologically similar to the mucosa of the cervix and vulva 3. Stratified cuboidal epithelium that is not histologically similar to the mucosa of the cervix and vulva 4. Stratified cuboidal epithelium that is histologically similar to the mucosa of the cervix and vulva Ans. 2. Stratified squamous epithelium that is histologically similar to the mucosa of the cervix and vulva. USMLE Case Scenario A 5-year-old child aspirates a peanut. Following bronchopulmonary segments would this foreign object most likely enter. 1. Superior segment of the right lower lobes 2. Inferior segment of the right lower lobe 3. Superior segment of the left lower lobe 4. Superior segment of the left lower lobe Ans. 1. Superior segment of the right lower lobe Because the right main bronchus is wider and more vertical than the left, foreign objects are more likely to be aspirated into the right main bronchus. The superior segmental bronchus of the lower lobar bronchus is the only segmental bronchus that exits from the posterior wall of the lobar bronchi. Therefore, if a patient is supine at the time of aspiration, the object is most likely to enter the superior segmental bronchus of the lower lobe. USMLE Case Scenario Fracture of neck of Fibula produces foot drop due to injury of: 1. Common peroneal nerve 2. Tibial nerve 3. Obturator nerve 4. Femoral nerve Ans: 1. Common peroneal nerv USMLE Case Scenario Which of the following embryonic structures gives rise to the adrenal cortex? 1. Ectoderm 2. Endoderm 3. Mesoderm 4. Mesonephros Ans. 3. Mesoderm USMLE Case Scenario The modified structures at the border of the epithelium are villi which are immotile in a patient. Which of the following would be a consequence of this lack of motility? 1. Implantation failure 2. Kartagener’s syndrome 92 USMLE Step 1 Platinum Notes 3. Increased gut motility 4. Decreased protein absorption Ans. 2. Kartagener’s syndrome USMLE Case Scenario The arterial blood supply to the palatine tonsil is derived from branches of the external carotid artery. The principal artery is the tonsillar artery, which is a branch of the: 1. Facial artery 2. Lingual artery 3. Superficial temporal artery 4. Maxillary artery 5. Superior thyroid artery Ans. 1. Facial artery USMLE Case Scenario Occlusion of which artery would result in insufficient perfusion of the urinary bladder: 1. Internal iliac 2. External iliac 3. Renal 4. Suprarenal Ans. 1. Internal iliac USMLE Case Scenario Statement True about Esophagus is: 1. The upper 2/3 of the esophagus contains striated muscle and is innervated by the vagus nerve (CNX). The lower 1/3 contains smooth muscle from splanchnic mesoderm and is innervated by the splanchnic plexus 2. The lower 2/3 of the esophagus contains striated muscle and is innervated by the vagus nerve (CNX). The upper 1/3 contains smooth muscle from splanchnic mesoderm and is innervated by the splanchnic plexus 3. The upper 2/3 of the esophagus contains smooth muscle and is innervated by the vagus nerve (CNX). The lower 1/3 contains skeletal muscle from splanchnic mesoderm and is innervated by the splanchnic plexus 4. The upper 2/3 of the esophagus contains striated muscle and is innervated by the splanchnic plexus. The lower 1/3 contains smooth muscle from splanchnic mesoderm and is innervated by the vagus nerve Ans. 1. The upper 2/3 of the esophagus contains striated muscle and is innervated by the vagus nerve (CNX). The lower 1/3 contains smooth muscle from splanchnic mesoderm and is innervated by the splanchnic plexus. USMLE Case Scenario The mesentery, a large fold of peritoneum, suspends the small intestine from the posterior abdominal wall. The base of the mesentery attaches to the posterior abdominal wall: 1. To the right of the third lumbar vertebra and passes obliquely to the left and inferiorly to the right sacroiliac joint 2. To the left of the third lumbar vertebra and passes obliquely to the left and inferiorly to the right sacroiliac joint 3. To the right of the second lumbar vertebra and passes obliquely to the left and inferiorly to the right sacroiliac joint 4. To the left of the second lumbar vertebra and passes obliquely to the right and inferiorly to the right sacroiliac joint Ans. 4. To the left of the second lumbar vertebra and passes obliquely to the right and inferiorly to the right sacroiliac joint. The mesentery contains blood vessels, nerves, lymphatics, and lymph nodes, as well as considerable fat. It attaches to the small intestine along the length of one side, the mesenteric border, leaving the remainder of the surface of the bowel covered by its visceral peritoneum, the serosa. The broad-based attachment of the mesenteric base stabilizes the small bowel and prevents it from twisting upon its blood supply. Anatomy 93 USMLE Case Scenario A 33-year-old person from Toledo is hit by a car has been said to develop extradural hematom1. Most likely vessel to bleed is: 1. Ophthalmic artery 2. Subdural veins 3. Occipital artery 4. Middle meningeal artery Ans. 4. Middle meningeal artery USMLE Case Scenario During an abdomino pelvic surgery a big, tortuous vessel was seen by a gynecologist on the lateral side of uterus. The vessel was found to be a branch of internal iliac artery. Most likely the vessel found by the gynecologists was: 1. Splenic artery 2. Ovarian artery 3. Vaginal artery 4. Uterine artery Ans. 4. Uterine artery USMLE Case Scenario A surgeon wishes to perform a splenectomy on a 77-year-old patient who has been in an automobile accident. Before removing the spleen, the splenic artery and splenic vein are ligated. Within which of the following peritoneal structures are the splenic artery and vein found? 1. Gastrocolic ligament 2. Gastrosplenic ligament 3. Lesser omentum 4. Splenorenal ligament Ans. 4. Splenorenal ligament USMLE Case Scenario A 44-year-old has a normal thyroid gland which normally moves with swallowing because the thyroid gland is enclosed by which of the following fascia? 1. Carotid sheath 2. Investing layer of the deep cervical fascia 3. Pretracheal fascia 4. Prevertebral fascia Ans. 3. Pretracheal fascia USMLE Case Scenario A 15-year-old typist from ilinos comes to the health clinic because of recurrent episodes of wheezing during basketball practices. His activity has been hampered by shortness of breath shortly after beginning practice and during games. The symptoms are accompanied by a nonproductive cough and chest tightness. He denies any symptoms at rest. The symptoms occur whether the practices are indoors or outdoors. On physical examination, he is comfortable and denies any symptoms. His physical examination is unremarkable. Which of the following cells are most likely to mediate his symptoms? 1. Eosinophils 2. Lymphocytes 3. Mast cells 4. Monocytes 94 USMLE Step 1 Platinum Notes 5. Neutrophils Ans. 3. Mast cells This patient has symptoms of exercise-induced asthma. The symptoms of exercise-induced asthma are due to mast cell release of histamines, which degranulate with the initiation of exercise. USMLE Case Scenario Carotid Sheath is an important structure. It contains a cranial nerve. The cranial nerve is: 1. IX 2. X 3. XI 4. XII Ans. 2. X USMLE Case Scenario The cranial nerve passing through the substance of parotid gland is: 1. Abducens 2. Facial 3. Optic 4. Trigeminal 5. Glossopharyngeal 6. Vagus Ans. 2. Facial USMLE Case Scenario A feature of Sharipos Syndrome is agenesis of: 1. Corpus callosum 2. Anterior commisure 3. Posterior commisure 4. Hippocampal commisure Ans. 1. Corpus callosum USMLE Case Scenario During cranial nerve examination, a neurologist asks her 33-year-old patient to protrude his tongue. On doing so, her tongue deviates to the right side. This finding results from paralysis of tongue muscle namely: 1. Genioglossus 2. Styloglossus 3. Palatoglossus 4. Hyoglossus Ans. 1. Genioglossus The genioglossus muscle is innervated by the hypoglossal nerve. The function of the genioglossus muscle is to pull the tongue forward (protrude) and toward the opposite side. When the right genioglossus muscle is paralyzed, the left genioglossus muscle pulls the tongue forward and to the right. USMLE Case Scenario Bells Palsy is a LMNL of a cranial nerve. The cranial nerve most commonly involved is: 1. Abducens 2. Facial 3. Optic 4. Trigeminal Ans. 2. Facial Anatomy 95 USMLE Case Scenario An inflammatory process in the temporal bone has resulted in a swelling of the facial nerve within the facial canal. Which muscle maybe paralyzed as a result of this compression? 1. Anterior belly of the digastrics 2. Geniohyoid 3. Stapedius 4. Stylopharyngeus Ans. 3. Stapedius The stapedius muscle is innervated by the facial nerve. This muscle is located in the middle ear and attaches to the neck of the stapes. Contraction of the Stapedius reduces the amplitude of oscillation of the stapes and thus reduces the perceived loudness of a sound. Paralysis of this muscle may result in hyperacusis. USMLE Case Scenario A 34-year-old male smoker notices loss of taste sensation in his anterior part of tongue. He reports to a physician who tells him that one of his nerves maybe damaged which supplies taste sensation to this part of his tongue. The nerve specifically most likely to be damaged is: 1. Glossopharyngeal 2. Lingual 3. Chorda tympani 4. Vagus Ans. 3. Chorda tympani USMLE Case Scenario The neck of the pancreas links the head and body. It is often the most anterior portion of the gland. The lower part of the neck lies anterior to the superior mesenteric vein. This is important during surgery for pancreatic cancer since malignant involvement of these vessels may make resection impossible. The anterior surface of the neck is covered with peritoneum. The posterior surface of neck is closely related to: 1. Pylorus of stomach 2. Aorta 3. Internal iliac vein 4. External iliac vein 5. Common iliac vein 6. Portal vein Ans. 6. Portal vein The neck of the pancreas is defined as that portion of the pancreas which lies anterior to the portal vein, and is closely related to the upper posterior surface. The lower part of the neck lies anterior to the superior mesenteric vein just before the formation of the portal vein. USMLE Case Scenario An ENT surgeon plainly tells his patient from North Carolina that he has got hyperacusis and that one of his important nerve is damaged. The nerve most likely to be damaged is: 1. Auriculotemporal 2. Greater Auricular 3. Auricular branch of Vagus 4. Nerve to Stapedius Ans. 4. Nerve to Stapedius USMLE Case Scenario A 66-year-old patient from Ohio has a large meningioma involving the parasagittal region and falx cerebri neurologic deficits expected to be produced by mass lesion in this region is: 1. Lower limb paralysis 96 USMLE Step 1 Platinum Notes 2. Upper limb paralysis 3. Motor aphasia 4. Sensory aphasia Ans. 1. Lower limb paralysis A meningioma of the parasagittal region and the falx cerebri would be located superiorly, between the two hemispheres. In this position, it could compress the sensory (postcentral gyrus) or motor cortex (precentral gyrus) supplying the lower extremities and cause lower limb paralysis. USMLE Case Scenario A 66-year-old man working in a bar complains of trouble swallowing and hoarseness. On physical exam, he is noted to have ptosis and a constricted pupil on the left, and a diminished gag reflex. Neurological examination shows decreased pain and temperature sensation on the left side of his face and on the right side of his body. Which vessel is most likely occluded? 1. Spinal artery 2. PICA 3. AICA 4. Vertebral artery Ans. 2. PICA The signs and symptoms in this patient are consistent with occlusion of the posterior inferior cerebellar artery (PICA). PICA is a branch of the vertebral artery (which is itself a branch of the subclavian artery). Occlusion of PICA causes a lateral medullary syndrome characterized by deficits in pain and temperature sensation over the contralateral body (spinothalamic tract dysfunction); ipsilateral dysphagia, hoarseness, and diminished gag reflex (interruption of the vagal and glossopharyngeal pathways); vertigo, diplopia, nystagmus and vomiting (vestibular dysfunction); ipsilateral Horner’s syndrome (disruption of descending sympathetic fibers); and ipsilateral loss of pain and temperature sensation of the face (lesion of the spinal tract and nucleus of the trigeminal nerve). USMLE Case Scenario Vessel lying within cavernous sinus is: 1. Internal carotid 2. External carotid 3. Common carotid 4. External jugular vein Ans. 1. Internal carotid USMLE Case Scenario A 55-year-old male received a hit on left hypochondriac region. Spleen was found to be lacerated. On operation, a large tortuous vessel was found to be seen. Doctor reported it as splenic artery. It is a branch of: 1. Celiac trunk 2. Superior mesenteric artery 3. Inferior mesenteric artery 4. Thoracic aorta Ans. 1. Celiac trunk USMLE Case Scenario A 55-year-old male had a surgery. His leino renal ligament was seen to contain an artery. Most likely the artery was: 1. Short gastric artery 2. Splenic artery 3. Pancreatic artery 4. Renal artery Ans. 2. Splenic artery Anatomy 97 USMLE Case Scenario A 55-year-old is to be operated for inguinal hernia. An antomist while discussing the hernia describes one artery as a land mark for differentiating direct and indirect inguinal hernias. The artery most likely is: 1. Superior epigastric artery 2. Inferior epigastric artery 3. Umbilical artery 4. Obliterated umbilical artery Ans. 2. Inferior epigastric artery Remember: Indirect inguinal hernias lie lateral to the inferior epigastric artery, whereas direct inguinal hernias lie medial to these vessels. USMLE Case Scenario The superficial perineal fascia is a continuation into the perineum of the membranous fascia from the anterior abdominal wall. The superficial perineal fascia is called as: 1. Colles fascia 2. Fascia colli 3. Campers fascia 4. Waldeyers fascia 5. Thoraco lumbar fascia Ans. 1. Colles fascia USMLE Case Scenario An aneurysm of the axillary artery within the axilla is most likely to compress which of the following neural structures? 1. Axillary nerve 2. Long thoracic nerve 3. Lower trunk of the brachial plexus 4. Medial cord of the brachial plexus Ans. 4. Medial cord of the brachial plexus Remember: Within the axilla, the axillary artery is within the axillary sheath and is surrounded by the three cords of the brachial plexus, which are also within the axillary sheath. An aneurysm of the axillary artery may compress any of the three cords. USMLE Case Scenario Physical examination of 32-year-old medical graduate from kansas reveals a winged left scapula and an inability to raise his left arm above the horizontal. Which of the following nerves is most likely affected? 1. Axillary nerve 2. Long thoracic nerve 3. Lower subscapular 4. Suprascapular nerve Ans. 2. Long thoracic nerve Remember: The serratus anterior, innervated by the long thoracic nerve, is responsible for stabilization of the scapula during abduction of the arm from 90 to 180 degrees. When the long thoracic nerve is damaged, it is difficult to elevate the arm above the horizontal. This nerve arises from C5, 6, and 7. Remember: ‘winged scapula’ is a classic clue for long thoracic nerve injury. USMLE Case Scenario Waldeyer’s ring is a circumpharyngeal ring of mucosa-associated lymphoid tissue which surrounds the openings into the digestive and respiratory tracts. It is made-up: 1. Posterosuperiorly by the lingual tonsil 98 USMLE Step 1 Platinum Notes 2. Anterosuperiorly by the lingual tonsil 3. Posteroinferiorly by the lingual tonsil 4. Anteroinferiorly by the lingual tonsil Ans. 4. Anteroinferiorly by the lingual tonsil Waldeyers Ring: Anteroinferiorly by the lingual tonsil, laterally by the palatine and tubal tonsils, and posterosuperiorly by the nasopharyngeal tonsil USMLE Case Scenario A 33-year-old female engineer complains to her orthopedician that her thumb does not work right. The physician notes weakness of the thumb in extension, although rotation, flexion, abduction, adduction, and opposition are normal. Which of the following nerves is most likely involved? 1. Ulnar 2. Radial 3. Median 4. Axillary Ans. 2. Radial •• Redial extension is provided by the extensors pollicis longus and brevis, which are innervated by the radial nerve •• The median nerve supplies the thenar group, which allows the thumb to oppose, flex, abduct, and rotate •• The ulnar nerve supplies the adductor pollicis, which adducts the thumb •• Axillary nerve supplies Teres Minor and Deltoid. USMLE Case Scenario A branch of the posterior cord of the brachial plexus particularly susceptible to injury in shoulder dislocations that displace the humeral head with impaired Arm abduction and loss of sensation over the lower half of the deltoid. The nerve involved is: 1. Ulnar 2. Radial 3. Median 4. Axillary Ans. 4. Axillary USMLE Case Scenario A nerve innervates the muscle of the anterior compartment of the arm but does not innervate any muscle in the hand is: 1. Ulnar 2. Radial 3. Musculocutaneous 4. Median Ans. 3. Musculocutaneous USMLE Case Scenario A 36-year-old Acromegaly patient complains of a tingling sensation in the 1st, 2nd, and 3rd digits of the right hand and loss of coordination and strength of the right thumb. The condition is most likely to be: 1. Claw hand 2. Carpal tunnel syndrome 3. Ape hand deformity 4. Dupynterns contracture Ans. 2. Carpal tunnel syndrome Overgrowth in the wrist area has compressed the carpal tunnel, thereby impinging on the median nerve. The median nerve (root C5T1) provides motor innervation to the forearm flexors, thenar muscles, and radial lumbricals. It provides sensory innervation to the radial 2/3 of the palm, volar surfaces of the thumb, 2nd and 3rd digits, and radial 1/2 of the 4th digit. Anatomy 99 USMLE Case Scenario A 55-year-old suffered trauma to his penis. His Dorsal artery of penis got damaged. The said vessel is a branch of: 1. Anterior division of internal iliac artery 2. Posterior division of internal iliac artery 3. Anterior division of external iliac artery 4. Posterior division of external iliac artery Ans. 1. Anterior division of internal iliac artery The internal pudendal is a branch of the anterior division of the internal iliac artery. It gives rise to the inferior rectal artery, perineal artery, artery of the bulb in men, urethral artery, deep artery of the penis and dorsal artery of the penis. USMLE Case Scenario A 66-year-old reports pain in his left upper extremity and tingling and numbness in his 4th and 5th digits of his left hand. There is mild swelling of the left hand. The man reports most of his pain and numbness occurs when he is doing electric work with his arms overhead. X-ray reveals the presence of a cervical rib. The artery liable to be compressed is: 1. Axillary 2. Radial 3. Brachial 4. Subclavian Ans. 4. Subclavian The subclavian artery passes laterally over the upper surface of the first rib and lies posterior to the scalenus anterior. In the case of thoracic outlet syndrome, this artery is usually compressed between the scalenus anterior and a cervical rib. Thoracic outlet syndrome is a broad term for a group of disorders in which there is compression of certain neurovascular bundles. The presence of a cervical rib adds to the compression, and repetitive motion and poor posture are other predisposing factors. When the neurovascular bundle is entrapped, the patient presents with neurological and/or circulatory changes in the upper extremity on the involved side. USMLE Case Scenario A 44-year-old complains of Galactorrhea and Amonorrhea. CT Scan was done. Image shows a pituitary tumor compressing optic chiasma. Hemianopia produced would be of type: 1. Bitemporal hemianopia 2. Binasal hemianopia 3. Unilateral hemianopia 4. Superior quadrant unilateral hemianopia Ans. 1. Bitemporal hemianopia 100 USMLE Step 1 Platinum Notes Parkinson’s disease USMLE Case Scenario The person shown in figure has features as identified in figure. Most likely he is suffering from a disease that affects which part of CNS. 1. Cerebellum 2. Substantia nigra 3. Nucleus basalis 4. Frontal lobe Ans. 2. Substantia nigra Midbrain Anatomy 101 USMLE Case Scenario The chorda tympani nerve of is a branch of cranial nerve. The cranial nerve is: 1. Abducens 2. Facial 3. Optic 4. Trigeminal Ans. 2. Facial USMLE Case Scenario A 45-year-old from India notices swelling in his groin. He is reported to have an abscess after further investigations reveal tuberculosis of spine. The abscess is found along sheath of a muscle whose function is: to flex the thigh at the hip. The muscle involved is: 1. Gluteus maximus 2. Psoas 3. Gluteus minimus 4. Sartorius Ans. 2. Psoas USMLE Case Scenario Pyramidalis is a triangular muscle that lies in front of the lower part of rectus abdominis within the rectus sheath. It is attached by tendinous fibers to the front of the pubis and to the ligamentous fibers in front of the symphysis. The muscle diminishes in size as it runs upwards, and ends in a pointed apex that is attached medially to the linea alba. This attachment usually lies midway between the umbilicus and pubis, but may occur higher. The pyramidalis is supplied by: 1. The terminal branches of the subcostal nerve 2. The terminal branches of the iliohypogastric nerve 3. The terminal branches of the ilioinguinal nerve 4. The terminal branches of the genitofemoral nerve Ans. 1. The terminal branches of the subcostal nerve USMLE Case Scenario The muscles of the pharynx with the exception of one muscle are supplied from the pharyngeal plexus by the pharyngeal branch of the vagus. The exception is: 1. Palatopharyngeus 2. Stylopharyngeus 3. Salpingopharyngeus 4. Inferior constrictor Ans. 2. Stylopharyngeus The muscles of the pharynx-with the exception of stylopharyngeus, which is supplied by the glossopharyngeal nerve are supplied from the pharyngeal plexus by the pharyngeal branch of the vagus. This branch emerges from the upper part of the inferior vagal ganglion. USMLE Case Scenario The paired renal arteries supply the kidneys through a number of subdivisions described sequentially as segmental, lobar, interlobar, and arcuate arteries. These are end arteries with no anastomoses. The renal arteries branch laterally from the: 1. Iliac vessels just below the origin of the superior mesenteric artery 2. Iliac vessels just above the origin of the superior mesenteric artery 3. Aorta just below the origin of the superior mesenteric artery 102 USMLE Step 1 Platinum Notes 4. Aorta just above the origin of the superior mesenteric artery Ans. 3. Aorta just below the origin of the superior mesenteric artery The renal arteries branch laterally from the aorta just below the origin of the superior mesenteric artery. Both cross the corresponding crus of the diaphragm at right angles to the aorta. The right renal artery is longer and often higher, passing posterior to the inferior vena cava, right renal vein, head of the pancreas and descending part of the duodenum. The left renal artery is a little lower and passes behind the left renal vein, the body of the pancreas and splenic vein. USMLE Case Scenario The aortic aperture is the lowest and most posterior of the large openings. It is at the level of the lower border of the twelfth thoracic vertebra and the thoracolumbar intervertebral disk, slightly to the left of the midline. It is an osseoaponeurotic opening defined by the diaphragmatic crura laterally, the vertebral column posteriorly and the diaphragm anteriorly. Strictly speaking, it lies behind the diaphragm and its median arcuate ligament. The aortic opening transmits: 1. The aorta, thoracic duct, azygos veins 2. The inferior vena cava, thoracic duct, azygos veins 3. Esophagus, thoracic duct, azygos veins 4. The phrenic nerve, thoracic duct, azygos veins Ans. 1. The aorta, thoracic duct, azygos veins USMLE Case Scenario The epithelial lining of the trachea is composed of: 1. Pseudostratified columnar nonciliated cells, goblet cells and basal cells 2. Pseudostratified columnar ciliated cells, goblet cells and basal cells 3. Stratified columnar nonciliated cells, goblet cells and basal cells 4. Stratified noncolumnar ciliated cells, goblet cells and basal cells Ans. 2. Pseudostratified columnar ciliated cells, goblet cells and basal cells USMLE Case Scenario Kidney is surrounded by a special layer of fascia called: 1. Waldeyers fascia 2. Fascia coli 3. Denonveliers fascia 4. Gerota’s fascia 5. Cruveilhier’s fascia 6. Camper’s fascia 7. Colles’ fascia 8. Scarpa’s fascia Ans. 4. Gerota’s fascia USMLE Case Scenario The ovarian vessels follow a downward course and pass between the layers of the infundibulopelvic ligament and the broad ligament to reach the ovary. The true statement regarding blood supply of ovary is: 1. The ovarian arteries arise from aorta, the left ovarian vein and the right ovarian vein empties into the vena cava 2. The ovarian arteries arise from aorta and the left ovarian vein empties into the left renal vein; the right ovarian vein empties into the vena cava 3. The ovarian arteries arise from uterine artery and the right ovarian vein empties into the left renal vein; the left ovarian vein empties into the vena cava 4. The ovarian arteries arise from uterine artery and the left ovarian vein empties into the left renal vein; the right ovarian vein empties into the vena cava Ans. 2. The ovarian arteries arise from aorta and the left ovarian vein empties into the left renal vein; the right ovarian vein empties into the vena cava. Anatomy 103 USMLE Case Scenario A 44-year-old suffers fracture of surgical neck of humerus. Most likely effected nerve is: 1. Radial 2. Musculocutaneous 3. Ulnar 4. Anterior interosseous c nerve 5. Cranial nerve XI 6. Subscapular 7. Axillary nerve Ans. 7. Axillary nerve USMLE Case Scenario Valves of Kerckring are seen in: 1. Appendix 2. Small intestine 3. Cecum 4. Sigmoid colon 5. Rectum 6. Anal canal Ans. 2. Small intestine The mucosal surface of the small intestine contains numerous circular mucosal folds called the plicae circulares (valvulae conniventes, or valves of Kerckring). These folds are 3 to 10 mm in height; they are taller and more numerous in the distal duodenum and proximal jejunum, becoming shorter and fewer distally. Intestinal villi barely visible to the naked eye resemble tiny finger-like processes projecting into the intestinal lumen. USMLE Case Scenario A nerve innervates the anconeus muscle of the arm. Most likely nerve supply of anconeus is: 1. Ulnar 2. Radial nerve 3. Musculocutaneous 4. Median Ans. 2. Radial nerve USMLE Case Scenario The cranial nerves lying in the cavernous sinus are: 1. VII , IX 2. X , XI 3. XII, VI 4. Divisions of V nerve 5. Divisions of VII nerve Ans. 4. Divisions of V nerve USMLE Case Scenario Annular bronchial cartilage is congenitally absent, leading to bronchomalacia and Bronchiectasis is termed as: 1. Cystic fibrosis syndrome 2. Ehlers-Danlos syndrome 3. Mounier-Kuhn syndrome 4. Kartageners syndrome 5. Immotile cilia syndrome 6. Williams-Campbell syndrome Ans. 6. Williams-Campbell syndrome 104 USMLE Step 1 Platinum Notes USMLE Case Scenario Fold of serous pericardium surrounding right and left pulmonary veins are connected by an irregular pericardial reflection creates a space termed the: 1. Oblique sinus 2. Transverse sinus 3. Coronary sinus Ans. 1. Oblique sinus USMLE Case Scenario After a fight a sharp instrument passed through the superior orbital fissure of a 45-year-old man. It would most likely damage the: 1. Abducens nerve 2. Facial nerve 3. Mandibular nerve 4. Maxillary nerve 5. Middle meningeal artery 6. Ophthalmic artery 7. Optic nerve Ans. 1. Abducens nerve Almost everything that innervates the eye, other than the optic nerve, passes through this fissure. This includes the oculomotor nerve (CN III), the trochlear nerve (CN IV), the ophthalmic nerve (V1), and the abducens nerve (CN VI). USMLE Case Scenario Meckel’s Diverticulitis is persistence of: 1. Portion of the vitelline duct on the mesenteric border of the distal ileum, may produce bleeding, intestinal obstruction 2. Portion of the vitelline duct on the mesenteric border of the proximal ileum, may produce bleeding, intestinal obstruction 3. Portion of the vitelline duct on the antimesenteric border of the proximal ileum, may produce bleeding, intestinal obstruction 4. Portion of the vitelline duct on the antimesenteric border of the distal ileum, may produce bleeding, intestinal obstruction Ans. 4. Portion of the vitelline duct on the antimesenteric border of the distal ileum, may produce bleeding, intestinal obstruction USMLE Case Scenario A 27-year-old woman presents with hyperthyroidism, and subtotal thyroidectomy is successfully performed, but following the surgery, the woman is extremely hoarse, and can barely speak above a whisper. This hoarseness is most probably related to damage to a nerve which is a branch of CRANIAL NERVE: 1. IX 2. X 3. XI 4. XII Ans. 2. X USMLE Case Scenario A physician is performing a cranial nerve examination on a patient. While testing the gag reflex, it is noted that when the right side of the pharyngeal mucosa is touched, the patient’s uvula deviates to the right. When the left side of the pharyngeal mucosa is touched, the patient does not gag. Which of the following is the most likely location of his lesion? 1. Left glossopharyngeal nerve and left vagus nerve 2. Right glossopharyngeal nerve and left vagus nerve 3. Left glossopharyngeal nerve and Right vagus nerve 4. Right glossopharyngeal nerve and Right vagus nerve Ans. 1. Left glossopharyngeal nerve and left vagus nerve Anatomy 105 USMLE Case Scenario A cranial nerve innervates the stylopharyngeus muscle and the parotid gland. Visceral afferents supply the carotid sinus baroreceptors and carotid body chemoreceptors, and mediate taste from the posterior one-third of the tongue. Somatosensory fibers supply pain, temperature, and touch information from the posterior one-third of the tongue, upper pharynx, middle ear and eustachian tube. The cranial nerve mentioned is: 1. IX 2. X 3. XI 4. XII Ans. 1. IX USMLE Case Scenario An injury to the lateral portion of the dorsal columns would most likely damage: 1. Fine motor control of fingers 2. Motor control of the contralateral foot 3. Sweating of the ipsilateral face 4. Proprioception from the ipsilateral leg 5. Vibratory sense from the ipsilateral arm 6. Vibratory sense from the contralateral arm 7. Sensory control of the contralateral foot Ans. 5. Vibratory sense from the ipsilateral arm USMLE Case Scenario Atresia (blockage) of this canal results from failure of the meatal plug to canalize. Usually the deep part of the meatus is open, but the superficial part is blocked by bone or fibrous tissue. Most cases are associated with the: 1. First arch syndrome 2. Second arch syndrome 3. Third arch syndrome 4. Fifth arch syndrome Ans. 1. First arch syndrome USMLE Case Scenario The tensor tympani muscle, attached to the malleus, is derived from mesenchyme in the first pharyngeal arch and is innervated by: 1. CN V, the nerve of this arch 2. CN VI, the nerve of this arch 3. CN VII, the nerve of this arch 4. CN VIII, the nerve of this arch Ans. 1.CN V, the nerve of this arch USMLE Case Scenario Fine motor control of the fingers would be carried principally by the: 1. Contralateral lateral corticospinal tract 2. Ipsilateral lateral corticospinal tract 3. Ipsilateral rubrospinal tract 4. Ipsilateral Tectospinal tract 5. Ipsilateral vestibulospinal tract Ans. 2. Ipsilateral lateral corticospinal tract 106 USMLE Step 1 Platinum Notes USMLE Case Scenario The rectum is separated from the prostate by: 1. Waldeyers fascia 2. Fascia coli 3. Denonveliers fascia 4. Gerota’s fascia 5. Cruveilhier’s fascia 6. Camper’s fascia 7. Colles’ fascia 8. Scarpa’s fascia Ans. 3. Denonveliers fascia USMLE Case Scenario An 89 years old elderly patient suffering from Picks disease also had multiple small strokes. During her stay in the nursing home on multiple occasions she aspirated food, and neurological examination reveals that her gag reflex is absent. These findings suggest involvement of the nucleus of which of the following cranial nerves? 1. Facial (VII) 2. Glossopharyngeal (IX) 3. Hypoglossal (XII) 4. Spinal accessory (XI) 5. Vestibulocochlear (VIII) Ans. 2. Glossopharyngeal (IX) Cranial nerve IX is the glossopharyngeal nerve, which has a nucleus in the medulla and is necessary for the gag reflex USMLE Case Scenario The esophagus begins at the lower border of the cricoid cartilage at the level of C6 vertebra. It is about 25 cm (10 inches) long. The intra-abdominal part of the esophagus varies in length according to the tone of its muscle and the degree of distension of the stomach. It passes through the diaphragm at the level of: 1. T6 vertebra 2. T8 vertebra 3. T10 vertebra 4. T12 vertebra Ans. 3. T10 vertebra USMLE Case Scenario The upper part of the anal canal above the pectinate line is endodermal, and the lower part is derived from the ectoderm. The upper half of the canal is lined by columnar epithelium and the lower half with stratified squamous epithelium. True statement would be: 1. A carcinoma of the lower canal is usually an adenocarcinoma, while that arising from the upper part would be a squamous cell carcinoma 2. A carcinoma of the upper canal is usually an adenocarcinoma, while that arising from the lower part would also be an adenocarcinoma 3. A carcinoma of the upper canal is usually a squamous cell carcinoma, while that arising from the lower part would also be a squamous cell carcinoma 4. A carcinoma of the upper canal is usually an adenocarcinoma, while that arising from the lower part would be a squamous cell carcinoma Ans. 4. A carcinoma of the upper canal is usually an adenocarcinoma, while that arising from the lower part would be a squamous cell carcinoma Anatomy 107 USMLE Case Scenario The cranial nerve carrying the pain sensations from tip of tongue is: 1. VI 2. V2 3. V3 4. VII 5. IX 6. X 7. XI 8. XII Ans. 3. V3 The mandibular division of the trigeminal nerve (V3) carries general somatic sensation from the anterior two-thirds of the tongue. USMLE Case Scenario Which of the following eye muscles rotates the eye downward and away from midline? 1. Inferior oblique 2. Superior oblique 3. Inferior rectus 4. Superior rectus Ans. 2. Superior oblique USMLE Case Scenario A 44-year-old engineer noticed that he has an eye that is persistent directed toward his nose. A lesion of which of the following nerves could produce this finding? 1. CN II 2. CN IV 3. CN V 4. CN VI Ans. 4. CN VI USMLE Case Scenario The Fascial layer separating the rectum from the coccyx is: 1. Waldeyers fascia 2. Fascia coli 3. Denonveliers fascia 4. Gerota’s fascia 5. Cruveilhier’s fascia 6. Camper’s fascia 7. Colles’ fascia 8. Scarpa’s fascia Ans. 1. Waldeyers fascia USMLE Case Scenario Carotid Sheath is an important structure. It contains: 1. Facial nerve and internal carotid artery 2. Facial nerve and external carotid artery 3. Facial artery and external carotid artery 4. Vagus nerve and external carotid artery 5. Vagus nerve and internal carotid artery Ans. 5. Vagus nerve and internal carotid artery 108 USMLE Step 1 Platinum Notes USMLE Case Scenario Meckels ganglion is related to a cranial nerve. The cranial nerve is: 1. Abducens 2. Facial 3. Optic 4. Trigeminal Ans. 4. Trigeminal USMLE Case Scenario The cranial nerve supplying the Trapezius muscle is: 1. VII 2. IX 3. X 4. XI 5. XII Ans. 4. XI USMLE Case Scenario A Nerve innervating the muscles of the Posterior compartment of the arm is: 1. Ulnar 2. Radial 3. Musculocutaneous 4. Median Ans. 2. Radial USMLE Case Scenario Physical examination of 36-year-old medical graduate from Texas reveals a winged left scapula and an inability to raise his left arm above the horizontal. Which of the following muscles is most likely affected? 1. Serratus posterior 2. Serratus anterior 3. Deltoid 4. Scalenus anterior 5. Scalenus medius 6. Scalenus posterior 7. Levator scapulae 8. Sternomastoid 9. Rhombidius minor Ans. 2. Serratus anterior Remember: The serratus anterior, innervated by the long thoracic nerve, is responsible for stabilization of the scapula during abduction of the arm from 90 to 180 degree. USMLE Case Scenario A Newborn boy does not pass meconium until 55 hours after his birth. Several weeks later his mother complains that he has not been passing stool regularly. Anorectal manometry reveals increased internal anal sphincter pressure on rectal distention with a balloon. The patient’s disorder is: 1. Intussusception 2. Hirschsprungs disease 3. Exomphalos 4. Dysphagia lusoria Anatomy 109 5. Anal atresia 6. Malrotation of gut Ans. 2. Hirschsprungs disease USMLE Case Scenario A physician during cranial nerve examination asks her patient to protrude his tongue. On doing so, her tongue deviates to the right side. This finding results from paralysis of tongue muscle. The likely nerve paralyzed is: 1. Facial 2. Vagus 3. Hypoglossal 4. Glossopharyngeal 5. Chorda tympani 6. Lingual Ans. 3. Hypoglossal The genioglossus muscle is innervated by the hypoglossal nerve. The function of the genioglossus muscle is to pull the tongue forward (protrude) and toward the opposite side. When the right genioglossus muscle is paralyzed, the left genioglossus muscle pulls the tongue forward and to the right. Tongue deviation USMLE Case Scenario As part of a complete neurological examination, a medical student takes a cotton-tipped applicator and touches the patient’s left eye with a thin wisp of cotton as the patient looks to the right. The patient closes both of his eyelids in response. Which of the following cranial nerves is responsible for the sensory limb of this reflex? 1. Abducens 2. Facial 3. Optic 4. Trigeminal Ans. 4. Trigeminal USMLE Case Scenario A 34-year-old patient arrives in the emergency room after having suffered severe head trauma in a accident. Radiographic studies of the head reveal a basilar skull fracture in the region of the foramen ovale. Which of the following nerve passes through this foramen: 1. Maxillary 110 USMLE Step 1 Platinum Notes 2. Mandibular 3. Ophthalmic 4. Occulomotor Ans. 2. Mandibular USMLE Case Scenario Annular pancreas is a condition that results when normal pancreatic tissue completely or partially encircles the duodenum. Annular pancreas is thought to arise from failure of normal clockwise rotation of the ventral pancreatic bud. In children, there is a common association with other serious congenital anomalies such as intracardiac defects, Down’s syndrome, and intestinal malrotation. It commonly encircles: 1. First part of duodenum 2. Second part of duodenum 3. Third part of duodenum 4. Fourth part of duodenum 5. Jujenum 6. Ileum Ans. 2. Second part of duodenum USMLE Case Scenario Pancreas is a mixed gland divided into four portions: the head, the neck, the body, and the tail. It is a retroperitoneal organ. The structure related to the head of the pancreas is: 1. Hilum of spleen 2. Uncinate process 3. Portal vein 4. Tuber omentale 5. Pappilary process 6. Foramen of Winslow 7. Ligament of Treitz 8. Linea semilunaris Ans. 2. Uncinate process USMLE Case Scenario The Distal portion of the gallbladder has the appearance of a diverticulum, which is called: 1. Morrisons pouch 2. Zenkers diverticulum 3. Meckel’s diverticulum 4. Spiral valve of Heister 5. Hartmann’s pouch 6. Uncinate process 7. Tuber omentale 8. Pappilary process 9. Foramen of Winslow Ans. 5. Hartmann’s pouch USMLE Case Scenario Pancreas is a mixed gland divided into four portions: the head, the neck, the body, and the tail. It is a retroperitoneal organ. The endocrine portion of pancreatic function is served by the structures termed the islets of Langerhans. The islets are nearly spherical collections of cells scattered throughout the pancreatic parenchyma and is composed of several distinctive cell types. True statement is: 1. The insulin-producing alpha cells compose the majority of the islet population 2. The insulin-producing beta cells compose the minority of the islet population Anatomy 111 3. The insulin-producing beta cells compose the majority of the islet population 4. The insulin-producing alpha cells compose the minority of the islet population Ans. 3. The insulin-producing beta cells compose the majority of the islet population USMLE Case Scenario Embryologically, the gut rotates and the rotation occurs in a way that: 1. The large intestine rotates in a clockwise manner around the axis of the celiac trunk 2. The large intestine rotates in a clockwise manner around the axis of the superior mesenteric artery 3. The large intestine rotates in a clockwise manner around the axis of the inferior mesenteric artery 4. The large intestine rotates in a counterclockwise manner around the axis of the celiac trunk 5. The large intestine rotates in a counterclockwise manner around the axis of the superior mesenteric artery 6. The large intestine rotates in a counterclockwise manner around the axis of the inferior mesenteric artery Ans. 5. The large intestine rotates in a counterclockwise manner around the axis of the superior mesenteric artery USMLE Case Scenario The ligaments that should be carefully considered during mobilization of the splenic flexure to avoid injury to the spleen are: 1. Leinorenal and splenocolic attachments 2. Phrenocolic and leinorenal attachments 3. Phrenocolic and splenocolic attachments 4. Greater omentum and splenocolic attachments 5. Lesser omentum and leinorenal attachments Ans. 3. Phrenocolic and splenocolic attachments The large intestine rotates in a counterclockwise manner around the axis of the superior mesenteric artery USMLE Case Scenario The anastomosis between the superior and inferior mesenteric vessels is known as the: 1. Marginal artery of Drumond 2. Sudecks point 3. Batesons Plexus 4. Vasa recta 5. Anastomosis of Riolan Ans. 5. Anastomosis of Riolan USMLE Case Scenario As Per the anatomical knowledge of a student, which is not true about pain: 1. A sudden burning pain in the epigastric region suggests a perforated viscus 2. Severe intermittent cramping pain with short pain-free intervals favors small bowel obstruction 3. Sudden excruciating tearing pain maybe associated with a ruptured aneurysm 4. Pain of acute cholecystitis frequently radiates around the right costal margin to the right scapula and to the shoulder 5. Pain in acute pancreatitis is usually epigastric in origin, with subsequent radiation along both costal margins to the back 6. Ureteral calculi causes pain radiating to the groin 7. Pain of stomach is referred to perineum Ans. 7. Pain of stomach is referred to perineum USMLE Case Scenario Maximal tenderness in the right lower quadrant over Mcburney’s point is suggestive of an inflammation of an organ. The characteristic feature of the organ implicated is: 1. It is rich in blood supply with rich anastomosis 112 USMLE Step 1 Platinum Notes 2. It is not covered by peritoneum 3. It is rich in lymphatic tissue 4. It is a derivative of foregut 5. It has a fixed location 6. It has a wide lumen Ans. 3. It is rich in lymphatic tissue USMLE Case Scenario The arterial supply to the hypothalamic-pituitary region is complex and arises from three sources. The inferior hypophyseal artery, the superior hypophyseal arteries and the middle hypophyseal arteries. These vessels drain into the hypophyseal portal system, which forms a secondary venous plexus in the anterior pituitary and ultimately empties into the cavernous sinus. The inferior hypophyseal artery is: 1. A branch of the internal carotid artery 2. A branch of the external carotid artery 3. A branch of the common carotid artery 4. A branch of the vertebral artery 5. A branch of the subclavian artery Ans. 1. A branch of the internal carotid artery USMLE Case Scenario Oxyphil cells are a feature of: 1. Spleen 2. Pituitary 3. Adrenals 4. Prostate 5. Lens of eye 6. Cochlea 7. Thymus 8. Thyroid 9. Parathyroid Ans. 9. Parathyroid USMLE Case Scenario The superior parathyroid glands are usually located on the posterior surface of the upper portion of the thyroid lobe. The lower parathyroid glands are more ventral, close to the lower pole of the thyroid gland. True statement about the development of parathyroids is: 1. The superior parathyroids arise from the second pharyngeal pouch and the inferior parathyroids arise from the third pharyngeal pouch 2. The superior parathyroids arise from the second pharyngeal pouch and the inferior parathyroids arise from the fourth pharyngeal pouch 3. The superior parathyroids arise from the third pharyngeal pouch and the inferior parathyroids arise from the fourth pharyngeal pouch 4. The superior parathyroids arise from the fourth pharyngeal pouch and the inferior parathyroids arise from the third pharyngeal pouch Ans. 4. The superior parathyroids arise from the fourth pharyngeal pouch and the inferior parathyroids arise from the third pharyngeal pouch USMLE Case Scenario The transition between the oblique fibers of the thyropharyngeus muscle and the transverse fibers of the cricopharyngeus muscle creates a point of potential weakness in the pharyngoesophageal segment, which is the site of origin of: 1. Rathkes pouch Anatomy 113 2. Foramen of morgagni 3. Pharyngoesophageal diverticulum 4. Laryngocele Ans. 3. Pharyngoesophageal diverticulum USMLE Case Scenario The esophagus is a hollow tube of muscle that is approximately 25 cm in length and extends from the pharynx to the stomach. It is arbitrarily divided into four segments: pharyngoesophageal, cervical, thoracic, and abdominal. True statement about esophagus is that: 1. The esophagus is a nonmucosal-lined muscular tube that has a serosa 2. The esophagus is a nonmucosal-lined muscular tube that lacks a serosa 3. The esophagus is a mucosal-lined muscular tube that has a serosa 4. The esophagus is a mucosal-lined muscular tube that lacks a serosa Ans. 4. The esophagus is a mucosal-lined muscular tube that lacks a serosa USMLE Case Scenario Throughout the fat of the breast, coursing from the overlying skin to the underlying deep fascia, strands of dense connective tissue provide shape and hold the breast upward. These strands, devoid of epithelial elements, are called: 1. Montogmerys tubercles 2. Sappys Plexus 3. Axillary tail of spence 4. Cooper’s ligaments 5. Milk line 6. Pectoral fascia Ans. 4. Cooper’s ligaments USMLE Case Scenario Retropubic space is named after: 1. Fallopius 2. Meckel 3. Camillo golgi 4. Hunter 5. Scarpa 6. Retzius 7. Tredlenburg Ans. 6. Retzius USMLE Case Scenario In the cochlear pathway, the axons terminate in the dorsal and ventral cochlear nuclei in the medulla and the pathway to the auditory cortex consists of at least four orders of neurons and includes the superior olivary complexes, the lateral lemnisci, the inferior colliculi, and the medial geniculate bodies. The auditory cortex: 1. Lies in the posterior portion of the Inferior temporal gyrus 2. Lies in the posterior portion of the superior temporal gyrus 3. Lies in the posterior portion of the superior frontal gyrus 4. Lies in the posterior portion of the middle frontal gyrus 5. Lies in the posterior portion of the inferior frontal gyrus Ans. 2. Lies in the posterior portion of the superior temporal gyrus 114 USMLE Step 1 Platinum Notes USMLE Case Scenario The primordia of the principal respiratory organs appear as a medial longitudinal groove in the ventral wall of the pharynx by the fourth week of gestation. True statement is: 1. The tube is lined with ectoderm, from which the epithelium of the respiratory tract develops 2. The tube is lined with mesoderm, from which the epithelium of the respiratory tract develops 3. The tube is lined with endoderm, from which the epithelium of the respiratory tract develops 4. The tube is lined with endothelium, from which the epithelium of the respiratory tract develops 5. The tube is lined with mesothelium, from which the epithelium of the respiratory tract develops Ans. 3. The tube is lined with endoderm, from which the epithelium of the respiratory tract develops USMLE Case Scenario Folds of serous pericardium surrounding the entrance of the right and left pulmonary veins are connected by an irregular pericardial reflection that creates a space called as: 1. Transverse sinus 2. Oblique sinus 3. Occipital sinus 4. Maxillary sinus 5. Coronary sinus 6. Sinus of morgagni 7. Sinus venosus Ans. 2. Oblique sinus USMLE Case Scenario The Mullerian ducts develop into the: 1. Ovaries, uterus, cervix, and lower vagina 2. Ovaries, uterus, cervix, and upper vagina 3. Cervix, and upper vagina only 4. Uterus, cervix, and upper vagina 5. Fallopian tubes, uterus, cervix, and upper vagina 6. Ovaries, fallopian tubes, uterus, cervix, and upper vagina Ans. 5. Fallopian tubes, uterus, cervix, and upper vagina USMLE Case Scenario A semicircular line which is about halfway between the umbilicus and pubic symphysis is named as line of: 1. Mc Burney 2. Nelaton 3. Rion 4. Douglas 5. Waldeyer 6. Morrison 7. Heister 8. Scarpa 9. Zuckderkand Ans. 4. Douglas USMLE Case Scenario Lymphatics from the gallbladder drain into the lymph node, located near the superior aspect of the junction of the infundibulum of the gallbladder and the cystic duct. It is known as: 1. Lymph node of Rossenmüller 2. Lymph node of Cloquet 3. Delphic node 4. Lymph node of lund Ans. 4. Lymph node of lund PHYSIOLOGY Physiology 2 Basics of Physiology Na+ K+ ATPase Pump Two ions are responsible: sodium (Na+) and potassium (K+). An unequal distribution of these two ions occurs on the two sides of a nerve cell membrane because carriers actively transport these two ions: sodium from the inside to the outside and potassium from the outside to the inside. As a result of this active transport mechanism (commonly referred to as the sodiumpotassium pump), there is a higher concentration of sodium on the outside than the inside and a higher concentration of potassium on the inside than the outside. •• Na K ATPase Pump is an active, electrogenic pump moving three sodium ions outside and in place two potassium ions inside utilizing ATP. It helps in intrusion of K+ •• It accounts for 20% of energy utilized by cells •• Thus its coupling ratio is 3:2 •• Extracellular binding site is Ouabain •• Its activity is inhibited by Ouabain and related cardiac glycosides •• It is a P type ATPase (super family of cation transporters) •• Also called E1/E2 Type ATPase responsible for carrying ions across cell membranes •• Type: Heterodimer Heterogeneous •• It is an example of active transport RMP (Resting Membrane Potential) •• Resting membrane potential of a skeletal muscle is – 90 mV •• Resting membrane potential of a smooth muscle is – 50 to – 75 mV •• Resting membrane potential of a cardiac muscle is – 85 to – 95 mV •• The resting membrane potential in the nerve fiber is – 70 mV •• The resting membrane potential in the rods is – 40 mV •• The resting membrane potential of inner ear cell is – 60 mV The Action Potential •• •• •• •• •• •• •• Neurons transmit information as action potentials An action potential is a temporary change in the membrane potential Usually initiated in the cell body Travels in one direction normally Action potential is conducted in an all-or-none fashion If the stimulus is too low there is no action potential If the stimulus is above a threshold the action potential is always the same size 118 USMLE Step 1 Platinum Notes Action potential Electrical changes during action potential •• Membrane potential depolarizes (becomes more positive) •• After the peak of the spike the membrane repolarises (becomes more negative) •• The potential becomes more negative than the resting potential (negative after potential) •• It then returns to normal •• The action potentials of most nerves last 5–10 milli seconds •• Action potentials are initiated by many different types of stimuli •• Sensory nerves respond to stimuli of many types including chemicals, light, electricity, pressure, touch and stretch •• In the central nervous system most nerves are stimulated by chemical activity at synapses •• Stimuli must be above a threshold level to initiate an action potential •• After a nerve has fired there is a period of time during which it cannot be stimulated again •• This is known as the refractory period Concepts •• Resting Membrane Potential is due to: K+ •• Resting Membrane Potential is close to isoelectric potential of: Cl— •• IPSP is due to Cl— influx •• EPSP is due to K+ influx •• For action potential; threshold stimulus is required •• Nerve conduction follows All or None phenomenon •• Axon has the lowest threshold potential in a nerve fiber •• Nerve impulse travels in one direction only at synapse Physiology •• •• •• •• RMP is close to isoelectric potential of chloride RMP is due to pottasium IPSP is due to chloride Amplitude is due to chloride •• Most of pottasium is intracellular •• Mx pottasium is found in skeletal muscles •• In response to tissue injury intracellular pottasium shifts to extracellular space The Cell Membrane: (USMLE Favorite) •• •• •• •• •• •• •• •• •• •• •• Main constituent is the protein Lipids are regular but assymetrically arranged Membrane lipids are amphiphatic Are arranged as a bilayer Signal transduction and enzyme activation are the functions of phospholipid part The fluidity of cell membrane is increased by Polyunsaturated fatty acids Lipids and proteins intract by hydrogen bonds RBC Membrane is specially having spectrin (maintains integrity) and glycophyrin Lipid bilayer is most permeable to urea Lipid bilayer acts as a gel Protein: lipid ratio is 2:1 Basement Membrane •• •• •• •• •• Contains laminin Nidogenin Enactin Type IV collagen Degeneration mediated by metalloproteineases Functions of Organalles Commonly Asked: (USMLE Favorite) •• •• •• •• •• •• Synthesis of lipids occurs in Agranular Endoplasmic Reticulum Synthesis of proteins occurs in Rough ER Intracellular sorting and packing is done in Golgi complex Cell shape and motility are a function of Microtubules Catabolism of H2O2 is a function of Peroxisomes Site of ATP synthesis is Mitochondria Marker of •• Plasma membrane: adenyl cyclase, 5 nucleotidase •• Golgi bodies: galactosyl transferase •• Mitochondria: Glutamic dehydrogenase Fluids and Electrolytes: (USMLE Favorite) •• Water constitutes between 50% and 70% of total body weight •• The water of the body is divided into three functional compartments 119 120 USMLE Step 1 Platinum Notes •• The intracellular water, represents between 30% and 40% of body weight •• The extracellular water represents approximately 20% of body weight and is divided between intravascular fluid, or plasma (5% of body weight), and interstitial, or extravascular, extracellular fluid (15% of body weight) •• Intracellular Fluid: Measurement of intracellular fluid (ICF) is determined indirectly by subtraction of the measured extracellular fluid (ECF) from the measured total body water. The intracellular water is between 30% and 40% of body weight, with the largest proportion in the skeletal muscle mass. Because of the smaller muscle mass in the female, the percentage of intracellular water is lower than in the male. The chemical composition of ICF with potassium and magnesium the principal cations, and phosphates and proteins the principal anions •• Extracellular Fluid: The total ECF volume represents approximately 20% of body weight. The ECF compartment has two major subdivisions. The plasma volume is approximately 5% of body weight in the normal adult. The interstitial, or extravascular, ECF volume, obtained by subtracting the plasma volume from the measured total ECF volume, accounts for approximately 15% of body weight •• The interstitial fluid is further complicated by having a rapidly equilibrating or functional component as well as several more slowly equilibrating, or relatively nonfunctioning, components. The nonfunctioning components include connective tissue water as well as transcellular water, which includes cerebrospinal and joint fluids. This nonfunctional component normally represents only 10% of interstitial fluid volume (1 to 2% of body weight) and is not to be confused with the relatively nonfunctional ECF, often called a third space, found in burns and soft tissue injuries •• The normal constituents of ECF are with sodium the principal cation and chloride and bicarbonate the principal anions. Electrolyte Function Distribution Sodium (Na ) •• Essential role in fluid and electrolyte balance — Represents about 90% of extracellular cations accounts for half the osmolarity of ECF Level in blood controlled by aldosterone, ANP and •• Role in generation of action potentials ADH Potassium (K+) •• Establishes resting membrane potential and Most abundant intracellular cation essential in the repolarization phase of action Blood serum level controlled by aldosterone. potentials in nervous and muscle tissue •• Aids maintenance of fluid volume in cells •• Helps regulate pH. Calcium (Ca2+) •• Roles in blood clotting, neurotransmitter release, Most abundant mineral in the body due to bone maintenance of muscle tone, and excitability of content nervous and muscle tissue Principally extracellular Blood level controlled chiefly by Parathyroid hormone (PTH) Chloride (Cl—) •• Helps balance anions in different fluid compartments. + Most prevalent extracellular anion Diffuses easily between interstitial space and ICF Level controlled indirectly by aldosterone – due to relationship with sodium Bicarbonate (HCO3—) •• Major buffer of H+ in plasma Second most prevalent anions in extracellular fluid •• Helps maintain correct balance of anions and A small amount found in intracellular fluid cations in ECF and ICF Blood level controlled by kidneys which can both form and excrete bicarbonate Remember •• If an isotonic salt solution is added to or lost from the body fluids, only the volume of the ECF is changed. The acute loss of an isotonic extracellular solution, such as intestinal juice, is followed by a significant decrease in ECF volume and little, if any, change in ICF volume. Fluid is not transferred from the intracellular space to refill the depleted extracellular space as long as the osmolality remains the same in the two compartments. Physiology 121 •• If water alone is added to or lost from the ECF, the concentration of osmotically active particles changes. Sodium ions account for most of the osmotically active particles in ECF and generally reflect the tonicity of other body fluid compartments. If ECF is depleted of sodium, water passes into the intracellular space until osmolality is again equal in the two compartments •• The concentration of most other ions within the ECF compartment can be altered without significant change in the total number of osmotically active particles, thus producing only a compositional change. For instance, a rise of the serum potassium concentration from four to eight mEq per liter would have a significant effect on the myocardium, but it would not significantly change the effective osmotic pressure of the ECF compartment. Normally functioning kidneys minimize these changes considerably, particularly if the addition or loss of solute or water is gradual •• An internal loss of ECF into a nonfunctional space, such as the sequestration of isotonic fluid in a burn, peritonitis, ascites, or muscle trauma, is termed a distributional change. This transfer or functional loss of ECF internally maybe extracellular (e.g. as in peritonitis) or intracellular (e.g. as in hemorrhagic shock). In any event, all distributional shifts or losses cause a contraction of the functional ECF space. Regulation of Fluid Transfer among Compartments The transfer of fluid between vascular and interstitial compartments occurs at the capillary level and is governed by the balance between hydrostatic pressure gradients and plasma oncotic pressure gradients This relation is stated by the Starling equation: Jv = Kf (DP – Dp) Where: •• Jv is rate of fluid transfer between vascular and interstitial compartments, Kf is the water permeability of the capillary bed •• DP is the hydrostatic pressure difference between capillary and interstitium, and •• Dp is the oncotic pressure difference between capillary and interstitial fluids Under normal circumstances, interstitial tissue pressure is low, and the DP term in the Starling equation represents the integrated hydrostatic pressure gradient from arteriolar to venular ends of a capillary. Since interstitial fluid is protein poor, the Dp term in the Starling equation represents the oncotic pressure of plasma proteins, principally albumin; five grams of albumin per deciliter of plasma exerts an oncotic pressure of about 15 mm Hg. Osmolal gap It is the difference between measured serum osmolality and calculated serum osmolality. It is typically calculated as: OG = measured serum osmolality – (2 × serum sodium + serum glucose + serum urea) Where: 2 × serum sodium + serum glucose + serum urea = the calculated serum osmolality and all measures are in mmol/L. OG = Osmolal gap. In US customary units the calculated osmolarity is: (2 × sodium) + glucose/18 + BUN/2.8 Causes of an Elevated Osmolal Gap are numerous •• Ethanol intoxication •• Methanol ingestion •• Isopropanol ingestion •• Ethylene glycol ingestion ‘Acidosis’ and ‘Alkalosis’: (USMLE Favorite) Refer to the mechanism by which a given acid base disturbance is reached •• ‘Primary’ refers to the initiating process of acid base disturbance, while ‘secondary’ refers to a compensatory process •• Mixed acid base disturbances are combinations of two or more primary acid base disturbances The pH of arterial blood and interstitial fluid normally ranges between 7.38 and 7.42 despite wide variations in dietary intake of acids or alkali The arterial pH range over which cardiac function, metabolic activity and CNS function can be maintained is narrow; the widest range of pH values compatible with life is from 6.8 to 7.8, or an interval of one pH unit. 122 USMLE Step 1 Platinum Notes The major buffer system in ECF is the bicarbonate-carbonic acid pair. The relation between pH, bicarbonate and carbonic acid concentrations in ECF maybe expressed according to the familiar Henderson-Hasselbalch equation: pH = pK + log HCO3/ H2CO3 Where pK is the carbonic acid dissociation constant, HCO3– is the plasma bicarbonate concentration and H2CO3 is the plasma carbonic acid concentration. The H2CO3 concentration is given by a PaCO2, where is the CO2 solubility constant and has a value of 0.0301, and PaCO2 is the arterial carbon dioxide tension. Therefore, the Henderson-Hasselbalch equation becomes pH = 6.1 + log HCO3/0.03 PCO2 Primary changes in the numerator (blood bicarbonate concentration) refer to primary metabolic changes, while primary changes in the denominator (blood carbon dioxide tension) refer to primary respiratory changes Proton shifts: Between the ECF and ICF stabilize the plasma pH against acute fluctuations. But the ultimate maintenance of pH balance requires that input of acid or base into the body be matched by output of acid or base so that the HCO3–/H2CO3 ratio and the total bicarbonate content in the ECF remain constant. The cardinal systems involved in these external processes are the kidneys for bicarbonate balance, and the lungs for CO2 balance. The Serum Anion Gap Sodium is the principal cation in extracellular fluids. The sum of plasma chloride plus bicarbonate concentrations is less than the serum sodium concentration; the remaining anions required for electroneutrality, generally not reported with routine serum electrolyte measurements, are referred to as unmeasured anions, or as the serum anion gap. A convenient formula for calculating the serum anion gap is the following: Serum anion gap = Na+ – (Cl– + HCO3–) Where Na+, Cl– and HCO3– are the serum sodium, chloride and bicarbonate concentrations, respectively The anion serum gap includes primarily phosphates and sulfates derived from tissue metabolism, lactate and keto acids arising from incomplete combustion of carbohydrates and fatty acids, and negatively charged protein molecules, principally albumin. The normal value for unmeasured anions, or the serum anion gap, is 10 to 12 mEq per liter; albumin and other proteins normally account for about half the anion gap An increased serum anion gap generally indicates the presence of metabolic acidosis A reduced serum anion gap provides an index to certain other disorders The anion gap will be reduced if the sodium concentration falls while the chloride plus bicarbonate concentrations are unchanged or, in other words, when the concentration of another cation in serum is increased while the serum osmolality remains normal. This may occur in multiple myeloma of the immunoglobulin G (IgG) variety if the myeloma proteins are cationic at pH 7.4. Hyperviscosity syndromes also may result in a reduced anion gap. The Urinary Anion Gap The urinary anion gap, defined as: Urinary anion gap = (Na+ + K+) – Cl– It is useful in evaluating patients with hyperchloremic acidosis. The test provides an approximate index to urinary NH4+ excretion, as measured by a negative urinary anion gap, that is, urinary (Na+ + K+) is less than urinary Cl–. Thus, in hyperchloremic metabolic acidosis, a normal renal response would be a negative urinary anion gap, generally in the range of 30 to 50 mEq per liter. In such an instance, the hyperchloremic acidosis is probably due to gastrointestinal losses rather than a renal lesion. In contrast, a positive urinary anion gap implies a renal tubular disorder. Remember •• Water constitutes roughly 60% of body weight •• Na, Cl, HCO3 are predominantly in ECF •• K, P, Mg are predominantly in ICF Measurement of Body Fluids Total Body water •• ICF •• ECF About 60% of body weight •• 40% •• 20% Physiology •• Total body water •• ECF •• Plasma volume Tritrated water, Deuterium Oxide, Antipyrine Inulin, Mannitol Evans Blue, radiolabelled albumin •• ECF is rich in: Na+ •• ICF is rich in: K+ •• Endolymph is rich in: K+ Anion Gap: (Repeat) •• •• •• •• •• •• Anion gap = unmeasured ions in plasma Normal cations in plasma: Na+, K+, Ca++, Mg++ Normal anions in plasma: Cl–, HCO3–, albumin, phosphate, lactate Sum of positive and negative charges is equal Anion gap = (Na+ + K+ ) – (Cl– + HCO3–) Normal AG = 10–12 mmol/l Terms Frequently Asked •• •• •• •• •• •• •• Endocytosis: Substance transported into cell by infoldings of cell membrane around substance and internalizing it Pinocytosis: Engulfing liquid substances by enfolding of cell membrane Phagocytosis: Engulfing soild substances by enfolding of cell membrane Exocytosis: Reverse of endocytosis Emiocytosis: Excretion of specific hormones and granules by cell is emiocytosis Requires calcium Transcytosis: Vesicular transport within cell. (epithelial cells of intestine) Proteins in Vesicular Transport AP 1 clathirin: Involved in transportation from Golgi bodies to lysosomes AP 2 clathirin: Involved in transportation to endosomes CO –PI: Coating proteins in vesicles for transportation between endoplasmic reticulum and Golgi apparatus CO –PII: Coating proteins in vesicles for transportation between endoplasmic reticulum and Golgi apparatus Dynamin: Vesicle formation from Golgi complex and cell membrane Docking protein: V snare protein and T snare proteins present on target cells Cutaneous Vascular Responses White reaction: Appearance of pale stroke line when pointed object is drawn lightly over skin Due to precapillary sphincter contraction Triple response: 1. Red reaction: Red line appearing at site of injury Due to dilatation of precapillary sphincter. (histamine and bradykinin) 2. Flare: Diffuse irregular outside red reaction due to dilatation of arteriole and precapillary sphincter 3. Wheal: Swelling or localized edema within area of flare Due to increased capillary permeability •• Dermatographia: Striking triple response on touching the skin 123 124 USMLE Step 1 Platinum Notes Muscle Contraction •• The skeletal muscle fibers are cylindrical in shape. •• The length varies from 1 mm to 15 cm. The width varies from 10 microns to 80 microns. •• Each muscle fiber has a thick sarcolemma •• The cytoplasm is acidophilic and granular and is composed of Actin, Myosin and Tropomyosin. •• The Cytoplasm contains longitudinal Myo fibrils or Sarcostyles which are striated transversely. •• Each Myofibril or Sarcostyles is formed of smaller filaments called as Myofilaments. •• The Myofilaments are of two types: •• Thin or Actin Filaments •• Thick or Myosin Filaments •• The Transverse striations are due to presence of dark and light bands •• The Sarcomere is the unit of contraction •• It is formed of Actin and Myosin •• Actin is present in light band and Myosin is present in the dark band Remember •• •• •• •• •• A: Anisotropic; broad, dark; remains constant in width despite degree of contraction I: Isotropic; broad, light; only thin filaments (no thick); narrows during contraction Z: (Zwischenscheiben) bisects I band; drawn together during contraction H: (Heller) light band bisects A band; only thick filaments (no thin); narrows during contraction M: (Mittelscheibe) denser band bisects H band. •• Heads of Myosin contain actin binding site and possess ATPase activity •• Tropomyosin is a relaxing protein –– Troponin I inhibits interaction of myosin with actin –– Troponin T binds other troponins to tropomyosin –– Troponin C has binding sites for calcium which initiates contraction •• Tropomyosin covers the active sites of actin •• RMP of skeletal and cardiac muscle is – 90 mV •• Repolarization is due to pottasium efflux •• Depolarization is due to sodium influx •• Treppe or stair case phenomenon is due to increased availability of Calcium for binding to troponin C •• Rheobase is the minimum amount of current to cause excitation •• Chronaxie is the shortest duration for a stimulation to excite tissue with a current strength twice the rheobase –– Newborns have longer chronaxies –– Skeletal muscles have shorter chronaxies –– Cold lenthens chronaxie –– Vagal stimulation shortens chronaxie •• For smooth muscle contraction presence of cellular calcium is essential to cause contraction •• Force of muscle contraction is independent of amplitude of action potential Nerve fibers and anesthesia: SUSCEPTIBILITY: Type C > Type B > Type A Nerve fibers and pressure SUSCEPTIBILITY: Type C < Type B < Type A Physiology 125 Golgi Tendon Organ •• •• •• •• •• •• •• It is an encapsulated sensory receptor Detects muscle tension Involved in inverse stretch reflex 3–25 muscle fibers on an average are attached to golgi tendon organ Impulses are transmitted by type nerve fibers It is inhibitory and protective Golgi tendon reflex is bisynaptic. Muscle Spindle •• 3–12 mm long structure containing intrafusal muscle fibers enclosed in capsule of connective tissue •• It is a receptor for myotactic or stretch reflex •• Central zone has no actin and myosin •• Peripheral zone has actin and myosin Are of two types: •• Intrafusal •• Extrafusal Intrafusal are of two types: •• Nuclear bag and •• Nuclear chain fibers Two types of sensory nerve endings are •• Primary annulospiral endings •• Secondary flower spray endings •• •• •• •• Neurapraxia : No anatomic disruption Axonometesis : Axon and myelin disruption Neurontemesis : Complete division of nerve Degeneration distal to cut end : Wallerian degeneration The skeletal muscle fibers are two types: Red Fibers and white fibers Red Fibers White Fibers •• Have irregular striations •• Have regular striations •• Have central nuclei •• Have peripheral nuclei •• Have rich vascular supply •• Have poorer blood supply •• Nonfatiguable •• Are fatiguable •• Are poor in mitochondria, Myoglobin, fats •• Are rich in Myoglobin, fats •• Example : Skeletal muscle •• Examples: diaphragm, muscles of eye, mastication •• They react quickly, with brief, forceful contractions, •• Their contraction in response to nervous stimulation is slow but cannot sustain contraction for long periods and steady, resulting in their designation as slow fibers •• They are thus termed fast fibers Red Blood Cell Mature Red cell is 8 micrometer in diameter Mature Red cell is anucleate 126 USMLE Step 1 Platinum Notes Mature Red cell is discoid in shape Mature Red cell is pliable •• Average life of red cell is 100–120 days •• Hematopoiesis is the process by which formed elements of the blood are produced •• In the BM (Bone Marrow) first morphologically recognizable precursor is the PRO normoblast Erythropoietin is produced by the peritubular cells within the kidney •• There is daily replacement of 0.8–1% of all circulating red cells ‘Hematopoiesis’ is the process by which formed elements of the blood are produced. Stem cells are capable of producing all classes of cells In the BM (Bone Marrow) first morphologically recognizable precursor is the ‘PRO normoblast.’ This cell can undergo 4–5 cell divisions that result in production of 16–32 mature red cells Erythropoietin (EPO) is produced by the peritubular cells within the kidney. These cells are specialized epithelial cells. A small amount of EPO is also produced by Hepatocytes. Cardiovascular Physiology •• Artery/Arteriole Resistance Vessel •• Capillary (Mx Surface area) Exchange Vessel •• Vein Capacitance Vessel •• BP = Cardiac output x Peripheral resistance •• BP measured by sphygmomanometer is less than arterial BP actually •• Small cuff = High BP •• Thick walled vessels = High BP •• Obesity = High BP •• Pulse Pressure = Systolic pressure – Diastolic Pressure •• Mean Arterial Pressure = Diastolic Pressure +1/3 of Pulse Pressure •• Ventricular End Diastolic Volume: Volume of blood in ventricular cavity at the end of atrial contraction (n) = 120 ml. Determines Preload •• Ventricular End Systolic Volume: Volume of blood in ventricular cavity at the end of ejection (n) = 40 ml •• Stroke Volume: Volume of blood ejected with each heart beat. CO/HR (n) = 70 – 80 ml •• Ejection Fraction: Ratio of stroke volume to End Diastolic Volume (SV/EDV) (n) = 50 – 70% •• Cardiac Output: Volume of blood expelled from one side of heart per minute Can be detected by: •• Ficks principle •• Echocardiography •• Thermodilution –– Cardiac index = CO/Body surface area –– Normal cardiac index IS 3.2 Frank–Starling Law This principle illustrates the relationship between cardiac output and left ventricular end diastolic volume (or the relationship between stroke volume and right atrial pressure.) Physiology 127 Determinant of cardiac output •• The Frank-Starling principle is based on the length-tension relationship within the ventricle. If ventricular end diastolic volume (preload) is increased it follows that the ventricular fiber length is also increased, resulting in an increased ‘tension’ of the muscle •• In this way, cardiac output is directly related to venous return the most important determining factor of preload. When heart rate is constant, cardiac output is directly related to preload (up to a certain point.) •• An increase in preload will increase the cardiac output until very high end diastolic volumes are reached. At this point cardiac output will not increase with any further increase in preload, and may even decrease after a certain preload is reached •• Also, any increase or decrease in the contractility of the cardiac muscle for a given end diastolic volume will act to shift the curve up or down, respectively. Frank-starling curve Regional Blood Flow •• Blood flow is controlled mainly by arterioles •• Velocity of blood is maximum in large veins 128 USMLE Step 1 Platinum Notes •• Blood flow of liver > kidney > brain > heart –– Carbon dioxide produces vasodilation in brain –– Exercise produces venoconstriction in splanchnic circulation –– Exercise produces increase in coronary circulation –– Hypoxia produces vasoconstriction in pulmonary circulation –– PGE1, PGI2 produce renal vasodilation. Myocardial Action Potential Phases of myocardial action potential Phase 0 — rapid depolarization •• Rapid sodium influx •• These channels automatically deactivate after a few ms Phase 1 — early repolarization •• Efflux of potassium Phase 2 — plateau •• Slow influx of calcium Phase 3 — final repolarization •• Efflux of potassium Phase 4 — restoration of ionic concentrations •• Resting potential is restored by Na+/K+ ATPase •• There is slow entry of Na+ into the cell decreasing the potential difference until the threshold potential is reached, triggering a new action potential Physiology 129 Ventricular Muscle •• •• •• •• Phase 0 Phase 1 Phase 2 Phase 3 •• •• •• •• Membrane Depolarization Rapid Repolarization Slow Repolarization Rapid Repolarization •• •• •• •• ↑permeability to Na ↓permeability to Na, ↑permeability to K ↑permeability to Ca Inactivation of Ca channels, ↑permeability to K Pacemaker Cells •• •• •• •• Slow upstroke Action Potential Smaller magnitude of Action Potential No Fast Sodium channels Spontaneous Depolarization Inotropic State: (Myocardial Contractility) A number of factors determine the level of ventricular performance at any given ventricular end-diastolic volume •• Adrenergic Nerve Activity: The quantity of norepinephrine released by adrenergic nerve endings in the heart is determined by the adrenergic nerve impulse traffic. This mechanism is the most important one that acutely modifies myocardial contractility under physiologic conditions •• Circulating Catecholamines: When stimulated by adrenergic nerve impulse, the adrenal medulla releases catecholamines, which, when they reach the heart, augment both heart rate and myocardial contractility •• The Force-Frequency Relation: The position of the myocardial force-velocity curve is also influenced by the rate and rhythm of cardiac contraction; e.g. ventricular extrasystoles result in postextrasystolic potentiation, presumably by increasing the quantity of Ca2+ that enters the cardiac cell. The contractility of the normal (but not of the failing) heart is augmented by an increase in frequency of contraction •• Exogenously Administered Inotropic Agents: Isoproterenol, dopamine, dobutamine, and other sympathomimetic agents, cardiac glycosides, Ca2+, amrinone, milrinone, and other phosphodiesterase inhibitors all improve the myocardial forcevelocity relation and therefore maybe used to stimulate ventricular performance •• Physiologic Depressants: Included among these are severe myocardial hypoxia, ischemia, and acidosis. Acting either singly or in combination, these influences depress the myocardial force-velocity curve and left ventricular work at any given ventricular end-diastolic volume •• Pharmacologic Depressants: These include many antiarrhythmic drugs such as procainamide and disopyramide; calcium antagonists such as verapamil; beta blockers; and large doses of barbiturates, alcohol, and general anesthetics as well as many other drugs •• Loss of Myocytes: When a sufficiently large portion of ventricular myocardium becomes nonfunctional or necrotic, as occurs transiently during ischemia and permanently in myocardial infarction total ventricular performance at any given level of enddiastolic volume becomes depressed. Exercise: Physiological Change Blood pressure •• Systolic increases, diastolic decreases •• Leads to increased pulse pressure •• In healthy young people the increase in MABP is only slight Cardiac output •• Increase in cardiac output maybe 3–5-fold •• Results from venous constriction, vasodilation and increased myocardial contractibility, as well as from the maintenance of right atrial pressure by an increase in venous return •• Heart rate up to 3-fold increase Stroke volume •• Up to 1.5-fold increase 130 USMLE Step 1 Platinum Notes Central Venous Pressure •• Normal Pressure: 2 cm H2O to 12 cm H2O •• Causes of ↓CVP: Noncardiogenic shock •• Causes of ↑CVP: Heart Failure, Expansion of Blood volume, PEEP Isometric Contraction Mitral and tricuspid valve close (c-c) Aortic and pulmonary valve open Isometric Relaxation Mitral and tricuspid valve open Aortic and pulmonary valve close •• •• •• •• •• Normal coronary blood flow is 250 ml at rest It is 5% of cardiac output Blood flow to left ventricle is twice that of right ventricle Atrial blood flow is half of ventricular flow Most of coronary blood flow occurs in diastole •• •• •• •• Chrontropic effect Ionotropic effect Dromotropic effect Bathmotropic effect Effect on heart rate Effect on force of contraction Effect on conduction of impulses through heart Effect on excitability of heart ECG and JVP Physiology •• SA node discharges most rapidly •• SA node is located sub epicardially •• Pacemaker cells are present in SA node •• AP of SA and AV node are due to calcium •• RMP of myocardial fibers is – 90 mV •• Depolarization is from endocardium to epicardium •• Repolarization is also from endocardium to epicardium •• Speed of conduction is fastest in Purkinje fibers •• Speed of conduction is least in AV node Waves of normal ECG Normal ECG Wave/Segment Cause Duration (Second) P wave From–To Atrial depolarization 0.1 QRS complex Ventricular Depolarization 0.08 – 0.10 T wave Ventricular Repolarization 0.2 P – R interval Onset of P wave to onset of Q wave 0.18 (0.12 to 0.2) Q – T interval Onset of Q wave and end of T wave 0.4 – 0.42 Intervals in ECG 131 132 USMLE Step 1 Platinum Notes The 12 conventional ECG leads record the difference in potential between electrodes placed on the surface of the body These leads are divided into two groups: Six extremity (limb) leads and six chest (precordial) leads. The extremity leads record potentials transmitted onto the frontal plane and the chest leads record potentials transmitted onto the horizontal plane The six extremity leads are further subdivided into three bipolar leads (I, II and III) and three unipolar leads (aVR, aVL and aVF) Each bipolar lead measures the difference in potential between electrodes at two extremities: •• Lead I left arm-right arm voltages •• Lead II left leg-right arm, and •• Lead III left leg-left arm The six chest leads are unipolar recordings obtained by electrodes in the following positions: •• Lead V1, fourth intercostal space, just to the right of the sternum; •• Lead V2, fourth intercostal space, just to the left of the sternum; •• Lead V3, midway between V2 and V4; •• Lead V4, midclavicular line, fifth intercostal space; •• Lead V5, anterior axillary line, same level as V4; and •• Lead V6, midaxillary line, same level as V4 and V5. Remember •• First-degree AV block, more properly termed prolonged AV conduction, is classically characterized by a PR interval > 0.20s •• Second-degree heart block (intermittent AV block) is present when some atrial impulses fail to conduct to the ventricles •• Mobitz type I second-degree AV block –– (AV Wenckebach block) –– It is characterized by progressive PR interval prolongation prior to block of an atrial impulse –– This type of block is almost always localized to the AV node and associated with a normal QRS duration, although bundle branch block may be present •• In Mobitz type II second-degree AV block •• Conduction fails suddenly and unexpectedly without a preceding change in PR intervals •• It is generally due to disease of the His-Purkinje system and •• It is most often associated with a prolonged QRS duration •• Third-degree AV block –– It is present when no atrial impulse propagates to the ventricles –– If the QRS complex of the escape rhythm is of normal duration, occurs at a rate of 40 to 55 beats per minute, and increases with atropine or exercise, AV nodal block is probable –– Congenital complete AV block is usually localized to the AV node •• Refractoriness is a property of cardiac cells that defines the period of recovery that cells require after being discharged before they can be reexcited by a stimulus. •• The absolute refractory period is defined by that portion of the actionpotential during which no stimulus, regardless of its strength, can evoke another response. •• The effective refractory period is that part of the action potential during which a stimulus can evoke only a local, nonpropagated response. •• The relative refractory period extends from the end of the effective refractory period to the time that the tissue is fully recovered. During this time, a stimulus of greater than threshold strength is required to evoke a response, which is propagated more slowly than normal. Physiology 133 Heart Sounds Heart sounds Occurs during Cause Characteristics First Isometric contraction and ejection Closure of AV valves (Mitral Tricuspid) period Second Protodiastole and part of isometric Closure of semilunar valves (Aortic, Short, sharp and high pitched. relaxation Pulmonary) Resembles the word ‘DUBB’ Long, soft and low pitched. Resembles the word ‘LUBB’ Third Heart Sound is due to Rapid Ventricular filling Fourth Heart sound It is due to ventricular distension caused by forceful atrial contraction Heard during ventricular filling phase Correlates with second filling phase Waves in JVP JVP waves •• •• •• •• •• •• ‘a’ wave – First positive wave and it’s due to atrial systole ‘x’ wave – Fall of pressure in atrium, coincides with atrial diastole ‘c’ wave – It is due to rise in atrial pressure during isometric contraction during which the AV valves bulges into atrium ‘x1’ wave – Occurs during ejection period, when AV ring is pulled towards ventricles causing distension of atria ‘v’ wave – Occurs during isometric relaxation period or during atrial diastole ‘y’ wave – Due to opening of AV valve and emptying of blood into ventricle. Pathological CVP Wave forms: •• In atrial fibrillation, a waves will be absent, and in atrioventricular disassociation, a waves will be dramatically increased (‘cannon waves’) as the atrium contracts against a closed tricuspid valve •• In tricuspid regurgitation, the c wave and x descent will be replaced by a large positive wave of regurgitation as the blood flows back into the right atrium during ventricular contraction. This can elevate the mean central venous pressure, but it is not an accurate measurement. A better way of estimating CVP in this case would be to look at the pressured between the regurgitation waves for a more accurate mean •• In cardiac tamponade, all pressure will be elevated, and the y descent will be nearly absent. 134 USMLE Step 1 Platinum Notes Reflexes The Bainbridge reflex, also called the atrial reflex •• It is an increase in heart rate due to an increase in central venous pressure •• Increased blood volume is detected by stretch receptors located in both atria at the venoatrial junctions •• The Bainbridge reflex and the Baroreceptor reflex act antagonistically to control heart rate •• The baroreceptor reflex acts to decrease heart rate when blood pressure rises –– When blood volume is increased, the Bainbridge reflex is dominant –– When blood volume is decreased, the Baroreceptor reflex is dominant The oculocardiac reflex •• Also known as Aschner phenomenon •• It is a decrease in pulse rate associated with traction applied to extraocular muscles and/or compression of the eyeball •• The reflex is mediated by nerve connections between the trigeminal cranial nerve and the vagus nerve of the parasympathetic nervous system. Respiratory Physiology •• Number of alveoli in man: 300 million •• Carbon dioxide is primarily transported in arterial blood as bicarbonate •• Oxygen delivery to tissues depends on –– Cardiac output –– Hb –– Affinity of Hb for oxygen •• Normal value of PO2 is: 80 mm Hg •• Arterial CO2 Level is: 40 mm Hg Physiology of Respiration •• •• •• •• •• •• During inspiration intrapleural pressure becomes more negative Respiration stops in late expiration because of dynamic compression of airways Total lung capacity depends on compliance Nitrogen wash out method detects functional residual capacity FRC is not estimated by spirometry Slow and deep breathing are the most economical way of breathing. The Respiratory neurons of the medulla are responsible for the main neural control of breathing. This control center is composed of two groups of respiratory neurons: •• The dorsal respiratory group (DRG) that consists primarily of inspiratory neurons that connect with phrenic motor neurons; and •• The ventral respiratory group (VRG) that contains a mixture of both I neurons and expiratory (E) neurons. Selective electrical stimulation of either I or E neurons in the ventral group will result in inspiration or expiration, respectively. The VRG, however, is especially important in sending expiratory signals to the abdominal group of muscles to increase pulmonary ventilation during times of increased respiratory drive. The basic medullary pattern of breathing can be modified by efferent activity arising in the apneustic and pneumotaxic centers of the pons, as well as by motor impulses originating in the cerebral cortex •• Transection of various brainstem structures and transection of the vagus nerves reveals information about the neural control of breathing •• Transection of the brainstem at the caudal end of the pons allows spontaneous respiration to continue, but the pattern of breathing is irregular. This indicates that the rhythmic, automatic control of breathing originates at some point inferior to the pons •• Transection of the brainstem below the medulla causes an immediate halt in breathing, reinforcing the concept of medullary control as the primary stimulus for ventilation. Physiology 135 •• Transection of the brainstem rostral to the pons results in normal breathing whereas transection at the caudal border of the pons causes irregular breathing. This finding indicates that the pons exhibits a modifying influence on the medulla. In fact, if the pontine pneumotaxic center (composed of the medial parabrachial and the Kölliker-Fuse nuclei) is damaged, respiration becomes slower and the tidal volume becomes greater. These nuclei contain both inspiratory and expiratory neurons that modify the medulla. If both vagi are cut, the depth of inspiration is markedly increased. This occurs because stretching of the lungs during inflation normally stimulates afferent pulmonary vagal fibers •• These afferent impulses limit inspiratory impulses to slow inspiration. Without intact vagi, prolonged inspiration occurs. Lung volumes The All Important Respiratory Volumes Measurement Value (Male/Female) Calculation Description Total lung capacity = 6.0/4.7 L (TLC) = IRV + Vt + ERV + RV The volume of air contained in the lung at the end of maximal inspiration Depends on lung compliance Vital capacity (VC) = IRV + Vt + ERV The amount of air that can be forced out of the lungs after a maximal inspiration. (Rohtak 97) = 4.8/3.6 L Forced vital capacity = 4.8/3.7 L (FVC) The amount of air that can be maximally forced out of the lungs after a maximal inspiration. Emphasis on speed. Tidal volume (Vt) = 500/390 mL IC-IRV Residual volume (RV) = 1.2/0.93 L Expiratory reserve volume (ERV) = 1.2/0.93 L Inspiratory reserve volume (IRV) = 3.3/2.3 L Functional residual capacity (FRC) = 2.4/1.9 L Inspiratory capacity (IC) = 3.8/2.7 L Measured IRV = VC - (TV + ERV) = ERV + RV = TV + IRV The amount of air breathed in or out during normal respiration. The volume of air an individual is normally breathing in and out. The amount of air left in the lungs after a maximal exhalation The amount of air that is always in the lungs and can never be expired (i.e. the amount of air that stays in the lungs after maximum expiration). The amount of additional air that can be pushed out after the end expiratory level of normal breathing. (At the end of a normal breath, the lungs contain the residual volume plus the expiratory reserve volume, or around 2.4 liters. If one then goes on and exhales as much as possible, only the residual volume of 1.2 liters remains). The additional air that can be inhaled after a normal tidal breath in. The maximum volume of air that can be inspired in addition to the tidal volume. The amount of air left in the lungs after normal expiration. The maximal volume that can be inspired following a normal expiration. 136 USMLE Step 1 Platinum Notes Anatomical dead space = 150/120 mL Physiologic dead volume = 155/120 mL The volume of the conducting airways. Measured with Fowler method. The anatomic dead space + alveolar dead space Under normal conditions equal to anatomic dead space. Lung volumes Intra-alveolar Pressure during Inspiration and Expiration As the external intercostals and diaphragm contract, the lungs expand. The expansion of the lungs causes the pressure in the lungs (and alveoli) to become slightly negative relative to atmospheric pressure. As a result, air moves from an area of higher pressure (the air) to an area of lower pressure (our lungs and alveoli). During expiration, the respiration muscles relax and lung volume descreases. This causes pressure in the lungs (and alveoli) to become slight positive relative to atmospheric pressure. As a result, air leaves the lungs. Spirometry Conventionally, a spirometer is a device used to measure timed expired and inspired volumes, and from these we can calculate how effectively and how quickly the lungs can be emptied and filled. The measurements that are usually made are as follows: •• VC (vital capacity) is the maximum volume of air which can be exhaled or inspired during either a forced (FVC) or a slow (VC) maneuver •• FEV1 (forced expired volume in one second) is the volume expired in the first second of maximal expiration after a maximal inspiration and is a useful measure of how quickly full lungs can be emptied •• FEV1/VC is the FEV1 expressed as a percentage of the VC or FVC (whichever volume is larger) and gives a clinically useful index of airflow limitation •• FEF 25–75% is the average expired flow over the middle half of the FVC maneuver and is regarded as a more sensitive measure of small airways narrowing than FEV1 •• PEF (Peak expiratory flow) is the maximal expiratory flow rate achieved and this occurs very early in the forced expiratory maneuver. Ventilation Perfusion Ratio •• •• •• •• Ideally Ventilation = Perfusion, i.e. V/Q = 1 Apex of Lung V > Q Wasted Ventilation Base of Lung V < Q Wasted Perfusion With exercise V/Q approaches zero Pulmonary Circulation •• It is a Low Resistance •• High Compliance Bed •• Hypoxia produces pulmonary vasoconstriction. (unique feature) Physiology 137 Response to High Altitude •• •• •• •• •• •• •• •• •• ↑Ventilation (EARLIEST CHANGE) ↑Sensitivity of central receptors ↑Response of carotid bodies ↑Erythropoietin ↑2 3 DPG ↑Mitochondria ↑Renal excretion of Bicarbonate Respiratory alkalosis Pulmonary edema when occurs is due to increased pulmonary capillary pressure •• A number of physiologic changes occur in a person living at high altitude. The diminished barometric pressure at high altitude causes alveolar hypoxia and arterial hypoxia. Pulmonary vasoconstriction occurs in response to alveolar hypoxia; therefore, the diameter of the pulmonary vessels would be greater in the brother living at sea level. Increased erythropoietin production (choice B), caused by arterial hypoxia, leads to increases in hematocrit in people living at high altitude •• Mitochondrial density increases in people chronically exposed to the hypoxemia caused by living at high altitude •• At high altitudes, the ventilation rate increases, causing a respiratory alkalosis. The kidney then compensates by increasing the excretion of HCO3 •• Increasing the rate of respiration is a very useful adaptation to the hypoxic conditions of high altitude. The primary stimulus is the hypoxic stimulation of peripheral chemoreceptors. •• Type I cells or type I pneumocytes –– These are squamous epithelial cells that make-up 97% of the alveolar surfaces –– They are specialized to serve as very thin (often only 25 nm in width) gas-permeable components of the blood-air barrier •• Type II cells –– Are also called type II alveolar cells, type II pneumocytes, great alveolar cells, and alveolar septal cells, cover the remaining 3% of the alveolar surface –– They are interspersed among the type I cells, to which they attach by desmosomes and occluding junctions –– Type II cells are roughly cuboidal with round nuclei –– Type II cells are secretory cells secreting pulmonary surfactant. •• Alveolar macrophages –– Known also as dust cells, these large monocyte-derived representatives of the mononuclear phagocyte system are found both on the surface of alveolar septa and in the interstitium –– They also phagocytose blood cells that enter the alveoli as a result of heart failure –– These alveolar macrophages, which stain positively for iron pigment (hemosiderin), are thus designated heart failure cells •• Clara cells –– Are nonmucous and nonciliated secretory cells found in the primary bronchioles of the lungs –– Main functions of Clara cells are to protect the bronchiolar epithelium by secreting a small variety of products, including Clara cell secretory protein (CCSP) and a component of the lung surfactant –– They are also responsible for detoxifying harmful substances inhaled into the lungs. Surfactant •• •• •• •• •• •• It is (Dipalmitoyl Lecithin) It is secreted by Type II Pneumocyte Synthesis begins at 16–18 weeks of gestation Maintains alveolar integrity Breaks structure of water in alveoli Deficiency causes Hyaline Membrane Disease 138 USMLE Step 1 Platinum Notes •• Smoking ↓ surfactant production •• Surfactant: –– ↓ Surface Tension –– ↑ Compliance •• Prevents pulmonary edema •• Glucocorticoids accelerate surfactant production •• It is used therapeutically nowadays •• Deficiency Causes –– IRDS –– HMD –– Patchy atelectasis –– Pulmonary alveolar proteinosis Nernest Equation/Chloride shift Bicarbonate diffuses intoplasma and same quantity of chloride diffuses into RBC in venous circulation •• In place of bicarbonate chloride moves into RBC from plasma •• Occurs in one second –– Bohr Effect •• Affinity of Oxygen for Hb decreases with fall in pH –– Haldane effect •• It is reverse of Bohr effect •• Binding of Oxygen with hemoglobin displaces carbon dioxide from blood •• Deoxygenated Hb binds more H+ than oxy hemoglobin •• Hering-Bruer reflex: Overinflation of lung causes stretch receptors in bronchi and bronchioles to send inhibitory signals to inspiratory center through vagus. (Distension of lung causes slowing of respiratory rate.) •• Heads Reflex Inflation of lungs induces more inflation •• Heads Reflex is due to irritant receptors in lungs •• J receptor reflex: J receptors are present in close association with pulmonary capillaries On stimulation of j receptors, apnea followed by hyperapnea, bradycardia and hypotension occurs. Bronchospasm also occurs. •• Davenport diagram is used to determine type and severity of Acidosis/Alkalosis •• Siggard-Anderson Nomogram is used for calculating abnormalities of acid base balance. (Plasma Bicarbonate) Control of Respiration •• •• •• •• Inspiratory center Expiratory center Pneumotaxic center Apneustic center •• •• •• •• •• •• •• •• •• •• •• •• Dorsal respiratory group of Neurons: Inspiration Ventral respiratory group of Neurons: Expiration Peripheral chemoreceptors are located in Carotid and Aortic bodies Transection of brainstem produces irregular and gasping respiration. (Less smooth respiration) Damage to pneumotaxic center causes slow and deep respiration Damage to vagi nerves causes increase in depth of inspiration Only hypercapnia not Hypocapnia stimulates receptors Respiratory center is inhibited during swallowing and vomiting. Dorsal Medulla Ventral Medulla Pons (DORSAL) Pons Physiology Oxygen Hb Dissociation Curve Oxygen Hb dissociation curve Oxygen Hb dissociation curve is ‘S’ shape or sigmoid shape Factors influencing oxygen - Hb dissociation 139 140 USMLE Step 1 Platinum Notes To left (←) To right (→) •• •• •• •• •• •• •• •• •• ↑CO HbF ↓PCO2 ↓2, 3-DPG ↓Temp ↑[H+] , ↓pH ↑Temp ↑PCO2 ↑2, 3-DPG Additional Shift to left Shift to right •• Increase pH •• Decrease pH •• Decrease in temp •• Increase in temp •• Fetal blood •• Oxygen affinity of Hb •• Excess of 2, 3 DPG •• •• •• •• •• Increase PCO2 (Bohr effect) Sickle cell Hb Shock RDS CHF •• In anemia 2, 3 DPG concentration increases •• 2, 3 DPG unloads oxygen to tissues •• •• •• •• •• •• •• •• •• •• •• •• •• In a healthy adult, 24 hour production of CO2 is about 330 liters Diffusion capacity for carbon dioxide as compared to that of O2 is 20 times Average area of the alveolar walls in contact with capillaries in both lungs is about 70 sq m Diffusion capacity of lungs for CO2 is 10 – 30 ml/min/mm Hg Normal composition of venous blood is PO2 – 40 mm Hg, PCO2 – 46 mm Hg and Hb saturation 75% Peak expiratory flow rate is 400 – 500 L/mt The presence of Hb increases the O2 carrying capacity of the blood by 70 fold Intrapleural pressure (recoil pressure) required to prevent collapse of the lung – 4 mm Hg in presence of surfactant Intrapleural pressure at the end of deep inspiration is – 4 mm Hg Intrapleural pressure during expiration is – 2 mm Hg Hypoxia causes ‘pulmonary vasoconstriction’ but ‘cerebral vasodilation.’ In lungs Angiotensin I is converted into Angiotensin II Transport of CO2 is maximum in the form of bicarbonate. Never to be Forgotten Respiratory Acidosis Respiratory Alkalosis Metabolic Acidosis Metabolic Alkalosis CO2 ↑ ↓ No change No change pH ↓ ↑ ↓ ↑ HCO3 ↑ ↓ ↓ ↑ •• PCO2 is the most important variable in regulation of ventilation •• Central chemoreceptors respond to changes in [H+] •• Peripheral chemoreceptors respond to changes in PO2, PCO2, H+ conc. of arterial blood Physiology 141 Clinically Important •• Cheyne-Stokes breathing is characterized by irregular pattern of respiratory dysfunction (apnea and hyper apnea) suggests that central respiratory mechanism are no longer functioning adequately Opium poisoning, uremia, CCF, Hypoxia. •• Apneustic breathing is seen after head trauma and is characterized by inspiratory breath holding that lasts many seconds, followed by brief exhalations. •• Biot’s breathing is seen in some patients with CNS disease (e.g. meningitis). It consists of periods of normal breathing interrupted suddenly by periods of apnea. •• Hysterical breathing may produce hyperventilation, i.e. rapid, intense breathing that causes the PaCO2 to decrease •• Kussmaul breathing occurs in diabetic coma and consists of continuous, rapid, deep breathing seen in Diabetic ketoacidosis, uremia •• Ondines curse loss of automatic respiratory control •• Apnea: Cessation of respiration Cyanosis •• •• •• •• Reduced Hb > 4 gm/dl Oxygen saturation < 85% Methemoglobin > 1.5 gm/dl Sulfhemoglobin > 0.5 gm/dl Difference in Hb and myoglobin Shift to right Difference between Obstructive Lung Disease and Restrictive Lung Disease Obstructive lung disease Restrictive lung disease •• TLC ↑ •• TLC ↓ •• RV↑ •• RV↓ •• TV↓ •• TV↓ •• VC↓ •• VC↓ •• FEV1↓ •• FEV1↓ •• FVC↓ •• FVC↓ •• FEV1/FVC↓ •• FEV1/FVC↑ •• PaCO2↑ •• PaCO2 (N )or ↓ 142 USMLE Step 1 Platinum Notes Carbon Monoxide Poisoning Causes: (USMLE Favorite) Carbon monoxide has approximately 240 times the affinity for hemoglobin than does oxygen. In a sense, the hemoglobinCO dissociation curve is shifted very far to the left compared to the hemoglobin-O2 dissociation curve. This means that the binding of hemoglobin to carbon monoxide is virtually irreversible. (The carbon monoxide that cigarette smokers inhale is cleared only when senescent red cells are phagocytized in the spleen and the hemoglobin is degraded.) In addition, the carbon monoxide shifts the hemoglobin-O2 dissociation curve to the left, making the unloading of O2 to the tissues very difficult. When too much hemoglobin is tied up with carbon monoxide, the person dies. The carbon monoxide-hemoglobin complex has a bright red color; a distinctive feature of carbon monoxide poisoning that can be helpful either at autopsy or in living patients is that this color makes the skin and organs also appear bright cherry red •• ‘Normal’ PO2 •• ↓Oxygen saturation •• Metabolic Acidosis •• Cherry red skin discoloration •• CO has 210 times more affinity for oxygen than hemoglobin •• Form of Hypoxia produced is anemic hypoxia •• Oxygen dissociation curve shifts to left Hypoxia •• •• •• •• Hypoxic Hypoxia: High altitude, Respiratory diseases Test by: PaO2 Anemic Hypoxia: Anemia, CO Poisoning: Test by Oxygen content (HB%) Stagnant Hypoxia: Cardiogenic shock: Test by A-V difference of O2 Histotoxic Hypoxia: Cyanide poisoning: Test by A-V difference/ PO2 of venous blood •• •• •• •• •• •• •• •• Low arterial PO2 Oxygen affinity also decreases Response to oxygen is good Hypoxic hypoxia is the mc type Causes rise in pulmonary arterial pressure Carbon dioxide is the most potent stimulus for respiration Carbon dioxide affects respiratory center by influence on H+ concentration in CSF ↓CO2 causes: –– CNS Depression –– ↓Ventilation –– ↓Sensory acuity –– Confusion, coma, death Oxygen Toxicity Causes CNS Effects (Bert Effect) •• Hyper irritability •• ↑Muscular twitching •• Convulsions •• Dizziness, Irritability, disorientation Pulmonary effects (Smith Effect) •• Tracheobronchial irritation •• Pulmonary edema •• Congestion and atelectasis Physiology 143 Retinal effects: •• Retrolental fibroplasia •• Retinal damage Burnt out Tissue •• Due to ↑metabolic rates and excess heat production with tissue damage Mountain Sickness Adverse effects of Hypoxia at High Altitude Develops 8–24 hours after arrival and lasts 4–8 days Low PO2 stimulation is the main cause leading to ↑ ventilation blowing of CO2 which inhibits respiratory center causing respiratory distress •• Expansion of gases in GIT occurs → Nausea, Vomiting •• Pulmonary edema (↑Permeability) → Breathlessness •• Cerebral edema (Cerebral vasodilation) → Headache, Irritability, Insomnias, Weakness Acclimatization is by: Hyperventilation ↑Hb Polycythemia ↑Mitochondria ↑Cardiac Output ↑2, 3 DPG ↑Diffusion capacity Reticulocytosis ↑Erythropoietin Renal Physiology Role of Kidneys: Primarily regulation or homeostasis •• Regulation of blood plasma and interstitial fluid composition (homeostasis), especially inorganic ions (e.g. Na+, K+, Cl–, Ca2+) and osmolality (osmotic activity of dissolved particles) •• Regulation of body fluid volume — fluid balance •• Regulation of blood plasma and interstitial fluid pH •• Excretion of (nonvolatile) metabolic end products (e.g. urea, uric acid, creatinine, NH4+) and ‘foreign’ solutes (e.g. some drugs) •• Endocrine organ, secreting a. Renin, for regulation of Na+, ECF (extracellular fluid) volume, vascular resistance b. Erythropoietin, for regulation of erythrocyte production c. Calcitriol, related to calcium regulation •• Metabolic functions e.g. peptide degradation, synthesis of NH3 and H+ RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM Adrenal Cortex •• Zona Glomerulosa (on outside) Mineralocorticoids mainly aldosterone •• Zona Fasciculata (middle) Glucocorticoids mainly cortisol •• Zona Reticularis (on inside) Androgens mainly dehydroepiandrosterone (DHEA) 144 USMLE Step 1 Platinum Notes Kidneys •• Each kidney contains about one million nephrons •• Juxtra medullary nephrons constitute only 15% of nephrons •• Filtration barrier of kidneys is formed by: –– Podocytes –– Endothelial cells –– Basement membrane Renin •• It is released by JG cells in kidney in response to reduced renal perfusion, low Na+ •• Converts angiotensinogen to angiotensin I •• Factors stimulating renin secretion –– Low BP –– Hyponatremiae –– Sympathetic nerve stimulation –– Catecholamines –– Erect posture Angiotensin •• •• •• •• •• ACE in lung converts angiotensin I → angiotensin II Produced in liver Vasoconstriction leads to raised BP Stimulates thirst Stimulates aldosterone and ADH release Aldosterone •• •• •• •• Released by zona glomerulosa Causes retention of Na+ in exchange for K+/H+ in distal tubule Aldosterone is produced in zona glomerulosa of adrenal glands It binds to MR (Mineralocorticoid receptors) in renal tubular cells It Causes •• •• •• •• •• Increased Na reabsorption Increased potassium excretion Increased hydrogen secretion Increased ammonia excretion Increased magnesium excretion Renin ↑Aldosterone •• •• •• •• •• Renovascular Hypertension Fibromuscular Dysplasia Diuretic use Malignant Hypertension Reninoma Physiology Sites of action of hormones •• •• •• •• Aldosterone: Cortical ducts and distal tubules Angiotensin II: Afferent arteriole constriction reduces GFR ADH: Medullary collecting duct ANP: Collecting duct Commonly asked and Repeated Questions in Renal Physiology •• •• •• •• •• •• •• •• •• •• •• •• •• •• •• •• •• •• •• •• •• •• Major part of glomerular filtrate is absorbed in PCT Substances completely reabsorbed in PCT Glucose Proteins, amino acids, vitamins, acetoacetate Bicarbonate Water In prescence of vasopressin mx reabsorption of water occurs in PCT Substances partially absorbed in PCT—Na, K, Cl (7/8 reabsorbed in PCT) Maximum water absorption occurs at PCT Glucose transport occurs with sodium Substances secreted in PCT: H+, PAH (para amino hippurate). Creatinine H+ are actively secreted in proximal tubules, distal tubules, collecting ducts Hyperosmilality in the interstitum is the prerequisite for excretion of concentrated urine Urea is reabsorbed from inner medullary collecting ducts only in presence of ADH K+ is actively secreted in Late Distal tubules and Collecting ducts Macula densa is the epithelial cells of the distal tubule that comes to contact with the arterioles Tubuloglomerular feedback is mediated by sensing NaCl in macula densa Juxtaglomerular cells produce renin Are smooth muscle cells of afferent arteriole Lies in relation to glomerulus Consists of macula densa Renin acts on angiotensinogen and convert it into angiotensin I. •• Loop of henle does not handle urea •• Urea has no T m value Effect of angiotensin, aldosterone 145 146 USMLE Step 1 Platinum Notes Site of Action of Diuretics Thiazides •• Chlorthiazide Distal tubule •• Hydrochlorthiazide Distal tubule •• Chlorthalidone Distal tubule •• Indapamide Distal tubule •• Metolazone Proximal and distal tubules Loop diuretics •• Frusemide Loop of Henle •• Bumetanide Loop of Henle •• Ethacrynic acid Loop of Henle Carbonic anhydrase inhibitors •• Acetazolamide Proximal tubule Potassium sparing diuretics •• Spironolactone Distal tubule and collecting duct •• Triamterene Distal tubule and collecting duct •• Amiloride Distal tubule and collecting duct Remember •• Filtration fraction = GFR/RPF = 20% •• Clearance = Urine concentration x flow rate/Plasma Concentration –– If Clearance < GFR, there is net tubular reabsorption –– If Clearance > GFR, there is net tubular secretion –– If Clearance = GFR, there is no net secretion/reabsorption •• GFR = insulin clearance ‘NOT’ Insulin = 125 ml/min •• RPF = PAH Clearance = 500–800 •• Normal creatinine levels: 0.6–1.2 mg% •• Urea clearance: 88 ml/minute. Excretion rate = Clearance × Plasma concentration or Clearance [C] = Excretion excretion rate/Plasma concentration [P] Excretion rate = Urine concentration[U] × Volume[V] of urine formed per unit time so Cx = Ux × V/Px Cx = Clearance of substance ‘x’ Ux = Concentration of ‘x’ in urine Px = Concentration of ‘x’ in blood plasma V = Rate of urine formation •• Determination of GFR (Glomerular filtration rate): If a substance is filtered but not reabsorbed or secreted (nor metabolized or synthesized) by the kidney, then its clearance must equal GFR. Substances which are only filtered include insulin and (more-or-less) creatinine •• Determination of RPF (Renal plasma flow): If a substance is completely cleared from the renal blood (combination of filtration and secretion) in one pass through the kidney, then its clearance is equal to RPF. A substance which fulfills this criteria is PAH (Para Amino Hippuric acid), as long at TmPAH Is not exceeded. •• Determination of tubular transport: If the clearance of a filtered substance is less than GFR, then that substance must be reabsorbed. If the clearance of a substance is greater than GFR, then that substance must be secreted. Physiology 147 •• Determination of fraction excreted: For substances filtered and reabsorbed, the fraction of the amount filtered (called the ‘filtered load’) that is excreted is given by the ratio of CX/GFR. Clearance Demonstrating: Relationship between arterial pressure and renal blood flow At low systemic arterial pressure, renal blood flow is reduced, compromising renal function and even kidney vitality. Important Enzyme Deficiencies •• 21α Hydroxylase deficiency •• Hypotension, Hyponatremia, Hyperkalemia •• 17 Hydroxylase deficiency •• Hypertension, Ambigious genitalia •• 5 α Reductase deficiency •• ↓Testosterone → Feminization GIT Physiology Substance Site of absorption •• •• •• •• •• Duodeneum Jejunum Jejunum Terminal ileum Terminal ileum Iron Calcium Folate Vit B 12 Bile salts 148 USMLE Step 1 Platinum Notes •• Oxyntic cells of gastric gland contain receptors for PGE2, ‘M3’, H2, Somatostatin •• Chief cells/Zymogen cells secrete Pepsinogen •• Oxyntic/Parietal Cells secrete Intrinsic Factor and HCl Remember: Other Important cells of GIT, Hormones and their Function Hormone Source of Secretion Actions Gastrin G cells of stomach; duodenum, jejunum, Stimulates the secretion of gastric juice Ant Pituitary, Pancreas and Brain Increase the gastric motility Stimulates the release of pancreatic hormones. Secretin S cells of duodenum, jejunum and ileum Stimulates secretion of watery, alkaline and pancreatic secretions Inhibits gastric secretion Causes contraction of pyloric sphincter Most potent stimulus is acidic chyme. Cholecytokinin I cells in duodenum, jejunum and ileum Stimulates contraction of gallbladder Activates secretin; Inhibits gastric motility; Increases secretion of enterokinase and intestinal motility Protein stimulates CCK section. Gastric inhibitory peptide (GIP) K cells in duodenum and jejunum Inhibits secretion of gastric juice, gastric motility and increase insulin secretion. Ingestion causing release Gastric Secretion Stimulated by: •• Stomach distension •• Acetylcholine •• Gastrin •• Histamine Decreased by: •• H2 blockers •• Secretin Gastric emptying: •• Stimulated by gastrin and distension of stomach •• Decreased by cholecystokinin. Physiology 149 Motilin Motilin is a polypeptide secreted by enterochromaffin cells •• It acts on G protein coupled receptors. Motilin is a 22 amino acid polypeptide hormone which in humans is encoded by the MLN gene •• Motilin secreted by endocrine M cells (these are not the same M cells that are in Peyer’s patches) that are numerous in crypts of the small intestine, especially in the duodenum and jejunum •• Based on amino acid sequence, motilin is unrelated to other hormones. Because of its ability to stimulate gastric activity, it was named ‘Motilin.’ •• Its circulating level increases at approximately 100 minutes in interdigestive state and is the major regulator of MMCs that control GIT motility in between meals •• Erythromycin binds to these motilin receptors and is used for treating ‘gastric hypomotility.’ •• Pacemaker of small intestine is in second part of duodenum. •• Cephalic phase of gastric secretion is mediated by: parasympathetics •• Gastric phase of gastric secretions is mediated by hormones •• Intestinal motility is stimulated by: –– Distension –– Ach Cholecystokinin •• Gastrocolic reflex is a mass reflex •• Enterogastric reflex: chyme entering intestines inhibits gastric motility •• Stimulated by: •• Duodenal distension •• Acidity of duodenal chyme •• Osmolarity of chyme •• Protein/fat breakdown products Sites of Absorption •• •• •• •• •• •• Iron is actively absorbed in duodenum Fat is maximally absorbed in jejunum Vitamin B12 is absorbed in ileum Calcium is maximally absorbed in ileum Maximum absorption of bile is seen in ileum Electrolytes are absorbed in colon Dietary Fiber •• •• •• •• •• •• •• •• Increases bulk of stools ↑metabolism of sugar in GIT Decreases stool transit time Prevent against colonic cancer Examples: Pectin Cellulose Hemicellulose Fat •• Fat is the largest reserve of energy in body •• Fat is maximally absorbed in jejunum 150 USMLE Step 1 Platinum Notes •• Short chain Fatty acids are maximally absorbed in Colon •• Digestion of fats occurs by: –– Gastric lipase –– Collipase –– Bile salts –– Pancreatic lipase •• Fat in stool > 6 gms/day is indicative of malabsorption •• Bile absorption is maximum in ileum Leptin •• Associated with puberty •• Secreted from adipose tissue •• Decreased hunger Physiology of Bile •• •• •• •• •• •• •• Secreted by hepatocytes Most potent stimulant for bile secretion is bile salts Composed of water, Bile salts, Cholesterol Bile salts are amphipathic Primary Bile Acids: Cholic acid, Chenodeoxycholic acid Secondary Bile Acids: Deoxycholic acid, Lithocholic acid Cholagogues are substances causing gallbladder contraction –– CCK –– Fatty acids –– Amino acids •• Cholerectics are substances increasing secretion of bile –– Secretin –– Bile salts –– Vagal stimulation Insulin •• Insulin acts through activation of ‘receptor tyrosine kinase activity’ •• Insulin receptor has two subunits: 1. Alpha subunit: which is extracellular and binds to insulin 2. Beta subunit: which is transmembranous and has tyrosine kinase activity functioning in signal transduction Insulin Increases •• Glucose uptake •• Glycogen synthesis •• Protein synthesis •• Fat synthesis Insulin Decreases •• Gluconeogenesis •• Glycogenolysis •• Lipolysis Physiology •• •• •• •• •• •• •• •• •• •• •• 151 Insulin is a ‘polypeptide’ Hormone Insulin is an ‘anabolic’ hormone It is a hypoglycemic hormone Insulin is secreted by Beta cells of Pancreas Secreted along with Cpeptide in 1: 1 ratio In fetus secretion begins by 3 month Insulin Secretion is stimulated by increased blood glucose Insulin Secretion is inhibited by epinephrine Insulin is prepared on a large scale by recombinant DNA technology from mRNA Pork insulin differs from human insulin by one amino acid only Insulin DOES NOT cross placenta •• Alpha cell — Glucagon •• Beta cells — Insulin •• Delta cells — Somatostatin •• F or PP cells — Pancreatic polypeptide Hormones Hormones can be divided into five major classes: 1. Amino acid derivatives such as: –– Dopamine –– Catecholamines, and –– Thyroid hormone 2. Small neuropeptides such as: –– Gonadotropin-releasing hormone (GnRH) –– Thyrotropin-releasing hormone (TRH) –– Somatostatin and –– Vasopressin 3. Large proteins such as: –– Insulin –– Luteinizing hormone (LH), and –– PTH produced by classic endocrine glands; 4. Steroid hormones such as: –– Cortisol and –– Estrogen that are synthesized from cholesterol-based precursors 5. Vitamin derivatives such as: –– Retinoids (vitamin A) and –– Vitamin D –– A variety of peptide growth factors, most of which act locally, share actions with hormones –– As a rule, amino acid derivatives and peptide hormone interact with cell-surface membrane receptors –– Steroids, thyroid hormones, vitamin D and retinoids are lipid-soluble and interact with intracellular nuclear receptors. Remember the Latest Source and Nature of Hormones Hormone Structure Source •• FGF-23 (phosphatonin) Protein Bone •• Osteocalcin Peptide 152 USMLE Step 1 Platinum Notes •• Glucocorticoids (e.g. cortisol) Steroids •• Mineralocorticoids (e.g. aldosterone) Steroids •• Androgens (e.g. testosterone) Steroids •• Adrenaline (epinephrine) Tyrosine derivative •• Noradrenaline (norepinephrine) Tyrosine derivative •• Estrogens (e.g. estradiol) Steroid Ovarian follicle •• Progesterone Steroid Corpus luteum and placenta •• Human chorionic gonadotropin (HCG) Protein Trophoblast and placenta •• Androgens (e.g. testosterone) Steroid Testes •• Erythropoietin (EPO) Protein Kidney •• Calcitriol Steroid derivative •• Calciferol (Vitamin D3) Steroid derivative Skin •• Atrial-natriuretic peptide (ANP) Peptides Heart •• Incretins Peptides Stomach and intestine •• Somatostatin Peptides •• Neuropeptide Y Peptide •• Ghrelin Peptide •• PYY3-36 Peptide •• Serotonin Tryptophan derivative •• Leptin Protein •• Retinol Binding Protein 4 Protein •• Adiponectin Protein Secondary Messengers •• cAMP •• DAG •• •• •• •• IP 3 Ca++ Protein kinase NO acts as cellular signalling molecule C AMP mediates action of •• PTH •• LH •• FSH, HCG •• ADH •• Calcitonin •• Glucagon C GMP mediates action of •• ANF •• NO •• Insulin acts through tyrosine kinase Adrenal cortex Adrenal medulla Fat cells (adipocytes) Physiology 153 Ca++, Phosphatidyl inophosphate mediates action of •• Ach •• Angiotensin II •• Oxytocin •• •• •• •• •• Thyroid hormones act on intracellular receptors Retinoic acid, act on intracellular receptors (Steroids) act on intracellular receptors Androgens, estrogen, progesterone, glucocorticoids, mineralocorticoids act on intracellular receptors Vitamin D3 and thyroid belong to steroid receptor family Calcium Metabolism Parathormone: •• Stimulates osteoclastic activity, thereby increasing bone resorption by mobilizing calcium and phosphate; •• Increases the reabsorption of calcium by the renal tubules, thus reducing the urinary excretion of calcium; •• Augments the absorption of calcium from the gut; Calcium reabsorption takes place from proximal small intestine •• Reduces the renal tubular reabsorption of phosphate, thus promoting phosphaturia. Calcitonin: •• It is secreted by the ‘Parafollicular cells’ of the ‘Thyroid’ (thyrocalcitonin) •• It lowers the serum calcium and affects calcium storage in bones; quite the opposite action of parathormone •• Acts by decreasing bone absorption •• That means inhibits osteoclastic activity. Parathyroid hormone-related protein (PTH-rP): •• It is a hypercalcemic factor with similar bioactivity to that of parathyroid hormone •• Low calcium levels stimulate its secretion •• Since its isolation from cancer cell lines and carcinoma of the breast, strong evidence has emerged that it is an important hormonal mediator of cancer-associated hypercalcemia in patients with solid tumors. PARATHYROID HORMONE MECHANISMS OF ACTION PTH binds to a plasma membrane receptor; the PTH receptor then causes a rise of cyclic 3’, 5-adenosine monophosphate (cAMP) and other second messengers in the cytoplasm of its target cells. The consequence is rapid effects of PTH on the target cells in bone and kidney. A different peptide, termed ‘parathyroid hormone-related peptide,’ with homology to PTH at the amino terminus, is secreted by many cancers, causing hypercalcemia through its interactions with PTH receptors PARATHYROID HORMONE ACTION IN BONE PTH in bone stimulates osteoblasts and osteoclasts. The effects on osteoclasts are indirect because these cells lack receptors for PTH. Very high PTH levels result in clear excess of bone resorption over bone formation. Controversy exists over whether mild PTH excess might have a net anabolic effect selectively in trabecular bone PARATHYROID HORMONE ACTION IN KIDNEY PTH acts in the kidney to stimulate the synthesis of 1, 25 (OH) 2D by increasing the activity of 25OHD3 1a-hydroxylase in the proximal tubules. PTH acts in the distal portions of the nephron to increase tubular reabsorption of calcium. In addition, PTH inhibits phosphate reabsorption in the distal, and perhaps also the proximal, tubules. PTH also inhibits bicarbonate reabsorption PARATHYROID HORMONE ACTION ON INTESTINE PTH has no important direct action on the intestine. However, the direct renal effect of PTH to increase serum 1, 25 (OH) 2D causes highly important secondary effects in the intestine 154 USMLE Step 1 Platinum Notes Calcium •• Calcium is absorbed in proximal small intestine •• Absorption is increased by acidic pH, proteins •• Absorption is decreased by phosphates and oxalates •• Ionized form is the active form of calcium A decrease in the concentration of free calcium ions in plasma results in •• Increased neuromuscular irritability and tetany •• Peripheral and perioral paresthesia •• Carpal spasm •• Pedal spasm, anxiety, seizures •• Bronchospasm, laryngospasm –– Chvostek’s sign –– Trousseau’s sign –– Erb’s sign –– Lengthening of the QT interval of the electrocardiogram Substance Serum calcium Serum phosphate Vitamin D ↑ ↑ PTH ↑ ↓ Calcitonin ↓ ↓ Pituitary Gland The anterior pituitary is often referred to as the ‘master gland’ Called Hypophysis cerebri Remember Epiphysis cerebri is Pineal Gland The anterior pituitary gland produces six major hormones: –– Prolactin (PRL) –– Growth hormone (GH) –– Adrenocorticotropin hormone (ACTH) –– Luteinizing hormone (LH) –– Follicle-stimulating hormone (FSH), and –– Thyroid-stimulating hormone (TSH) •• Pituitary hormones are secreted in a pulsatile manner •• The pituitary gland weighs ~600 mg •• It is located within the sella turcica ventral to the diaphragm sella •• The hypothalamic-pituitary portal plexus provides the major blood source for the anterior pituitary •• The posterior pituitary is supplied by the inferior hypophyseal arteries The Posterior Lobe is directly innervated by hypothalamic neurons (supraopticohypophyseal and tuberohypophyseal nerve tracts) via the pituitary stalk Thus, posterior pituitary production of vasopressin (antidiuretic hormone; ADH) and oxytocin It is particularly sensitive to neuronal damage by lesions that affect the pituitary stalk or hypothalamus •• Vasopressin and oxytocin are typical Neural Hormones. They are secreted into the circulation by nerve cells •• The term neurosecretion is classic for these two hormones • • B oth are synthesized in Para ventricular and Supraoptic nuclei and transported via hypothalmoneurohypophyseal tracts to posterior pituitary •• Posterior lobe of pituitary is important in their formation and they are synthesized as a part of large precursor molecule Physiology 155 •• Both vasopressin and oxytocin have a characteristic neurophysin attached with them. In the granules of the neurons that secrete them •• Neurophysin I in case of oxytocin and Neurophysin II in case of Vasopressin •• These neurophysins were initially thought to be binding molecules but now they are thought to be parts of precursor molecule •• The vasopressin and Neurophysin II after being secreted forms secretory granules called Herrings bodies. Reproductive Physiology •• Potency: Dihydrotestosterone > Testosterone > Androstenendione •• Testosterone is converted to DHT by enzyme ‘5 α reductase’ •• Testosterone is converted into estrogen and estrodial by ‘aromatase’ •• •• •• •• •• •• FSH stimulates formation of Secondary follicle to Graffian Follicle Estrogen is responsible for ‘Proliferative’ phase LH stimulates ovulation LH maintains corpus luteum FSH receptors are present on granulosa cells Progesterone is responsible for ‘Secretory’ phase Male sex hormones are called the androgens (secreted by leydig cells); testosterone, dihydro testosterone and androstenedione Mullerian ducts gives rise to female accessory sex organs such as vagina, uterus and fallopian tube Wolffian duct gives rise to male accessory sex organs such as epididymis, vas deferens and seminal vesicles Fetal testes begin to secrete the testosterone at about 2nd to 4th month of embryonic life The secretion from seminal vesicles contains fructose, phosphorylcholine, fibrinogen, ascorbic acid, citric acid, pepsinogen, acid phosphatase and prostaglandin •• Fructose and citrate acts as fuel for the spermatozoa •• Prostatic secretion is rich in enzymes, zinc and citrate •• Androgen appears to be essential for spermatogenesis. Whereas FSH is required for spermatic maturation •• •• •• •• •• Menopause Causes HAVOC •• Hot flushes •• Atrophy vagina •• Osteoporosis •• Coronary artery disease •• Features –– ↓Estrogen –– ↑FSH↑LH –– ↑GnRH •• Prolactin increases Dopamine Synthesis •• Dopamine inhibits Prolactin Synthesis •• Dopamine agonists (Bromocriptine) inhibit Prolactin synthesis Important Points in Reproductive Physiology •• Spermatogenesis occurs at lower temperatures at about 32 °C •• Spermatozoa acquire motility in epididymis 156 USMLE Step 1 Platinum Notes •• Capacitation (Fertilization capabilities) occurs in female genital tract •• Sperms move at a speed of 1–3 mm/min •• Semen contains high concentration of prostaglandins •• Sperms reach uterine tubes in 30–60 minutes after copulation •• In female genital tract do not survive for more than 48 hours •• Estrogen content of fluid in Rete Testis is high •• Spermatozoa contain a special enzyme Germinal Angiotensin II Converting enzyme •• Testosterone is produced from pregnanalone •• Testosterone is produced by Leyding cells •• CART WHEEL appearance of nucleus is seen in sertoli cells •• Blood testis barrier is formed by sertoli cells •• Receptors for FSH are present in sertoli cells •• Inhibin is secreted by sertoli cells Thyroid Hormones •• The thyroid gland produces two related hormones, thyroxine (T4) and triiodothyronine (T3) Thyroid hormones act through nuclear hormone receptors to modulate gene expression •• TSH, secreted by the thyrotrope cells of the anterior pituitary serves as the most useful physiologic marker of thyroid hormone action •• Thyroid hormones feedback negatively to inhibit TRH and TSH production •• Thyroid hormones are derived from a large iodinated glycoprotein •• Iodide uptake is a critical first step in thyroid hormone synthesis •• Iodide uptake is mediated by the Na+/I– symporter (NIS), which is expressed at the basolateral membrane of thyroid follicular cells, followed by Organification, Coupling, Storage, Release •• TSH is the dominant hormonal regulator of thyroid gland growth and function •• Excess iodide transiently inhibits thyroid iodide organification, a phenomenon known as the Wolff-Chaikoff effect •• T4 is secreted from the thyroid gland in at least 20-fold excess over T3 •• Both hormones circulate bound to plasma proteins, including thyroxine-binding globulin (TBG), transthyretin (TTR, formerly known as thyroxine-binding prealbumin, or TBPA) and albumin •• Thyroid hormones act by binding to nuclear receptors, termed thyroid hormone receptors (TRs) a and b. Effects •• Brain Maturation •• Bone Growth •• BMR ↑ •• Beta adrenergic effects Wolf Chaikoff effect is Iodine itself inhibits organic binding. •• •• •• •• •• Hypertrophy of Zona Glomerulosa Conns Syndrome Hypertrophy of Zona Fasiculata Cushings Syndrome Adrenal Cortical Atrophy Addisons Disease Hypertrophic Adrenal Medulla Pheochromocytoma Hypertrophic Adrenal Medulla Neuroblastoma Physiology 157 Hormones ↑in Stress •• Adrenaline •• Vasopressin •• Cortisol •• Glucagon •• Epinephrine Insulin is not increased Melatonin It is a pineal hormone It is serotegenic It is secreted predominantly at night in both day- and night-active species Exogenous melatonin increases sleepiness and may potentiate sleep when administered to good sleepers attempting to sleep during daylight hours at a time when endogenous melatonin levels are low •• Increased serotonin N acetyl transferase activity occurs in darkness. •• •• •• •• Sleep 158 •• •• •• •• •• •• •• USMLE Step 1 Platinum Notes EEG waves are called Berger rhythm Normal EEG is bilaterally symmetrical Alpha waves: 8–13 Hz seen in awake patient with eyes closed Beta waves: ≥14 Hz seen in awake with eyes open Theta waves: 4–7 Hz seen in hippocampus Delta waves: 3–5 Hz seen in deep sleep DTAB is order of increasing frequency. (Digest TAB) Sleep stages REM Sleep: •• Light phase with difficult arrousal •• Called paradoxical sleep Disorders of REM sleep: •• Nightmares (remembered) •• Narcolepsy •• Nocturnal penile trumescene NREM Sleep •• ↓ BP •• ↓ HR Disorders of NREM sleep: •• Sleep walking •• Sleep talking •• Night terror •• Bruxism •• Nocturnal enuresis Iron Metabolism •• •• •• •• •• The major role of iron is to carry O2 as part of the heme O2 also is bound by a heme protein in muscle, myoglobin Iron also is a critical element in iron-containing enzymes, including the cytochrome system in mitochondria Iron absorbed from the diet or released from stores circulates in the plasma bound to transferrin, the iron transport protein In a normal individual, the average red cell life span is 120 days •• The balance of iron metabolism in the organism is tightly controlled and designed to conserve iron for reutilization •• There is no excretory pathway for iron, and the only mechanisms by which iron is lost from the body are blood loss (via gastrointestinal bleeding, menses, or other forms of bleeding) and the loss of epidermal cells from the skin and gut •• Iron absorption takes place largely in the proximal small intestine Physiology Factors influencing iron absorption Hemoglobin •• •• •• •• •• •• Hb A Hb F Hb A 2 Hb H Hb S Hb Barts •• •• •• •• •• •• Alpha 2, Beta 2 Alpha 2, Gamma 2 Alpha 2, Delta 2 Beta 4 Beta 6 val- glu Gamma 4 Blood Coagulation Factors •• •• •• •• •• 1, 2, 5, 7, 9, 10 2, 7, 8, 9, 10 2, 7, 9, 10 5, 8 5, 10 •• •• •• •• •• Produced in liver Levels increased with oral contraceptives Vitamin K required Unstable in stored blood Good for growth of hemophilus organisms Physiology of Eye •• •• •• •• •• •• Rods are responsible for dim light or night vision or scotopic vision. (Electric Rods are used at night) Cones are responsible for color vision, sensitive to day light and acuity of vision Rhodopsin is the photosensitive pigment of rods cells Hemholtz Theory states that there are three kinds of cones in retina corresponding to three colors Most sensitive in Green light and least sensitive in Red light Photosensitive pigment in cones are: –– Porpyropsin — Red –– Iodopsin — Green –– Cyanopsin — Blue •• Test for visual acuity — Snell’s chart (distant vision) and Jaeger’s chart (near vision) •• Test for color blindness — Ishihara’s color chart •• Mapping of visual field — Perimetry •• Nearest point at which the object is seen clearly is about 7 to 40 cm •• Farthest point is infinite •• Protanomoly refers to defect in red cones •• Deutranomoly refers to defect in green cones •• Trianamoly refers to defect in blue cones 159 160 USMLE Step 1 Platinum Notes Cell Adhesion Molecules Cells are attached to Basal Lamina and each other by cell adhesion molecules (CAMs) They are: •• Integrins •• Adhesion molecules of IgG Superfamily •• Cadherins •• Selectins Nitric Oxide Nitric oxide is NO It is also called as EDRF (Endothelial derived relaxing factor) It is produced from arginine by enzyme NO synthetase NO has a short t ½ (4 seconds) It acts via c GMP pathway –– It relaxes smooth muscles specifically –– It prevents platelet aggregation –– It functions as a neurotransmitter –– It mediates bactericidal actions of macrophages Acts as: •• Free radical •• Vasodilator •• Oxidizing agent •• Catalyst –– NO, ANP, BNP act through c GMP Remember: •• Calmodulin is Ca Dependent •• Calmodulin acts through Protein Kinase •• •• •• •• •• Inflammatory Mediators •• •• •• •• •• Histamine is present in mast cells, basophils, enterochromaffin cells Has three types of receptors H1, H2, H3 Formed by decarboxylation of histidine Alter venular permeability Mediates triple response Natriuretic Peptides Atrial distention and/or a sodium load cause release into the circulation of atrial natriuretic peptide (ANP), a polypeptide; a highmolecular-weight precursor of ANP is stored in secretory granules within atrial myocytes. Release of ANP causes •• Excretion of sodium and water by augmenting glomerular filtration rate •• Inhibiting sodium reabsorption in the proximal tubule, and •• Inhibiting release of renin and aldosterone; and •• Arteriolar and venous dilatation by antagonizing the vasoconstrictors Thus, ANP has the capacity to oppose sodium retention and arterial pressure elevation in hypervolemic states The closely related brain natriuretic peptide (BNP) is stored primarily in cardiac ventricular myocardium and is released when ventricular diastolic pressure rises. Physiology 161 Its actions are similar to those of ANP Circulating levels of ANP and BNP are elevated in congestive heart failure but not sufficient to prevent edema formation In addition, in edematous states (particularly heart failure), there is abnormal resistance to the actions of natriuretic peptide increase the concentrations of cyclic GMP in the kidney, adrenal glomerulose, vascular smooth muscle and platelets. Elevated circulating concentrations of ANP and particularly BNP correlate with a poor prognosis in heart failure: •• Natriuretric substance •• Promotes sodium excretion •• Decreases blood pressure •• Acts by c GMP Pathway The 'Encapsulated'mechanoreceptors include: •• Pacinian corpuscles in skin and connective tissues that sense (rapidly adapting touch) pressure and vibration. They look like onion bulbs •• Meissner’s corpuscles in dermal papillae of non-hair bearing skin of hands, feet, genitalia, nipples and mouth that provide tactile discrimination. They look like nutmegs •• Ruffini’s corpuscles in skin and joints that respond to stretch and pressure •• Golgi tendon organs located where muscle inserts into tendon sense stretch for proprioception •• Muscle spindles in skeletal muscles are composed of nerve endings in association with specialized intrafusal muscle fibers that function to detect stretch for reflexes The ‘Nonencapsulated’ endings include: •• Peritricial nerve endings around hair follicles that detect touch through movement of hair •• Merkel’s disks on nonhair bearing skin such as the hands that perceive touch. It is present in epidermis. Important Regions of CNS •• The Locus Ceruleus is adense collection of neuromelanin—containing cells in the rostralpons. It appears blue-black in unstained brain tissue. These cells contain norepinephrine •• The Basal nucleus of Meynert is one of the structures that degenerates in Alzheimer’s disease •• The Caudate nucleus degenerate in Huntington’s disease (GABAergeic) neurons •• The Substantianigra contains the nigrostriatal neurons that are the source of striat aldopamine. This cell group degenerates in Parkinson’s disease •• The Ventral Tegmentalarea is located in the midbrain and is an important source of dopamine for the limbic and cortical areas. Over activity of this cell group is a popular theory of the etiology of Schizophrenia •• Aphasia should be diagnosed only when there are deficits in the formal aspects of language such as naming, word choice, comprehension, spelling and syntax •• Dysarthria and mutism do not, by themselves, lead to a diagnosis of aphasia •• In approximately 90% of right handers and 60% of left handers, aphasia occurs only after lesions of the left hemisphere •• A language disturbance occurring after a right hemisphere lesion in a right hander is called crossed aphasia Wernicke’s Aphasia •• Damage: Comprehension is impaired for spoken and written language •• Language output is fluent •• The tendency for paraphasic errors maybe so pronounced that it leads to strings of neologisms, which form the basis of what is known as ‘jargon aphasia’. Broca’s Aphasia •• Brocas area is present in inferior frontal gyrus •• Concerned with word formation 162 USMLE Step 1 Platinum Notes •• Damage: Speech is nonfluent, labored, interrupted by many word finding pauses and usually dysarthric •• Brocas: Broken Speech Global Aphasia •• Speech output is nonfluent and comprehension of spoken language is severely impaired. Naming, repetition, reading and writing are also impaired •• This syndrome represents the combined dysfunction of Broca’s and Wernicke’s areas and usually results from strokes that involve the entire middle cerebral artery distribution in the left hemisphere. Conduction Aphasia •• Speech output is fluent but paraphasic, comprehension of spoken language is intact, and repetition is severely impaired. Naming and writing are also impaired. Anomic Aphasia •• This form of aphasia maybe considered the ‘minimal dysfunction’ syndrome of the language network. Articulation, comprehension, and repetition are intact, but confrontation naming, word finding and spelling are impaired. Main Hypothalamic Nuclei and Their Functions •• Thirst and water balance Supraoptic nucleus Supraoptic nucleus controls ADH secretion •• Hunger Lateral nucleus •• Satiety Ventromedial nucleus •• Regulation of Autonomic Nervous system Anterior Hypothalamus •• Circadian Rhythm Suprachiasmatic nucleus •• Heat production Posterior hypothalamus •• Cooling Anterior hypothalamus •• Sexual functions Septate nucleus •• Control of anterior pituitary By releasing factors •• Control of posterior pituitary By hormones produced in hypothalamic nuclei Functions of Hypothalamus •• Food intake •• Temperature control •• Hypophyseal control •• Nonshivering thermogenesis is because of noradrenaline •• Nonshivering thermogens are secreted by heart, liver small intestine •• Nonshivering thermogenesis is mediated by β3 receptors •• Heat loss depends mostly on environmental temperature Physiology 163 Ascending Tracts of Spinal Cord Situation Tract Function Anterior white funiculus Anterior spinothalamic tract ‘Crude’ touch sensation Lateral white funiculus Lateral spinothalamic tract Pain and temperature sensation Ventral spino cerebellar tract Subconscious kinesthetic sensations Dorsal spino cerebellar tract Subconscious kinesthetic sensations Spinotectal tract Concerned with spinovisual reflex Fasiculus dorsolateralis Pain and temperature sensations Spinoreticular tract Conciousness and awareness Spinoolivary tract Proprioception Spinovestibular tract Proprioception Fasciculus gracilis Fasciculus cuneatus •• •• •• •• •• •• Posterior white funiculus Tactile sensation Tactile localization Tactile discrimination ‘Vibratory’ sensation ‘Conscious kinesthetic sensation’ ‘Stereognosis’ Descending Tracts of Spinal Cord Situation Tract Function Pyramidal tracts Anterior corticospinal tract Lateral corticospinal tract •• Control voluntary, skilled movements •• Forms upper motor neurons •• Forms pyramids Extra Pyramidal tracts Medial longitudinal fasciculus •• Coordination of reflex ocular movement •• Integration of movements of eyes and neck Anterior vestibulospinal tract •• Maintenance of muscle tone and posture •• Maintenance of position of head and body during acceleration Lateral vestibulospinal tract Reticulospinal tract •• Coordination of voluntary and reflex movements •• Control of muscle tone •• Control of respiration and blood vessels. Tectospinal tract •• Control of movement of head in response to visual and auditory impulses. Rubrospinal tract •• Facilitatory influence on flexor muscle tone Olivospinal tract •• Control of movements due to proprioception •• Main excitatory neurotransmitter in CNS is: Glutamate •• Main inhibitory neurotransmitter in CNS is GABA Action of Sympathetic and Parasympathetic Divisions of ANS Effector Organ Eye Sympathetic Division Parasympathetic Division Ciliary muscle Relaxation Contraction Pupil Dilatation Constriction 164 USMLE Step 1 Platinum Notes Effector Organ Sympathetic Division Parasympathetic Division Lacrimal secretion Decrease Increase Salivary secretion Decrease in secretion and vasoconstriction Increase in secretion and vasoconstriction Motility Inhibition Acceleration Secretion Decrease Increase Sphincters Constriction Relaxation Relaxation Contraction Detrusor muscle Relaxation Contraction Internal sphincter Constriction Relaxation Sweat glands Increase in secretion – Heart rate and force Increase Decrease Blood vessels Constriction of all blood vessels except Dilatation those in heart and skeletal muscle Bronchioles Dilatation GIT Gallbladder Urinary bladder Constriction Flight or Fright response is seen in Sympathetic stimulation. Example of seeing a lion and subsequent body respone •• ↑BMR: To runaway •• Vasodilation of vessels of heart and skeletal muscle •• Dilatation of Pupils: To increase field of vision to escape not to frighten the lion •• Urinary and fecal spincters need to close. No need of micturating/defecating at this stage •• Increase heart rate •• Increase blood pressure •• Increase total peripheral resistance Cerebellum •• Purkinje cells are the largest neurons in the body •• The axons of Purkinje cells are the only output from cerebellar cortex and these pass to deep nuclei •• From the cerebellar nuclei they project to other parts (Thalamus, Brainstem) Layers of Cerebellum •• Molecular layer •• Purkinje layer •• Granular layer Nuclei of Cerebellum •• Dentate •• Emboliform •• Globoose •• Fastigial Types of Neurons in Cerebellum •• Golgi cells •• Basket cells •• Granule cells •• Stellate cells •• Purkinje cells (end in cerebellar nuclei) Physiology 165 Remember •• •• •• •• •• •• •• •• The Cerebellum is not a Sensory Organ Removal of cerebellum does not result in loss of any sensation The Cerebellum Is not a motor Organ Stimulation of cerebellum does not produce movement The function of cerebellum is It coordinates and smoothens the action of different muscle groups It times their contraction properly In this way it produces smooth and accurate movements Diseases of the Cerebellum •• Diseases of the cerebellum result in inability to do movements smoothly and accurately. This condition is called cerebellar ataxia or cerebellar asynergia •• Disturbance of Gait: Gait is similar to that of as drunken person; Lesion in one cerebellar hemisphere results in a tendency to fall towards that side. {Right Side of Body is under control of Right Cerebellar hemisphere}. Lesions of cerebellar ataxia are not corrected by vision •• Decomposition of movements: A movement is broken into components i.e. the Shoulder, elbow and the wrists move separately and not in a synchronized way •• Dysmetria: Inability to stop a movement at a desired point, i.e. overshooting, past pointing, etc. •• Dysadiadochokinesia: Inability to stop one movement and immediately to follow it up with other movement of opposite nature, i.e. rapid pronation and supination •• Scanning speech: Due to lack of synergy of muscles used in speaking, the spacing of sounds is irregular with pauses at wrong places •• Hypotonia •• Decreased tendon reflexes •• Intention tremor •• Sometimes Nystagmus Basal Nuclei or Basal Ganglia •• ‘Subcortical’ •• ‘Intracerebral’ •• ‘Grey matter masses’ •• They are concerned with planning and programming of movements They include: •• Caudate nucleus + Lentiform nuclei (Corpus Straitum) •• Amygdaloidal nucleus •• Claustrum Functions: The basal ganglia are concerned with the control of skilled movements, coordinated movements as well as involuntary movements and regulation of reflex and muscular activity As a result disease processes effecting basal ganglia can lead to diseases which can be: More Movements (Hyper kinetic), Less Movement (Hypo kinetic) Movement Disorders and their nuclei: •• Parkinsonism: Lesion of Globus Pallidus 166 USMLE Step 1 Platinum Notes •• Chorea: Lesion of Caudate Nucleus •• Athetosis: Lesion of Putamen •• Hemiballismus: Lesion of Subthalamic nucleus Parkinson's disease Parkinsonism Patient 1. Acalculia: A selective impairment of mathematical ability 2. Achalasia: Condition in which food accumulates in the esophagus and the organ becomes highly diluted. It is due to increased resting lower esophageal sphincter tension and incomplete relaxation of this sphincter on swallowing. 3. Ageusia: Absence of the sense of taste 4. Agnosia: Inability to recognize objects by a particular sensory modality even though the sensory modality itself is intact. Lesions producing these defects are generally in the parietal lobe. 5. Akinesia: Difficulty in initiating movements and decreased spontaneous movement. 6. Ataxia: In coordination due to errors in the rate, range, force and direction of movement. Superficial Reflexes- Mucus Membrane Reflexes Reflex Corneal reflex Stimulus Irritation of cornea Response Blinking of eye (closure of eyelids) Afferent Nerve V Cranial nerve Center Pons Efferent Nerve VII Cranial nerve Physiology 167 Conjunctival reflex Irritation of conjunctiva Blinking of eye V Cranial nerve Pons VII Cranial nerve Nasal reflex (sneezing reflex) Irritation of nasal mucus membrane Sneezing V Cranial nerve Motor nucleus of V Cranial nerve X Cranial nerve and upper cervical nerves Pharyngeal reflex mucus membrane Irritation of Retching or of pharyngeal gagging mouth opening IX Cranial nerve X Cranial Nuclei of nerve X Cranial nerve IX Cranial nerve X Cranial Nuclei of nerve X Cranial nerve Uvular reflex (while Irritation of uvula talking) Raising of uvula Superficial Reflexes- Cutaneous Reflexes Reflexes Stimulus Response Center-Segments of Spinal Cord Involved Scapular reflex Irritation of skin at the interscapular Contraction of scapular muscles C5 to T1 space and drawing in of scapula Upper abdominal reflex Stroking the abdominal wall below Ipsilateral contraction of abdominal T6,7,8,9 the costal margin muscle and movement of umbilicus towards the site of stroke Lower abdominal reflex Stroking the abdominal wall at Ipsilateral contraction of abdominal T10,11,12 umbilical and iliac level muscle and movement of umbilicus towards the site of stroke Cremasteric reflex Stroking the skin at upper and inner Elevation of testicles aspect of thigh L1,2 Gluteal reflex Stroking the skin over glutei Contraction of glutei L4,5 S1,2 Bulbocavernous reflex Stroking the dorsum of glans penis Contraction of bulbocavernous S3,4 Anal reflex Stroking the perianal region Contraction of anal sphincter S4,5 Deep Reflexes Reflex Stimulus Response Center-Spinal Segments Involved Jaw Jerk Tapping the middle of the chin Closure of mouth with slightly opened mouth Pons – V Cranial nerve Biceps Jerk Percussion of biceps tendon Flexion of forearm C 5, 6 Triceps Jerk Percussion of triceps tendon Extension of forearm C 6, 7,8 Supinator Jerk or radial periosteal reflex Percussion of tendons over distal Supination end (styloid process) of radius forearm and flexion of C7, 8 Wrist tendon or finger flexion reflex Percussion of wrist tendons Flexion of corresponding finger C 8, T1 Knee Jerk or patellar tendon reflex Extension of leg L2,3,4 Planter flexion of foot L5 S1S2 Percussion of patellar ligament Ankle Jerk or Achilles tendon reflex Percussion of Achille’s tendon Susceptibility of Nerve Fibers •• Pressure •• Type A •• Hypoxia •• Type B •• Anesthesia •• Type C 168 •• •• •• •• USMLE Step 1 Platinum Notes Type A α have largest diameter, Highest conduction velocity, function in Proprioception Type A and B are Myelinated Type C has least diameter, least conduction velocity, unmyelinated Nerve conduction velocity is more in upper limbs than in lower limbs Neurotransmission Chemical Classification of Neurotransmitters Acetylcholine Biogenic Amines •• Catecholamines: Dopamine, norepinephrine (NE) and epinephrine •• Indolamines •• Serotonin and histamine (5-Hydroxytryptamine or 5-HT) Amino Acids •• GABA—Gamma (-aminobutyric acid) •• Glycine •• Aspartate •• Glutamate Neuropeptides •• Substance P •• Endorphins and Enkephalins •• Somatostatin, gastrin, cholecystokinin, oxytocin, vasopressin, Leutinizing hormone releasing hormone (LHRH) Purines •• Adenosine •• ATP Physiology Gases and Lipids •• Nitric Oxide (NO) •• Carbonmonooxide (CO) •• Cannabinoids Acetylcholine (Ach) Acetylcholine (Ach) was the first neurotransmitter to be identified. It is the most abundant neurotransmitter in the brain •• Released at neuromuscular junctions and some ANS neurons •• Synthesized by enzyme choline acetyltransferase •• Degraded by the enzyme acetylcholinesterase (AChE) Catecholamines Catecholamines-Dopamine, norepinephrine (NE), and epinephrine are synthesized from Tyrosine •• It is involved in reward-pleasure and learning •• Dopamine is the principle neurotransmitter involved in Addiction pathway Serotonin •• Broadly distributed in the brain, derived from Tryptophan •• Involved in sleep, dreaming, hunger and arousal •• Play roles in emotional behaviors and the biological clock •• Depletion of serotonin in brain leads to depression GABA •• GABA—Gamma (-aminobutyric acid) is the major inhibitory neurotransmitter in CNS •• Synthesized from decarboxylation of Glutamate Involved in regulating anxiety Maybe related to eating or sleep disorders Endorphins, Enkephalins and Substance P •• Substance P is the mediator of pain signals •• Endorphins and Enkephalins act as natural opiates; reduce pain perception •• They also depress physical functions like breathing and may produce physical dependence Purines such as ATP •• Purines such as ATP •• Act in both the CNS and PNS •• Produce fast or slow responses •• Induce Ca2+ influx in astrocytes •• Provoke pain sensation 169 170 USMLE Step 1 Platinum Notes Nitric Oxide (NO) •• Synthesized on demand •• Activates the intracellular receptor guanylyl cyclase to cyclic GMP •• Involved in learning and memory Endocannabinoids •• Lipid soluble; synthesized on demand from membrane lipids •• Bind with G protein–coupled receptors in the brain •• Involved in learning and memory Blood Brain Barrier It is formed by •• Capillary Endothelium •• Basement Membrane •• Foot Processes of Astrocytes Features It is a selective barrier, only certain substances can pass across the barrier The permeability of the barrier is inversely related to the size of the molecules The permeability of the barrier is directly related to the lipid solubility of the substance The barrier is more permeable to certain substances in the newborn than in the adults. It is because of the fact that it is under developed in the newborn and especially in the preterm fetuses •• The barrier undergoes breakdown in case of direct injury to brain or secondary to toxin/chemical induced damage •• The Tight Junction between the endothelial cells is responsible for the Blood Brain Barrier •• The Blood Brain Barrier is deficient at some regions in the CNS, e.g. in next table •• •• •• •• •• •• •• •• Area Postrema Organum Vasculosum of the lamina terminalis Subfornical organ The posterior pituitary These areas are called Circum Ventricular Organs Important Molecules •• •• •• •• •• •• P53 bcl2 fas c myc ras Caspaces Tumor suppressor gene •• Negative regulator of Apoptosis •• Activator of apoptosis •• Transcription factor which commits cells to mitosis •• G protein. Most commonly mutated gene in Solid Tumors •• Activates Apoptosis Changes in Exercise •• ↑Oxygen uptake •• Left shift of oxygen Hb Dissociation curve. Physiology •• •• •• •• 171 –– ↑ ventilation –– ↑ CO2 Excretion –– ↑ PaO2 –– ↑ HR –– ↑CO –– ↑ RR –– ↑ BP Blood flow To brain unaltered ↑ Insulin Sensitivity Causes Hyperkalemia ↑ Endorphin levels (Relieves depression) Changes in Aging •• •• •• •• •• •• •• •• •• •• Vital capacity decreases Glucose tolerance decreases GFR decreases Colonic motility decreases Bone mass decreases BP increases Prostate size usually increases Brain atrophies Vaginal mucosa atrophies Hematocrit remains same Some Laws of Physiology: (Frequently Asked) 1. Laplace’s Law For a globular structure, P = 2T / r Where P: transmural force T: wall tension r : Radius of the globular structure 2. Frank-Starling’s Law: The force of contraction is directly proportional to the initial length of muscle fiber. 3. All or None Law: The action potential fails to occur if the stimulus is subthreshold in magnitude, and it occurs with constant amplitude and from regardless of the strength of the stimulus, if the stimulus is at or above threshold intensity. 4. Bell- Magendie Law: In the spinal cord, the dorsal roots are sensory and the ventral roots are motor. 5. Landsteiner’s Law: a. Where an agglutinogen is present on the membrane of RBC, the corresponding agglutinin must be absent in the plasma of that person b. Where, in an individual, the RBCs are devoid of an agglutinogen, plasma shall contain the corresponding agglutinin. 6. Fick’s Law This law states: Vg = A / T × D (P1 – P2) Where Vg = volume of the gas diffusing through the membrane per min A = total surface area of alveolo-capillary membrane of the two lungs taken together T = thickness of alveolo-capillary membrane D = diffusion constant of the gas P1 – P2 = pressure of the gas in the alveoli and within the capillary blood 172 USMLE Step 1 Platinum Notes 7. Dermatomal Rule: When pain is referred, it is usually to a structure that developed from the same embryonic segment or dermatome as the structure in which the pain originates. 8. Monro- Kellie Doctrine: Brain tissue and spinal fluid are essentially incompressible; hence the volume of blood, spinal fluid and brain in the cranium at anytime must be relatively constant. 9. Weber Fechner Law It states that the magnitude of the sensation felt is proportionate to the log of the intensity of the stimulus In other words: R = KSA Where R = sensation felt S = intensity of the stimulus and for any specific sensory modality K and A = are constants 10. Law of Projection: No matter where a particular sensory pathway is stimulated along its course to the cortex, the conscious sensation produced is referred to the location of the receptor. This principle is called Law of Projection Involved in phantom limb sensation 11. Size principle: In general, slow muscle units are innervated by small, slowly conducting motor neurons and fast units by large, rapidly conducting motor neurons Sites of Important Receptors •• •• •• •• •• Hearing Rotational acceleration Linear acceleration Arterial BP Arterial PO2 and PCO2 •• •• •• •• •• Hair cells of organ of Corti Hair cells of semicircular canals Hair cells of utricle and saccule Stretch receptors in Carotid sinus/Aortic arch Glomus cells of Aortic and Carotid Bodies Carotid body Important Substances and their Role: (USMLE Favorite) •• Bradykinin: stimulation of visceral smooth muscle •• Nitric oxide: vasodilator •• Clathirin: receptor mediated endocytosis Physiology 173 Natriuretic Peptides: (USMLE Favorite) Atrial distention and/or a sodium load cause release into the circulation of atrial natriuretic peptide (ANP), a polypeptide; a highmolecular-weight precursor of ANP is stored in secretory granules within atrial myocytes Release of ANP causes •• Excretion of sodium and water by augmenting glomerular filtration rate •• Inhibiting sodium reabsorption in the proximal tubule, and •• Inhibiting release of renin and aldosterone; and •• Arteriolar and venous dilatation by antagonizing the vasoconstrictors –– Thus, ANP has the capacity to oppose sodium retention and arterial pressure elevation in hypervolemic states –– The closely related brain natriuretic peptide (BNP) is stored primarily in cardiac ventricular myocardium and is released when ventricular diastolic pressure rises –– Its actions are similar to those of ANP –– Circulating levels of ANP and BNP are elevated in congestive heart failure but not sufficient to prevent edema formation –– In addition, in edematous states (particularly heart failure), there is abnormal resistance to the actions of natriuretic peptide increase the concentrations of cyclic GMP in the kidney, adrenal glomerulose, vascular smooth muscle, and platelets. Elevated circulating concentrations of ANP and particularly BNP correlate with a poor prognosis in heart failure •• Natriuretric substance •• Promotes sodium excretion •• Decreases blood pressure •• Acts by c GMP Pathway Cell Adhesion Molecules Cells are attached to Basal Lamina and each other by cell adhesion molecules (CAMs) They are: •• Integrins •• Adhesion molecules of IgG Superfamily •• Cadherins •• Selectins Nitric Oxide: (USMLE Favorite) Nitric oxide is NO It is also called as EDRF (Endothelial derived relaxing factor) It is produced from arginine by enzyme NO synthetase NO has a short t ½ (4 seconds) It acts via c GMP pathway –– It relaxes smooth muscles specifically –– It prevents platelet aggregation –– It functions as a neurotransmitter –– It mediates bactericidal actions of macrophages Acts as: •• Free radical •• Vasodilator •• Oxidizing agent •• Catalyst –– NO, ANP, BNP act through cGMP •• •• •• •• •• 174 USMLE Step 1 Platinum Notes REMEMBER Somatomedins: (USMLE Favorite) •• Are polypeptide growth factors secreted by liver, and other tissues, which mediate the growth-promoting effects of GH •• Somatomedins exhibit sequence homology with insulin and proinsulin, they belong to the insulin family •• Because of their resemblance to insulin, they can bind to insulin receptors and elicit insulin-like effects •• At least four somatomedins have isolated, but by far the most important of these is somatomedin C (also called IGF-I) The somatomedins, have characteristics: •• Regulation of their concentration in serum by growth hormone •• Stimulation of sulfate incorporation into the cartilage proteoglycan chondroitin sulfate •• Insulin- like effects on both adipose and muscle tissue, and •• Mitogenicity for fibroblasts Effects of IGF-I Ubiquitin •• •• •• •• •• Ubiquitin is ‘itself a protein’ that ‘degrades other proteins’ i.e. ‘unfriendly’, for proteins It is a ‘highly conserved’ protein Degradation by Ubiquitin occurs in ‘Proteosomes’ by a process which is ‘ATP dependent’ Before degradation proteins are bound to binding proteins Ubiquitin tags proteins for degradation. Physiology 175 USMLE Case Scenario A matrix glycoprotein inhibits the cell adhesion effect of fibronectin and permits cells to detach from the matrix and migrate. The appearance of this glycoprotein in the wound matrix correlates with the initiation of epithelial and mesenchymal cell migration. The matrix glycoprotein is: 1. Tenascin 2. Laminin 3. Brabykinin 4. Heparin 5. Incertin 6. Fibronectin Ans. 1. Tenascin USMLE Case Scenario Maximum absorption of the water occurs at: 1. Proximal convoluted tubule 2. Distal convoluted tubule 3. Collecting duct 4. Loop of henle Ans. 1. Proximal convoluted tubule USMLE Case Scenario Ghrelin is secreted from: 1. Endocrinal cells of the pancreas 2. Epithelium of the fundus 3. Epithelium of the antrum 4. Epithelial cells of the jejunum Ans. 2. Epithelium of the fundus USMLE Case Scenario During embryological development, hematopoiesis occurs in different organs at different times. Which of the following are the correct organs, in the correct sequence, at which hematopoiesis occurs embryologically? 1. Amnion, yolk sac, placenta, bone marrow 2. Placenta, liver and spleen, yolk sac, bone marrow 3. Placenta, spleen and lymphatic organs, bone marrow 4. Yolk sac, bone marrow, liver and spleen 5. Yolk sac, liver, spleen and lymphatic organs, bone marrow Ans. 5. Yolk sac, liver, spleen and lymphatic organs, bone marrow By the third week of development, hematopoiesis begins in the blood islands of the yolk sac. Beginning at 1 month of age and continuing until 7 months of age, blood elements are also formed in the liver. Hematopoiesis occurs in the spleen and lymphatic organs between 2 and 4 months, and in the bone marrow after 4 months. USMLE Case Scenario Calcitonin is secreted by: 1. Thyroid gland 2. Parathyroid gland 3. Adrenal glands 4. Ovaries Ans. 1. Thyroid gland 176 USMLE Step 1 Platinum Notes USMLE Case Scenario QRS complex is due to: 1. Ventricular repolarization 2. Ventricular depolarization 3. Atrial repolarization 4. Atrial depolarization Ans. 2. Ventricular depolarization USMLE Case Scenario GABA is produced from: 1. Alanine 2. Glycine 3. Glutamate 4. Glutamine Ans. 3. Glutamate USMLE Case Scenario Broca’s area is concerned with: 1. Word formation 2. Comprehension 3. Repetition 4. Reading Ans. 1. Word formation USMLE Case Scenario Agranular endoplasmic reticulum is involved in the synthesis of: 1. Protein 2. Lipid 3. Carbohydrate 4. Vitamin D Ans. 2. Lipid USMLE Case Scenario CO2 is primarily transported in the arterial blood as: 1. Dissolved CO2 2. Carbonic Acid 3. Carbamino-hemoglobin 4. Bicarbonate Ans. 4. Bicarbonate USMLE Case Scenario The enzyme associated with the conversion of androgen to estrogen in the growing ovarian follicle is: 1. Desmolase 2. Isomerase Physiology 177 3. Aromatase 4. Hydroxylase Ans. 3. Aromatase USMLE Case Scenario Respiratory acidosis is compensated by: 1. Renal excretion of bicarbonate and excretion of base 2. Renal excretion of bicarbonate and excretion of acid 3. Renal retention of bicarbonate and excretion of acid 4. Renal retention of bicarbonate and excretion of base Ans. 3. Renal retention of bicarbonate and excretion of acid USMLE Case Scenario Cortisol is secreted by: 1. Zona glomerulosa 2. Zona fasciculata 3. Zona reticularis 4. Zona medulla Ans. 2. Zona fasciculata USMLE Case Scenario Broca’s area situated in: 1. Superior temporal gyrus 2. Inferior temporal gyrus 3. Superior frontal gyrus 4. Inferior frontal gyrus Ans. 4. Inferior frontal gyrus USMLE Case Scenario The extracellular matrix is the complex, cross-linked structure of proteins and polysaccharides that surrounds cells and organizes the geometry of tissues. Collagen is the principal component of the extracellular matrix. The rate-limiting enzyme in collagen synthesis is: 1. Lysyl hydroxylase 2. Prolyl hydroxylase 3. Lysyl oxidase 4. Prolyl oxidase Ans. 2. Prolyl hydroxylase USMLE Case Scenario A 50-year-old drug addict man was brought to the emergency room in a stuporous state. Blood pressure is 100/50 mm Hg, heart rate 110 beats/min, respiratory rate 34/min, and his temperature is 103F. Below are his lab results: •• Sodium 152 mEq/L (135–145) •• Potassium 2.4 mEq/L (3.5–5.0) •• Chloride 108 mEq/L (95–105) •• Bicarbonate 11 mEq/L (24–26) 178 USMLE Step 1 Platinum Notes •• pH 7.2 (7.35–7.45) •• PCO2 25 mm Hg (35–45) It implies an acid base status suggestive of: 1. Metabolic acidosis and metabolic alkalosis 2. Metabolic acidosis with partial respiratory compensation 3. Respiratory acidosis and partial metabolic compensation 4. Respiratory acidosis Ans. 2. Metabolic acidosis with partial respiratory compensation USMLE Case Scenario A 55-year-old man is brought to the emergency room by his son in a stuporous and obtunded condition. Physical examination reveals BP 120/70 and pulse 90 (supine); and BP 90/50 and pulse 120 (standing). Serum chemistries are: Na+ = 141 mEq/L Cl = 87 mEq/L K+ = 2.9 mEq/L HCO3 = 42 mEq/L Arterial pH = 7.53 PCO2 = 50 mm Hg The disease process that best accounts for this problem: 1. Ethylene glycol poisoning 2. Chronic obstructive pulmonary disease 3. Congestive heart failure 4. Lactic acidosis 5. Vomiting 6. Chronic renal failure Ans. 5. Vomiting USMLE Case Scenario Capacitance of sperm is attained in: 1. Epididymis 2. Genital tract 3. Vagina 4. Fallopian tube Ans. 4. Fallopian tube USMLE Case Scenario Neuroendocrine responses contributes to meeting the enhanced energy demands during exercise is: 1. Glucagon stimulation of hepatic glycogen synthesis 2. Epinephrine stimulation of hepatic glycogenolysis 3. Epinephrine inhibition of hepatic glycogenolysis 4. Norepinephrine-induced stimulation of insulin release 5. Cortisol inhibition of gluconeogenesis Ans. 2. Epinephrine stimulation of hepatic glycogenolysis USMLE Case Scenario Elevated fasting plasma glucose levels in pregnant women with no history of diabetes maybe related to: 1. Increased estrogen production 2. Decreased progesterone clearance Physiology 179 3. Increased h PL/GH production 4. Increased insulin degradation 5. Decreased prolactin levels Ans. 3. Increased hPL/GH production USMLE Case Scenario Testosterone production is mainly contributed by: 1. Leydig cells 2. Sertolie cells 3. Seminiferous tubules 4. Epididymis Ans. 1. Leydig cells USMLE Case Scenario The processing of short-term memory to long-term memory is done in: 1. Prefrontal cortex 2. Hippocampus 3. Neocortex 4. Amygdala Ans. 2. Hippocampus USMLE Case Scenario Basal ganglia is involved primarily in: 1. Planning and programming of voluntary movements 2. Processing of cognitive functions 3. Sensory-motor integration 4. Language function Ans. 1. Planning and programming of voluntary movements USMLE Case Scenario Which of the following can be present in hyperosmolar coma in a diabetic patient? 1. Low plasma glucose 2. Low plasma potassium 3. High plasma pH 4. High plasma ketones Ans. 4. High plasma ketones USMLE Case Scenario A 88-year-old woman from Mexico is admitted to the hospital following about of severe vomiting and generalized weakness. Initial laboratory values reveal elevated Ca2 levels. The referring physician tells you that she has breast cancer and her bone scan indicates metastasis to bone. The most likely cause of hypercalcemia is: 1. Increased PTH production 2. Increased responsiveness of the PTH receptor 1 3. Increased PTHrP production 4. Decreased responsiveness to calcitonin Ans. 3. Increased PTHrP productions 180 USMLE Step 1 Platinum Notes USMLE Case Scenario FIGLU excretion in the urine, is an index of the deficiency of: 1. Thiamine 2. Niacin 3. Pyridoxine 4. Folate Ans. 4. Folate USMLE Case Scenario In a 55-year-old anion gap needs to be calculated. The anion gap is calculated as: 1. [K+] + [HCO3– + Cl–] 2. [Na+] + [Cl– + HCO3–] 3. [Na+] – [HCO3– + Cl–] 4. [Mg] + [HCO3– + Cl–] 5. [Mg] + [HCO3– + Cl–] Ans. 3. [Na+]– [HCO3– Cl–] USMLE Case Scenario Intrinsic Factor of Castle is secreted by which of the following cells in gastric glands: 1. Chief cells 2. Parietal cells 3. Enterochromaffin cells 4. Β cells Ans. 2. Parietal cells USMLE Case Scenario A 25-year-old man from New Jersy after a fight incurs blunt trauma to his upper outer arm. On physical examination, there is a 2 × 3 cm contusion. He bleeds but the initial soft tissue bleeding stops in a few minutes and the size of the bruise does not increase. Which of the following chemical mediators is most important in this episode of hemostasis? 1. Leukotriene 2. Neurokinin 3. Bradykinin 4. Prostaglandin 5. Prostacyclin 6. Plasminogen 7. Thromboxane Ans. 7. Thromboxane It is released by platelets to promote formation of a stable ‘secondary plug’ to achieve hemostasis USMLE Case Scenario A 55-year-old man has severe chest pain for the past 6 hours. Laboratory studies show an elevated serum troponin I. A coronary angiogram is performed emergently and reveals >85 % occlusion of the left anterior descending artery (LAD). An irreversible injury to myocardial fibers will have occurred when? 1. Cellukar swelling 2. Fat stores are depleted—+ 3. Glycogen stores are depleted Physiology 181 4. Cytoplasmic sodium increases 5. Karyorrhexis 6. Intracellular pH ↓ 7. Blebs form on cell membranes Ans. 1. Cellukar swelling USMLE Case Scenario Ovulation is primarily caused by preovulatory surge of: 1. Estradiol 2. Luteinizing hormone 3. Progesterone 4. Follicle stimulating hormone Ans. 2. Luteinizing hormone USMLE Case Scenario The parvocellular pathway, from the lateral geniculate nucleus to the visual cortex, carries signals for the detection of: 1. Movement, depth and flicker 2. Color vision, shape and fine details 3. Temporal frequency 4. Luminance contrast Ans. 2. Color vision, shape and fine details USMLE Case Scenario A single-breath carbon monoxide diffusion capacity (DLCO) is done in a 33-year-old patient. In this test, the patient is required to inhale low, nontoxic concentrations of carbon monoxide, hold the breath for 10 seconds, and then exhale. This test is rapid, simple, safe and painless. DLCO is an estimate of: 1. Pulmonary capillary surface area 2. Respiratory reserve 3. Elastic recoil 4. Airway resistance Ans. 1. Pulmonary capillary surface area USMLE Case Scenario The supraoptic nucleus of the hypothalamus is believed to control secretion of which of the following hormones? 1. Serotonin 2. Oxytocin 3. Growth hormone 4. Adrenocorticotropic hormone Ans. 2. Oxytocin USMLE Case Scenario Central Chemoreceptors are most sensitive to following changes in blood: 1. ↑ PCO2 2. ↓ PCO2 3. ↑ H+ 4. ↑ PO2 Ans. 1. ↑ PCO2 182 USMLE Step 1 Platinum Notes USMLE Case Scenario The Hyperkinetic features of the Huntington’s disease are due to the loss of: 1. Nigrostriatal dopaminergic system 2. Intrastriatal cholinergic system 3. GABA-ergic and cholinergic system 4. Intrastriatal GABA-ergic and cholinergic system Ans. 3. GABA-ergic and cholinergic system USMLE Case Scenario The Myelin sheath is formed around the nerve fibers in the central nervous system by: 1. Astrocytes 2. Microglia 3. Oligodendrocytes 4. Protoplasmic astrocytes Ans. 3. Oligodendrocytes BIOCHEMISTRY Biochemistry 3 DNA: (HIGH YIELD POINTS FOR USMLE) •• Deoxyribonucleic acid (DNA) is the ‘hereditary material’ of the cell •• Important points about Structure of DNA •• DNA consists of two strands of nucleotides wrapped around each other to form a complex double helix •• The building blocks of each strand are deoxyribonucleotides, which consist of one of four bases—adenine (A), guanine (G), cytosine (C), and thymine (T)—a sugar-deoxyribose, and a covalently joined phosphate group •• The deoxyribose molecules are linked by phosphates to form the backbone of DNA •• The double helix is held together by the hydrogen bonds that form between the bases on the two complementary strands oriented in antiparallel directions •• RNA is similar to DNA except that the deoxyribose sugar of DNA is replaced by a ribose moiety in RNA, and instead of Thymine T, RNA uracil (U) •• ‘Transcription’ results in the production of a precursor messenger RNA (pre-mRNA) that contains both intron and exon sequences •• The ‘introns’ are excised •• Exons are ligated together in a two-stage splicing process that results in a mature mRNA that can be exported from the nucleus and translated to produce the desired protein •• While still in the nucleus, the spliced mRNA undergoes further processing •• The 5’ end of the RNA is capped by a guanosine derivative •• A string of adenylic acid residues (polyA) is added to its 3’end to stabilize the transcript for transit within the cellular environment •• Watson and Crick theory pertains to DNA •• Human genome contains 3 x 109 base pairs •• Histones are proteins present in DNA •• New DNA synthesis occurs in interphase High Yield Points •• Most DNA occurs as ‘Right Handed’ Double Helical called ‘B DNA.’ •• ‘Rare’ ‘Left Handed’ Double Helical called ‘Z DNA’ •• ‘Negative’ super coiling occurs if DNA is wound loosely •• ‘Positive’ super coiling occurs if DNA is wound Tightly •• Topoisomerases are enzymes that change amount of supercoiling in DNA molecules •• DNA Topoisomerase II can induce negative supercoiling or Remove Positive super coils •• DNA Topoisomerase I can relax supercoiling Heterochromatin Euchromatin •• Highly condensed •• Inactive •• Loosely condensed •• Active 186 USMLE Step 1 Platinum Notes •• Prokaryotes have single origin of Replication •• Eukaryotes have multiple origin of Replication Remember New synthesized strand is made in 5’ → 3’ direction Template is scanned in 3’ → 5’direction New synthesized strand is complimentary and antiparallel Daunorubicin and Doxorubicin exert their effect by intercalating between bases of DNA and thereby interfering with activity of Topoisomerase II •• Cisplatin on the other hand binds tightly to DNA causing structural Distortion •• •• •• •• Important Points about DNA and RNA (Repeated in USMLE Frequently) DNA repair: Single strand DNA/RNA/ protein synthesis direction Types of RNA Polymerases: RNA •• •• •• •• •• •• •• •• •• •• •• Start and Stop codons •• •• ‘Promoter’ ‘Enhancer’ •• •• •• Single strand, excision-repair-specific glycosylase recognizes and removes damaged base Endonuclease makes a break several bases to the 5’ side Exonuclease removes short stretch of nucleotides. DNA polymerase fills gap DNA ligase seals DNA and RNA are both synthesized in 5’→3’ direction Protein synthesis also proceeds in the 5’→ 3’ direction mRNA is largest type of RNA rRNA is the most abundant type of RNA tRNA is the smallest type of RNA Eukaryotes: –– RNA polymerase I make rRNA –– RNA polymerase II makes mRNA –– RNA polymerase III makes t RNA –– No proofreading function. RNA polymerase II opens DNA at promoter site (A-T-rich upstream sequenceTATA and CAAT) –– α-amanitin inhibits RNA polymerase II Prokaryotes: –– RNA polymerase makes all three kinds of RNA AUG (or rarely GUG) is the initiation codon AUG codes for methionine, which may be removed before translation is completed. In prokaryotes the initial AUG codes for a formyl-methionine (f-met) Stop codons: UGA, UAA, UAG Site where RNA polymerase and multiple other transcription factors bind to DNA upstream from gene locus Stretch of DNA that alters gene expression by binding transcription factors. May be close to, far from, or even within (in an intron) the gene whose expression it regulates Transcription and translation Biochemistry 187 Functions of Different Types of DNA Polymerases In Eukaryotes •• DNA Polymerase δ synthesizes leading strand •• DNA Polymerase α synthesizes lagging strand •• DNA Polymerase γ replicates mitochondrial DNA •• DNA Polymerase β, DNA polymerase ε participate in DNA Repair Functions of Different Enzymes (Remember Thoroughly) Site Prokaryotic Eukaryotic Recognition of origin of replication •• DNA A Protein Unwinding of DNA Helix •• Helicase •• Helicase Stabilization of unwound Template strand •• Single stranded binding protein (SSB) •• Single stranded binding protein (SSB) Synthesis of RNA Primers •• Primase •• Primase Synthesis of DNA Leading strand+ Proof reading Lagging strand •• DNA Polymerase III •• DNA Polymerase δ •• DNA Polymerase III •• DNA Polymerase α Removal of RNA Primers •• DNA Polymerase I Joining of Okazaki Fragments •• DNA ligase •• DNA ligase Removal of Positive super coils •• DNA Topoisomerase II •• (DNA gyrase) •• DNA Topoisomerase II RNA Polymerase •• In bacteria RNA polymerase synthesizes almost all of the RNA •• RNA polymerase is a multi subunit enzyme •• One component of RNA polymerase is the sigma subunit ‘which enables RNA Polymerase to recognize promoter regions on the DNA’ •• Other component is ‘the rho factor or termination factor’ which enables RNA Polymerase to recognize termination regions on the DNA Mitochondrial DNA: (Cases asked in USMLE) •• Thirteen out of 100 polypeptides required for oxidative phosphorylation are coded by mitochondrial DNA •• Defects in oxidative phosphorylation are most likely as a result of alterations in mitochondrial DNA as it has a mutation rate about ten times greater than nuclear DNA •• This is because there are no introns and a mutation invaribly strikes a coding sequence (axon) •• Tissues with greatest ATP requirement (CNS, Skeletal muscle, Heart muscle, Kidney, Liver) are most affected •• Mitochondrial DNA is maternally inherited because mitochondria from sperms do not enter the fertilized egg •• Mitochondrial DNA is closed and circular and 16.5 kb in length •• MELAS (Mitochondrial Encephalopathy, Lactic Acidosis and Stroke like episodes) are attributed to mitochondrial mutations. Other diseases associated with mitochondrial DNA are: –– Lebers Hereditary Optic Neuropathy –– MELAS (Mitochondrial encephalopathy with lactic acidosis and stroke like episodes) –– Myopathy 188 USMLE Step 1 Platinum Notes –– MERRF Syndrome: (Myoclonic epilepsy and ragged red fibers.) –– Cardiomyopathy –– Strokes –– Lactic acidosis –– External Ophthalmoplegia –– Optic atrophy –– NARP (Neuropathy, ataxia and retinitis pigmentosa) –– Pearsons syndrome –– Sensorineural deafness –– Diabetes mellitus Hereditary DNA Repair Disorders •• Xeroderma pigmentosum: Hypersensitivity to sunlight/UV, resulting in increased skin cancer Incidence and premature aging •• Cockayne syndrome: Hypersensitivity to UV and chemical agents •• Trichothiodystrophy: Sensitive skin, brittle hair and nails •• Werner’s syndrome: Premature aging and retarded growth •• Bloom’s syndrome: Sunlight hypersensitivity, high incidence of malignancies (Especially leukemias) •• Ataxia telangiectasia: Sensitivity to ionizing radiation and some chemical agents All of the above diseases are often called ‘segmental progerias’ (‘accelerated aging diseases’) because their victims appear elderly and suffer from aging-related diseases at an abnormally young age Other diseases associated with reduced DNA repair function include •• Fanconi’s anemia •• Hereditary breast cancer and •• Hereditary colon cancer Xeroderma pigmentosa: (Repeated in USMLE) •• •• •• •• •• •• Extreme UV sensitivity Exposure of cell to UV light can result in the covalent joining of two adjacent pyrimidines (Usually Thymines) producing a dimer These Thymine dimmers prevent DNA polymerase from replicating the DNA strands Pyrimidine dimmers can be formed in the skin cells of humans exposed to ‘unfiltered sunlight’ In Xeroderma Pigmentosa, ‘the cells cannot repair the damaged DNA’, resulting in accumulation of mutations and skin cancers The most common form is produced by absence of enzyme UV specific Exonuclease/Endonuclease’ –– Excessive freckling –– Multiple skin cancers –– Corneal ulcers Biochemistry 189 Transposons •• Are pieces of DNA that move readily from the one site to another either within or between the DNA’s of bacteria, plasmids and bacteriophages •• They are also known as ‘Jumping Genes’ •• They can code for drug resistance, enzyme, toxin or a variety of metabolic enzymes •• They can either cause mutation in the gene into which they insert or alter the expression of nearby genes •• In contrast to plasmids or bacterial viruses, transposons are not capable of independent replication •• They replicate as a part of recipient DNA Prions Prions are proteins which are normally found in the body. Prions become infectious or pathogenic due to misfolding of the proteins •• Prions are normally present in human. The prion protein, endogenous to the human is PrP (which is a glycoprotein rich in b sheets) •• PrPsc is the infectious form of the Prion. (It is formed due to mutation in PrP) •• The key to become infectious lies in changes in three dimensional conformation of PrP, i.e. there is abnormality in protein folding (the a helical secondary structure of PrP changes to b sheets in PrPsc) •• So, PrPsc is a misfolded PrP and this conformational difference cause PrPsc to resist proteolytic degradation •• Misfolded proteins are quite dangerous for the body because they possess a remarkable property that they can cause other normally folded prions to distort into the same misfolded state. Thus, misfolded proteins, i.e. prions are able to replicate and spread throughout tissue without using either DNA or RNA •• The infective agent is thus an altered version of a normal protein which acts as a template for converting more normal protein to the pathogenic conformation Enzymology •• •• •• •• Enzymes do not alter Energy of Reaction Enzymes lower Energy of Activation Vmax = Maximum velocity with specified amount of enzyme Km = Concentration of substrate required to produce half V max ‘Competitive’ Inhibition •• It is reversible •• Substrate and inhibitor resemble each other •• V max is same, Km is increased •• Substrate affinity to enzyme is lowered ‘Noncompetitive’ Inhibition •• •• •• •• It is reversible or irreversible Substrate and inhibitor do not resemble each other V max is decreased, Km is unaltered Substrate affinity to enzyme is not lowered ‘Allosteric’ Inhibition •• Here inhibitor binds to enzyme at a site different than active site 190 USMLE Step 1 Platinum Notes •• Does not follow Michaelis Menten Kinetics •• Follows sigmoid kinetics •• Km is raised but V max is unchanged in some allosteric inhibition reactions •• Substances that reduce the activity of an enzyme are called inhibitors •• Reversible inhibitors bind to an enzyme but rapidly dissociate from it in contrast to irreversible inhibitors which bind tightly and dissociate very slowly from the enzyme There are several types of reversible inhibitors: •• Competitive inhibitors usually resemble the substrate and compete with it for binding at the active site Thus, increasing the concentration of substrate will decrease the percent inhibition of the enzyme. The Vmax is unchanged, but the Km is increased •• A noncompetitive inhibitor binds with equal affinity to both enzyme and enzyme-substrate complex This binding leads to a distortion of the substrate binding site, so new substrate cannot bind and/or the product cannot be released. In this kind of inhibition, the Vmax is decreased but the Km is not altered •• An uncompetitive inhibitor does not bind to free enzyme, but binds to the enzyme-substrate complex at a site other than the catalytic site. Once bound by the inhibitor, the enzyme is trapped in the enzyme-substrate complex state until the inhibitor dissociates. In this kind of inhibition, the slope of the reaction (which is the ratio Km/Vmax) remains the same, but both Vmax and Km are reduced. Remember •• Michaelis Menten (Km) reflects the affinity of enzymes to that substrate •• It is equal to the substrate concentration at which reaction velocity is half of V max •• Low Km reflects high affinity of enzyme •• High Km reflects low affinity of enzyme Metabolic Processes and their Sites Processes occurring in cytosol: •• Glycolysis •• Glycogenolysis •• Glycogenesis •• HMP Shunt (Pentose phosphate synthesis) •• Fatty acid synthesis •• Bile acid synthesis •• Cholesterol synthesis Processes occurring in Mitochondria: •• Fatty acid oxidation(Beta) •• Electron transport chain •• Krebs/TCA Cycle •• Oxidative phosphorylation Processes occurring in both mitochondria and cytosol: •• Urea synthesis •• Gluconeogenesis Biochemistry 191 Sites of metabolic processes Sites of •• Protein synthesis: RER •• Steroid synthesis: Smooth ER •• Sorting of Proteins: Golgi bodies (Dictyosome) Medically Important Enzymes Frequently asked Reverse Transcriptase: •• It is an RNA dependent DNA polymerase that requires an RNA Template to direct the synthesis of new DNA •• AZT, ddC, ddI (Antiretrovirals) act on reverse transcriptase Restriction Endonucleases: •• Are Bacterial enzymes that cleave double stranded DNA into smaller fragments •• Each enzyme cleaves DNA at a specific 4–6 base long nucleotide sequence producing DNA segments called ‘restriction fragments’ •• These enzymes form either sticky ends or blunt ends on the DNA •• The DNA sequence recognized by a restriction enzyme is called a restriction site Telomerase •• Is an enzyme that completes replication of Telomers •• Telomeres are repetitive sequences at ends of DNA 192 USMLE Step 1 Platinum Notes •• Telomerase is present in embryonic cells, stem cells and cancer cells •• DNA polymerase is unable to replicate the end of a DNA chain completely, resulting in loss of DNA with each replication. This problem has been solved by a mechanism that replicates tandem repeats of a six-nucleotide sequence (GGGTTA) to the ends of each chromosome. These repeated sequences are called telomeres and are replicated through an RNA-dependent DNA polymerase called telomerase •• Normal somatic cells do not express telomerase, and the replicative lifetime of such cells is limited to approximately 30 cell divisions due to the progressive loss of telomere repeats; the limit imposed on somatic cell division is called the Hayflick limit, at which time replicative senescence occurs Germ cells express telomerase and have a long (possibly unlimited) replicative lifetime •• Cancer cells express telomerase and in cancer cells is thought to be a component of the neoplastic process, assuring that the cell will be able to undergo many divisions without inducing senescence or genetic catastrophe. Inhibition of telomerase activity in cancer cells could have antitumor effects •• Human pluripotential stem cells express high levels of telomerase, an enzyme that is essential for allowing repeated replication of the ends of eukaryotic chromosomes •• The capacity to divide indefinitely is provided by activation of telomerase, which allows continued replication of chromosomes by addressing the unique need of chromosome ends to be continually renewed to a proper length to allow normal mitosis •• The capacity to invade and metastasize is conveyed by elaboration of matrix metalloproteases and plasminogen activators and the capacity to recruit host stromal cells at the site of invasion through tumor-induced angiogenesis. Classification of Enzymes Class 1 Oxidoreductases: Transfer of hydrogen or addition of oxygen; e.g. Lactate dehydrogenase (NAD); Glucose-6-phosphate dehydrogenase (NADP); Succinate dehydrogenase (FAD); di-oxygenases Class 2 Transferases: Transfer of groups other than hydrogen Example, Aminotransferase. (Subclass: Kinase, transfer of phosphoryl group from ATP, e.g. Hexokinase) Class 3 Hydrolases: Cleave bond and add water, e.g. Acetyl choline esterase; Trypsin Class 4 Lyases: Cleave without adding water, e.g. Aldolase; HMG CoA lyase; ATP Citrate lyase. (Subclass: Hydratase; add water to a double bond) Class 5 Isomerases: Intramolecular transfers. They include racemases and epimerases. Examples, Triose phosphate isomerase Class 6 Ligases: ATP dependent condensation of two molecules, e.g. Acetyl CoA carboxylase; Glutamine synthetase; PRPP synthetase USMLE Case Scenario The lack of chromosomal shortening allows the malignant cells to undergo many more divisions than the normal cells. Which of the following enzymes is most likely to have this effect? 1. Reverse transcriptase 2. DNA polymerase 3. Isomerase 4. Phosphodiesterase 5. Telomerase 6. Protein kinase 7. Topoisomerase Ans. 5. Telomerase Mutations •• Transistion: A point mutation that replaces purine-pyrimidine base pair with different purine-pyrimidine base pair •• Transversion: A point mutation that replaces purine-pyrimidine base pair with different pyrimidine-purine base pair Biochemistry Mutation 193 Effect on Protein Silent New codon specifies ‘same’ amino acid None Missense New codon specifies ‘new’ amino acid Decrease in function Non sense New codon is ‘Stop’ codon Usually non functional Frameshift Deletion/addition of base Usually non functional USMLE Case Scenario A 2-month-old, breastfed baby that was normal at birth begins to develop GI problems and cirrhosis of the liver. Molecular analysis indicates a normal amount of galactose-1-phosphate uridyl transferase (GALT) mRNA, but no observable enzyme activity. Which of the following would be the best possible explanation for this? 1. Gene deletion 2. Nonsense mutation 3. Premature transcription termination sequence in the DNA 4. Promoter mutation 5. RNA splicing mutation Ans. 2. Nonsense mutation It is a mutation in the DNA that leads to a premature stop codon when the mRNA is being translated into protein. The mRNA would be transcribed correctly, but when the protein was being translated, it would be stopped prematurely, leading to a truncated protein. Collagen •• •• •• •• •• •• •• •• •• Collagen formation begins with transcription of mRNA from appropriate DNA genes in the nucleus. While still within the nucleus, the mRNA is spliced It is then transported through the cytoplasm to the ribosomes on the rough endoplasmic reticulum Individual chains are translated on the ribosomes, with the ends feeding into the endoplasmic reticulum lumen. Within the lumen, glycosylation of the individual chains occurs The material then moves toward the Golgi bodies (whose lumens are connected to the endoplasmic reticulum) where the triple helices of procollagen form The procollagen is then secreted into the extracellular space, where cleavage of pro-peptides and cross- linking of different triplehelices occurs, maturing the collagen The extracellular space is the site of procollagen cleavage and cross- linking The nucleus is the site of mRNA transcription and splicing The rough endoplasmic reticulum is the site of chain translation and glycosylation Disorders of Collagen Synthesis Scurvy •• Deficient hydroxylation secondary to Ascorbate deficiency Osteogenesis imperfecta •• Mutations in collagen genes Ehler Danhlos syndrome •• Mutations in collagen genes, Lysine and Hydroxylase genes Menkes disease •• Deficent cross linking secondary to Cu deficiency Scurvy [ USMLE CASE ] •• A 72-year-old retired engineer alcoholic male who lives alone is admitted to the hospital for evaluation of wounds on limbs that are not healing well –– On physical examination, multiple ecchymoses are noted on the posterior aspect of his thighs and front of arm. Careful examination of his skin reveals minute hemorrhages around hair follicles and splinter hemorrhages in the nail beds. Laboratory examination is remarkable for hemoglobin of 9 (normal 14—18 g/dL); no other hematologic abnormalities are noted. He is most probably suffering from ‘Scurvy’. 194 USMLE Step 1 Platinum Notes USMLE High Yield Points •• Vitamin C deficiency causes scurvy •• Seen primarily among poor and elderly people and alcoholics who consume <10 mg/d of vitamin C. Symptoms of scurvy primarily reflect impaired formation of mature connective tissue and include bleeding into skin (petechiae, ecchymoses, perifollicular hemorrhages); •• Absence of vitamin C leads to impaired hydroxylation of proline residues in the nascent procollagen chains, leading to weakness of blood vessel walls Clinical Features: •• It is characterized by perifollicular hemorrhages, fragmentation of hairs, purpura, ecchymoses •• Splinter hemorrhages, and hemorrhages into muscle. In patients with normal dentition, gum changes •• (Swelling, bleeding, loosening of teeth) are also noted •• Without supplementation with vitamin C •• Death may eventually occur •• Other generalized symptoms include weakness, fatigue, and depression •• In children, vitamin C deficiency may cause impaired bone growth •• Laboratory diagnosis of vitamin C deficiency is made on the basis of low plasma or leukocyte levels •• Administration of vitamin C (200 mg/d) results in marked improvement in the symptoms of scurvy in a matter of several days Osteogenesis Imperfecta (OI): (USMLE Case Scenario) A 5-month-old infant has fracture clavicle, fracture left radius, fracture right clavicle. Fractures are in different stages of healing. X-ray reveals thin bones with thin cortices. There is no evidence of child abuse The child has most likely: Osteogenesis imperfect. USMLE High Yield Points •• •• •• •• •• OI is also called as Brittle bone disease or ‘Lobstein syndrome’ Basic defect is in Collagen Type 1 It is transmitted either as AD or AR Inheritance Type 1 OI is THE MOST COMMON TYPE OI is inherited as autosomal dominant trait mostly – – ‘Blue sclera’ is present in several types of OI But not all Grey sclera is a feature as well. Other ocular features of OI are: - Saturn ring, Arcus juvenilis, Hypermetropia and Retinal Detachment are seen - The sclera is normal in some types of OI •• Feature of OI is generalized osteopenia with recurrent fractures and skeletal deformity. Fracture healing however is normal. Fracture in utero may be seen. Laxity of joint ligaments leads to hypermobility •• Some people have associated ’dentogenesis imperfecta’: small fragile and discolored teeth •• Dermis may be abnormally thin and skin is susceptible to easy bruising – Hearing loss due to involvement of inner and middle ear bones may produce deafness – Wormian bones are a feature – ‘Pop corn calcification’ and ‘whorls of radiodensities’ are a radiographic feature •• Treatment is largely supportive Biochemistry 195 Ehler Danlos Syndrome •• Defect in normal synthesis and processing of collagen •• Thin skin with easy bruising •• Arterial intestinal or uterine rupture can occur Menkes Disease: USMLE HighYield Points •• Menkes disease also known as kinky hair disease, is an X-linked neurodegenerative disease of impaired copper transport •• Named after noting the similarity of kinky hair to the brittle wool of Australian sheep raised in areas with copper-deficient soil, he demonstrated abnormal levels of copper and ceruloplasmin in these patients •• In Menkes disease, transport of dietary copper from intestinal cells is impaired, leading to the low serum copper levels. Abnormal copper transport in other cells leads to paradoxical copper accumulation in duodenal cells, kidney, pancreas, skeletal muscle, and placenta. •• Hair changes: Abnormal kinky hair, eyebrows, and eyelashes. Often lightly or abnormally pigmented; can be white, silver, or gray •• Associated are abnormal facies, Progressive cerebral degeneration and connective-tissue abnormalities. Loose skin at the nape of the neck and over the trunk •• Joint hyper mobility, Polypoid masses, which can be multiple, in the gastrointestinal tract, umbilical and inguinal hernias, which can be bilateral, Bladder diverticula, Dilated ureters, Emphysema, Arterial rupture Brachial, lumbar, and iliac artery aneurysms, Internal jugular vein aneurysms. •• Menkes’ Kinky hair syndrome is associated with the defecive functioning of several copper-dependent enzymes due to impaired copper absorption, transport, or metabolism. Lysyl oxidase is a copper-requiring enzyme that catalyzes the oxidative deamination of lysyl residues linking two adjacent chains of tropoelastin polypeptides into an insoluble network. •• Decreased lysyl oxidase (LO) activity accounts for the connective-tissue fragility and vascular abnormalities in Menkes disease Vitamins Important Vitamin Deficiencies: (Repeated in USMLE) Vitamin Enzyme Deficiency State Thiamine (B1) •• Pyruvate dehydrogenase •• α Ketoglutarate dehydrogenase •• Transketolase •• Wernicke Korsakoff Syndrome •• Wet Beriberi •• Dry Beriberi Biotin •• Pyruvate carboxylase •• Acetyl CoA carboxylase •• Propionyl CoA carboxylase •• Consumption of eggs containing avidin •• Alopecia, Muscle pains Pyridoxine •• Aminotransferases •• •• •• •• Riboflavin •• Dehydrogenases •• Corneal neovascularization •• Chielosis/stomatitis •• Magenta tongue Niacin •• Dehydrogenases •• Pellagra •• Diarrhea, Dementia, Dermatitis, Death Pantothenic •• Fatty acid Synthase •• Fatty acyl CoA synthase •• Rare •• Burning foot syndrome Isoniazid therapy Sidderoblastic anemia Chielosis/stomatitis Convulsions 196 USMLE Step 1 Platinum Notes Folic Acid •• Thymidylate synthase •• •• •• •• Alcholics and pregnancy Homocystenemia Macrocytic anemia Neural tube defects Vitamin B12 Extrinsic factor of castle •• Homocysteine methyltransferase •• Methyl malonyl CoA mutase •• •• •• •• •• Pernicious anemia Megaloblastic anemia Neuropathy SACD Methyl malonic aciduria Vitamin C post translation modifier •• Propyl and Lysyl hydroxylase •• Dopamine hydroxylase •• Diet deficient in citrus •• Scurvy Fat Soluble Vitamins Vitamin A (acts as hormone) •• Night blindness •• Xerophthalmia •• Follicular Hyperkeratosis Vitamin D •• Rickets •• Osteomalacia Vitamin E Prevents lipid peroxidation •• Hemolysis •• Retinitis pigmentosa •• Neurological problems Vitamin K (Gamma carboxylation) Post translation modifier •• Bleeding tendency with ↑PT normal BT •• Deficiency of vitamin K produces a clotting disorder characterized by an elevated prothrombin time and easy bleeding, particularly in neonates (hemorrhagic disease of the newborn). The biochemical basis for this hemorrhagic tendency is that glutamate residues on Factors II (Thrombin), VII, IX, and X must be converted to gamma-carboxyglutamate residues (in a vitamin K-requiring reaction) for optimal activity. Synthesis of vitamin D Vitamin K Deficiency The symptoms of vitamin K deficiency are due to hemorrhage, and newborns are particularly susceptible because of low fat stores, low breast milk levels of vitamin K, sterility of the infantile intestinal tract, liver immaturity, and poor placental transport. Intracranial bleeding, as well as gastrointestinal and skin bleeding, can occur in vitamin K–deficient infants 1–7 days after birth. Thus, vitamin K (1 mg IM) is given prophylactically at the time of delivery. Biochemistry 197 USMLE Clinical Scenario A child has cystic fibrosis. His parents report a history of recurrent respiratory tract infections and bulky, foul-smelling stools. After assessment of his respiratory tract illness, the practitioner should also look for signs of which vitamin deficiency. Fat soluble vitamin deficiency (A, D, E, K) Remember: Conversions: Vitamins are required for •• •• •• •• The conversion of homocysteine to methionine requires vitamin B12 Conversion of methylmalonyl CoA to succinyl CoA requires vitamin B12 Degradation of cystathionine requires vitamin B6 Hydroxylation of proline requires vitamin C •• Vitamin A is necessary for formation of retinal pigments (deficiency can cause night blindness) and for appropriate differentiation of epithelial tissues (including hair follicles, mucous membranes, skin, bone, and adrenal cortex) •• Vitamin C is necessary for collagen synthesis •• Vitamin D is important in calcium absorption and metabolism •• Vitamin E is important in the stabilization of cell membranes •• Vitamin K is necessary for normal blood coagulation Hypervitaminosis (A): USMLE Favorite Acute toxicity It is manifest by increased intracranial pressure, vertigo, diplopia, bulging fontanels in children, seizures, and exfoliative dermatitis; it may result in death Chronic vitamin A intoxication has Manifestations Include: •• Dry skin, cheilosis, glossitis, vomiting, alopecia, bone pain, hypercalcemia, lymph node enlargement, hyperlipidemia, amenorrhea, and features of: –– Pseudotumor cerebri with increased intracranial pressure and papilledema –– Congenital malformations, spontaneous abortions, craniofacial abnormalities, and valvular heart disease USMLE Clinical Scenario A chronic alcoholic develops severe memory loss with marked confabulation. Deficiency of which of the vitamins would be most likely to contribute to the neurologic damage? Wernicke-Korsakoff syndrome refers to the constellation of neurologic symptoms caused by thiamine deficiency A severe memory deficit, which the patient may attempt to cover by making up bizarre explanations (confabulation), is prominent Anatomical damage to the mamillary bodies and periventricular structures has been postulated as the cause In the US severe thiamine deficiency is seen most commonly in chronic alcoholics Thiamine deficiency can also damage peripheral nerves (‘dry’ beriberi) and the heart (‘wet’ beriberi). High Yield Facts •• •• •• •• Folic acid deficiency produces megaloblastic anemia without neurologic symptoms Niacin deficiency produces pellagra, characterized by depigmenting, dermatitis, chronic diarrhea, and death Riboflavin deficiency produces ariboflavinosis, characterized by glossitis, corneal opacities, dermatitis, and erythroid hyperplasia Vitamin B12 deficiency produces megaloblastic anemia accompanied by degeneration of the posterolateral spinal cord 198 USMLE Step 1 Platinum Notes ‘Substance Accumulation in Different Diseases’ •• Accumulation of galactocerebrocide occurs in Krabbe disease, which is due to galactocerebrocide deficiency •• Accumulation of glucocerebroside occurs in Gaucher disease, which is due to defects in β-glucocerebrosidase. The reticuloendothelial cells and CNS are affected •• Accumulation of GM2 ganglioside occurs in Tay •• Sachs disease because of hexosaminidase deficiency. The swollen ganglion cells of the retina contribute to a classic sign of TaySachs—the macular cherry-red spot •• Accumulation of sphingomyelin in a variety of organs occurs in Niemann-Pick disease, which is due to a defect in sphingomyelinase •• Accumulation of sulfatide occurs in Metachromatic leukodystrophy, caused by aryl sulfatase A deficiency USMLE Case Scenario A 3-year-old retarded child is seen by a specialist. The child’s history is significant for failure to thrive and progressive neurologic deterioration, including deafness and blindness. Physical examination is remarkable for hepatosplenomegaly, as well as a cherry-red spot on funduscopic examination. These symptoms are consistent with a diagnosis of: Tay-sachs Disease Lysosomal Storage Disease Fabry’s Disease Lysosomal Storage Disease X-Linked Recessive Angiokeratomas (skin lesions) over lower Alpha-Galactosidase A deficiency–build up of trunk, fever, severe burning pain in extremities, cardiovascular and cerebrovascular involvement. ceramide trihexoside in body tissues Hunter’s Syndrome Lysosomal Storage Disease X-Linked Recessive. L-iduronosulfate sulfatase Similar to but less severe than Hurler Syndeficiency–build up of mucopolysaccharides drome. No corneal clouding. Hepatospleno(heparan sulfate and dermatan sulfate) megaly, micrognathia, retinal degeneration, joint stiffness, mild retardation, cardiac lesions Hurler’s Syndrome Lysosomal Storage Disease Autosomal Recessive. -L-iduronidase deficiency - ‘Gargoyle-like facies’, progressive mental accumulation of mucopolysaccharides (heparan deterioration, stubby fingers, death by age 10. sulfate, dermatan sulfate) in heart, brain, liver, Similar to Hunter’s Syndrome other organs MPS IV (Morquio Syndrome) Characterized by severe skeletal diseases that resemble the spondyloepiphyseal dysplasias There is extreme shortening of the trunk due to multiple vertebral collapses The long bones are relatively spared Joint laxity can lead to osteoarthritis-like destruction of the joints Upper cervical spinal cord compression due to atlanto axial instability predisposes to subluxation and paralysis Many patients have mitral valve insufficiency that can be functionally significant I Cell Disease USMLE Case Scenario A Child with large tongue, coarse facial features and club foot is seen by a pediatrician. You hear the doctor talking to his colleague that the child has a problem with Phosphorylation of their mannose residues. The most likely possibility is a disease called I-cell disease. Biochemistry 199 It is an inborn error that led to the discovery of how enzymes are imprinted to reside in lysosomes. Patients with I-cell disease have inherited defects in the recognition markers required to direct enzymes to the endocytic receptor of plasma membrane and to its capture in the acidic milieu of the lysosome. Patients lack all cellular lysosomal enzymes. Instead cells are filled with inclusion bodies (hence ‘I-cell’). The misdirected lysosomal enzymes are secreted and are present in excess in plasma but are missing from cells. These extracellular enzymes were found to lack mannose 6-phosphate residues and lead to importance of the post-translational mechanisms by which enzymes are directed to the lysosome by adding phosphorylated mannose. Individuals with I-cell disease lack this phosphotransferase activity. •• Lysosomal enzymes are glycosylated and modified •• In the Golgi complex specific mannose residues are phosphorylated •• This phosphorylation directs them towards lysosomes. In absence of Phosphorylation of their mannose residues, these enzymes are (not directed to lysosomes) but to extracellular space and inclusions accumulate in cell •• Specifically, the Golgi apparatus incells of these patients has an abnormal N-acetyl-glucosaminotransferase (N-acetylglucosamine1-phosphotransferase), and is not able to add the necessary recognition marker mannose phosphate to enzymes usually destined to enter lysosomes. A complete deficiency of this enzyme (type I form of I cell disease) causes death early in life; partial deficiencies (Type III form) produce milder disease (pseudo-Hurler syndrome) with survival to adulthood Features: •• Coarse facial features •• Macroglossia, Gingival hyperplasia •• Club foot, club hand •• Cardiorespiratory failure USMLE Case Scenario A child with coarse facies, corneal clouding, joint stiffness and mental retardation is found to have a partial defect in N-acetylglucosaminotransferase. Damage to this enzyme directly affects which of the following biochemical functions? Targeting of enzymes for lysosomes: N-acetylglucosamine-1-phosphotransferase to add the recognition marker mannose phosphate to enzymes destined to enter lysosomes. Consequently, there is a generalized defect in lysosome function. Glycolysis •• Glycolysis is conversion of glucose to pyruvate under aerobic condition •• Glycolysis is conversion of glucose to lactate under anerobic condition •• Mature RBC do not contain enzymes of TCA cycle •• Glycolysis occurs in cytosol •• Cancer cells derive energy by glycolysis •• Sodium fluoride is used as an anticoagulant for estimating blood glucose to prevent glycolysis •• Flouride inhibits enolase •• Glycolysis is regulated at three steps involving irreversible reactions catalysed by enzymes namely –– Hexokinase –– Phosphofructokinase –– Pyruvate kinase Citric Acid Cycle Also called Krebs cycle First substrate is pyruvate 200 USMLE Step 1 Platinum Notes ATP is produced in steps catalyzed by: –– Isocitrate dehydrogenase –– Succinate dehydrogenase –– Succinate thiokinase –– Malate dehydrogenase Pyruvate dehydrogenase contains: •• Decarboxylase •• Transacetylase •• Dehydrogenase Substrate level phosphorylation occurs in reaction catalyzed by: Succinyl Co A thiokinase Glycogen Synthesis •• Insulin is produced in the beta cells of the pancreatic islets •• It is initially synthesized as a single-chain 86-amino-acid precursor polypeptide, ‘preproinsulin.’ •• The mature insulin molecule and C peptide are stored together and cosecreted from secretory granules in the beta cells •• Human insulin is now produced by recombinant DNA technology •• Glucose is the key regulator of insulin secretion by the pancreatic beta cell, although amino acids, ketones, various nutrients, gastrointestinal peptides, and neurotransmitters also influence insulin secretion •• Glucose stimulates insulin secretion through a series of regulatory steps that begin with transport into the beta cell by the GLUT2 glucose transporter •• Glucose phosphorylation by glucokinase is the rate-limiting step that controls glucose-regulated insulin secretion •• Insulin binding to the receptor stimulates intrinsic tyrosine kinase activity, leading to receptor autophosphorylation •• In the fasting state, low insulin levels promote hepatic gluconeogenesis and glycogenolysis to prevent hypoglycemia •• Low insulin levels decrease glycogen synthesis, reduce glucose uptake in insulin-sensitive tissues, and promote mobilization of stored precursors •• Reduced insulin levels are also permissive in allowing glucagon to stimulate glycogenolysis and gluconeogenesis by the liver and renal medulla •• These processes are of critical importance to ensure an adequate glucose supply for the brain REGULATION Glycogen Synthesis (Glycogen synthetase) Activated by •• Insulin •• Glucose Inhibited by •• Glucagon •• Epinephrine Glycogen Breakdown (Glycogen Phosphorylase) Activated by •• Glucagon •• Epinephrine Inhibited by •• Insulin •• Glucose Biochemistry 201 Gluconeogenesis •• •• •• •• Occurs from glycerol, alanine, lactate Major contributor is alanine Gluconeogenic capability is determined by fructose 1, 6 biphosphate Enzyme common to gluconeogenesis and glycolysis is phosphofructokinase Enzymes Controlling •• •• •• •• Fructose 1,6 Biphosphate Pyruvate carboxylase Phosphoenol pyruvate carboxykinase Glucose 6 phosphatase Well Fed State ↑Ingestion of glucose.→↑blood glucose→↑insulin release→↑phosphatase activity→↑fructose 2,6 biphosphatase Fasting State ↓Ingestion of glucose.→↓blood glucose→↑glucagon release→↑cAMP→↑Protein kinase →↓fructose 2,6 biphosphatase Remember: High Yield Points about Important Enzymes •• The Three irreversible steps of glycolysis are catalyzed by hexokinase,phosphofructokinase-1 and pyruvate kinase •• Fructose-1,6-bisphosphatase is the enzyme that splits fructose-1,6-bisphosphate into fructose-6-phosphate and inorganic phosphate. It is required for gluconeogenesis •• Glucose-6-phosphatase is a liver enzyme that hydrolyzes glucose-6-phosphate to glucose. A deficiency of this enzyme leads to von Gierke disease, also known as glycogen storage •• Pyruvate dehydrogenase is a mitochondrial enzyme that converts pyruvate to acetyl CoA. This enzyme requires thiamine pyrophosphate, lipoamide, and FAD as cofactors •• Glucokinase is a liver enzyme that converts glucose to glucose-6-phosphate. Unlike hexokinase, it is specific for glucose and is unresponsive to the level of glucose-6-phosphate. Its function is to store excess glucose so it has a very high Km (i.e. a low affinity) for glucose, becoming active only when the concentration of glucose is very high. 202 USMLE Step 1 Platinum Notes •• Pyruvate kinase catalyzes the conversion of phosphoenol pyruvate to pyruvate in the glycolytic pathway. It is activated by fructose-1, 6-biphosphate, the product of the committed step of glycolysis, and is allosterically inhibited by ATP, alanine, and acetyl CoA •• Glycogen synthase is involved in the synthesis of glycogen. Glucagon (and epinephrine) stimulates the phosphorylation and inactivation of glycogen synthase •• Pyruvate kinase catalyzes the last reaction of glycolysis. It is inhibited by glucagon (thus decreasing the amount of glucose consumption). Glucagon promotes the phosphorylation of pyruvate kinase, which renders it inactive. Glucose 6 Phosphate Dehydrogenase Deficiency A child who develops hemoglobinuria following a meal of beans •• •• •• •• •• It is X linked Recessive Most common enzyme deficiency Causes episodic hemolytic anemia because of decreased ability of RBC’S to withstand oxidative stress G6PD is the first and rate limiting step of HMP shunt responsible for NADPH production NADPH is the cofactor for production for glutathione reductase forming reduced glutathione which is a potent antioxidant •• In its absence H2O2 accumulates in RBC causing cell membrane damage leading to hemolysis. •• Pallor, Hemoglobinuria, Jaundice, Heinz bodies, Bite Cells are seen. •• Oxidized hemoglobin denatures and precipitates in the form of Heinz bodies. Pyruvate Kinase Deficiency Pyruvate kinase is a glycolytic enzyme; pyruvate kinase deficiency is an autosomal recessive disorder, affecting males and females approximately equally. If this enzyme is deficient, red cells have trouble producing enough ATP to maintain the Na+/K+ pump on the plasma membrane, secondarily causing swelling and lysis. HMP Shunt •• Present in cytoplasm and also known as Pentose phosphate pathway •• No ATP is directly produced or consumed in this cycle •• Particularly important in liver and mammary glands Biochemistry 203 •• Generates –– NADPH –– Ribose 5 P for Nucleotide synthesis –– Xylulose 5 phosphate –– 6 Phosphogluconolactone –– Glyceraldehydes 3 phosphate –– Seodoheptulose 7 phosphate NADPH is used for •• •• •• •• •• •• Fatty acid synthesis Steroid synthesis Drug metabolism Glutathione reduction Generation of superoxide in phagocytes by NADPH oxidase Uronic acid pathway ATP Yield •• •• •• •• •• •• Anaerobic glycolysis: 2 ATP per glucose molecule Aerobic glycolysis: 8 ATP per glucose molecule Krebbs cycle: 12 ATP per acetyl co A HMP Shunt: O Palitic acid oxidation:129ATP Stearic acid oxidation: 146 ATP Remember •• Brain, liver, muscles uses glucose as primary fuel •• Heart uses fatty acids as primary fuel •• In starvation brain and heart use ketone bodies as fuel Glycogen Storage Diseases 1. von Gierke’s Disease Glucose-6-phosphatase •• Protruding abdomen because of marked hepatomegaly, hypotrophic deficiency muscles, truncal obesity, a rounded ‘doll face’ •• Severe symptomatic hypoglycemia is frequent, often occurring during the night or after even short periods of reduced caloric intake •• Even minor delays or reduction of carbohydrate intake may provoke hypoglycemic attacks that are accompanied by lactic acidosis 2. Pompe Disease Lysosomal alpha-1, •• Profound muscle hypotonia, weakness, hyporeflexia, glossomegaly, 4-glucosidase massive cardiomyopathy without murmurs but no hepatomegaly except deficiency with cardiac failure Acid maltase deficiency •• The ECG shows a huge QRS complex, left or biventricular hypertrophy and (AMD), shortened PR interval 3. Cori Disease Debranching enzyme 4. Andersons Disease Branching enzyme •• Mild Hypoglycemia, Hepatomegaly •• Infantile Hypotonia, cirrhosis 204 USMLE Step 1 Platinum Notes 5. Mc Ardle Disease Muscle Phosphorylase •• Increasing intolerance for strenuous exercise •• Strenuous muscle activity is accompanied by severe cramps and may be followed by myoglobinuria, which can precipitate anuria and renal failure 6. Hers Disease Liver phosphorylase •• Pronounced hepatomegaly, without splenomegaly •• Protuberant abdomen due to muscle hypotonia are the most striking features 7. Tauris Disease Phosphofructokinase Deficency USMLE Case Scenario A 3-month-old boy is evaluated for failure to thrive, seizure. Examination Shows truncal obesity, hepatomegaly. Serum chemistries demonstrate severe hypoglycemia, hyperlipidemia, lactic acidosis, and ketosis. Which of the following diseases best accounts for this presentation? Von Gierkes Disease USMLE Case Scenario A 23-year-old engineer to a physician with complaints of severe muscle cramps and weakness with even mild exercise. Muscle biopsy demonstrates glycogen accumulation, but hepatic biopsy is unremarkable. Which of the following is the most likely diagnosis? Mc Ardles Disease Galactosemia •• Galactosemia occurs in two very different clinical forms •• Deficiency of galactokinase produces very mild disease with the only significant complication being cataract formation. In contrast, homozygous deficiency of galactose-1-phosphate uridyltransferase produces severe disease culminating in death in infancy. In addition to galactosemia and galactosuria, these patients have impaired renal tubular resorption leading to aminoaciduria, gastrointestinal symptoms, hepatosplenomegaly, cataracts, bleeding diathesis, hypoglycemia, and mental retardation •• Pathologically, the CNS shows neuronal loss and gliosis and the liver shows fatty change progressing to cirrhosis. •• Three enzyme deficiencies implicated –– GPUT Deficiency( Galactose 1 Po4 uridyl transferase) most common –– UDP galactose 4 epimerase deficiency –– Galactokinase deficiency •• AR condition •• Newborn presents with failure to thrive, vomiting, diarrhea and Jaundice •• Hepatomegaly, Cataract (oil drop cataract), Mental retardation, E.coli sepsis •• Cataract because of accumulation of galactilol •• Reducing sugar seen in urine •• Rapid diagnosis and rapid removal of galactose from diet Essential Fructosuria •• •• •• •• Fructokinase deficiency AR Condition Benign, asymptomatic Fructose accumulates in urine Biochemistry Hereditary Fructose Intolerance: •• Aldolase B deficiency •• Sever hypoglycemia, vomiting, hepatomegaly and hyperuricemia •• Hepatic failure and death if not treated Electron Transport Chain •• Electron transport chain is located in inner mitochondrial membrane •• Internal respiration is exorgenic and catabolic •• Mitochondrial membrane protein contain transporter of NADH, NADPH and ATP •• In electron transport chain FADH gives 2 ATP •• In electron transport chain NADH gives 3 ATP •• Cyanide inhibits cytochrome oxidase •• Cyanide inhibits Complex IV •• Carbon monoxide, cyanide and azide inhibit cytochrome oxidase •• Dinitrophenol is uncoupler of oxidation and phosphorylation •• Uncouplers of oxidative phosphorylation are: Snake venom, ↑ Serum bilirubin, ↑T 4,↑ Free fatty acids Electron Transport Inhibitors •• Rotenone, amobarbital, chlorpromazine (complex I) •• Antimycin A, BAL, phenformin (complex II) •• Cyanide, azide, CO, H2S (complex III) ATP ase Inhibitors •• Oligomycin, atractyloside, bongregate Uncoupling agents •• 2, 4 Dinitrophenol Fatty Acids ‘Saturated’ fatty acids: •• Butyric acid •• Palmitic acid •• Stearic acid ‘Monounsaturated’ fatty acids: •• Oleic acid •• Elaidic acid ‘Polyunsaturated’ fatty acids PUFA: •• Linoleic Acid •• Linolenic Acid •• Arachdonic Acid Essential Fatty Acids are •• •• •• •• •• Linoleic acid Linolenic acid Ecosopantanoic acid Docosa Hexanoic acid Arachidonic acid 205 206 USMLE Step 1 Platinum Notes Fatty Acid Synthesis •• Occurs in cytoplasm –– Most fatty acids are synthesized in the ‘liver.’ –– Fatty acids to a lesser extent are also synthesized in Lactating breast, adipose tissue and kidney –– Fatty acids are synthesized in ‘cytosol.’ –– Carbon atoms needed for fatty acid synthesis are provided by acetyl COA –– Energy for fatty acid synthesis is provided by ATP –– Reducing equivalents for fatty acid synthesis are provided by NADPH –– The regulated step in fatty acid synthesis is catalyzed by acetyl COA carboxylase which requires Biotin –– Citrate is the allosteric activator of enzyme acetyl CO A carboxylase and long chain fatty acyl COA is the inhibitor –– Insulin also activates the enzyme –– Epinephrine and glucagon inactivate the enzyme •• ‘Acetyl co A carboxylase’ containing Biotin is the rate limiting step •• It is activated by insulin (Promotes fatty acid synthesis) •• Fatty acid synthetase is a large multi enzyme complex containing Acyl carrier protein, Pantothenic acid. •• Ketosis results from a marked increase in free fatty acid release from adipocytes, with a resulting shift toward ketone body synthesis in the liver. Reduced insulin levels, in combination with elevations in catecholamines and growth hormone, lead to an increase in lipolysis and release of free fatty acids •• In Diabetic Keto Acidiosis, the ketone body, b-hydroxybutyrate, is synthesized at a threefold greater rate than acetoacetate •• Ketone body formation occurs in Liver •• Ketone bodies are by products of fatty metabolism •• Ketone bodies are normally produced from Acetyl CoA •• Normal excretion of ketone bodies daily is 1 mg •• Ketone bodies are utilized by conversion of acetoactetate to acetoacetyl COA •• Ketone body formation without glycosuria is a feature of starvation Bile Major components of bile by weight include water (82%), bile acids (12%), lecithin and other phospholipids (4%), and unesterified cholesterol (0.7) •• The ‘primary bile acids’, cholic acid and chenodeoxycholic acid (CDCA), are synthesized from cholesterol in the liver •• Are conjugated with glycine or taurine •• Are excreted into the bile •• ‘Secondary bile acids’, including deoxycholate and lithocholate, are formed in the colon as bacterial metabolites of the primary bile acids •• In normal bile, the ‘ratio of glycine to taurine’ conjugates is about 3:1 •• Bile acids are detergents that in aqueous solutions and above a critical concentration of about 2 mM form molecular aggregates called micelles •• Cholesterol alone is poorly soluble in aqueous environments, and its solubility in bile depends on both the total lipid concentration and the relative molar percentages of bile acids and lecithin •• Normal ratios of these constituents favor the formation of solubilizing mixed micelles, while abnormal ratios promote the precipitation of cholesterol crystals in bile Lipoproteins and their clinical significance •• Lipoproteins are spherical particles made-up of lipid and protein molecules •• The major lipids of the lipoproteins are cholesterol, triglycerides, and phospholipids Biochemistry 207 •• Triglycerides and the esterified form of cholesterol (cholesteryl esters) are nonpolar lipids that are insoluble in aqueous environments (hydrophobic) and comprise the core of the lipoproteins. •• Phospholipids and a small quantity of free (unesterified) cholesterol, which are soluble in both lipid and aqueous environments (amphipathic), cover the surface of the particles, where they act as the interface between the plasma and core components. •• Apolipoproteins also occupies the surface of the lipoproteins; the apolipoproteins play crucial roles in the regulation of lipid transport and lipoprotein metabolism. Lipoproteins have been classified on the basis of their densities into five major classes: •• Chylomicrons •• Very low density lipoproteins (VLDL) •• Intermediate-density lipoproteins (IDL) •• LDL •• High-density lipoproteins (HDL) •• Chylomicrons Transports dietary cholesterol/ TG from intestine to tissues(Apo B) •• Apo B 48 •• Apo C II •• Apo E •• VLDL Transports TG from Liver to Tissues •• Apo B 100 •• Apo C II •• Apo E •• LDL Delivers cholesterol to cells •• Apo B 100 •• IDL •• HDL •• Apo E Picks up cholesterol from blood vessels •• Apo A1 APOLIPOPROTEINS The apolipoproteins (apos) provide structural stability to the lipoproteins and determine the metabolic fate of the particles upon which they reside Important Points to be remembered •• LDL has only one apoprotein B100 •• •• •• •• •• LDL has the highest Cholesterol content and is most atherogenic Chylomicrons have highest triglyceride content Chylomicrons contain Apo A, Apo B, Apo C, Apo E LDL delivers cholesterol to extrahepatic tissues (Cells) LDL has scavenging action •• LDL receptors are widely present on cell membranes, liver and extrahepatic tissues •• After binding with receptors LDL is taken in by endocytosis •• A rise of intracellular cholesterol inhibits the synthesis of new LDL receptors HDL is ‘good’ as it scavenges body cholesterol and transports cholesterol from liver to tissues. (reverse cholesterol transport) Secondary Hyperlipidemias Disease Diabetes Nephritic syndrome Hypothyroidism Biliary obstruction Serum cholesterol Increased Increased Increased Increased Serum triglyceride Increased Increased Increased Normal Contd... 208 USMLE Step 1 Platinum Notes Contd... Disease Pregnancy Alcoholism Oral contraceptives Serum cholesterol Normal Normal Normal Serum triglyceride Increased Increased Increased Familial Hypercholesterolemia •• •• •• •• •• FH is due to mutations in the gene for the LDL receptor and is genetically heterogeneous Plasma levels of LDL cholesterol are elevated at birth and remain so throughout life In untreated adults, total cholesterol levels range from (275 to 500 mg/dL) Plasma triglyceride levels are typically normal, and HDL cholesterol levels are normal or reduced •• As would be expected of a disorder with decreased numbers of LDL receptors, the fractional clearance of LDL apo B is reduced •• LDL production is increased because the liver secretes more VLDL and IDL and more IDL particles are converted to LDL rather than taken up by the hepatic LDL receptors •• FH heterozygotes usually develop severe atherosclerosis in early or middle age •• Tendon xanthomas, which are due to both intracellular and extracellular deposits of cholesterol, most commonly involve the Achilles tendons and the extensor tendons of the knuckles •• Tuberous xanthomas, which are softer, painless nodules on the elbows and buttocks, •• Xanthelasmas, which are barely elevated deposits of cholesterol on the eyelids, are common •• Successful therapy should be aimed at increasing Apo B 100 receptor gene products in hepatocyte cell membranes •• Type II Familial Hyper cholestrolemia is due to defective LDL receptors with high LDL and cholesterol levels •• Type I Familial Hyperlipoproteinemia is due to deficiency of lipoprotein lipase or Apo C II with increased chylomicrons and triglycerides Familial hypercholesterolemia, which is due to defective function of the LDL receptor More than 200 mutations in the gene for the LDL receptor have been identified. The gene has 5 general domains and 18 exons. Defects near exons 7 to 14 are in the region of homology with epidermal growth factor receptor precursor. This region of the molecule is needed for dissociation of LDL from the receptor in the endosome. Receptors with a defect in this area (sometimes called class II mutations) also have trouble being initially transported to the Golgi complex (transport-deficiency alleles) and become trapped in endoplasmic reticulum. Familial Lipoprotein Lipase Deficiency Autosomal recessive disorder: •• It is due to the severe impairment or absence of LPL, leading to massive accumulation of chylomicrons in plasma •• Manifestations begin in infancy and include pancreatitis, eruptive xanthomas, hepatomegaly, splenomegaly, foam cell infiltration of the bone marrow and when the level of triglycerides is (1000 mg/dL), lipemia retinalis. Atherosclerosis is not accelerated •• The diagnosis is suspected by finding a creamy layer (chylomicrons) at the top of plasma that has incubated overnight; Abetalipoproteinemia •• •• •• •• It is AR disease Defective synthesis or secretion of Apo B with Low levels of chylomicrons, VLDL and LDL Low levels of Cholesterol and Triglycerides Biochemistry 209 •• Clinical features include: –– Fat Malabsorption –– Failure to thrive –– Neuropathy –– Spinocerebellar degeneration –– Retinitis pigmentosa –– Acantholysis Treatment is with low fat, High calorie diet •• Chylomicrons are Lipoproteins lowest in density •• Chylomicrons are Lipoproteins largest in size •• Chylomicrons are Lipoproteins with highest percentage of lipid •• Chylomicrons are Lipoproteins lowest percentage of protein Lipid Metabolism Disease Deficiency •• Fabry’s Alpha galactoside- A (Ceramide trihexoside accumulates) •• Niemann- Pick’s Sphingomyelinase (RBC appear as foam cells) •• Tay- Sach’s Hexosaminidase A •• Sandhoff disease Hexosaminidase A and B •• Krabbe Leukodystrophy Galacto Cerebrosidase •• Metachromatic Leukodystrophy Arylsulfatase A •• Gaucher disease Gluco Cerebrosidase •• Tangier Disease Lipid Metabolism Disturbed (Low Alpha lipoprotein) Gauchers Cells Glucocerebrosides accumulate in massive amounts within phagocytic cells throughout the body in all forms of Gaucher disease. The distended phagocytic cells, known as Gaucher cells, are found in the spleen, liver, bone marrow, lymph nodes, tonsils, thymus, and Peyer patches. Similar cells may be found in both the alveolar septa and the air spaces in the lung. Tangiers Disease •• •• •• •• Αlpha lipoprotein (HDL)deficiency ↓HDL, ↓LDL, ↓Apo A because of high catabolic rates; abnormal cholesterol uptake into and/or efflux from macrophages; increased apo AI clearance –– Large orange tonsils –– Corneal opacities –– Relapsing polyneuropathy •• No premature atherosclerosis It is a rare familial disorder characterized by alpha-lipoprotein deficiency, which leads to very low high-density lipoprotein (HDL), recurrent polyneuropathy, lymphadenopathy, and hepatosplenomegaly due to storage of cholesterol esters in reticuloendothelial cells. The association of orange-yellow tonsillar hyperplasia (due to the cholesterol ester deposition there as well) with Tangier disease is a sufficiently distinctive clue in physical diagnosis to be worth remembering. 210 USMLE Step 1 Platinum Notes Lecithin: cholesterol acyltransferase (LCAT) deficiency (Fish-eye disease) •• Decreased LCAT activity in plasma leads to accumulation of excess unesterified cholesterol in plasma and body tissues •• Total plasma cholesterol level variable with •• Decrease in esterified cholesterol and •• Increase in unesterified cholesterol •• Elevated VLDL level; structure of all lipoproteins is abnormal •• Corneal opacities, hemolytic anemia, renal insufficiency, premature atherosclerosis Wolmans Disease •• AR disorder •• Lipid storage disease •• Lysosomal acid lipase deficiency causes accumulation of triglycerides,cholestrylesters and other fats within the cells of affected individuals •• Lipids accumulate in various organs •• Calcification of adrenals •• Hepatospleenomegaly, poor weight gain, anemia, jaundice, and features of severe malnutrition occur Lipid Mobilization: •• Adipose Tissue breakdown yields Fatty acids plus Glycerol •• Hormone sensitive lipase is responsible •• Hormone sensitive lipase is activated by: –– ↑Epinephrine –– ↓ Insulin –– ↑Cortisol Sphingolipids •• Sphingomyelin: Phosphorylcholine •• Cerebrosides: Galactose or glucose •• Gangliosides: N acetyl neuraminic acid Disease Enzyme deficiency Substance Accumulated Symptoms Tay sachs Hexosaminidase Ganglioside •• Cherry red spot in macula •• Psychomotor retardation Gauchers Glucocerebrosidase Glucocerebroside •• Erosion of bones •• Hepatosplenomegaly •• Crumpled paper inclusions in macrophages Niemann Picks Sphingomyelinase Sphingomyelin •• •• •• •• •• Cherry red spot in macula Mental Retardation Zebra body inclusions Foamy Macrophages Tay-Sachs Disease An autosomal recessive disorder caused by the deficiency of hexosaminidase A, which leads to the accumulation of ganglioside GM2 in neurons, producing a degenerative neurologic disease. Children appear normal at birth, but then begin to suffer from diminished responsiveness, deafness, blindness, loss of neurologic function, and seizures. A cherry-red spot on the Biochemistry 211 macula may be seen by ophthalmoscopic examination. The incidence is higher among Jews of Eastern European descent. Since the parents must be heterozygotes for the mutant hexosaminidase. A allele, they would be expected to have diminished levels of the enzyme. Ketoacidosis •• Occurs In type I IDDM •• Urinary Acetoacetate, β Hydroxy butyrate ↑ •• Urinary Nitroprusside test Positive –– The hyperglycemia of DKA results from increased hepatic glucose production (gluconeogenesis and glycogenolysis) and impaired peripheral glucose utilization –– The decreased ratio of insulin to glucagon promotes gluconeogenesis, glycogenolysis, and ketone body formation in the liver, as well as increasing substrate delivery from fat and muscle (free fatty acids, amino acids) to the liver –– Insulin deficiency also reduces levels of the GLUT4 glucose transporter, which impairs glucose uptake into skeletal muscle and fat and reduces intracellular glucose metabolism Amino Acid Metabolic Defects Phenylketonuria: Phenylalanine Hydroxylase •• Mental retardation, seizures, hyperactivity •• Tremor Mousy odor of urine •• Microcephaly, Hypopigmentation •• Failure to grow are features •• Musty urine Alkaptonuria: Homogentisate oxidase •• Urine darkens on standing •• Pigmentation of the sclerae and ears •• Generalized darkening of the concha, anthelix and helix of the ear are typical •• Arthritis •• Pigmentation of heart valves, larynx, tympanic membranes, and skin •• Arthritis Maple syrup urine disease (MSUD) Branched chain α Ketoacid •• Valine, Leucine, Isoleucine defect dehydrogenase •• Maple syrup urine •• Lethargic baby, Loses weight, Ketosis, Coma Homocystinuria Cystathionine synthetase •• Mental retardation, MI, Osteoporosis •• Dislocation of lens (Abnormal methionine metabolism) •• It is inherited as AR triat •• Patients can be responsive to Vitamin B6 (Pyridoxine) Albinism Tyrosinase •• White hair •• Photosensitivity •• Strabismus •• Nystagmus •• Photophobia 212 USMLE Step 1 Platinum Notes USMLE Case Scenario A 10-year-old girl is seen by a doctor for removal of multiple squamous cell carcinomas of the skin. The patient has nearly white hair, pink irises, very pale skin, and a history of burning easily when exposed to the sun. This patient’s condition is albinism •• The most common form of albinism is caused by a deficiency of copper-dependent tyrosinase (tyrosine hydroxylase), blocking the production of melanin •• From the aromatic amino acid tyrosine. Affected individuals lack melanin pigment in skin, hair, and eyes, and are prone to develop sun-induced skin cancers, including both squamous cell carcinomas and melanomas •• This question is simple if you know that tyrosinase is an enzyme in the –– Biosynthetic pathway for melanin formation from tyrosine. A lack of tyrosinase causes one form of albinism; a second form is caused by defective tyrosine uptake •• Patients with albinism are: –– Vulnerable to developing cancers of the skin of all types, including basal cell carcinoma, squamous cell carcinoma, and melanoma. The melanomas are unusual in that they are non-pigmented (amelanotic) rather than black, since the patients cannot form melanin. Albinism •• It is an example of an inborn error in which the pathophysiologic mechanism is directly related to the lack of an end product. Tyrosine is converted by the action of a cytosolic tyrosinase first to dopa and then dopamine. •• Dopamine can then be converted either to the red-yellow pigment phenomelanin or to the black-brown pigment eumelanin. These reactions occur in the melanosomes produced in the melanocytes and exported to the keratinocytes. Color of skin is an inherited factor that depends on several genes and is a function of the intensity of the pigment in the skin and not the number of melanocytes, which is constant for all humans. Although skin color is a polygenic trait, single genes can have a profound effect on this color, as evidenced by the albino phenotype. In humans, oculocutaneous albinism (OCA) is inherited as an autosomal recessive trait. •• An X-linked and autosomal recessive form of ocular albinism also exists. Individuals with OCA are classified as either tyrosinase-negative or positive for tyrosine activity in hair bulbs. Tyrosinase-negative individuals form no pigment, and prenatal monitoring for tyrosinase activity in cultured amniocytes is possible. •• A tyrosinase-positive OCA has been associated with an autosomal recessive gene located on chromosome 15q11-13 (the P gene). A wide variation in phenotypic expression of OCA is reported from very severe neurologic deficiency with ocular and sarcomatous skin cancers to mild cosmetic problems. Amino Acid Transport Defects Cystinuria •• Defective transport of Basic amino acids (COAL: Cystine, Ornithine, Arginine, Lysine) •• Cystine calculi and cystine crystals in urine •• Cyanide Nitrosoprusside Test positive Hartnups Disease •• Defective renal and intestinal transport of Tryptophan •• Malabsorption, Ataxia, Pellagrous rash USMLE Case Scenario A 10-year-old child is suspected of having pellagra because of chronic symptoms including diarrhea, a red scaly rash, and mild cerebellar ataxia. However, his diet is not deficient in protein and he appears to be ingesting adequate amounts of niacin. A sister has a similar problem. Chemical analysis of his urine demonstrates large amounts of free amino acids. Which of the following is the most likely diagnosis? Biochemistry 213 1. Alkaptonuria 2. Carcinoid syndrome 3. Ehlers-Danlos syndrome 4. Hartnup’s disease 5. Scurvy Ans. 4. Hartnup’s disease The child has Hartnup’s disease. This condition clinically resembles pellagra (‘diarrhea, dementia, and dermatitis’), and may be misdiagnosed as this nutritional (niacin) deficiency. In fact, niacin therapy may actually be helpful in controlling the symptoms. The underlying problem is a defect in the epithelial transport of neutral amino acids, including tryptophan, which can act as a precursor of niacin. The defective amino acid transport leads to poor absorption of dietary amino acids as well as excess amino acid secretion in the urine. Fanconis Syndrome •• Generalized Tubular damage •• Aminoaciduria, Glycosuria, Phosphaturia (AGP) •• Renal Tubular disorders, Progressive Renal Failure Exopeptidases: •• Carboxypeptidases •• Aminopeptidase •• Prolidase Endopeptidases: •• Elastase •• Trypsin •• Chymotrypsin •• Collagenase Urea Cycle •• •• •• •• Takes place in liver and brain 1st two reactions occur in mitochondria 1st two reactions are rate controlling reactions Combination of ‘Hyperammonemia+ ↑Blood Glutamine+↓Blood urea’ suggests defect in Urea Cycle. Lethargy, vomiting, coma are associated Genetic Defects in Urea Synthesis Carbomyl Phosphate Synthetase ↑Ammonia +↑Blood Glutamine+↓Blood urea Ornithine Transcarbomylase ↑Ammonia +↑Blood Glutamine+↓Blood urea No increase in Uracil or orotic acid Increase in Uracil or orotic acid Urea Cycle Disorders Diseases Hyperammonemia type 1 Hyperammonemia type 2 Enzyme deficit CPS-I (OTC) Ornithine transcarbamoylase Features Very high NH3 level levels in blood. Autosomal recessive Mental retardation •• Ammonia level high in blood •• Increased glutamine in blood, CSF and urine •• Orotic aciduria due to the channelling of carbamoyl phosphate into Pyrimidine synthesis •• X–linked Contd... 214 USMLE Step 1 Platinum Notes Contd... Diseases Hyperornithinemia Enzyme deficit Defective ornithine transporter protein Features •• Failure to import ornithine from cytoplasm to mitochondria •• Defect in ORNT1 gene •• Hyperornithinemia, hyperammonemia and homocitrullinuria is seen (HHH syndrome) •• Decreased urea in blood •• Autosomal recessive condition. Citrullinemia Argininosuccinate synthetase •• Autosomal recessive inheritance. High blood levels of ammonia amd citrulline. Citrullinuria (1–2 g/day). Argininosuccinic aciduria Argininosuccinate lyase •• Argininosuccinate in blood and urine. Friable brittle tufted hair (Trichorrhexis nodosa). Hyperargininemia Arginase •• Arginine increased in blood and CSF. Instead of arginine, cysteine and lysine are lost in urine. Ammonia is Generated •• •• •• •• From amino acids: by Aminotransferase and Glutamate dehydrogenase From urea by urease From amines by amine oxidase From glutamine by glutaminase Defects of Purine and Pyrimidine Metabolism •• Orotic Aciduria Orotic acid phosphoribosyltransferase/ OMP decarboxylase Autosomal recessive A newborne with Megaloblastic anemia Lack of pyrimidine synthesis with orotic acid crystals in urine needed for hematopoesis •• Lesch Nyhan Syndrome Deficiency of HGPRT X linked recessive A child with cerebral palsy,repeated self biting and needle shaped crystals in urine with hyperuricemia Autosomal recessive A boy with severe immunodeficiency with ↓B and↓ T cells •• Severe combined Adenosine deaminase immunodeficiency deficency •• SCID USMLE Case Scenario •• A baby that was apparently normal at birth begins to show a delay in motor development by 6 months of age. At three year of age, the child begins to develop spasticity and writhing movements. At age four, compulsive biting of fingers and lips and head-banging appear. At puberty, the child develops arthritis, and death from renal failure occurs at age 21 •• The patient has a classical case of Lesch-Nyhan syndrome, an X-linked disorder due to severe deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). This defect is associated with excessive de novo purine synthesis, hyperuricemia, and the clinical signs and symptoms described. The biochemical basis of the often striking self-mutilatory behavior. Treatment with allopurinol inhibits xanthine oxidase and reduces gouty arthritis, urate stone formation, and urate nephropathy •• A Partial deficiency of HPRT, the Kelley-Seegmiller syndrome, is associated with hyperuricemia but no central nervous system manifestations Allopurinol •• Allopurinol and its metabolite, oxipurinol (alloxanthine), decrease the production of uric acid by inhibiting the action of xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. Biochemistry 215 •• Allopurinol thereby decreases uric acid concentrations in both serum and urine •• Also, allopurinol increases reutilization of hypoxanthine and xanthine for nucleotide and nucleic acid synthesis via an action involving the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) •• The resultant increase in nucleotide concentration leads to feedback inhibition of de novo purine synthesis. Hyperuricemia •• •• •• •• Increased Purine synthesis: Lesch Nyhan Syndrome,Type I glycogen storage disease Increased Purine Turnover: High purine diet, Myeloproliferative disorders, Exfoliative diseases (Psoriasis) Decresed uric acid excretion: Primary gout, Renal failure, alcohol, starvation Drugs: –– Thiazides –– Loop diuretics –– Pyrimidine –– Ethambutol –– Salicylates –– Cytotoxic agents USMLE Case Scenario •• A 47-year-old male patient presents with painful arthritis in the right big toe and uric acid renal stones. He has been taking allopurinol for his condition. He is suffering from Gout •• This patient has gout, characterized by painful joints due to the precipitation of uric acid crystals caused by excessive production of uric acid (a minority of cases are associated with underexcretion of uric acid) •• Kidney disease is also seen due to accumulation of uric acid in the tubules. The disease mostly affects males, and is frequently treated with allopurinol, an inhibitor of xanthine oxidase. Xanthine oxidase catalyzes the sequential oxidation of hypoxanthine to xanthine to uric acid. ‘Important Molecules/Substances Frequently asked In Examinations’ Glycoproteins Glycoproteins are also called mucoproteins Glycoproteins are proteins that have oligosaccharide side chains covalently attached to their polypeptide back bones Most of the plasma proteins in humans except albumin are glycoproteins Certain hormones (HCG, TSH) are also glycoproteins ‘Glycoproteins contain N terminal signal sequences which direct the growing polypeptide chain to ER (Endoplasmic Reticulum and Golgi Complex) where Carbohydrates are added and Proteins are sorted to their proper destination.’ •• Functions of glycoproteins: –– Cell surface recognition –– Cell surface antigenicity –– Components of extracellular matrix –– Composition of globular proteins in plasma •• •• •• •• •• Glycosaminoglycans •• (GAG) Glycosaminoglycans are large complexes of ‘negatively charged, unbranched heteropolysaccharide chains’ usually composed of ‘repeating disaccharide’ units •• They produce ‘gel like matrix’ and hold large quantities of water •• They are also called as ‘mucopolysaccharides’ 216 USMLE Step 1 Platinum Notes •• They are synthesized in Golgi bodies •• They are degraded by lysosomal hydrolases •• Deficency of lysosomal hydrolases results in accumulation of GAG causing mucopolysaccharidoss. Examples are: –– Chondritin 4 sulfate –– Chondritin 6 sulfate –– Heparin –– Heparin sulfate –– Keratin sulfate –– Dermatin sulfate –– Hyaluronic acid Glutathione •• Glutathione is a tripeptide (Glutamyl-cysteinyl-glycine) present in most cells. It serves as an important reducing agent along with ascorbate, vitamin E and beta carotene •• It detoxifies hydrogen peroxide. This reaction catalyzed by selenium requiring glutathione peroxidase forms oxidized glutathione •• After this cells regenerate the essential glutathione in a reaction catalyzed by glutathione reductase •• Glutathione also helps in transport of certain amino acids into the cell •• It has ‘electron donating properties’ and functions as an intracellular reducing agent (antioxidant effects). •• Reduced glutathione detoxifies hydrogen peroxide •• It acts as a carrier of amino acids in kidney •• It helps in conjugation reactions and detoxification of xenobiotics •• Following an acute ingestion of Acetaminophen, sulfate and glucuronide pathways become saturated, resulting in an increased fraction and amount of acetaminophen metabolized to NAPQI and eventual glutathione depletion when this occurs, free NAPQI binds covalently to hepatocytes and causes their lysis (centrilobular necrosis). Less often, hepatotoxicity develops following the chronic ingestion of therapeutic or slightly greater amounts in conditions associated with decreased glutathione reserves (e.g. alcoholism, childhood, acute starvation, chronic malnutrition). Other Antioxidants •• •• •• •• •• •• Vitamin A Vitamin E Vitamin C Catalase Superoxide dismutase NADPH PAF •• PAF is a potent ‘Glycerophospholipid ‘and a phospholipid activator and mediator of leucocyte functions such as inflammation, platelet aggregation, anaphylaxis •• Neutrophils, basophils, platelets and endothelial cells produce PAF •• PAF Mediates ‘bronchoconstriction’ •• PAF Causes ‘platelet aggregation’ Prostaglandins LTA4: •• Produced in leucocytes, platelets, mast cells, vascular tissue Biochemistry 217 LTC4, LTD4, LTE4: •• Contraction of smooth muscle •• Bronchoconstriction •• Vasoconstriction •• ↑vascular permeability •• Components of SRSA LTB4: •• ↑Chemotaxis •• Adhesion of WBC •• Release of lysosomal enzymes Thromboxanes: •• Produced mainly in platelets •• Promotes platelet aggregation •• Vasoconstriction •• Smooth muscle contraction Prostacyclins: •• Produced by endothelium of vessels •• Vasodilation •• Inhibits platelet aggregation •• Cortisol inhibits Phospholipase A2 •• Aspirin, Indomethacin, Phenylbutazone inhibit Both COX 1 and COX 2 •• Coxibs are selective COX 2 inhibitors (Celecoxib) Ionophores •• •• •• •• •• 1. 2. 3. 4. 5. 6. 7. 8. Ionophores are ’organic molecules’ synthesized by microbes to ‘facilitate movement of ions across membranes’ Their properties are because of ‘lipophilic nature’ and penetrate lipid membranes They have hydrophilic core and hydrophobic periphery Valinomycin is an ionophore Representative ionophores (with the ion(s) they act upon) 2, 4 - Dinitrophenol (H+) Beauvericin (Ca2+, Ba2+) Gramicidin A (H+, Na+, K+) Ionomycin (Ca2+) Monensin (Na+, H+) Nigericin (K+, H+, Pb2+) Salinomycin (K+) Valinomycin (K+) Zellweger’s Syndrome Peroxisomes are single membrane organalles that are responsible for β oxidation of fatty chains. Deficiency of Peroxisomes causes Zellweger’s syndrome with accumulation of long chain fatty acids. Rate Limiting Steps •• •• •• •• Cholesterol synthesis Ketone body synthesis Fatty acid synthesis Bile acid synthesis HMG CoA reductase HMG CoA Synthetase Acteyl Co A Carboxylase 7 α hydroxylase 218 USMLE Step 1 Platinum Notes Important Inhibitors of Medically Important Enzymes •• •• •• •• •• Xanthine oxidase: Folate reductase: Lactate Dehyrogenase: Dihydrofolate reductase: Vitamin K synthesis: Allopurinol Methotrexate Oxamates Amethroptin Dicumarol Diagnostic Techniques Blot Type Material Analyzed •• Southern blot •• ASO titer DNA DNA •• Northern blot •• Microarray RNA RNA or c DNA •• Western blot •• ELISA •• Proteomics Protein Protein/antibodies Proteins •• Dot Blot DNA, RNA or Protein •• Proteomics: Study of all proteins expressed in a genome, including their abundance, distribution, post translational modification, function and interaction with other molecules. •• DNA library: Collection of cloned restriction fragments of DNA of an organism •• Genomic library: It is a collection of fragments of double stranded DNA obtained by digestion of total DNA of an organism with restriction endonucleases and subsequent ligation to appropriate vector. •• Probe: It is a single stranded piece of DNA usually labeled with radio isotope that has nucleotide sequence complimentary to DNA molecule of interest •• Nucleotide sequence of a probe is complimentary to DNA of interest called Target DNA •• Vector is a molecule of DNA to which fragment of DNA to be joined is attached. Polymerase Chain Reaction •• The polymerase chain reaction (PCR) is now the most frequently used technique in molecular biology. •• Used to study a specific area of DNA using short complementary sequences of DNA (oligonucleotides) from both the 3’ and the 5’ ends of the DNA to be studied. •• These oligonucleotides build copies of the DNA (amplifies) using a heat stable polymerase (Taq 1). •• It is then possible to heat the mixture and the DNA strands will separate. •• On cooling, the DNA can once more be duplicated and the process repeated again and again leading to an exponential increase in the copies of the two fragments. •• The main advantages of this technique are that it is very quick, highly sensitive and very robust and it can be used to study mRNA as well as DNA. •• It can also be used to study very small amounts of almost any tissue, e.g. the blood spots on a Guthrie card or the cells found in a mouth wash sample. •• The technique is widely used in molecular diagnosis of genetic disease. It is also being used in infectious disease to confirm the presence of infectious agents and in immunology to identify the human leukocyte antigen (HLA) haplotype. Biochemistry 219 Ion-exchange Chromatography Process in which exchange of ions in solution form with that on to surface form occurs in is Ion exchange: •• Ion-exchange chromatography is a process that allows the separation of ions and polar molecules based on their charge. •• It can be used for almost any kind of charged molecule including large proteins, small nucleotides and amino acids. The solution to be injected is usually called a sample, and the individually separated components are called analytes. •• It is often used in protein purification, water analysis, and quality control. Ion exchange chromatography retains analyte molecules on the column based on coulombic (ionic) interactions. •• The stationary phase surface displays ionic functional groups (R-X) that interact with analyte ions of opposite charge. This type of chromatography is further subdivided into cation exchange chromatography and anion exchange chromatography. •• The ionic compound consisting of the cationic species M+ and the anionic species B-can is retained by the stationary phase. Cation exchange chromatography retains positively charged cations because the stationary phase displays a negatively charged functional group. Salting out •• •• •• •• •• •• •• •• •• •• Proteins are purified using differences in protein solubility in varying salt concentrations The solubility of proteins varies according to the ionic strength of the solution and hence according to the salt concentration Two distinct effects are observed At low salt concentrations, the solubility of the protein increases with increasing salt concentration (increasing ionic strength), and effect termed salting in As the salt concentration (ionic strength) is increased further, the solubility of the protein begins to decrease At high ionic strength, the protein will be almost completely precipitated from the solution (salting out) Since proteins differ markedly in their solubilities at high ionic strength, salting-out is a very useful procedure to assist in the purification of a given protein. The commonly used salt is Ammonium sulfate, as it is very water soluble The ammonium sulfate concentration is increased stepwise, and the precipitated protein is recovered at each stage The precipitated protein is then removed by centrifugation and then the ammonium sulfate concentration is increased to a value that will precipitate most of the protein of interest whilst leaving the maximum amount of protein contaminants still in solution This technique is useful to quickly remove large amounts of contaminant proteins, as a first step in many purification schemes. It is also often employed during the later stages of purification to concentrate protein from dilute solution following procedures such as gel filtration. Restriction Fragment Length Polymorphism (RFLP) •• It is a difference in homologous DNA sequences that can be detected by the presence of fragments of different lengths after digestion of the DNA samples in question with specific restriction endonucleases •• It is a DNA Variation sequence •• RELP, as a molecular marker, is specific to a single clone/restriction enzyme combination •• An RFLP probe is a labeled DNA sequence that hybridizes with one or more fragments of the digested DNA sample after they were separated by gel electrophoresis, thus revealing a unique blotting pattern characteristic to a specific genotype at a specific locus. Short, single-or-low-copy genomic DNA or cDNA clones are typically used as RFLP probes •• RFLPs are visualized by digesting DNA from different individuals with restriction enzyme, followed by gel electrophoresis to separate fragments according to size, then blotting and hybridization to a labeled probe that identifies the locus under investigation. An RFLP is demonstrated when ever the Southern blot pattern obtained with one individual is different from the one obtained with another individual •• RFLP is an important tool in •• Genome mapping •• Localization of genes from genetic disorders •• Determination of risk for diseases, and paternity testing •• Test which uses oligomer with single base pair substitution: RFLP 220 USMLE Step 1 Platinum Notes Paper Chromatography •• Technique for identification and determination of amino acids •• The Principle: A small amount of solvent is put at the bottom of a jar. A strip of absorptive paper, with a concentrated spot of the mixed amino acids near the bottom, is suspended in the jar so that its end dips into the solvent. The solvent moves slowly up the strip of paper, carrying the amino acids with it. As the amino acids travel at different speeds, they separate from one another. The paper is then treated with a reagent which strains the amino acids so they can be detected and identified. The location reagent used for amino acids is ninhydrin •• Chromatography paper contains about 15–20% water, held to the paper fibers. This water acts as the stationary phase in paper chromatography. Amino acids are separated according to their solubility in the water and in an organic solvent (the mobile phase) moving up the paper. The most non-polar amino acids migrate the furthest, due to their greater solubility in the organic solvent •• Paper also acts as an adsorbent, having an affinity for polar groups. Amino Acids •• Phenylalanine and Tyrosine are precursors of Cathecolamines. •• Tryptophan is precursor for Serotonin, Niacin. •• Valine and isoleucine are branched chain amino acids whose metabolism is abnormal in MSUD. (Maple Syrup Urine Disease). •• Proline has an imino group. •• Essential AA: Arginine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Threonine, Tryptophan, Valine. •• Histidine is a buffer at normal pH. It can protonate or deprotonate. •• Glycine is the smallest and simplest AA. •• Glycine is responsible for flexibility of proteins. •• Hydrophilic AA are present on outer surface of membrane. •• Hydrophobic AA are present in transmembrane region •• Most of the amino acids do not absorb visible light and hence are colorless •• Aromatic amino acids are the only amino acids that absorb light. They are: –– Tryptophan (contains indole ring) –– Tyrosine –– Phenylalanine –– Histidine –– Tryptophan is the major amino acid contributing to ability to absorb light in the range of 250–290 nm. Biochemistry 221 ‘Glucogenic’ amino acids are: •• Alanine, Arginine, Asparagine, Aspartate •• Cysteine •• Glutamate, Glutamine, Glycine •• Methionine, Theronine, Valine ‘Ketogenic’ Amino acids are: •• Leucine, Lysine Mechanism Pathway of Important Enzymes Pathway G protein Protein Kinase Examples •• c AMP Adenyl cyclase Protein Kinase A •• Glucagon •• Epinephrine •• PIP2 Phospholipase Protein Kinase B •• Vasopressin •• C GMP Guanyl cyclase Protein Kinase C •• ANF •• NO Proteins •• 1o Structure specific order of Amino Acids in peptide chain •• 2o Structure spatial relationship of neighboring Amino Acid residues, e.g. α Helix •• 3o Structure spatial relationship of distant Amino Acid residues by arrangement of secondary structure •• 4o Structure spatial relationship between individual Polypeptide chains Alpha Helix, Beta Sheet and Beta Bends are Secondary Structures •• Alpha helix can be composed of more than one polypeptide chains. It is a spiral structure with polypeptide backbone and side chains of amino acids •• It is stabilized by hydrogen bonds •• Each turn of the helix has 3.6 amino acids •• Proline disrupts alpha helix because of geometric incompatibility of imino group of proline •• Beta sheets are secondary structures in which all peptide bonds are involved in hydrogen bonding •• Beat sheets are both parallel and anti parallel •• Beta bends are also called reverse turns •• Beta bends often contain glycine •• Proline can also be present •• Motifs are super secondary structures •• Domains are a type of tertiary structure 222 USMLE Step 1 Platinum Notes Levels of protein structure •• Hydroxylation of proline in fibroblasts generates the modified amino acid hydroxyproline. This is an example of post-translational modification. •• Hydroxyproline is involved in stabilizing the three-dimensional triple helix structure of collagen. •• Cysteine is unique in its ability to form a covalent disulfide bond with another cysteine residue elsewhere in the protein molecule, thereby forming a cystine residue. •• Such strong disulfide bonds stabilize the three-dimensional structure of the protein. •• Glycine is abundant in fibroblasts since it constitutes every third amino acid in the primary sequence of collagen. However, glycine is not hydroxylated. •• Serine tyrosine and threonine can all be phosphorylated post-translationally to form phosphoserine, phosphotyrosine, and phosphothreonine, respectively. These phosphorylated amino acids are believed to play a role in signal transduction. •• Primary structure: Peptide bonds •• Secondary structure: hydrogen bonds •• Tertiary structure: disulfide bonds Important Elements •• •• •• •• •• Magnesium: Kinases, Phosphatases, Ribonuclease, Adenyl cyclase, Transketolase Copper: Cytochrome Oxidase, Tyrosinase, Superoxide dismutase Zinc: Carboxy peptidase Molybedenum: Xanthine Oxidase Manganese: Pyruvate Carboxylase Effects of Mineral Deficiencies •• Arsenic (Impaired growth, infertility) •• Boron (Impaired energy metabolism, Impaired brain function) •• Nickel (Impaired-growth and reproduction) •• Silicon (Impaired growth) and •• Vanadium (Impaired skeletal formation) Biochemistry Zn is a cofactor in many enzymes. Some of the important ones are: •• Carbonic anhydrase •• Lactate/Alcohol Dehyrogenase •• DNA polymerase •• RNA polymerase •• Alkaline phosphatase Globulins •• Alpha 1 globulins: AFP, α1 AT, Trypsin •• Alpha 2 globulins: Cerruloplasmin, Haptoglobin •• Beta globulin: Transferrin, CRP, Hemopexin Important Tests in Biochemistry •• Zwengers test: Cholesterol •• Fouchets test bile pigments •• Hays sulfur test bile salts •• Xanthoproteic test: Proteins •• Selivanoffs test: Fructose in urine •• Rotheras test: Ketone bodies •• Gerhardts test: Ketosis •• Molishs test: Color test for sugar •• Guthries test: Phenylketonuria •• Exton Rose test: Glucose Tolerance test •• Cyanide nitroprusside test: Phenyl ketonuria •• Benedicts test: Glucose in urine •• Sulkowitz test: Urinary calcium •• Biurate test: protein Heme Protein 1. 2. 3. 4. Cytochrome Hemoglobin Myoglobin Catalase •• Heme proteins are specialized proteins containing Heme as a prosthetic group •• Heme itself is a complex of Protoporphyrin IX and Ferrous iron •• Hemoglobin binds four molecules of oxygen •• Hemoglobin exists in two forms Deoxygenated form or (T) Taut form and •• Oxygenated form or (R) relaxed form •• Oxygen dissociation curve of Hb is sigmoidal 223 224 USMLE Step 1 Platinum Notes •• Myoglobin binds one molecule of oxygen •• Oxygen dissociation curve of Myoglobin is Hyperbolic Gems about Hemoglobin Earliest Hemoglobin •• •• •• •• Hb Gowers Hb Fetal Hb Adult Hb A2 α2ε2 α2γ2 α2β2 α2δ2 Configuration of Hemoglobins •• •• •• •• Most common Hb is: HbA Adult Hb is HbA is: α2β2 Fetal Hb is Hb F is: α2γ2 Minor Adult Hb is HbA2 is: α2δ2 Clinically Important Points About Methemoglobin •• •• •• •• Form of oxidized HB (Fe2+ replaced by Fe3+) Oxygen carrying capacity ↓ Phenacetin, Primaquine, Sulfonamides, Nitrites, Nitrates cause ‘Methemoglobinemia.’ Carboxy Hemoglobin •• Hb combines with CO (Carbon Monoxide NOT Dioxide) to form Carboxy Hemoglobin •• Affinity of Hb for CO is 200 times more than that of O2, hence CO displaces O2 Glycosylated Hemoglobin •• •• •• •• •• Adult Hb binds with glucose during 120 day life cycle of RBC It is an irreversible reaction Normally up to 9% of adult Hb is Glycosylated In diabetes >9 % Hb is glycosylated It is useful for providing picture of ‘long-term’ state of diabetic control Important Inhibitors of Medically Important Enzymes •• •• •• •• •• Xanthine oxidase Folate reductase Lactate Dehyrogenase Dihydrofolate reductase Vitamin K synthesis Allopurinol Methotrexate Oxamates Amethroptin Dicumarol Biochemistry •• •• •• •• •• •• Aconitase Citrate α ketoglutarate dehydrogenase arsenate Succinate dehydrogenase Enolase Glyceraldehydes 3 phosphate Flouroacetate Flouroacetate Malonate Fluoride Iodoacetate Metabolic Functions of Subcellular Organelles Organelle Nucleus Endoplasmic Reticulum Golgi body Lysosome Mitochondria Cytosol Function •• DNA replication, transcription •• Biosynthesis of proteins, glycoproteins, lipoproteins •• Drug metabolism •• Ethanol oxidation •• Synthesis of cholesterol (partial) •• Maturation of synthesized protein •• Degradation of proteins, carbohydrates, lipids and nucleotides •• Electron transport chain •• ATP generation •• TCA cycle •• Beta oxidation of fatty acids •• Ketone body production •• Urea synthesis (part) •• Heme synthesis (part) •• Gluconeogenesis (part) •• Pyrimidine synthesis (part) •• Protein synthesis •• Glycolysis •• Glycogen metabolism •• HMP shunt pathway, transaminations, fatty acid synthesis •• Cholesterol synthesis, heme synthesis (part), urea synthesis (part) •• Pyrimidine synthesis (part), purine synthesis Enzymes used for Diagnostic Purpose Enzyme •• Urease •• Uricase •• Glucose oxidase •• Peroxidase •• Hexokinase •• Cholesterol oxidase •• Lipase •• Horse radish peroxidase •• Alkaline phosphatase •• Restriction endonuclease •• Reverse transcriptase Used for Testing •• Urea •• Uric acid •• Glucose •• Glucose; Cholesterol •• Glucose •• Cholesterol •• Triglycerides •• ELISA •• ELISA •• Southern blot; RFLP •• Polymerase chain reaction (RT = PCR) 225 226 USMLE Step 1 Platinum Notes Nonfunctional Plasma Enzymes used in Clinical Diagnosis Serum Enzymes Diagnostic use •• Amylase and lipase •• Acute pancreatitis •• Aminotransferases •• Myocardial infarction •• Aspartate aminotransferase (AST or SGOT) •• Alanine aminotransferase (ALT or SGPT) •• Viral hepatitis •• Acid Phosphatase •• Prostate cancer •• Alkaline phosphatase •• Obstructive liver diseases, bone diseases and hyperparathyroidism •• Creatine kinase •• Muscle disorders and Myocardial infarction •• Ceruloplasmin •• Wilson’s disease •• Gamma-glutamyl transpeptidase •• Liver diseases •• Lactate dehydrogenase •• Myocardial infarction Sub cellular Organelle Marker enzyme •• •• •• •• •• Inner membrane: •• ATP Synthase •• Cathepsin •• Galactosyl transferase •• Glucose-6-phosphatase •• Lactate dehydrogenase Mitochondria Lysosome Golgi complex Microsomes Cytoplasm Key Enzymes under Well Fed Conditions, Fasting and Starvation Enzyme Glucokinase Phosphofructokinase 1 Fructose 1,6 biphosphatase Pyruvate carboxylase PEPCK Glycogen phosphorylase Glycogen synthase Carnitine acyl transferase Acetyl CoA carboxylase Hormone sensitive lipase Fed Increase Increase Decrease Decrease Decrease Decrease Increase Increase Decrease Fasting Decrease Decrease Increase Increase Increase Increase Decrease Increase Decrease Increase Starvation Decrease Decrease Increase Increase Increase Decrease Increase Decrease Increase PEPCK = phospho enol pyruvate carboxy kinase; F-6-P = fructose-6-phosphate; F-2, 6-bisP=fructose-2, 6-biphosphate; G-6-P = glucose-6-phosphate. Enzyme Deficiencies in Porphyrias •• •• •• •• •• •• Erythropoetic porphyria Heridetary Porphyria Vaiegate Porphyria Acute Intermittent porphyria Porphyria cutanea Tarda Congenital Erythropoetic porphyria Ferrochelatase Coproporphynogen Oxidase Protoporphyrinogen Oxidase Porphobilinogen Deaminase URO Decarboxylase URO III cosynthetase Biochemistry Important Biochemical Tests •• Barfoed’s test Differentiates monosaccharides disaccharides •• Mucic acid test Detects galactose •• Biuret test Detects proteins •• Xanthopretic test Detects phenylalanine, tyrosine, tryptophan •• Million’s test Detects tyrosine •• Sullivan reaction Detects cysteine •• Acrolein test Detects triglycerides •• Leiberman Burchard reaction •• Salkowsky’s reaction Detects cholesterol •• Rothera test •• Legal’s test •• Gerhardt’s test Detects ketone bodies Biochemically useful Competitive Inhibitors Drug Enzyme Inhibited Allopurinol Xanthine oxidase 6-mercapto-purine Adenylosuccinate synthetase 5-fluorouracil Thymidylate synthase Azaserine Phosphoribosyl-amidotransferase Cytosine arabinoside DNA polymerase Acyclovir DNAP of virus Neostigmine ACh-esterase Alpha-methyl dopa Dopa-decarboxylase Lovastatin HMGCoA-lowering Oseltamiver Neuraminidase Dicoumarol Vit.K-epoxide-reductase Penicillin Transpeptidase Sulphonamide Pteroid synthetase Trimethoprim FH2-reductase Pyrimethamine FH2-reductase Methotrexate FH2-reductase 227 228 USMLE Step 1 Platinum Notes USMLE Case Scenario Tangier disease is a rare familial disorder characterized by deficiency of an enzyme, which leads to very low high density lipoprotein (HDL), recurrent polyneuropathy, lymphadenopathy, and hepatosplenomegaly due to storage of cholesterol esters in reticuloendothelial cells. The enzyme deficency is: 1. G6 Phosphatase 2. Pyruvate kinase 3. alpha-lipoprotein deficiency 4. Urea cycle enzyme deficiency 5. Multiple carboxylase deficiency Ans. 3. Alpha-lipoprotein deficiency USMLE Case Scenario A baby presents with refusal to feed, skin lesions, seizures, ketosis organic acids in urine with normal ammonia; likely diagnosis is: 1. Proprionic aciduria 2. Multiple carboxylase deficiency 3. Maple syrup urine disease 4. Urea cycle enzyme deficiency Ans. 2. Multiple carboxylase deficiency USMLE Case Scenario The primary role of chaperones is to help in: 1. Protein synthesis 2. Protein degradation 3. Protein denaturation 4. Protein folding Ans. 4. Protein Folding USMLE Case Scenario A young man finds that everytime he eats dairy products he feels very uncomfortable. His stomach becomes distended. He develops gas and diarrhea frequently. These symptoms do not appear when he eats foods other than dairy products. Which of the following is the most likely enzyme in which this young man is deficient? 1. a-amylase 2. b-galactosidase 3. a-glucosidase 4. Sucrase Ans. 4. Sucrase USMLE Case Scenario A child with large tongue, coarse facial features and club foot is seen by a pediatrician. You hear the doctor talking to his colleague that the child has a problem with Phosphorylation of their mannose residues. The most likely possibility is a disease called: 1. Fabrys disease 2. Gauchers disease 3. Mc Ardles disease 4. Forbes disease 5. I-cell disease Ans. 5. I-cell disease Biochemistry 229 USMLE Case Scenario Proteins targeted for destruction in eukaryotes are covalently linked to: 1. Clathrin 2. Pepsin 3. Laminin 4. Ubiquitin Ans. 4. Ubiquitin USMLE Case Scenario The defect in sickle cell anemia is amino acid substitution/s but the globin chain is still made. The gene may less commonly be present in some Mediterranean and eastern Arabian populations. There is enough fetal hemoglobin at birth to prevent sickling with sickle cell disease. Sickle cell disease represents: 1. Missense mutations involve a change in many amino acids 2. Missense mutations involve a change in a single amino acid (valine for glutamic acid) 3. Missense mutations involve a change in a single amino acid (glutamic acid for valine) 4. Nonsense mutations involve a change in a single amino acid (valine for glutamic acid) 5. Nonsense mutations involve a change in a single amino acid (glutamic acid for valine) Ans. 2. Missense mutations involve a change in a single amino acid (valine for glutamic acid) USMLE Case Scenario Northern blot test is used for: 1. DNA analysis 2. RNA analysis 3. Analysis of proteins 4. Enzyme analysis Ans. 2. RNA analysis USMLE Case Scenario Which Apoprotein helps in the transport of chylomicrons from intestine to liver? 1. Apoprotein B 2. Apoprotein A 3. Apoprotein C 4. Apoprotein E Ans. 1. Apoprotein B USMLE Case Scenario True about G protein coupled receptors is: 1. G proteins bind to hormones on the cell surface 2. All the three subunits alpha, beta and gamma should bind to each other for G protein to act 3. G proteins act as inhibitory and excitatory because of difference in alpha subunit 4. G protein is bound to GTP in resting state Ans. 3. G proteins act as inhibitory and excitatory because of difference in alpha subunit 230 USMLE Step 1 Platinum Notes USMLE Case Scenario Collagen of which type is found in hyaline cartilage: 1. Type I 2. Type II 3. Type III 4. Type IV Ans. 2. Type II USMLE Case Scenario A 34-year-old male patient presents with pain in the right big toe and uric acid renal stones. He has been taking allopurinol for his condition. What biochemical defect would likely be found in this patient? 1. A defect in fatty acid synthesis 2. An abnormality of the purine degradation pathway 3. An inability to synthesize essential amino acids 4. Defective topoisomerases 5. Increased levels of leukotrienes Ans. 2. An abnormality of the purine degradation pathway This patient has gout, characterized by painful joints due to the precipitation of uric acid crystals caused by excessive production of uric acid (a minority of cases are associated with underexcretion of uric acid). Kidney disease is also seen due to accumulation of uric acid in the tubules. The disease mostly affects males, and is frequently treated with allopurinol, an inhibitor of xanthine oxidase. Xanthine oxidase catalyzes the sequential oxidation of hypoxanthine to xanthine to uric acid. USMLE Case Scenario Vitamin K is required for: 1. Hydroxylation 2. Chelation 3. Transamination 4. Carboxylation Ans. 4. Carboxylation USMLE Case Scenario NO is synthesized from: 1. Uracil 2. Aspartate 3. Guanosine 4. Arginine 5. Alanine Ans. 4. Arginine USMLE Case Scenario A one and a half year-old retarded child’s history is significant for failure to thrive and progressive neurologic deterioration, including deafness and blindness. Physical examination is remarkable for hepatosplenomegaly, as well as a cherry-red spot on funduscopic examination. The most likely diagnosis is: 1. Fabrys Disease 2. Mcardles Disease Biochemistry 231 3. Hunter syndrome 4. Niemann-Pick disease 5. Pompe’s disease 6. Tyrosinosis 7. Cystinosis 8. Von Gierke’s disease Ans. 4. Niemann-Pick disease It is due to a deficiency of sphingomyelinase, leading to an accumulation of sphingomyelin. The cherry-red spot is also a characteristic of Tay-Sachs disease, but hepatosplenomegaly suggests Niemann-Pick disease rather than Tay-Sachs. USMLE Case Scenario Vitamin A intoxication causes injury to: 1. Lysosomes 2. Mitochondria 3. Endoplasmic reticulum 4. Microtubules Ans. 1. Lysosomes USMLE Case Scenario A 23-year-old engineer to a physician with complaints of severe muscle cramps and weakness with even mild exercise. Muscle biopsy demonstrates glycogen accumulation, but hepatic biopsy is unremarkable. Which of the following is the most likely diagnosis? 1. Fabrys Disease 2. Hunter syndrome 3. Niemann-Pick disease 4. Pompe’s disease 5. Tyrosinosis 6. Cystinosis 7. Von Gierke’s disease 8. Mcardles Disease Ans. 8. Mcardles Disease USMLE Case Scenario Lead inhibits incorporation of iron into heme. The diminished heme synthesis leads to a hypochromic, microcytic anemia, and there may be mild hemolysis. Basophilic stippling can be an indicator of toxic injury to RBCs. Lead poisoning is characterized by: 1. Elevated zinc protoporphyrin and decreased free erythrocyte protoporphyrin 2. Decreased zinc protoporphyrin and elevated free erythrocyte protoporphyrin 3. Decreased zinc protoporphyrin and decreased free erythrocyte protoporphyrin 4. Elevated zinc protoporphyrin and elevated free erythrocyte protoporphyrin Ans. 4. Elevated zinc protoporphyrin and elevated free erythrocyte protoporphyrin USMLE Case Scenario The Similarity between Vit C and Vit K is: 1. Both help in conversion of proline to hydroxy-proline 2. Both help in post-translational modification 3. Both have anti infective activity 4. Both are involved in coagulation cascade Ans. 2. Both help in post-translational modification 232 USMLE Step 1 Platinum Notes USMLE Case Scenario A patient was diagnosed with isolated increase in LDL. His father and brother had the same disease with increased cholesterol. The likely diagnosis is: 1. Familial type III hyperlipoproteinemia 2. Abetalipoproteinemia 3. Familial lipoprotein lipase deficiency (type I) 4. LDL receptor mutation Ans. 4. LDL Receptor Mutation USMLE Case Scenario The gaps between segments of DNA on the lagging strand produced by restriction enzymes are rejoined/sealed by: 1. DNA Ligases 2. DNA Helicase 3. DNA topoisomerase 4. DNA phosphorylase Ans. 1. DNA Ligases USMLE Case Scenario Intron is not found in: 1. Nuclear DNA 2. Mitochondrial DNA 3. B DNA 4. Z DNA Ans. 2. Mitochondrial DNA USMLE Case Scenario Agranular cytoplasmic reticulum is involved in the synthesis of: 1. Protein 2. Lipid 3. Vitamin 4. Carbohydrate Ans. 2. Lipid USMLE Case Scenario A 45-year-old obese female from Mexico presents to her dermatologist. She noticed that her ‘hair is falling out.’ On questioning, she reports having followed a strict fat-free diet. Her alopecia is probably related to a deficiency of which of the following vitamins? 1. Vitamin A 2. Vitamin C 3. Vitamin D 4. Vitamin E 5. Vitamin K Ans. 1. Vitamin A Vitamin A is necessary for formation of retinal pigments (deficiency can cause night blindness) and for appropriate differentiation of epithelial tissues (including hair follicles, mucous membranes, skin, bone and adrenal cortex). Biochemistry 233 USMLE Case Scenario Coenzyme responsible for carboxylation reaction is: 1. Biotin 2. FAD 3. NADH 4. Thiamine pyrophosphate Ans. 1. Biotin USMLE Case Scenario Xeroderma pigmentation is caused due to a group of closely related abnormalities in: 1. Mismatch repair 2. Base excision repair 3. Nucleotide excision repair 4. Phagosomes Ans. 3. Nucleotide excision repair USMLE Case Scenario If cellular proteins do not fold into a specific conformation, their functions are affected. Certain disorders arise, if specific proteins are misfolded. Which of the following disorders arises due to conformational isomerization? 1. Familial fatal insomnia 2. Hepatitis delta 3. Pernicious anemia 4. Lesch-Nyhan syndrome Ans. 1. Familial fatal insomnia USMLE Case Scenario Fluoride, used in the collection of blood samples for glucose estimation, inhibits the enzyme: 1. Glucokinase 2. Hexokinase 3. Enolase 4. Glucose-6-phosphatase Ans. 3. Enolase USMLE Case Scenario During replication of DNA, which one of the following enzymes polymerizes the Okazaki fragments? 1. DNA Polymerase I 2. DNA Polymerase II 3. DNA Polymerase III 4. RNA Polymerase I Ans. 3. DNA Polymerase III USMLE Case Scenario In an experiment, biologic characteristics of neoplastic and non-neoplastic cells are analyzed in culture. The biochemical experts report that it is observed that cell division in cells derived from malignant neoplasms, but not in normal cells, is aided by the presence of an enzyme which repairs progressive chromosomal shortening. The lack of chromosomal shortening allows the malignant cells to undergo many more divisions than the normal cells. Which of the following enzymes is most likely to have this effect? 1. Reverse transcriptase 2. DNA polymerase 234 USMLE Step 1 Platinum Notes 3. Isomerase 4. Phosphodiesterase 5. Telomerase 6. Protein kinase 7. Topoisomerase Ans. 5. Telomerase USMLE Case Scenario Refsum’s disease is due to deficiency of: 1. Malonate dehydrogenase 2. Thiophorase 3. Succinate thiokinase 4. Phytanic alpha oxidase 5. HGPRT 6. Telomerase 7. Galactokinase Ans. 4. Phytanic alpha oxidase USMLE Case Scenario A 10-year-old girl is seen by a doctor for removal of multiple squamous cell carcinomas of the skin. The patient has nearly white hair, pink irises, very pale skin, and a history of burning easily when exposed to the sun. This patient’s condition is due to deficency of: 1. Malonate dehydrogenase 2. Thiophorase 3. Succinate thiokinase 4. Phytanic alpha oxidase 5. HGPRT 6. Tyrosine hydoxylase 7. Galactokinase Ans. 6. Tyrosine hydoxylase The disease is albinism. The most common form of albinism is caused by a deficiency of copper-dependent tyrosinase (tyrosine hydroxylase), blocking the production of melanin from the aromatic amino acid tyrosine. Affected individuals lack melanin pigment in skin, hair, and eyes, and are prone to develop sun-induced skin cancers, including both squamous cell carcinomas and melanomas. USMLE Case Scenario The molecule, which is the intiator of cataract formation in the eye lens is: 1. Sorbitol 2. Mannitol 3. Inositol 4. Galacticol Ans. 4. Galacticol USMLE Case Scenario A newborn infant refuses breast milk since the 2nd day of birth, vomits on force-feeding but accepts glucose-water, develops diarrhea on the third day, by 5th day she is jaundiced with liver enlargement and eyes show signs of cataract. Urinary reducing sugar was positive but blood glucose estimated by glucose oxidation method was found low. The most likely cause is deficiency of: 1. Galactose-1-phosphate uridyl transferase Biochemistry 235 2. Beta galactosidase 3. Glucose-6-phosphatase 4. Galactokinase Ans. 1. Galactose-1-phosphate uridyl transferase USMLE Case Scenario Excessive ultraviolet radiation is harmful to life. The damage caused to the biological systems by ultraviolet radiation is by: 1. Inhibition of DNA synthesis 2. Formation of thymidine dimmers 3. Ionization 4. DNA fragmentation Ans. 2. Formation of thymidine dimmers USMLE Case Scenario Euchromatin is the region of DNA that is relatively: 1. Uncondensed 2. Condensed 3. Overcondensed 4. Partially condensed Ans. 1. Uncondensed USMLE Case Scenario Proteins are linear polymers of amino acids. They fold into compact structures. Sometimes, these folded structures associate to form homo-or hetero-dimers. Which one of the following refers to this associated form? 1. Denatured state 2. Molecular aggregation 3. Precipitation 4. Quaternary structure Ans. 4. Quaternary structure USMLE Case Scenario Basement membrane degeneration is mediated by: 1. Metalloproteinases 2. Oxidases 3. Elastases 4. Hydroxylases Ans. 1. Metalloproteinases USMLE Case Scenario A ten year old child with aggressive behavior and poor concentration is brought with presenting complaints of joint pain and reduced urinary output. Mother gives history of self mutilitative behavior stating that he tends to mutilate his fingers. Which of the following enzymes is likely to be deficient in this child? 1. HGPRT 2. Adenosine Deaminase 3. Galactokinase 4. Acid Maltase 5. Hydroxylase Ans. 1. HGPRT 236 USMLE Step 1 Platinum Notes USMLE Case Scenario A child presents with massive hepatomegaly and hypoglycemia. There is no improvement in blood glucose on administration of Glucagon. The probable diagnosis is: 1. von Gierke disease 2. McArdle disease 3. Cori’s disease 4. Forbe’s disease Ans. 1. von Gierke Disease USMLE Case Scenario A 2-month-old, breastfed baby that was normal at birth begins to develop GI problems and cirrhosis of the liver. Molecular analysis indicates a normal amount of galactose-1-phosphate uridyl transferase (GALT) mRNA, but no observable enzyme activity. Which of the following would be the best possible explanation for this? 1. Gene deletion 2. Nonsense mutation 3. Premature transcription termination sequence in the DNA 4. Promoter mutation 5. RNA splicing mutation Ans. 2. Nonsense Mutation A nonsense mutation is a mutation in the DNA that leads to a premature stop codon when the mRNA is being translated into protein. The mRNA would be transcribed correctly, but when the protein was being translated, it would be stopped prematurely, leading to a truncated protein. USMLE Case Scenario A child has cystic fibrosis. His parents report a history of recurrent respiratory tract infections and bulky, foul-smelling stools. After assessment of his respiratory tract illness, the practitioner should also look for signs of which vitamin deficiency. 1. Vitamin C 2. Vitamin A 3. Vitamin B1 4. Vitamin B6 Ans. 2. Vitamin A USMLE Case Scenario A 10-year-old child is suspected of having pellagra because of chronic symptoms including diarrhea, a red scaly rash, and mild cerebellar ataxia. However, his diet is not deficient in protein and he appears to be ingesting adequate amounts of niacin. A sister has a similar problem. Chemical analysis of his urine demonstrates large amounts of free amino acids. Which of the following is the most likely diagnosis? 1. Alkaptonuria 2. Carcinoid syndrome 3. Ehlers-Danlos syndrome 4. Hartnup’s disease 5. Scurvy Ans. 4. Hartnup’s Disease MICROBIOLOGY Microbiology 4 HIGH YIELD USMLE POINTS Prokaryotes •• •• •• •• •• •• Absence of nuclear membrane Absence of nucleolus Absence of DNA Absence of cytoplasmic organalles Absence of sterols/muramic acid Bacteria are prokaryotes Eukaryotes •• •• •• •• •• Presence of nuclear membrane Presence of nucleolus Presence of DNA Presence of cytoplasmic organalles Presence of sterols/ muramic acid USMLE Case Scenario After a skin infection in the nail, A Pathologist is talking about a nonmotile organism is found to be eukaryotic, with both RNA and DNA present. Ribosomes are 80 S and reproduction occurs by budding. Most likely the organism is: 1. Virus 2. Bacteria 3. Fungus 4. Viroid Ans. 3. Fungus Characteristics of Different Organisms Characteristics Viruses Bacteria Fungi •• Nucleic acid Either DNA/RNA Both Present Both Present •• Nucleus Absent Prokaryotic Eukaryotic •• Ribosomes Absent 70 S 80 S •• Mitochondria Absent Absent Present •• Motility Nil Present Nil Binary fission Budding •• Reproduction 240 USMLE Step 1 Platinum Notes USMLE Case Scenario ‘Lipopolysaccharide’ is an important component of: 1. Gram-positive cells 2. Gram-negative cells 3. Neither gram-positive nor gram-negative cells 4. Both gram-positive and gram-negative cells Ans. 2. Gram-negative cells Difference between Gram-Positive and Gram-Negative Cells Component Gram-Positive Cells Gram-Negative Cells Peptidoglycan Thick Thin Teichoic acid Present Absent Periplasmic space Absent Present Lipopolysaccharide Absent Present USMLE Case Scenario Which of the following structures is found only in gram-negative microorganisms: 1. Cell envelope 2. Exotoxin 3. Peptidoglycan 4. Periplasmic space Ans. 4. Periplasmic space FUNCTIONS OF DIFFERENT COMPONENTS OF CELL ENVELOPE (USMLE High Yield Points) •• Capsule: Antiphagocytic and immunogenic •• Capsulated organisms: –– Pneumococus –– Anthrax bacillus –– Bordetella –– Meningococci –– –– –– –– •• •• •• •• •• •• Klebsiella Cryptococcus, H. influenza Bacteroids V. parahemolyticus Teichoic acid: Attachment to epithelial surfaces and immunogenic Cell wall: Rigid support, protection from osmotic damage Cytoplasmic membrane: Membranous matrix for respiratory pathways and cell wall synthesis Porin proteins: Passive transport of aqeous materials Perplasmic space: Extracellular enzymes, ↓osmotic pressure Inner membrane: Matrix for enzymes of respiratory pathways and cell wall synthesis Detection Techniques •• •• •• •• Flagella are detected by Dark ground microscopy Fimbriae are detected by Hemagglutination Spores are detected by Acid fast (ZN staining) Capsules are detected by India ink/Quelling reaction Microbiology 241 Phases of Bacterial Growth Cycle Lag Phase Nutrients incorporated Log Phase Rapid cell division Stationary Phase Cell Death = Cell formation Death Phase Cell death > Cell formation Phases of bacterial growth USMLE Case Scenario An antibiotic, such as penicillin, which modifies cell wall synthesis, tends to be most effective during which phase of bacterial growth in a closed system? Ans. Log phase BACTERIAL CONJUGATION: (USMLE FAVORITE) •• Bacterial conjugation is the transfer of genetic material between bacteria through direct cell-to-cell contact. •• Discovered in 1946 by Joshua Lederberg and Edward Tatum. •• Conjugation is a mechanism of horizontal gene transfer •• The prototype for conjugative plasmids is the F-plasmid, also called the F-factor.The F-plasmid is an episome (a plasmid that can integrate itself into the bacterial chromosome by genetic recombination) of about 100 kb length.The host bacterium is called F-positive or F-plus(d enoted F+). Strains that lack F plasmids are called F-negative or F-minus (F-). •• Bacterial conjugation is often incorrectly regarded as the bacterial equivalent of sexual reproduction or mating. •• It is merely the transfer of genetic information from a donor cell to a recipient. Transduction Transduction is the process by which DNA is transferred from one bacterium to another by a virus It also refers to the process whereby foreign DNA is introduced into another cell via a viral vector This is a common tool used by molecular biologists to stably introduce a foreign gene into a host cell’s genome. When bacteriophages (viruses that infect bacteria) infect a bacterial cell, their normal mode of reproduction is to harness the replicational, transcriptional, and translation machinery of the host bacterial cell to make numerous virions, or complete viral particles, including the viral DNA or RNA and the protein coat. 242 USMLE Step 1 Platinum Notes Bacterial Transformation Bacteria transformation maybe referred to as a stable genetic change brought about by taking up naked DNA (DNA without associated cells or proteins), and competence refers to the state of being able to take up exogenous DNA from the environment. Procedure Process DNA Transferrred •• Conjugation Bacterium to Bacterium Chromosomal/Plasmid •• Transduction By Virus Any Gene •• Transformation DNA taken Directly Any DNA Plasmids: (USMLE Favorite) •• Extrachromosomal genetic material •• Generally have covalently, closed, circular DNA (ccc) •• One class of plasmids, Episomes maybe integrated into bacterial DNA •• Plasmids carry genetic material for variety of genes, (Fertility genes, antibiotic resistance, exotoxins) Involved in multi drug resistance transfer. Bacteriophage Viral DNA maybe inserted into bacterial chromosome as prophage by a temperate virus which directs the synthesis of a virulence factor making bacterium more pathogenic. Transposons •• •• •• •• Mobile genetic elements that can move themselves from one DNA to other Jumping genes Create additional mutations Have sequences of indirect repeats of bases at each end According to Shape Bacteria are Classified into •• •• •• •• •• •• •• Cocci: Spherical shaped bacteria Bacilli: Rod shaped cell Vibrio: Comma shaped cells Spirilla: Rigid spiral forms Spirochetes: Flexuous spiral forms Actinimycetes: Branching filamentous form Mycoplasma: Lacks cell wall, hence do not possess stable morphology USMLE Case Scenario An intravenous drug abuser is found to have infective endocarditis. Most common organism in Acute Endocarditis: Staph aureus. The organism is: 1. A Gram-positive coccocus 2. A Gram-negative rod 3. A Gram-positive coccus 4. A Gram-positive rod Ans. 3. A Gram-positive coccus Microbiology 243 USMLE Case Scenario Among the following which is an obligate intracellular organism: 1. Nocardia 2. Chlamydia 3. Bacillus 4. Legionella Ans. 2. Chlamydia USMLE Case Scenario A 26-year-old male complains of a severe headache and weakness. His condition rapidly deteriorates over a period of hours. A lumbar puncture is performed and a Gram’s stain of spinal fluid reveals Neisseria meningococcus. The organism is: 1. Gram-negative diplococci 2. Gram-positive cocci 3. Gram-positive bacillus 4. Obligate intracellular organism Ans. 1. Gram-Negative Diplococci CLASSIFICATION: FREQUENTLY ASKED IN USMLE Gram-Positive Cocci: •• Streptococcus •• Staphylococcus Gram-Positive Spore forming Bacilli: •• Bacillus Anthraxus (Aerobic) •• Clostridium (Anaerobic) Gram-Positive Nonspore forming Bacilli: •• Corynebacterium diphtheriae •• Listeria •• Actinomyces •• Nocardia Gram-Negative Cocci: •• Neisseria gonococcus, meningococcus Gram-negative Rods: •• Hemophilus •• Bordetella •• Legionella •• E coli •• Serratia •• Klebsiella •• Salmonella •• Shigella •• Vibrio •• Pseudomonas 244 USMLE Step 1 Platinum Notes Obligate intracellular parasites: •• Rickettsia •• Chlamydia Thin walled spirochetes: •• Treponema •• Borrelia •• Leptospira Wall less: •• Mycoplasma USMLE Case Scenario A 33-year-old Indian reported in New York and is found to have chronic weight loss, pyrexia and easy fatiguibility. A chest X-ray reveals miliary form of tuberculosis. The feature of the organism causing the disease is: 1. Aerobe 2. Obligate aerobe 3. Anaerobe 4. Obligate anaerobe Ans. 2. Obligate aerobe USMLE Case Scenario Gastric ulcers are associated with malignancy, and therefore biopsy should be performed when they are discovered. This association with malignancy is not found with duodenal ulcers. The increased risk for malignancy with gastric ulcers is a good reason to test patients for H pylori and initiate treatment if it is found. H pylori is a: 1. Aerobe 2. Anaerobe 3. Obligate aerobe 4. Microaerophilic Ans. 4. Microaerophilic Obligate aerobes Use oxygen dependent mechanisms to generate ATP Examples •• Pseudomonas aeruginosa •• Mycobacterium tuberculosis •• Nocardia Obligate anaerobes Lack catalase and superoxide dismutase Examples (ABC) •• Actinomyces •• Bacteroids •• Clostridium Microaerophilic •• Campylobacter •• H pylori Microbiology 245 USMLE Case Scenario An organism causing otitis media in children and pneumonia in adults. With a peculiar growth requirement, requiring factor X (hematin) and factor V (NAD). The most likely organism is: 1. H. influenza 2. B. pertusis 3. M. tuberculosis 4. Klebsiella Ans. 1. H. Influenza Remember Bacterial Cultures: (High Yield for USMLE) •• Smith noguchi medium: Spirochetes •• Selenite F Broth: Salmonella, shigella •• Dorset egg medium: Mycobacterium •• Noguchi medium : Borellia •• BYCE medium: Legionella •• Lofflers serum slope: Corynebacterium diphtheria •• Tellurite media: Corynebacterium diphtheria •• Thayer martin media: N.gonorrhea •• Korthof media: Leptospira •• Staurts media: Leptospira •• Fletcher media: Leptospira •• Chocolate agar: H.influenza •• Bordet gengou: B.pertusis •• Lownstein Johnson: M.tuberculosis •• Sabourdars media: Fungi •• Skirrows media: Campylobacter Jejuni USMLE Favorite EXOTOXIN ENDOTOXIN •• Mostly Gram-positive bacteria •• Gram-negative bacteria •• Polypeptides •• Lipopolysaccharides •• Highly toxic •• Low toxicity •• Highly antigenic •• Poorly antigenic •• Toxoids used as vaccines •• No toxoids, no vaccines •• Heat sensitive •• Heat stable •• Secreted from cell •• Not secreted from cell Antiphagocytic Structures (CAMP) •• •• •• •• Capsule Pilli of Neisseria Gonorrhea M protein of streptococcus pyogenes A protein of staph aureus 246 USMLE Step 1 Platinum Notes Pathogenesis of shock Capsulated Organisms •• •• •• •• •• •• Streptococcus Pneumoniae Klebsiella Pneumoniae Hemophilus influenza Pseudomonas Aeruginosa Neisseria meningitidis Cryptococcus neoformans USMLE Case Scenario Cryptococcus is nondimorphic yeast, meaning that it exists only in the yeast form and it reproduces by budding. It is found worldwide in bird droppings (think pigeons). It can also cause transient pulmonary illness in otherwise healthy individuals. The feature of Cryptococcus is that: 1. It is capsulated so takes India ink stain 2. It is noncapsulated so takes India ink stain 3. It is capsulated so does not take India ink stain 4. It is noncapsulated so does not take India ink stain Ans. 1. It is capsulated so takes India ink stain Understanding Toxins Commonly asked in USMLE Examination •• ‘Pseudomonas alpha toxin,’ which is responsible for the tissue damage, inhibits Protein synthesis by acting on EF-2 with a primary target cell in the liver •• The diphtheria toxin has a similar action, although its target cells are heart and nerve •• Anthrax toxin is an ‘Adenylate cyclase’ that causes fluid loss from cells •• Botulinum toxin is a ‘neurotoxin’ that decreases acetylcholine synthesis •• Cholera toxin acts to increase ‘adenylate cyclase’ activity by ribosylation of GTP-binding protein •• Clostridium perfringens alpha toxin is a ‘lecithinase’ •• Escherichia coli labile toxin works in a fashion similar to the cholera toxin •• Pertussis toxin causes fluid loss by ‘ribosylating Gi’ •• Shiga toxin decreases protein synthesis by inhibiting the ‘60S’ ribosomal subunit •• Streptococcal ‘erythrogenic’ toxins act similarly to the diphtheria toxin, but do so by increasing cytokine production •• Tetanus toxin is a ‘neurotoxin’ that ‘inhibits the inhibitory neurotransmitters glycine and GABA’ •• TSST-1 is a ‘superantigen’ that acts by increasing cytokine production and decreasing liver clearance. A superantigen, such as TSST- 1 or staphylococcal enterotoxin, cross-links the variable domain of the TCR b chain to the MHC class II molecule and specifically induces massive T cell activation. Microbiology 247 REMEMBER Clostridial Associations in USMLE USMLE Case Scenario Among the following organisms would most likely cause infection after a sterilization procedure that killed vegetative cells but did not kill spores? 1. Chlamydia 2. Clostridium 3. Pseudomonas 4. Streptococcus Ans. 2. Clostridium Clostridium botulinum spores (found in honey) in the baby’s gastrointestinal tract. Patients improve when honey is removed from the diet. This disorder is most common in children under the age of six months; older children and adults do not appear to be vulnerable to this form of botulism, but are susceptible to botulism caused by ingestion of preformed toxin Clostridium difficile causes pseudomembranous colitis, especially after antibiotic therapy Clostridium perfringens causes gas gangrene and gastroenteritis, and it is not associated with ingestion of honey Clostridium tetani causes tetanus, and does not cause a foodborne illness in infants. Important Bacterial Toxins: (USMLE Favorite) Corynebacterium Diphtheria Diphtheria Inactivates EF2: shuts down protein synthesis Clostridium tetani Tetanus Blocks release of Glycine Clostridium boutilinium Boutilism Blocks release of Acetyl choline Clostridium difficile Pseudomembranous colitis Exotoxin BCytotoxin disaggregates actin filaments Clostridium perfringens Gas gangrene Alpha toxin acting as lecithinase Bacillus anthraxus Anthrax Edema factor, Lethal factor Staph aureus TSS Superantigen binding directly to MHC II Stret pyogenes Scarlet fever Superantigen E coli Watery diarrhea Stimulates adenylate cyclase (Gs) Vibrio cholera Cholera Stimulates adenylate cyclase (Gs) Bordetella Pertussis Whooping cough Stimulates adenylate cyclase (Gi) Main toxins USMLE Case Scenario Pseudomembranous colitis occurs as a result of treatment with clindamycin or ampicillin. You would confirm your suspicion by sending a stool culture to be tested for the presence of the: 1. Toxin 2. Flagella 248 USMLE Step 1 Platinum Notes 3. Bacteria 4. Virus Ans. 1. Toxin USMLE Case Scenario An injection of a substance from gram-negative bacteria into the vascular system will rapidly produce myocardial dysfunction, hypotension, disseminated intravascular coagulation and coma resembling septic shock. The substance is most likely: 1. Lipopolysaccharide 2. Protein only 3. Saccharide 4. Hapten Ans. 1. Lipopolysaccharide USMLE Case Scenario A 18-year-old, ill-appearing woman comes OPD with a fever. She notes the recent development of nausea, diarrhea, and a rash. Her last menstrual period began 3 days ago. Physical examination is remarkable for blood pressure of 90/40 mm Hg and heart rate of 120 beats per minute. A diffuse erythematous rash with desquamation over feet is noted. Infection with which of the following toxin is the most likely cause of these signs and symptoms? 1. Clostridium perfringens toxin 2. Shigella dysenteriae toxin 3. Staphylococcus aureus toxin 4. Staphylococcus epidermidis toxin Ans. 3. Staphylococcus aureus toxin Toxins ↑c AMP levels (PACE) •• •• •• •• Pertusis toxin Anthrax toxin Cholera toxin E coli toxin (labile) Site Important organism •• Skin •• Staph Epidermidis •• Nose •• Staph Aureus •• Mouth •• Strept Viridians •• Dental plaque •• Strept Mutans •• Vagina •• Lactobacillus, E coli, Group B Strept •• Colon •• Bacteroids, E coli •• Throat •• Strept Viridians USMLE Case Scenario Bacillus anthracis is found in many animal species, and humans can acquire the organism either through contact with the animals or from locally contaminated soiL Feature of colonies of Anthrax bacillus is: 1. Swimming Growth 2. Swarm of Gnats or Fish in Stream 3. Stalactite Growth 4. Medusa Head Ans. 4. Medusa Head Microbiology 249 Colony Appearances Colony Appearance in culture Organism 1. Draughtsman (Concentric Rings) –– –– –– –– Pneumococci Medusa Head Frosted Glass Inverted Fir Tree in Stab Culture String of pearls B Anthracis 2. Swimming Growth (Fishy or Seminal Smell) Proteus 3. Swarm of Gnats or Fish in Stream V Cholerae 4. Stalactite growth Yersinia Pestis 5. Thumb print appearance, Bisected pearls or mercury drops, B Pertussis Aluminium Paint appearance 6. Cigar bundle (globi) appearance M Leprae 7. Fried egg Mycoplasma 8. Bread crumb Actinomyces israelii 9. Oil Paint Staphylococci 10. School of Red fish H ducreyi 11. Stately Motility Clostrida Gram-Positive Bacilli •• Corynebacterium Diphtheriae Aerobic Catalase + Nonhemolytic Toxin production •• Diphtheria •• Listeria monocytogenes Aerobic Hemolytic •• Meningoencephalitis in neonates, immunocompromised •• Bacillus anthracis •• Bacillus cereus •• Bacillus anthracis Aerobic spore forming •• •• •• •• Anthrax Food poisoning (reheated rice) Most common form: cutaneous (hide porters disease) Most fatal form: pulmonary (wool sorters disease) Anaerobic, spore forming •• •• •• •• •• Food poisoning, gas gangrene Gas gangrene Tetanus Botulism Pseudomembranous colitis Aerobic, rod shaped •• Tuberculosis •• •• •• •• •• Clostridium welchii Clostridium septicum Clostridium tetani Clostridium botulinium Clostridium difficile •• Mycobacterium tuberculosis •• M aviumintercellulare •• M leprae •• Cervical LAP •• Cannot be cultured •• Acid fast rods •• Cooler parts of body •• Do not follow kochs postulates •• Leprosy 250 USMLE Step 1 Platinum Notes USMLE Case Scenario A gram-positive spore-forming rod that is associated with food poisoning outbreaks following the ingestion of fried rice. The organism survives the boiling of the rice because it is a spore-former. It germinates as the rice cools, grows, and elaborates an enterotoxin that is responsible for the nausea and vomiting characteristic of the disease. The most likely organism is: 1. Bacillus anthracis 2. Bacillus cereus 3. Staph aureus 4. Salmonella Ans. 2. Bacillus cereus USMLE Case Scenario A 33-year-old cave digger who has been excavating acave develops a pustule on his hand. The pustule then ruptures to form a black eschar surrounded by expanding brawny edema. Which of the following gram-positive organisms is the most likely cause of this condition: 1. Clostridium welchii 2. Clostridium tetani 3. Bacillus anthracis 4. Clostridium botulinium Ans. 3. Bacillus anthracis USMLE Case Scenario A 58-year-old has developed thick, erythematous nodules on her ears and nose with significant associated sensory loss. The nodules have grown slowly over the course of many years. Biopsy of the lesions shows dermal granulomas with giant cells but no acid-fast bacteria. Culture on blood agar and Lowenstein-Jensen medium shows no growth. The disease is identified as leprosy. The organism is: 1. Gram-positive, acid fast rod 2. Gram-positive, nonacid fast rod 3. Gram-negative, acid fast rod 4. Gram-negative, nonacid fast rod Ans. 1. Gram-positive, acid fast rod Hansen’s disease: A key feature in the description is the fact that the organism is acid-fast. Both of the mycobacteria, M avium-intracellulare and M leprae are strongly acid-fast, that is they retain the carbol fuchsin dye in the face of acidalcohol decolorization. M leprae has a predilection for the skin and cutaneous nerves, thereby producing the symptoms of depigmentation and anesthetic cutaneous lesions. This loss of peripheral nerve function leads to many of the disfiguring features of the disease; because the patients do not have normal pain sensation, they sustain repeated injuries. In addition, the organism attacks cartilage and causes granuloma formation in the skin, leading to some of the facial disfigurement. Gram-Negative Bacilli: (High Yield for USMLE) Hemophilus influenza Hemophilus parainfluenza Hemophilus aegyptius Hemophilus ducreyi Needs factor X and V, satellite phenomenon Koch weeks bacillus Acute epiglottitis, meningitis in children, otitis media COPD Exacerbations Conjunctivitis Genital ulcers, chancroid Bordetella pertusis Cocco bacillus Bordet Gengou media Whooping cough Yersenia pestis Yersenia enterocolitica Aerobic, bipolar staining Bubonic plague, pneumonic plague Gastroenteritis, Pseudoappendicitis Microbiology 251 Pasturella multicoida Aerobic Wound sepsis following dog bites Vibrio cholera Vibrio para hemolyticus Aerobic curved motile rod Cholera Food poisoning (sea food) shellfish Campylobacter Microaerophilic Acute diarrhea (bloody) Gullian barre syndrome Reactive arthritis E coli Aerobic, lactose fermenter, enterotoxin UTI, Peritonitis, cholecystitis, neonatal meningitis, travelers diarrhea HUS, TTP, hemorrhagic colitis Verocytotoxin, shiga like toxin E coli 0157: H7 Nonsorbitol fermenting Klebsriella pneumoniae Aerobic, lactose fermenter Proteus mirabilis •• •• •• •• Shigella Nonlactose fermenters Nonmotile Bacillary dysentery •• Bacteroids •• Anaerobic, nonsporing •• Abscesses, septicemia •• Fusobacterium •• Anaerobic, nonsporing •• Vincents angina, gingivitis Acinetobacter Anaerobes Hospital acquired infections •• •• •• •• Borrelia vincenti Borrelia recurrentis Borrelia duttoni Borrelia burgdorfei Helicobacter pylori Swarming growth on agar Aerobic nonlactose fermenter Peritrichous flagella Urease positive Aerobic Anaerobic Anaerobic Anaerobic •• •• •• •• •• Pneumonia (currant jelly) Spiral, flagellate Microaerophilic Urease positive Invasive Campys medium, Skirrows agar UTI •• •• •• •• Vincents angina Relapsing fever (r-r) Relapsing fever Lyme disease Peptic ulcer, gastric cancer, gastric lymphoma Extra gastric diseases •• Treponema pallidum •• Treponema pertenue •• Treponema carateum Anaerobic, spiral, motile Anaerobic Anaerobic •• Syphilis •• Yaws •• Pinta Leptospira icterohemorrhagica Leptospira canicola Anaerobic Anaerobic Weils disease Canicola fever Obligate intracellular bacteria •• •• •• •• Obligate intracellular bacteria smallest free living bacteria no cell wall sterols in membrane Primary atypical pneumonia Urethritis, PID •• •• •• •• Rickettsia prowazekii Ricketssia mooseri Ricketssia burnetti Ehrlichia chaffeensis Mycoplasma pneumonia (Eaton agent) Ureaplasma urealyticum M hominis Epidemic typhus Endemic typhus Q fever Ehrlichiosis Pyelonephritis PID 252 USMLE Step 1 Platinum Notes USMLE Case Scenario An organism is causing urinary tract infections. It has ability to breakdown urea is thought to contribute to the development of struvite kidney stones due to the elevation of urine pH by production of ammonia. The said organism is also having swarming motility. The organism is identified as proteus species. It is a: 1. Aerobic nonlactose fermenter 2. Anaerobic nonlactose fermenter 3. Aerobic lactose fermenter 4. Anaerobic lactose fermenter Ans. 1. Aerobic nonlactose fermenter USMLE Case Scenario A 33-year-old patient presents with a red macule or papule at the site of the tick bite. This lesion, called erythema chronicum migrans, slowly expands to form a large annular lesion with a red border and central clearing. The patient also has severe headache, stiff neck, chills, arthralgias and profound malaise and fatigue. The causative organism is: 1. Borrelia vincentii 2. Borrelia recurrentis 3. Borrelia duttonii 4. Borrelia burgdorferi Ans. 4. Borrelia burgdorferi USMLE Case Scenario A child presents with chronic enteritis, failure to thrive, hypoalbuminemia, and hypokalemia. Other findings include acute right lower quadrant abdominal pain, tenderness, nausea and vomiting. The infection mimics appendicitis or Crohn’s disease. Most likely organism is: 1. Yersinia enterocolitica 2. Hemophilus aegyptius 3. Borrelia duttonii 4. Hemophilus ducreyi Ans. 1. Yersinia enterocolitica USMLE Case Scenario A 66-year-old man is brought to a rural hospital. He has severe bronchopneumonia after sudden onset of chills, fever, and headache several days ago. One day later, he coughed up blood-tinged sputum. Chest X-ray reveals patchy infiltrates and segmental consolidation. Which organism with bipolar staining pattern is the most likely cause of this man’s pneumonia? 1. Yersinia Pestis 2. Streptococcus pneumonia 3. Staph aureus 4. Leptosporia Ans. 1. Yersinia Pestis USMLE Case Scenario A curved, gram-negative rod which is microaerophilic is causing enterocolitis with diarrhea and less commonly, chronic gastritis. Most likely the organism is: 1. Vibrio cholera 2. H pylori 3. E coli 4. Campylobacter jejuni Ans. 4. Campylobacter jejuni Microbiology 253 USMLE Case Scenario A 8-year-old girl is bitten in the leg by a dog. She presents the next day with fever and bone pain localized to her right calf. X-ray reveals a lytic lesion of the left femur. Results of the boneculture are pending. Infecting organism is most likely to be: 1. Pasteurella 2. Bartonella 3. Yersinia 4. Bordetella Ans. 1. Pasteurella USMLE Case Scenario An infection is characterized by rapidly evolving cellulitis starting at the site of the bite. A gram-negative rod was found to be spread via dog bites. Most likely organism is: 1. Pasteurella 2. Bartonella 3. Yersinia 4. Bordetella Ans. 1. Pasteurella •• Actinomyces israelli Anaerobic, branching filaments, non acid fast, sulfur •• Actinomycosis, lumpy jaw granules •• Nocardial asteroids Anaerobic, branching filaments, partially acid fast Staph Aureus: USMLE High Yield •• Gram-positive •• Cluster-forming coccus, nonmotile, nonspore forming facultative anaerobe •• Fermentation of glucose produces mainly lactic acid.+ •• Ferments mannitol (distinguishes from S epidermis)+ •• Catalase positive+ •• Coagulase positive + •• Coagulase is responsible for pathogenecity •• Golden yellow colony on agar •• Normal flora of humans found on nasal passages, skin and mucous membranes •• Food poisoning is due to preformed endotoxin •• Occurs within 6 hours of food intake •• Panton valentine leucocidin is seen in staph infections •• Especially diary products involved in poisoning CAUSES: •• Acute osteomyelitis •• Acute mastitis •• Botromycosis •• SSSS •• Furunculosis, carbuncle •• Acute endocarditis •• Sycosis barbae •• Tropical polymyositis •• Nocardiosis 254 USMLE Step 1 Platinum Notes Methicillin Resistant Staphylococcus Aureus (MRSA) •• MRSA is a major nosocomial pathogen •• Causes severe morbidity and mortality worldwide •• 40% of nosocomial Staph aureus infections are methicillin resistant •• Hospital personnel maybe carriers •• Spread by hand, usually of health care workers Microbiology •• Methicillin resistance is mediated by the mecA gene •• Encodes a single additional penicillin binding protein PBP2a •• Expression of mecA can be either constitutive or inducible Risk factors for MRSA coloniation (USMLE Favorite) •• Advanced age •• Male gender •• Previous hospitalization •• Length of hospitalization •• Stay in ICU •• Chronic medical illness •• Prior and prolonged antibiotic therapy •• Presence and size of a wound •• Exposure to colonized or infected patient •• Presence of invasive indwelling device Clinical presentations •• Pneumonia •• Surgical site infections •• Line sepsis •• Intra-abdominal infections •• Osteomyelitis •• Toxic shock syndrome Infection control •• Screening of patients and staff •• Handwashing •• Use of gowns and gloves •• Topical antimicrobials •• Isolation of patients •• Environmental cleaning Management •• Vancomycin is used •• Teicoplanin maybe used if the isolate is resistant to vancomycin •• Linezolid is new class of antimicrobial agent, active against MRSA and VRE •• Quinupristin/Dalfopristin are newer alternative USMLE Case Scenario Microbiologic studies on a gram-positive coccus isolated from a skin abscess demonstrate a positive catalase test and a positive coagulase test. This is most consistent with which of the following organism: 1. Staph aureus 2. Streptococcus 3. Neisseria gonorrhea 4. Neisseria meningococcus Ans. 1. Staph Aureus Microbiology 255 USMLE Case Scenario A 22 -year-old, ill-appearing woman comes to the emergency room with a fever. She notes the recent development of nausea, diarrhea, and a rash. Her last menstrual period began 2 days ago. Physical examination is remarkable for blood pressure of 88/40 mm Hg. A diffuse erythematous rash with areas of desquamation over the hands and feet is noted. Infection with which of the following agents is the most likely cause of these signs and symptoms? 1. Streptococcus 2. Neisseria gonorrhea 3. Neisseria meningococcus 4. Staph aureus Ans. 4. Staph Aureus USMLE Case Scenario A 4-year-old girl with a history of hydrocephalus is brought to the neurologist by her parents with a severe headache and fever. The girl underwent a surgery for a ventricular-peritoneal shunt 2 months ago and the neurologist suspects that an infection has occurred. Organisms would most likely be isolated from the shunt tubing is: 1. Staph aureus 2. Streptococcus 3. Staphylococcus epidermidis 4. Meningococcus Ans. 3. Staphylococcus epidermidis USMLE Case Scenario A 56-year-old has developed acute osteomyelitis in his left tibia. The most common organism a pathologist would be thinking about is: 1. Streptococcus 2. Staphylococcus epidermidis 3. Meningococcus 4. Staph aureus Ans. 4. Staph aureus Streptococci: USMLE High Yield •• C carbohydrate is used for Lancfield classification •• M protein is mainly responsible for pathogenecity •• MC organism causing cellulitis: streptococcus pyogenes Causes: •• Erysipelas •• Scarlet fever •• Purpureal sepsis •• Non suppurative infections: rheumatic fever, glomerulonephritis Are usually initially speciated by their hemolytic capacity on sheep blood agar. Beta-hemolytic streptococci include groups A, B, and D S agalactiae is the classic group B streptococcus. The non beta-hemolytic streptococci consist principally of the pneumococci and the viridans group. High Yield Points Repeated Often: (USMLE Favorite) •• Str. agalactiae •• Neonatal meningitis, neonatal sepsis •• Str. Bovis •• Endocarditis •• Str. Pneumonia •• Pneumoniae, Otitis media 256 USMLE Step 1 Platinum Notes •• Str. Mutans •• Dental caries •• anaerobic streptococci •• Purpureal sepsis •• Str. Pyogenes •• Erysipelas, Cellulitis •• Impetigo, scarlet fever, Rheumatic fever, Acute Glomerulonephritis •• Str. Viridians •• Endocarditis USMLE Case Scenario A 1-week-old female infant with symptoms of vomiting and anorexia has a temperature of 102° F. A bulging fontanel is noted on physical examination. The most likely coccusis: 1. Streptococcus agalactiae 2. Streptococcus pneumonia 3. Streptococcus viridians 4. Streptococcus pyogenes Ans. 1. Streptococcus agalactiae USMLE Case Scenario A 55-year-old man presents with an episode of shaking chills the previous night. He has now developed right-sided pleuritic chest pain, fever, sweats, malaise, purulent sputum, and mild hemoptysis. On examination, the patient is diaphoretic but alert, with right basilar rales. Chest X-ray films show a right lower lobe infiltrate with blunting of the right costophrenic angle. The causative organism implicated is: 1. Streptococcus agalactiae 2. Streptococcus pneumonia 3. Streptococcus viridians 4. Streptococcus pyogenes Ans. 2. Streptococcus pneumonia ‘Streptococcus agalactiae’ •• •• •• •• •• Group b Streptococci. Gram-positive Beta hemolytic Bacitracin Resistant Hydrolyses hippurate C AMP test positive Acute Meningitis: Commonest Bacterial Organisms •• Neonates: Group B streptococci, E coli •• Adolescents and young adults: N meningitidis •• Elderly: Strept Pnemoniae, Listeria Monocytogenes Beta hemolysis is shown by: •• Strep pyogenes •• Strept agalataciae •• Staph aureus •• Listeria monocytogenes •• Bacillus subtilis Alpha hemolysis is shown by: •• Strep pneumonia •• Strep viridians Microbiology 257 •• Sterpt mutans •• Strep sanguis •• Enterococcus USMLE High Yield •• The catalase test is used to differentiate Staphylococci from Streptococci. Staphylococci are catalase positive, Streptococci are catalase negative •• The coagulase test is used to differentiate Staph aureus from the other Staph spp. Staph aureus is coagulase positive; the others are negative •• Sensitivity to novobiocin is used to differentiate Staph saprophyticus (resistant) from Staph epidermidis (sensitive) •• Sensitivity to optochin is used to differentiate Strep pneumoniae (sensitive) from viridans Strep (resistant). Catalase + ve Coagulase + ve Staph aureus Catalase – ve Coagulase – ve Streptococcus Catalase + ve Coagulase – ve Novibocin sensitive → st epidermidis Novibocin resistant → st saprophyticus Distinguishing strept and staph Streptococcus Bovis •• •• •• •• The main nonenterococcal group D streptococcal species that causes human infections is S bovis S bovis endocarditis is often associated with neoplasms of the gastrointestinal tract 3/4 Most frequently a colon carcinoma or polyp 3/4 but is also reported in association with other bowel lesions S bovis are reliably killed by penicillin as a single agent, and penicillin is the treatment of choice for S bovis infections. USMLE Case Scenario A 88-year-old patient from North America with colorectal cancer develops severe septicemia complicated by bacterial type of endocarditis among the below mentioned choices. You would expect the blood cultures to grow. 1. Streptococcus agalactiae 2. Streptococcus bovis 3. Streptococcus pneumonia 4. Streptococcus pyogenes Ans. 2. Streptococcus bovis Catalase Positive Organisms are Staph aureus Pseudomonas Aspergillus Candida Citrobacter Enterobacter E coli Klebsiella Shigella Yersinia 258 USMLE Step 1 Platinum Notes Gems about Pneumococcus •• Gram-positive •• Capsulated •• Most virulent: Type C •• Draughtsman colonies •• Quelling reaction seen •• Vaccine is made from capsule •• Lanceolate, flame shaped diplococcus •• Bile soluble •• Optochonin sensitive •• Virulence is due to capsule USMLE Case Scenario A Eight year-old boy from California presents to the pediatrician because his mother noticed a ‘smoky’ color to his urine. The child suffered a sore throat several weeks ago that was left untreated. Physical examination reveals hypertension and mild generalized edema. Urinalysis is significant for red blood cell casts. Which of the following accurately describes the microorganism responsible for this child’s illness? 1. Streptococcus 2. Staphylococcus 3. Gonococcus 4. Camplyobacter Ans. 1. Streptococcus USMLE Case Scenario Which of the following organisms is the most common cause of community-acquired pneumonia? 1. Chlamydia pneumoniae 2. Mycoplasma pneumoniae 3. Staphylococcus aureus 4. Streptococcus pneumonia Ans. 4. Streptococcus pneumonia Neisseria Gonococcus USMLE High Yield •• •• •• •• •• •• Means flow of seeds Intracytoplasmic Gram-negative Noncapsulated Do not ferment maltose. Ferments glucose Kidney shaped Causes: –– Urethritis –– Cervicitis –– Salpingitis –– Vaginitis –– Conjunctivitis –– Meningitis, arthritis, endocarditis Microbiology 259 USMLE Case Scenario A sexually active 22-year-old manfrom Kansas develop sacute epididymitis and orchitis. Needle biopsy demonstrates a prominent leukocytic infiltrate with numerous neutrophils. Which of the following organisms is the most likely cause of this man’s infection? 1. Escherichia coli 2. Mycobacterium tuberculosis 3. Neisseria gonorrheae 4. Staphylococcus Ans. 3. Neisseria gonorrheae Neisseria Meningococcus •• •• •• •• •• •• Gram-negative diplococcic Capsulated Carriers are a source of infection Cause Waterhouse-Friderichsen syndrome, Meningitis Neisseria meningitides: Capsule + Maltose Fermentation+ Neisseria gonococcus: Capsule-Maltose Fermentation– Corynebacterium Diphtheriae: USMLE High Yield •• •• •• •• •• •• •• •• •• •• •• •• •• Gram-positive, nonmotile, nonsporing, noncapsulated Babes ernest/volutin granules seen/Metachromatic granules seen Loefflers serum slope, Tellurite media used Eleks gel precipitation test used Incubation period 2–6 days Faucial (tonsillar) not facial diphtheria is the commonest type of diphtheria Pseudomembrane formation is a feature Bulls neck (cervical lymphadenopathy) occurs in diphtheria Diphtheria toxin inhibits protein synthesis Toxin is phage mediated Corynebacterium parvum is used as immunomodulator Corynebacterium pseudotuberculosis is Nocards bacillus Corynebacterium minnusitum causes Erythrassma. Diphtheria •• Daisy head colony (C Diphtheriae) gravis •• Frogs egg colony (C Diphtheriae) intermedius •• Poached egg colony (C Diphtheriae) mitis 260 USMLE Step 1 Platinum Notes Corynebacterium Minutissimum •• It is a part of normal skin flora •• It is lipophilic, Gram-positive, aerobic, catalase positive but nonspore forming diphtheroid •• It ferments glucose, dextrose, sucrose, maltose and mannitol Erythrassma is a chronic superficial infection of intertriginous areas •• Organism causing erythrassma is Corynebacterium Minutissimum •• Erythrassma produces coral red fluorescene under wood light secondary to production of porphyrins Anthrax USMLE Case Scenario An organism produces cutaneous disease (malignant pustule or eschar) at the site of inoculation in handlers of animal skins. Most likely organism is: 1. Bacilus anthracus 2. Pseudomonas Aeruginosa 3. Neisseria meningitides 4. Cryptococcus neoformans Ans. 1. Bacilus anthracus USMLE Case Scenario A disease is found to produce severe hemorrhagic pneumonia in a person handling carcasses or skins. The organism causing the disease is a gram-positive rod. Most likely organism is: 1. Yersinia 2. Francisella 3. Spirillum 4. Anthrax Ans. 4. Anthrax Anthrax: USMLE High Yield •• •• •• •• •• •• •• •• •• •• •• •• It is a Zoonosis Gram-positive, nonmotile, capsulated, sporing Cutaneous anthrax commonest Painless malignant pustule. (CHARBON) Hide porters disease is cutaneous anthrax Wool sorters disease is pulmonary anthrax –– Colony woes for a student –– Colony characteristics for the organism Medusa head Inverted fir tree appearance Frosted glass appearance String of pearl appearance Mc Faydens reaction positive PLET medium used Gems about Clostridia Clostridium Tetani: •• Gram-positive •• Anaerobic spore forming bacilli •• Motile with swarming tendency •• Strict anaerobe Microbiology 261 •• Spherical and terminal spores:  (drum stick) CL tetani •• Oval and terminal spores:  (tennis racket) CL difficile •• Central or sub terminal:  (spindle) other species •• Tetanospasmin is the toxin. Blocks release of inhibitory neurotransmitters glycine/GABA. •• Generalized tetanus is the mc form •• Most effective way of preventing tetanus is tetanus toxoid. Clostridial Myonecrosis (Gas Gangrene) 80% of cases are caused by C perfringens Alpha toxin is the most important toxin responsible C novyi, C septicum, and C histolyticum cause the other cases Typically, gasgangrene begins with the sudden onset of pain in the region of the wound, which helps to differentiate it from spreading cellulitis •• Once established, the pain increases steadily in severity but remains localized to the infected area and spreads only if the infection spreads. •• •• •• •• Clostridium Botulinium •• •• •• •• The CNS is not affected by the toxin of CL botulinium Blocks release of Ach at synapses and NM junction Infant botulism is caused by ingestion of spores food borne botulism is due to ingestion of preformed toxin Symmetric descending paralysis is a feature of botulinism Clostridium Gifficile •• •• •• •• •• •• Causes pseudomembranous colitis It is a normal gut commensal Almost all antibiotics even the ones used in treatment of pseudomembranous colitis can cause the disease Metronidazole is the DOC Vancomycin is also effective in treatment Cytotoxin assay in stools is the best test USMLE Case Scenario A 6-month-old infant presents with failure to thrive, progressive muscular weakness, and poor head control Mother typically feeds the baby food sweetened with honey. Which of the following organisms is most likely to be responsible for the child’s presentation? 1. Clostridium botulinum 2. Clostridium difficile 3. Clostridium perfringens 4. Clostridium tetani Ans. 1. Clostridium botulinum USMLE Case Scenario A 10-month-old baby presents to the pediatric emergency room with a 1-day history of poor feeding and generalized weakness. The mother states that she often feeds the baby honey to pacify her. The most likely organism is: 1. Clostridium botulinum 2. Clostridium difficile 3. Clostridium perfringens 4. Clostridium tetani Ans. 1. Clostridium botulinum 262 USMLE Step 1 Platinum Notes USMLE Case Scenario A 66-year-old alcoholic man with brain and pulmonary abscess and is treated with antibiotics for last two weeks. He develops nausea, vomiting, abdominal pain and voluminous green diarrhea. Which of the following organisms can be most likely responsible for this patient’s symptoms? 1. Clostridium botulinum 2. Clostridium difficile 3. Clostridium perfringens 4. Clostridium tetani Ans. 2. Clostridium difficile USMLE Case Scenario An obligate anaerobic, spore-forming, gram-positive bacillus. Which is an important cause of infection following trauma and surgery and can cause gas gangrene and food poisoning is: 1. Clostridium botulinum 2. Clostridium difficile 3. Clostridium perfringens 4. Clostridium tetani Ans. 3. Clostridium perfringens USMLE Case Scenario A 7-month-old baby presents to pediatrician with a 1-day history of poor feeding and generalized weakness. The mother states that she often feeds the baby honey. The toxin responsible for this presentation works by which of the following mechanisms? 1. It blocks the release of acetylcholine from the nerve terminal 2. It blocks the release of inhibitory neurotransmitters such as glycine and GABA 3. It has a subunit that inactivates an elongation factor by ADP-ribosylation 4. It stimulates guanylate cyclase Ans. 1. It blocks the release of acetylcholine from the nerve terminal Gems about Enterobacteriaceae •• E coli, Klebsiella, enterobacter: Ferments lactose •• Salmonella, shigella, proteus, pseudomonas: Do not Ferment lactose •• Capsular •• Antigen •• Flagellar antigen •• Ferment glucose: E coli, Proteus, Klebsiella Includes: •• Escherichia •• Klebsiella •• Proteus •• Enterobacter •• Serratia •• Citrobacter •• Morganella •• Providencia, and •• Edwardsiella as well as the genus Actinetobacter from the family Neisseriaceae Six distinct ‘pathotypes’ of intestinal pathogenic E coli exist: (1) enterotoxigenic E coli (ETEC); (2) Shiga toxin-producing E coli (STEC)/ enterohemorrhagic E coli (EHEC); (3) enteropathogenic E coli (EPEC); (4) enteroinvasive E coli (EIEC); (5) enteroaggregative E coli (EAEC); and (6) diffusely adherent E coli (DAEC). Organisms of these pathotypes are acquired via the fecal-oral rout. Microbiology 263 •• ETEC is the most common cause of traveler’s diarrhea •• EHEC estimated 50% of all cases of HUS are caused by EHEC infection •• EPEC is an important cause of infant diarrhea •• EIEC shares many features with Shigella infection; however, unlike Shigella, EIEC causes disease only at a high inoculum (108 to 1010 CFU). Penetrate Hela cells in tissue culture Sereny test in diagnosis used. Nonmotile and Noniactose fermenting •• EAEC: These pathotypes have been described primarily in developing countries and mostly affect young children. These strains may also cause some cases of traveler’s diarrhea. A high inoculum is required for infection. In vitro, the organisms exhibit a diffuse or ‘stacked-brick’ adherence pattern. USMLE Case Scenario An organism is found to be a major cause of traveler’s diarrhea with watery stools and is a very important pathogen in neonates, who become infected during passage through the birth canaL The most likely organism is: 1. E coli 2. Rota virus 3. Norwalk virus 4. Campylobacter Ans. 1. E coli USMLE Case Scenario A 42-year-old man from New Jersy presents to surgery department with a tender prostate gland. An acute bacterial infection of prostate is suspected. Which of the following organisms is the most common pathogen in this setting? 1. Enterobacter 2. Escherichi 3. Klebsiella 4. Proteus Ans. 2. Escherichi USMLE Case Scenario Acute pyelonephritis is an infectious disease involving the kidney parenchyma and the renal pelvis. The most common organism causing acute pyelonephritis in an adult is: 1. E coli 2. Proteus 3. Klebsiella 4. Pseudomonas Ans. 1. E coli Gems about Proteus •• Causes only 1 to 2% of cases of UTI in healthy women, and Proteus species cause only 5% of cases of hospital-acquired UTI •• Swarming motality •• Fishy/seminal odor •• Urease positive •• Dienes phenomenon shown Proteus is responsible for 10 to 15% of cases of complicated UTI, primarily those associated with catheterization; in the setting of longterm catheterization. This high prevalence is due to the ability of Proteus to produce high levels of urease, which hydrolyzes urea to ammonia and results in alkalization of the urine This situation, in turn, leads to precipitation of organic and inorganic compounds, with the 264 •• •• •• •• USMLE Step 1 Platinum Notes Formation of struvite and carbonate-apatite crystals Biofilm formation on catheters, and/or the Development of calculi Proteus becomes associated with the stones and usually can be eradicated only by complete stone removal overtime, staghorn calculi may form and lead to obstruction and renal failure. USMLE Case Scenario A 33-year-old male presents with UTI. An organism isolated is found to have ‘swarming’ growth on solid media and production of urease and hydrogen sulfide), associated with urinary tract infections and development of struvite kidney stones. The most likely organism is: 1. E coli 2. Proteus 3. Klebsiella 4. Pseudomonas Ans. 2. Proteus Gems about Klebsiella •• Causes only a small proportion of cases of community-acquired pneumonia •• Friedlanders bacillus •• This infection occurs primarily in hosts with underlying disease, such as alcoholics, diabetics, and individuals with chronic lung disease •• Presentation with earlier, less extensive infection is more common than that with the classic lobar infiltrate with a bulging fissure •• Currant jelly sputum is a feature in lung infections USMLE Case Scenario An highly encapsulated organism is found to cause a bronchopneumonia with patchy infiltrates involving one or more lobes with red sputum in a debilitated alcoholic. Most likely organism is: 1. E coli 2. Proteus 3. Klebsiella 4. Pseudomonas Ans. 3. Klebsiella Shigella: USMLE High Yield •• •• •• •• •• •• •• •• Gram-negative Noncapsulated Nonmotile Lactose nonfermenters Ferment mannitol except S dysentrae Subdivided on basis of Mannitol fermentation Most virulent type is S dysentiae Stool culture is the best test USMLE Case Scenario A Gram-negative, noncapsulated nonlactose fermenting organism is causing dysentery (multiple, small-volume stools with blood, mucus and pus associated with abdominal cramps and tenesmusin a 33-year-old male. Most likely organism is: 1. Proteus 2. E coli Microbiology 265 3. Pseudomonas 4. Shigella, dysentrae Ans. 4. Shigella dysentrae Salmonella: USMLE High Yield •• •• •• •• •• •• •• •• •• •• Gram-negative Peritrichate flagella Need tryptophan as growth factor Selenite F is used as growth medium Affects Payer’s patches in intestines H antigen is the most immunogenic VI agglutination detects carriers VI antigen is not seen in normal population Blood culture is the gold standard for diagnosis Diazo reaction is also used for diagnosis USMLE Case Scenario A 26-year-old woman with a history of sickle cell disease presents with fever and severe bone pain localized to her left tibia. X-ray reveals a lytic lesion and blood cultures reveal infection. A bone culture grows gram-negative rods. The organism responsible is: 1. Salmonella 2. Klebsiella 3. E coli 4. Francisella Ans. 1. Salmonella USMLE Case Scenario A 4-year-old boy presents with a 1-day history of loose stools, fever, abdominal cramping, headache and myalgia. He has no blood in the stool. The incubation period is 36 hours after ingestion of contaminated food or water. Which of the following is most likely the causative agent of his diarrhea? 1. Vibrio 2. Bacillus cereus 3. Francisella 4. Salmonella Ans. 4. Salmonella Vibrio Cholera: USMLE High yield •• •• •• •• •• •• •• •• •• Isolated by Koch Most cases are subclinical Gram-negative bacilli, aerobic Noncapsulated, comma shaped Motile with polar flagellum Ferments glucose, transported in alkaline medium Toxin action is CAMP mediated Darting motility Cary Blair medium used 266 •• •• •• •• •• •• USMLE Step 1 Platinum Notes Venkata Raman medium used Humans are the reservoir Survives boiling for 30 seconds Survives in cold temperature (ice for 4–6 weeks) Causes rice water stools/ Pea soup diarrhea Nonhalophilic USMLE Case Scenario A comma-shaped organism is found to be sensitive to acidic pH, is a gram-negative rod and causes severe enterotoxin-induced diarrhea, with ‘rice-water’ stools and dehydration. Most likely organism is: 1. Proteus 2. Vibrio cholera 3. Klebsiella 4. Francisella Ans. 2. Vibrio cholera Pseudmonas: USMLE High Yield Pseudomonas aerugenosais a gram-negative, aerobic, motile bacillus Cetrimide agar is the selective media for Pseudomona saerugenosa EXOTOXIN A inhibits protein synthesis Pseudomonas aerugenosa produces pigments •• Pyocyanin •• Pyoverdin •• Pyorubin and •• Fluorescein •• Produces blue green pus Virulence factors are: •• Pilli, Elastase, Exotoxin, Endotoxin, Alkaline protease, Hemolysin Alginate •• Grape like odor •• Slime layer formation •• Pseudomonas aerugenosagrows at 37—42 °C •• Pseudomonas aerugenosa hydrolyses arginine to citrulline and ammonia •• Pseudomonas aerugenosa oxidises indophenols •• Pseudomonas aerugenosa does not ferment lactose •• Piperacillin is an antipseudomonal pencillin. (p-p) USMLE Case Scenario A 5-year-old child with cystic fibrosis presents with chronic productive cough. On physical exam, he is febrile and lung exam reveals intercostal retractions, wheezing, rhonchi, and rales. Chest X-ray demonstrates patchy infiltrates and atelectasis and Gram’s stain of the sputum reveals slightly curved, motile gram-negative rods that grow aerobically. The microorganism responsible for this child’s pneumonia is also the most common cause of which of the following diseases? 1. Pseudomonas 2. E coli 3. Proteus 4. Klebsiella Ans. 1. Pseudomonas Microbiology 267 USMLE Case Scenario A 85-year-old man with a history of diabetes presents with left ear pain and drainage of pus from the ear canal. He has swelling and tenderness over the left mastoid bone. Most likely organism is: 1. E coli 2. Proteus 3. Klebsiella 4. Pseudomonas Ans. 4. Pseudomonas USMLE Case Scenario A 23-year-old engineer was involved in a serious accident and received second- and third-degree burns over his body. He was placed in the burn unit and, on his twelfth day of his admission, developed a wound infection with a bluish-green exudate. A gram-negative, motile organism was isolated that was oxidase-positive, did not ferment lactose, sucrose, or glucose, but grew on MacConkey’s agar and produced a fruity aroma on that medium. Which of the following organisms was most likely isolated? 1. Pseudomonas 2. E coli 3. Proteus 4. Klebsiella Ans. 1. Pseudomonas USMLE Case Scenario A 70-year-old diabetic patient presents with an unresolved skin lesion on his foot. The lesion began several weeks ago as a blister and has since become a painful, erosive, expanding sore 6 cm in diameter, with a black necrotic center and raised red edges. Most likely diagnosis is Ecthyma Gangrenosum. Disease is caused by: 1. E coli 2. Proteus 3. Klebsiella 4. Pseudomonas Ans. 4. Pseudomonas USMLE Case Scenario A 2-year-old boy with an indwelling urinary catheter in place develops a urinary tract infection. Urine culture grows out a lactose-negative, oxidase-positive, gram-negative rod. Which of the following agents is the most likely cause of this boy’s urinary tract infection? 1. Escherichia coli 2. Klebsiella pneumonia 3. E Proteus mirabilis 4. Pseudomonas aeruginosa Ans. 4. Pseudomonas aeruginosa Pseudomonas aerugenosa causes: •• Serious infections in burn patients •• Shock with bullous lesions •• Ecthyma gangrenosum •• Shanghai fever •• Hot tub folliculitis •• Multi drug resistance is due to biofilm production in cornea 268 USMLE Step 1 Platinum Notes Pseudomonas pseudomallei •• Causes ‘Meliodosis’ •• Also called Whitmores bacillus •• Great imitator disease Pseudomonas Mallei •• Causes ‘glanders’ Gems about Yersinia •• •• •• •• •• •• •• •• •• •• •• •• •• •• •• •• •• •• Plague is an acute, febrile, zoonotic disease caused by infection with Yersinia pestis Y pestis is a gram-negative coccobacillus in the family Enterobacteriaceae It is microaerophilic, nonmotile, nonsporulating, oxidase and urease negative and biochemically unreactive Bipolar staining Safety pin appearance Waysons staining done for identification Stalactite growth The organism is nonfastidious and infective for laboratory rodents. It grows well, if slowly, on routinely used microbiologic media (e.g. sheep blood agar, brain-heart infusion broth and MacConkey agar) The colonies are gray-white with irregular surfaces, described as having a ‘hammered-metal’ appearance when viewed microscopically When stained with a polychromatic stain (e.g. Wayson or Giemsa), Y. pestis isolated from clinical specimens exhibits a characteristic bipolar appearance, often resembling closed safety pins Bubonic plague, the most common form It is almost always caused by the bite of an infected flea but occasionally results from direct inoculation of infectious fluids Septicemic and pneumonic plague can be either primary or secondary to metastatic spread Because fleas often bite the legs, femoral and inguinal nodes are most commonly involved; axillary and cervical nodes are next most commonly affected. The enlarging bubo becomes progressively painful and tender The bubo of plague is distinguishable from lymphadenitis of most other causes, however, by its rapid onset, its extreme tenderness, the accompanying signs of toxemia, and the absence of cellulitis or obvious ascending lymphangitis Pneumonic plague is most infectious. pneumonic plague develops most rapidly and is most frequently fatal Streptomycin is the drug of choice Tetracycline is the doc for prophylaxis Erysipelothrix rhusiopathiae is a pleomorphic, gram-negative rod that causes a localized skin infection. It is an occupational disease of fishermen, fish handlers, butchers, meat-processing workers, poultry workers, farmers, veterinarians, abattoir workers, and housewives. USMLE Case Scenario A 44-year-old man from rural America is brought to a rural hospital with severe bronchopneumonia. He suffered sudden onset of chills, fever and headache several days ago. Two-day later, he complained of chest pain and difficulty breathing and coughed up blood-tinged sputum. Chest X-ray reveals patchy infiltrates and segmental consolidation. Which of the following organisms is the most likely cause of this man’s pneumonia? 1. Clostridium perfringens 2. Francisella tularensis 3. Listeria monocytogenes 4. Yersinia pestis Ans. 4. Yersinia pestis Gems about Hemophilus •• Gram-negative cocco bacillus •• Grows on chocolate agar •• Capsulated Microbiology 269 •• Requires factor X and V •• Satellitism is seen Chancroid is caused by H ducreyi •• Shows school of fish appearance USMLE Case Scenario A 3-year-old boy from rural America is brought to the ENT emergency room in extreme respiratory distress, with a temperature of 104 degrees Fahrenheit. He is drooling and has great difficulty swallowing, and on physical examination, an inspiratory stridor is noted. An immediate lateral X-ray done shows swelling of the epiglottis. He has had no previous vaccinations. Which of the following agents is the most likely cause of these symptoms? 1. Klebsiella pneumoniae 2. Hemophilus influenzae 3. Legionella pneumophila 4. Streptococcus Ans. 2. Hemophilus influenzae Gems about Bordetella •• •• •• •• •• •• •• Gram-negative cocco bacillus Capsulated Bordet gengou media used Causes whooping cough Incubation period 1–2 weeks Thumb printing appearance in culture films Erythromycin prevents spread of disease in children USMLE Case Scenario A seven-week-old infant is brought to the emergency room with a 10-day history of coughing and choking spells. The white blood cell count is elevated with 85% lymphocytes. The child is gasping for breath, experiencing paroxysms of coughing, and vomits twice in the examination room. Encapsulated, gram-negative rods grow out on Bordet-Gengou media. Which of the following microorganisms is the likely cause of these symptoms? 1. Hemophilus influenzae type b 2. Bordetella pertussis 3. Klebsiella pneumonia 4. Legionella pneumophila Ans. 2. Bordetella pertussis Gems about Brucellosis •• •• •• •• •• •• •• It is a zoonosis Malta fever/undulant fever/meditarrean fever Gram-negative Noncapsulated Nonmotile Nonsporing No person–person transmission Causative Organisms •• •• •• •• B militensis from goat, sheep, cattle (most common) B abortus from cattle B suis from hogs B canis from dogs 270 USMLE Step 1 Platinum Notes USMLE Case Scenario A 55-year-old veterinarian presents with a 2-month history of malaise, chills, sweats, fatigue, and weakness. He has anorexia and has lost 5 kgs. He has intermittent fevers. A physical examination reveals mild lymphadenopathy, petechiae. What is the most likely gram-negative etiologic agent? 1. Pseudomonas 2. Brucella 3. Vibrio 4. Klebsiella Ans. 2. Brucella •• Brucella survive in unpasteurized milk for up to 8 weeks •• Brucella is transmitted most commonly through UN pasteurized milk/milk products, raw meat and bone marrow •• It can also be contracted through inhalation in farm houses, slaughter houses, labs. Other routes are skin abrasion, inoculation, conjunctival splashing •• The common symptoms are fever, chills, diaphoresis, headache, myalgias, fatigue •• Patient can look deceptively well with just fever •• In severe cases Hepatosplenomegaly, Lymphadenopathy, arthritis, meningitis or pneumonia can occur •• Rose Bengal Card test used •• Milk Ring test used •• Diagnosis is by culture, Phage typing, DNA Characteristics, Metabolic profiling (BACTEC) •• Treatment is by combination therapy of aminoglycoside plus doxycycline for 4 weeks followed by doxycycline plus rifampin for 4-8 weeks •• In pregnancy TMP-SMZ plus rifampin for 8–12 weeks is given. Gems about Mycobacterium Tuberculosis Mycobacterium tuberculosis complex (consisting of M. tuberculosis, M. bovis, and M. africanum) USMLE Case Scenario Achronic meningoencephalitis, with a prolonged clinical course. Characterized pathologically by a dense granulomatous infiltrate of the base of the brain with increased lymphocytes and slightly decreased glucose is usually caused by: 1. Mycobacterium tuberculosis 2. Neisseria meningococcus 3. Listeria 4. Bordetella Ans. 1. Mycobacterium tuberculosis USMLE Case Scenario Which of the following microorganisms is an obligate aerobe? 1. Bacteroides fragilis 2. Clostridium perfringens 3. Escherichia coli 4. Mycobacterium tuberculosis Ans. 4. Mycobacterium tuberculosis •• •• •• •• •• Discovered by Robert Koch Obligate aerobe Acid fast Acid fastness is due to mycolic acid and cell wall Slightly curved rod Microbiology •• •• •• •• •• •• •• •• LJ Medium (Lowenstein Jonson Medium) used Usually affects apical and posterior segments of upper lobes Lung is the mc organ involved Tubercular lymphadenitis is the mc extra pulmonary TB Rapid diagnosis is by Auramine Rhodamine stain Production of niacin is an important feature Cord factor promotes virulence Mycobacteium Para tuberculosis is Johnes bacillus Caseation necrosis Atypical Mycobacteria •• Photochromogen: M kanasi •• Scotochromogen: M scofulaceum •• Nonchromogen: MAI •• Rapid grower: M smegmatis Buruli ulcer is caused by: M ulcerans Swimming pool granuloma/Fish tank granuloma is caused by M marinum Gems about M. Leprae •• •• •• •• •• •• •• •• Gram-positive Generation time 12 days Acid fast bacilli. Less acid fast than M tuberculosis Globi and cigar bundle appearance are a feature Cultivated in Armadillo Can be grown in foot pad of mice Spreads by skin–skin contact Lepra cells are histiocytes Treponema Pallidium •• •• •• •• Causes syphilis Gram-negative spirochete with polar flagellum Has hylauronidase Incubation period 9-90 days 271 272 •• •• •• •• •• •• •• USMLE Step 1 Platinum Notes Primary lesion is a chancre. Painless ulcer with nontender inguinal lymphadenopathy Condyloma lata is seen in secondary syphilis Dark ground microscopy is used for diagnosis.104 organisms/ml are needed to be detected Leviditti stain is used for staining FTAABS is a specific test VDRL is a slide flocculation test VDRL is positive in secondary syphilis USMLE Case Scenario A 44-year old from New Orleans is referred to a neurologist because of ataxia. Neurological examination reveals a loss of Proprioception and a wide-based, slapping gate. MRI reveals degeneration of the dorsal columns and dorsal roots of the spinal cord. Organism implicated is most likely: 1. Mycobacterium leprae 2. Mycobacterium tuberculosis 3. Treponema pallidium 4. Klebsiella Ans. 3. Treponema pallidium USMLE Case Scenario Aspirochete is causing a (a painless, indurated ulcer) at the site of inoculation. Most likely organism is: 1. Chlamydia 2. Mycoplasma 3. Mycobacteria 4. Treponema Pallidium Ans. 4. Treponema Pallidium USMLE Case scenario An organism identified on dark ground microscopy caused testicular involvement with gumma formation, endarteritis, and/ or a prominent plasma cell infiltrate. Most likely organism is: 1. Chlamydia 2. Mycoplasma 3. Mycobacteria 4. Treponema Pallidium Ans. 4. Treponema Pallidium Borellia •• Borrelia burgdorferi Causes Lymes disease. (erythema migrans) •• Borrelia recurrentis causes relapsing fever •• Kellys medium used Lymes Disease: –– Causative agent: B. burgdorferi –– Vector: Ixodes tick Features: –– STAGE I: Localized disease, IP: 3–32 days, Erythema migrans at local site –– STAGE II: Disseminated disease, Secondary skin lesions, meningitis, carditis –– STAGE III: Oligoarticular arthritis, Encephalopathy, Polyneuropathy. Acrodermatitis atrophicans Microbiology 273 USMLE Case Scenario A 44-year-old woman vacationing in US is bitten by a tick. She does not seek medical treatment and eventually develops chronic arthritis of the knee and hip joints and paralysis of the left facial muscles. Most likely disease is: 1. Erythema migrans caused by Borrelia burgdorferi 2. Erythema migrans caused by Borrelia recurrentis 3. Erythema nodosum caused by virus 4. Erythema abigne Ans. 1. Erythema migrans caused by Borrelia burgdorferi Erythema chronicum migrans is usually the first sign of the illness. This is a large red patch on the buttocks or chest that slowly expands as the center blanches. Generally, patients also have constitutional symptoms, such as fever and chills + Stiff neck may develop, along with other signs of meningeal irritation, because of an aseptic meningitis. +Bell’s palsy due to involvement of branches of the facial nerve. + Arthritis + Cardiac abnormalities in Lyme disease include pericarditis and heart block. Leptospirosis •• •• •• •• •• •• •• Spirochetal infection Rats, rice and rain associations Transmitted by rat urine Seen in sewage workers Acute renal failure and jaundice is a feature Leptospira icterohemorrhagica causes Weils disease Weil’s syndrome, the most severe form of leptospirosis, is characterized by jaundice, renal dysfunction, hemorrhagic diathesis, and high mortality. This syndrome is frequently but not exclusively associated with infection due to icterohemorrhagiae/ copenhageni. USMLE Case Scenario A 39-year-old American farmer develops fever with chills, myalgias, headache, skin rash, and vomiting. He is quite ill and is hospitalized. Blood cultures demonstrate tightly coiled, thin, flexible spirochetes. The spirochetes are easily cultured in serum-enriched nutrient agar. Which of the following organisms should be suspected: 1. Brucella 2. Treponema 3. Leptospira 4. Pseudomonas mallei Ans. 3. Leptospira USMLE Case Scenario An Spirochetal infection is caused by contact with urine from infected animals such as rats. The disease is characterized by abrupt-onset headache (98%), fever, chills, conjunctivitis, severe muscle aches, gastrointestinal symptoms, changes in sensorium, rash, and hypotension. This phase lasts from 3 to 7 days. Meningeal symptoms hepatic dysfunction and renal failure develops is later. 1. Brucella 2. Treponema 3. Leptospira 4. Pseudomonas mallei Ans. 3. Leptospira Gems about Mycoplasma •• Eaton agent •• The smallest free-living organisms known •• Are prokaryotes that are bounded only by a plasma membrane 274 USMLE Step 1 Platinum Notes •• Their lack of a cell wall is associated with cellular pleomorphism and resistance to cell wall-active antimicrobial agents, such as penicillins and cephalosporins •• Fried egg colonies •• L forms seen. (Concept has changed now) –– Mycoplasma pneumoniae causes primary atypical pneumonia, upper and lower respiratory tract infections –– M genitalium and Ureaplasma urealyticum are established causes of urethritis and have been implicated in other genital conditions –– M hominis and U. urealyticum are part of the complex microbial flora of bacterial vaginosis Mycoplasma Pneumoniae –– M pneumoniae causes upper and lower respiratory tract symptoms –– The infection is acquired by inhalation of aerosols USMLE Case Scenario A 22-year-old college student from Ohiopresents to the chest clinic complaining of weakness, malaise, and a chronic cough. He has a fever of 100 degrees F and a dry cough; no sputum can be obtained for laboratory analysis, so a bronchial lavage is performed and the washings are submitted to the laboratory. The laboratory reports that the organism is ‘slow-growing.’ Serodiagnosis reveal sagglutinins in the patient’s serum. Which of the following organisms is the most likely cause of this student’s illness? 1. Mycoplasma pneumonia 2. Mycobacterium tuberculosis 3. Treponema pallidium 4. Chlamydia Ans. 1. Mycoplasma pneumonia USMLE Case Scenario Certain organisms are found by a pasthologist in Main Hospital New York to be susceptible to the macrolide family of antibiotics (erythromycin). These organisms lack a cell wall, hence they are indifferent to antibiotics that interfere with peptidoglycan synthesis, such as penicillin. The organisms are most likely: 1. Mycobacteria 2. Mycoplasma 3. Treponema 4. Leptospira Ans. 2. Mycoplasma Actinomyces •• •• •• •• •• •• •• Gram-positive Nonmotile Nonsporing Nonacid fast Noncapsulated Mc form cervico facial Lumpy jaw is a feature Growth of actinomycetes usually results in the formation of clumps called grains or sulfur granules Oral-Cervicofacial Disease Actinomycosis occurs most frequently at an oral, cervical, or facial site, usually as a soft tissue swelling, abscess, or mass lesion that is often mistaken for a neoplasm The angle of the jaw is generally involved. Microbiology 275 USMLE Case Scenario Pathologist in New Orleans Pathology clinic finds Organisms to be normal inhabitants of the gastrointestinal tract that grow under anaerobic and microaerophilic conditions. They are gram-positive rods; they grow as branching filaments and have been confused with fungi. The yellow colonies are found in abscesses. Most Likely organism is: 1. Actinomyce 2. Anthrax 3. Aspergillus 4. Blastomyce Ans. 1. Actinomyce Nocardia •• •• •• •• •• •• Strict aerobe Acid fast Causes Nocardiosis Paraffin bait is used for isolation Soil is natural habitat Pneumonia is the mc manifestation Listeria Monocytogenes It is a gram-positive cocobacillus in short chains That can be isolated from soil, vegetation and many animal reservoirs Shows tumbling motility Survives and multiplies in phagocytes Human disease due to L monocytogenes generally occurs in the setting of pregnancy or of immunosuppression caused by illness or medication •• Antons test used •• •• •• •• •• •• L monocytogenes grows well in cold temperatures •• L monocytogenes causes meningitis and sepsis in neonates •• L monocytogenes causes meningitis and sepsis in immunocompromised patients •• L monocytogenes during pregnancy can cause abortion, premature delivery or sepsis during postpartum period. Campylobacter: (USMLE Favorite) •• Are motile •• Nonspore-forming, curved gram-negative rods •• Microaerophilic •• The principal diarrheal pathogen is c. jejuni, which accounts for 80 to 90% of all cases of recognized illness due to campylobacters •• Skirrows medium is culture medium •• Butzlers medium is culture medium H pylori: (USMLE Favorite) •• •• •• •• •• It is a gram-negative, spiral, flagellate bacillus It is noninvasive, living in gastric mucus; a small proportion of the bacterial cells are adherent to the mucosa Its spiral shape and flagellae render H pylori motile in the mucous environment Its efficient urease protects it against acid by catalyzing urea hydrolysis to produce buffering ammonia In vitro, H pylori is microaerophilic and slow-growing and requires complex growth media 276 •• •• •• •• •• USMLE Step 1 Platinum Notes Complete genomic sequence has been studied Causes duodenal ulcers (stronger relation) Causes gastric ulcers Prevalence increases with age Transmitted from man-man, fecal orally and orogastric route Urease Positive Organisms •• •• •• •• •• •• •• •• •• S aureus Proteus H pylori Klebsiella Cryptococcus Nocardia Diphtheroids Yersinia pseudotuberculosis Yersinia enterocolitica USMLE Case Scenario A 32-year-old pregnant woman develops a severe flu-like illness with fever, headache, myalgia, and backpain. As a complication she has a spontaneous abortion. Examination of the abortus demonstrates severe amnionitis. Which of the following organisms with tumbling motility would most likely be isolated from the placental membranes? 1. Borrelia burgdorferi 2. Leptospira interrogans 3. Listeria monocytogenes 4. Group B streptococcus Ans. 3. Listeria monocytogenes USMLE Case Scenario An actinomycete causes a chronic lobar pneumonia that may metastasize to the brain. It is more common in the immunocompromised. It is found in soil and aquatic environments. Organism is: 1. H pylori 2. Nocardia 3. Leptospira 4. Blastomyce Ans. 2. Nocardia USMLE Case Scenario A Gram-positive coco bacillus is causing Infection during pregnancy that may result in sepsis, abortion or premature delivery. Infection in the neonate may produce meningitis. In immunocompromised adults, either meningitis or sepsis may occur. The organism is: 1. H pylori 2. Legionella 3. Leptospira 4. Listeria Ans. 4. Listeria USMLE Case Scenario An organism is foud to be gram-negative, spiral, flagellate bacillus with microaerophilic character. Among the choices mentioned below the most likely organism is: 1. H pylori 2. Legionella Microbiology 277 3. Leptospira 4. Listeria Ans. 1. H pylori Legionellosis •• •• •• •• •• •• •• •• •• •• Weakly gram-negative bacillus Motile, nonencapsulated Pleomorhic rods requiring Cysteine and Iron Aerosols from natural reservoirs are the most common source of infection No man to man transmission occurs No animal reservoir occurs Disease is limited to humans Lungs are primarily effected Legionellosis is an infectious disease caused by bacteria belonging to the genus Legionella Over 90% of legionellosis cases are caused by Legionella pneumophila, a ubiquitous aquatic organism that thrives in warm environments (25 to 45°C F) Legionellosis Takes Two Distinct Forms •• Legionnaires’ disease, also known as ‘Legion Fever’ (archaic), is the more severe form of the infection and produces pneumonia •• Pontiac fever is caused by the same bacterium, but produces a milder respiratory illness without pneumonia which resembles acute influenza •• The time between the patient’s exposure to the bacterium and the onset of illness for Legionnaires’ disease is 2 to 10 days; •• For Pontiac fever, it is shorter, generally a few hours to 2 days •• Grown on BYCE medium (Bufferred Charcoal Yeast Extract) USMLE Case Scenario A pathologist reports mild ‘walking pneumonia-like’ condition. The organism is motile, encapsulated and can be cultured on a charcoal yeast extract medium, but identification is usually accomplished by immunofluorescent examination of the pulmonary specimen. Most likely cause is: 1. Legionella 2. Leptospira 3. Listeria 4. Chlamydia Ans. 1. Legionella Remember: (USMLE Favorite) •• Meleney’s gangrene: Anaerobic bacterial synergistic gangrene is characterized by exquisite pain, redness, and swelling followed by induration. These infections usually involve a combination of Peptostreptococcus spp. and S. aureus; the usual site of infection is an abdominal surgical wound or the area surrounding an ulcer on an extremity •• Necrotizing fasciitis, a rapidly spreading destructive disease of the fascia, is usually attributed to group A streptococci but can also be caused by anaerobic bacteria, including Peptostreptococcus and Bacteroides spp. Gas maybe found in the tissues •• Fournier’s gangrene consists of cellulitis involving the scrotum, perineum, and anterior abdominal wall, with mixed anaerobic organisms spreading along deep external fascial planes and causing extensive loss of skin. •• Neutropenic enterocolitis (typhlitis) has been associated with anaerobic infection of the cecum but ¾ in the setting of neutropenia may involve the entire bowel. The primary pathogen is thought by some authorities to be C. septicum, but other clostridia and mixed anaerobic infections have also been implicated •• Brain abscesses are frequently associated with anaerobic bacteria If optimal bacteriologic techniques are employed, as many as 85% of brain abscesses yield anaerobic bacteria ¾ most often anaerobic gram-positive cocci (especially peptostreptococci), which are followed in frequency by Fusobacterium and Bacteroides spp. 278 USMLE Step 1 Platinum Notes Enterococci: (USMLE High Yield Facts) •• Lancefield group D includes the enterococci •• Enterococci are distinguished from nonenterococcal group D streptococci by their ability to grow in the presence of 6.5% sodium chloride •• Significant pathogens for humans are E faecalis and E faecium •• These organisms tend to produce infection in patients who are elderly or debilitated or in whom mucosal or epithelial barriers have been disrupted or the balance of the normal flora altered by antibiotic treatment •• Urinary tract infections due to enterococci are quite common, particularly among patients who have received antibiotic treatment or undergone instrumentation of the urinary tract •• Enterococci are a frequent cause of nosocomial bacteremia in patients with intravascular catheters •• These organisms account for 10 to 20% of cases of bacterial endocarditis on both native and prosthetic valves •• Enterococci are frequently cultured from bile and are involved in infectious complications of biliary surgery and in liver abscesses •• Moreover, enterococci are often isolated from polymicrobial infections arising from the bowel flora (e.g. intraabdominal abscesses), from abdominal surgical wounds, and from diabetic foot ulcers. Anaerobic Infections Nonsporing anaerobic bacteria are: •• Bacteroids fragilis •• Fusobacterium •• Peptostreptococcus •• Actinomyces israelli USMLE Case Scenario A 36-year-old female in New Jersy is diagnosed with subacute bacterial endocarditis after urologic instrumentation. Organisms causing the same are gamma-hemolytic, gram-positive cocci that grow on bile-esculin agar. Most likely organisms are: 1. Streptococci 2. Staphylococci 3. Enterococci 4. Meningococci Ans. 3. Enterococci Rickettsial Diseases •• •• •• •• •• Rickettesia are obligate intracellular parasites Rickettesia divide by binary fission Rickettesial diseases are transmitted by bites of arthropods Typical lesion is vasculitis and these organisms effect endothelial lining of vessel walls Lab diagnosis is based on serology rather than isolation of organisms. •• Rocky mountain spotted fever: The most severe of the rickettsial diseases, is caused by Rickettsia rickettsii •• Mediterranean spotted fever (boutonneuse fever) and other spotted fevers: The etiologic agent of mediterranean spotted fever, R conorii •• Rickettsial pox: caused by R akari •• Endemic murine typhus (flea-borne) caused by R typhi •• Epidemic typhus (louse-borne): Due to infection with R prowazekii is transmitted by the human body louse (pediculus humanus corporis), which lives on clothes and is found in poor hygienic conditions (especially in jails, where the disease it causes is called jail fever) and usually in cold areas •• Brill-zinsser disease is a recrudescent, mild form of epidemic typhus occurring years after the acute disease, probably as a result of immunosuppression or old age. Microbiology 279 •• Scrub typhus caused by R tsutsugamushi •• Ehrlichioses: Ehrlichiae are small, obligately intracellular bacteria with a gram-negative-type cell wall that grow in cytoplasmic vacuoles to form clusters called morulae •• Two distinct ehrlichia species cause human infections that can be severe and frequent •• E chaffeensis, the agent of Human monocytotropic ehrlichiosis infects predominantly mononuclear phagocytic cells in tissues and blood monocytes •• A member of the E. phagocytophila group that infects cells of myeloid lineage is the agent of Human granulocytotropic Ehrlichiosis •• Q fever: Results from infection with C burnetii. USMLE Case Scenario A Disease is found to be due to reactivation of epidemic typhus infection caused by Rickettsia prowazekii. It can occur many years after an infection that was not treated with antibiotics. The most likely disease is: 1. Human granulocytotropic Ehrlichiosis 2. Epidemic typhus 3. Brill-Zinsser disease 4. Endemic typhus Ans. 3. Brill-Zinsser disease USMLE Case Scenario Organism most likely to be implicated as a cause of urethritis that persists after antibiotic therapy for gonorrhea: 1. Chlamydia 2. Rickettsia 3. Mycoplasma 4. Mycobacteria Ans. 1. Chlamydia USMLE Case Scenario An obligate intracellular parasite that induces endocytosis and resides in the phagosome of infected epithelial cell is: 1. Rickettsia 2. Mycoplasma 3. Mycobacteria 4. Chlamydia Ans. 4. Chlamydia Chlamydia •• •• •• •• •• •• Are obligate intracellular bacteria Gram-negative They possess both DNA and RNA Have a cell wall and ribosomes Mc Coy and HeLa cells used for detection Multiply by binary fission •• •• •• •• •• •• Elementary body is metabolically inert. (Extracellular) Reticulate body is active. (Intracellular) IDENTIFIED BY Nucleic acid amplification test NAAT Inclusion body in conjunctivitis: HP (Halberstaedter prowazek bodies) Inclusion bodies in LGV: Miyagawa bodies Inclusion bodies in Psittacosis: Levinthal Colles Lille bodies 280 USMLE Step 1 Platinum Notes Pecularities •• •• •• •• •• Meta chromatic staining: Corynebacterium Lancet shaped diplococcic: Pneumococci Bean shaped diplococcic: Neisseria Bipolar staining: Yersenia Gulls wing: Campylobacter Clinical scenarios: Most Likely Organism: (USMLE Favorite) •• MC cause of lobar pneumoniae in elderly •• Streptococcus pneumonia •• lobar pneumonia with deep red (Currant jelly) sputum •• Klebsiella pneumonia •• Meningitis in neonate (Gram-positive organism) •• Strep Agalactiae •• Meningitis in neonate (Gram-negative organism) •• E coli •• Meningitis in neonate (Gram-positive Rod) •• Listeria monocytogenes •• Joint pains, skin petechiae, fever, in young female •• Gonococcal arthritis •• Patient on clindamycin complaining of diarrhea •• Clostridium difficile •• Abdominal pain, bloody diarrhea and flask shaped ulcers •• Entameba histolitica Important Culture Media •• Thayer Martinmedia Neisseria Gonorrhea •• Chocolate agar with Factor X and V H. influenza •• Bordet Gengou Bordetella Pertussis •• Lownstein Johnson Mycobacterium Tuberculosis •• Charcoal Yeast Agar Legionella USMLE Case Scenario A 4-week-old infant is brought with a 6-day history of coughing and choking spells. The white blood cell count is elevated with 92 % lymphocytes. The child is gasping for breath, experiencing paroxysms of coughing. Encapsulated; gram-negative rods grow out on Bordet-Gengou media. Which microorganism is the likely cause of these symptoms? 1. Borellia 2. Legionella 3. Bordetella pertussis 4. Listeria Ans. 3. Bordetella pertusis Eponyms: USMLE •• Eponyms •• Whitmoores bacillus •• Pseudomonas pseudomallei •• Eaton agent •• Mycoplasma •• Johnes bacillus •• Mycobacterium paratuberculosis •• Batteys bacillus •• Mycobacterium intercellulare •• Freidlanders bacillus •• Klebsiella Pneumoniae •• Koch weeks bacillus •• Hemophilus aegipticus •• Nocard bacillus •• Cornyebacterium Pseudotuberculosis Microbiology Tests for Organisms •• Ascolis thermoprecipitation test Anthrax, Plague •• Xeno Diagnosis Rickettsia •• Naegler’s reaction (is due to Lecithinase) Clostrida •• Green fluorescent on media with neutral red CL Tetani •• Cholera Red reaction indole formation and Nitrates to Nitrites Cholera •• Strauss reaction Pseudomonas Mallei •• Neil Mooser reaction (Tunica reaction) Rickettsia Mooseri •• Satellitism H Influenza –– Diphtheria –– Diphtheria –– Diphtheria a. Chinese letter pattern b. Eleks test c. Schick test •• Dick test Streptococci/pneumococci •• Schultz- charlton reaction Streptococci •• M’Fadyean’s reaction B Anthrax •• Stormy reaction in Culture Cl Welchii •• Milk Ring test (Rose Bengal Card test) Brucellosis •• Von- Pirquet test Tuberculosis •• Kochs’ phenomenon Tuberculosis •• Francis test (Dick test) Pneumococci/streptococci •• String Test V Cholerae Typical Appearances: (USMLE Favorite) •• School of fish Hemophilus ducreyi •• Satellitism Hemophilus influenza •• Fried egg colony Mycoplasma •• Draughtsman colony Pneumococcus •• Swarming growth Proteus •• Oil paint appearance Staph Different Motilities: (USMLE Favorite) •• Darting motility Cholera •• Swarming motility Proteus •• Spinning motility Fusobacterium •• Tumbling motility Listeria Diagnosis of Urethritis and Causative Organism •• •• •• •• Gram-negative diplococcic in PMNs in urethral Exudate: Culture negative specimen with inclusion bodies: Organisms without cell wall and urease positive: Flagellate protozoa with motility: •• •• •• •• Neisseria gonorrhea Chlamydiae trachomatis Ureaplasma Urealyticum Trichomonas vaginalis 281 282 USMLE Step 1 Platinum Notes Vaginal Discharge •• Yellow, pH>5, clue cells, amine odor •• Cottage cheese discharge, pruritis, Vulvovaginitis •• Frothy, Foamy discharge and motile trophozites seen •• Vaginosis •• Candida •• Trichomonas vaginalis USMLE Case Scenario A Pap smear from a 33-year-old woman demonstrates protozoal parasites. These organisms are likely to be: 1. Treponema 2. Trichomonas vaginalis 3. Vaginosis 4. Candida Ans. 2. Trichomonas vaginalis USMLE Case Scenario A 33-year-old female has Sexually transmitted disease. Pear-shaped flagellated protozoal infection characterized by a malodorous, cheesy exudate and erythema of the external genitalia is caused by: 1. Treponema 2. Trichomonas vaginalis 3. Bacterial vaginosis 4. Candida Ans. 2. Trichomonas vaginalis USMLE Case Scenario Chagas’ disease is an important cause of cardiac failure in some Latin American countries, and Brazilian cases can be associated with megaesophagus and megacolon. The disease is Chagas’ disease, which is caused by: 1. Bacteria 2. Mycoplasma 3. protozoa 4. Virus Ans. 3. Protozoa Virology •• •• •• •• •• •• Viruses: Smallest infectious agent containing only one kind of nucleic acid as their genome Virion: Extracellular infectious particle Largest virus: Poxvirus (300 nm) Smallest Virus: Foot and Mouth Disease Virus (20 nm) Capsid is a protein coat surrounding nucleic acids Capsid+nucleic acid is Nucleocapsid Features of Virus: (USMLE Favorite) •• •• •• •• Ribosomes absent Mitochondria absent Motility absent Nucleus absent But Nucleic acid Either DNA or RNA Present. That is why some viruses are DNA Viruses and others are RNA Viruses. (Common Sense) Microbiology 283 •• Virusoids are nucleic acids that depend on helper viruses to package the nucleic acids into virus-like particles •• Viroids are simply molecules of naked, cyclical, mostly double-stranded, small RNAs and appear to be restricted to plants, in which they spread from cell to cell and are replicated by cellular RNA polymerase II •• Prions are protein molecules that can spread from cell to cell and effect changes in the structure of their normal counterparts (cellular proteins). Prions have been implicated in neurodegenerative conditions such as Creutzfeldt-Jakob disease, Kuru, and Gerstmann-Straussler disease. Prions have also been implicated in neurodegeneration associated with human infection with bovine spongiform encephalopathy (‘mad cow disease’). Classification of Viruses Nucleic Acid DNA Nucleic Acid RNA •• •• •• •• Capsid Symmetry Enveloped/Naked Family Type of Strand Icosahedral Icosahedral Icosahedral Icosahedral Complex Naked Naked Naked Enveloped Complex Coat Parvoviridae Papovaviridae Adenoviridae Herpes viridae Pox Hepadna Positive strand Capsid Symmetry Enveloped/Naked Family Type of Strand Icosahedral Icosahedral Icosahedral Icosahedral Naked Naked Naked Enveloped Picorna Calci Reo Toga Positive strand Unknown or Complex Unknown or Complex Unknown or Complex Unknown or Complex Enveloped Enveloped Enveloped Enveloped Flavi Areana Corona Retro Positive strand Helical Enveloped Enveloped Enveloped Enveloped Buny Orthomyxo Negative strand Paramyxo Rhabdo Virus with ‘smallest’ genome: Parvo virus Virus with genome having double stranded nucleic acid: Poxvirus, Reo virus Virus with ‘Segmented’ RNA: Influenza virus Virus with ‘split’ genome: Rota virus Human Slow Virus Infections: (USMLE Favorite) Virus/agent Disease Measles •• Subacute sclerosing panencephalitis Papovavarus (JC Virus) •• Progressive multifocal leucoencephalopathy •• HIV encephalopathy Rubella •• Progressive rubella panencephalitis Retrovirus •• Acquired Immuno Defeciency Syndrome Prion disease •• Kuru •• Creutzfeldt-Jakob disease 284 USMLE Step 1 Platinum Notes Poxviruses Causing Human Disease Smallpox •• Molluscumcontagiosum •• Vaccina •• Cow pox •• Monkey pox •• Buffalo pox •• Orf Herpesvirus Group Includes •• •• •• •• •• •• HSV 1 HSV 2 Varicella zoster virus EBV CMV RK Virus Herpes Simplex Virus •• Double stranded DNA virus •• Orofacial infection mc caused by HSV 1 •• Genital infection mc caused by HSV 2 Causes: •• Gingivostomatitis •• Herpetic whitlow •• Corneal infection •• Esophagitis •• Genital herpes •• Herpetic gladiatorum •• Meningitis/encephalitis (HSV 1). MC cause of sporiadiac viral encephalitis –– Herpes virus 1 causes ‘Herpes labialis’ –– Herpes virus 2 causes ‘Genital herpes’. Varicella Zoster Infection •• •• •• •• •• •• Caused by VZV Reactivates and can involve eye Remains dormant in trigeminal ganglion Causes herpes zoster Post herpetic neuralgia Infectivity lasts 6 days after onset of rash EBV •• Belongs to herpes group •• Binds through CD 21receptor •• Diseases caused by EBV: –– Oral hairy leukoplakia –– Chronic fatigue syndrome –– Burkitt’s lymphoma Microbiology –– –– –– –– –– –– –– –– –– 285 Anaplastic nasopharyngeal carcinoma Tonsillar carcinoma Angioimmunoblastic lymphadenopathy Angiocentric nasal NK/T cell immuneproliferative lesions T cell lymphoma Thymoma Gastric carcinoma, and CNS lymphoma from patients with no underlying immunodeficiency Paul bunnel test is done in infectious mononucleosis USMLE Case Scenario A 22-year-old college student from New York complains of a sore throat and fever. He describes feeling tired for the past few days and reports a loss of appetite. On examination; he has pharyngitis with cervical lymphadenopathy. Blood tests reveal lymphocytosis and the presence of heterophil antibodies. The virus responsible is: 1. EBV 2. HSV 3. CMV 4. Pox Ans. 1. EBV USMLE Case Scenario An African child develops massive unilateral enlargement of his lower face in the vicinity of the mandible. Biopsy demonstrates sheets of medium-sized blast cells with admixed larger macrophages. This type of tumor has been associated with viral infection: 1. EBV 2. HSV 3. CMV 4. Pox Ans. 1. EBV USMLE Case Scenario Encephalitis typically affects the inferomedial temporal lobes and orbitofrontal gyri. Most likely Double stranded DNA virus implicated is: 1. EBV 2. HSV 3. CMV 4. Pox Ans. 2. HSV USMLE Case Scenario A viral organism was isolated from a painful blister on the lip of a girl. The agent was found to double-stranded, linear DNA and was enveloped. Most likely causative organism is: 1. EBV 2. HSV 3. CMV 4. Pox Ans. 2. HSV 286 USMLE Step 1 Platinum Notes CMV •• •• •• •• MC congenital infections Petechiae, hepatospleenomegaly, jaundice are the mc presenting features of congenital CMV infection Cause of heterophile negative mononucleosis. (Kindly remember). Different from infectious mononucleosis Fifty percent of renal transplant patients with fever 1–4 months after transplant have CMV infection. USMLE Case scenario Cytomegalovirus produces neonatal infections and infections in immunocompromised patients such as AIDS patients. CD4 counts are usually <100 cells/mm3. The most common clinical presentation is chorioretinitis producing floaters, +visual field deficits+painless loss of vision. CMV also produces encephalitis and may produce calcifying lesions in the CNS. USMLE Case scenario A 29-year-old was given a renal graft after a month of hemodialysis for end-stage renal failure. Later given immunosuppressive therapy and presented one month after with general malaise, muscle aches and IgM anti-CMV antibodies were detected in a current serum sample accompanied by a positive PCR signal for CMV antigen. These findings indicated primary CMV infection in the recipient due to transplantation of a CMV-positive kidney into a CMV-negative recipient. He made a complete recovery following prompt treatment with a combination of ganciclovir (a CMV-specific drug) and CMV-specific immune globulin. USMLE Case Scenario Intranuclear ‘owl’s eye’ inclusion bodies causing, a common STD in the United States manifested by mononucleosis-likes symptoms. Most likely organism is: 1. EBV 2. HSV 3. CMV 4. Pox Ans. 3. CMV Adenovirus •• Nonenveloped DNA virus •• Mc manifestation is URTI in children •• Mc manifestation is RDS in adults Causes: •• Diarrhea •• Hemorrhagic cystitis •• Epidemic keratoconjunctivitis Picarnovirus •• •• •• •• •• •• •• Poliovirus Coxsackie A Coxsackie B Echovirus Enterovirus Hepatitis A virus Rhinovirus Microbiology •• •• •• •• 287 Enterovirus 70 causes: Acute hemorrhagic conjunctivitis Enterovirus 70 causes: Acute epidemic keratoconjunctivitis Adenovirus causes: Epidemic keratoconjunctivitis Herpesvirus causes: Acute keratoconjunctivitis Coxsackievirus Herpangina •• It is most commonly seen in infants and children, though can occur in adults •• The incubation period lies between 3 and 5 days and fecal infectivity may last for several weeks •• Local examination of the mouth will usually reveal hyperemia of the pharynx and characteristic papulovesicular lesions, approximately 1–2 mm in diameter and surrounded by an erythematous ring •• Most commonly the lesions are present over the tonsillar pillars, soft palate and uvula though on occasion the tongue maybe involved Aseptic Meningitis •• It is the most common clinical manifestation and may result from infection by several different Coxsackie A virus strains •• Coxsackievirus A7 is the most frequently implicated but other strains such as A9 have also been involved •• Severe and fatal encephalitis has been described in only a small number of cases of Coxsackie A virus infection Hand, foot and mouth disease (HFM) •• Examination of the mouth often shows some mild ulceration over the tongue and further examination indicates the pearly white vesicles, sometimes surrounded by a red halo, on the extremities •• The lesions are mainly found over the ventral surface of the fingers and toes and have a characteristic distribution along the sides of the feet. Some cases also show a maculopapular rash over the buttocks •• Coxsackie A causes herpangina and hand-foot-and-mouth disease •• Coxsackie B is seen in patients with pleurodynia, myocarditis, and pericarditis Poliovirus Poliovirus belongs to picarnoviradiae family and has icosahedral symmetry Poliovirus is ether ‘resistant’ Poliovirus is a single stranded, positive sense, RNA Virus Most common type is Type 1 Polio virus Mc cause of epidemics: Type 1 Most difficult to eradicate: Type 1 Mc associated with paralysis: Type 1 Mc cause of vaccine induced paralysis: Type III Most antigenic strain is Type 2 Most common manifestation is subclinical infection. (90%) –– Descending assymetrical paralysis is the predominant sign –– Proximal muscles are more involved than distal –– No sensory loss –– No autonomic disturbance •• Inapparent infections mc feature transmitted by feco oral route •• Spreads by both hematogeneous and neural route •• Death in polio is mostly due to respiratory paralysis •• •• •• •• •• •• •• •• •• •• Influenza Virus •• Belongs to orthomyxovirus group •• Enveloped RNA virus •• Type A: Causes all pandemics and most epidemics 288 •• •• •• •• •• •• USMLE Step 1 Platinum Notes Type C: Causes endemics Type B: Causes Reyes syndrome. (mc) Hemaglutinin and Neuraminidase is strain specific Antigenic variation seen as: Antigenic drift (minor change) seen. Small mutations in H and N Antigenic shift (major change) seen The Bird Flu Virus: (USMLE Favorite) •• •• •• •• •• •• H5N1 IS THE ‘AVIAN FLUE INFLUENZA VIRUS’ ALSO CALLED AS ‘THE BIRD FLU VIRUS.’ H5N1 was previously believed to cause outbreak in birds only. (enzootic) H5N1 is a highly pathogenic virus Risk factor is handling of infected poultry H stands for Hemaglutinin and N in H5N1 Stands for Neuraminidase Virus can pass vertically from mother to fetus ‘Swine Flu’ •• •• •• •• •• •• •• •• •• Occurred in Mexico in may 2009 with threat of a pandemic spreading as far as Newzeland, Australia, Asia, UK, etc Caused by swine influenza virus (SIV) SIV usually infects pigs Undercooked pork is a common cause When infection spreads to humans, it is called zoonotic flu Clinical features: chills, fever, sore throat, headache, coughing weakness SIV subtype: H1N1CAUSED 2009 OUTBREAK This strain has human to human transmission The US Centers for Disease Control and Prevention recommends the use of ‘Tamiflu’ (oseltamivir) or (zanamivir) for the treatment and/or prevention of infection with swine influenza viruses •• However, the majority of people infected with the virus make a full recovery without requiring antiviral drugs •• The virus isolates in the 2009 outbreak have been found resistant to amantadine and rimantadine Measles •• Paramyxovirus •• Causes rubeola (measles) •• Infective period 4 days before and 5 days after appearance of rash •• •• •• •• Kopiloks spots+maculopapular rash a feature Otitis media is the MC complication Hechts pneumonia/primary giant cell pneumonia is seen in measles SSPE is a late complication. (RARE) Mumps •• •• •• •• •• •• •• Paramyxovirus Bilateral parotid enlargement seen Orchitis is the MC complication in post pubertal males Meningoencephalitis can precede parotitis One attack gives life long immunity Incubation period varies from 2–3 weeks Pain and swelling of parotids (earache) is a feature Microbiology 289 •• Orchitis, ovaritis, pancreatitis, meningoencephalitis, throditis, neuritis, hepatitis and myocarditis are a feature •• Mumps is leading cause of parotitis in children •• Control of mumps is difficult because disease is infectious before a diagnosis is made. Rubella •• Toga virus •• No carrier state •• Cervical lymphadenopathy •• Rubella can cause a congenital infection characterized by ocular problems (cataracts, retinopathy, microphthalmos, glaucoma), cardiovascular problems, deafness, thrombocytopenic purpura, hepatosplenomegaly, CNS problems, and bony lesions •• Congenital rubella causes: cataract+deafness+heat diseases. Arboviruses: (USMLE Favorite) •• Chikungunya •• •• •• •• •• •• •• •• Japanese encephalitis West nile Yellow fever Dengue Kyanasaur forest disease Sandfly fever Rift valley fever Hanta virus •• alphavirus •• •• •• •• •• •• •• •• flavivirus flavivirus flavivirus flavivirus flavivirus bunyavirus bunyavirus bunyaviridae Hantavirus •• •• •• •• It is a RNA virus Belongs to arbovirus Causes hemorrhagic fever with nephritis Causes hantavirus pulmonary syndrome Rabies Virus •• Rabies virus has negative polarity •• Rhabdoviridae •• Bullet shaped, neurotropic •• Enveloped virus with ss RNA •• It is Lyssavirus serotype 1 •• Inactivated by Phenol, UV radiation, Beta propiono lactone •• Negri bodies are present inside nerve cells. Most characteristic finding in CNS is the formation of cytoplasmic inclusion bodies called Negri Bodies (composed of fibrillary matrix and rabies virus particles) within neurons of ammons horn, Cerebral cortex, Brainstem, Hypothalamus, Cerebellum and Dorsal spinal ganglia •• Since first described by Negri in 1903, the Negri body has been regarded as a pathognomonic •• Finding signifying the presence of rabies encephalitis. Negri bodies (light microscope) were found in the brain of a patient with conclusive evidence in favor of the presence of rabies encephalitis –– Brainstem encephalitis is a feature –– Fluorescent stains are used for antemortem diagnosis. 290 USMLE Step 1 Platinum Notes Hepatitis A virus •• •• •• •• •• •• It is a nonenveloped 27-nm, heat-, acid- and Ether-resistant RNA virus In the hepatovirus genus of the picornavirus family Previously called enterovirus 72 No chronic course Inactivated by boiling, formalin, uv radiation Hepatitis B Virus: (USMLE Favorite) It is a DNA virus Hepadnavirus Contains DNA dependent DNA polymerase and RNA dependent reverse transcriptase Reverse transcriptase is coded by P gene Dane particle is HBV HBV strain in India is Ayw, Adr HBV has maximum perinatal transmission risk Oncogenicity present in Hepatitis B especially after neonatal infection –– Carrier state present in Hepatitis B –– Hepatitis B virus may present in blood and other body fluids and excretions such as saliva, breast milk, semen, vaginal secretions, urine, bile, etc. –– Feces not known to be infectious –– HBs Ag is the first viral marker to appear in blood after infection; it remains in circulation throughout icteric course of disease. In a typical case it disappears within roughly 2 months but may last for 6 months –– HBs Ag is not demonstrable in circulation but antibody, anti H-Be appear in serum a week or two after appearance of Hbs Ag –– Anti-Hbe Ag is the antibody marker to be seen in blood –– Serological marker of acute hep B is: HBs Ag + core antibody –– Epidemological marker of Hep B is: core antibody –– HBe Ag (HB envelop antigen) appears in blood concurrently with HBs Ag –– Hbe Ag is an indicator of intrahepatic viral replication and its presence in blood Indicates high infectivity •• For diagnosis of HBV infection, simultaneous presence of IgM, HBC indicates recent infection •• Presence of IgG; anti H-Be indicates remote infection •• Hep B vaccine is cell fraction derived. •• •• •• •• •• •• •• ‘Other Hepatitis Viruses’ •• Hepatitis C virus –– Which, before its identification was labeled ‘non-A, non-B hepatitis,’ –– It is a linear, single-stranded, positive-sense, RNA virus; (Enveloped) –– HCV belongs to family Flaviviridae –– Mc cause of post transfusion hepatitis –– Causes chronic hepatitis •• Hepatitis D –– The delta hepatitis agent, or HDV, is a defective RNA virus –– Coinfects with and requires the helper function of HBV (or other hepadnaviruses) for its replication and expression –– Resembles plant viruses •• Hepatitis E Previously labeled ‘epidemic or enterically transmitted non-A, non-B hepatitis’, HEV is an enterically transmitted virus It is a Calci virus –– Mortality in pregnancy is a feature of Hep E virus Microbiology 291 –– Hepatic encephalopathy in pregnancy is seen –– Fulminant hepatic failure can occur with Hep C in pregnancy •• Hepatitis G –– Also called GB virus –– RNA virus –– Blood borne virus –– Resembles Hep C virus –– Lamuvudine responsive •• Spreads by fecal oral route -Hepatitis A and E •• Spreads by percutaneous route -Hepatitis B, C and D •• HTLV I cause adult T cell Leukemia/Lymphoma and Tropical spastic paraplegia. Other putative HTLV-I-related diseases In areas where HTLV-I is endemic, diverse inflammatory and autoimmune diseases have been attributed to the virus, including uveitis, dermatitis, pneumonitis, rheumatoid arthritis and polymyositis •• HTLV II causes Hairy cell leukemia •• HTLV III causes AIDS USMLE Case Scenario HTLV-1, or human T-cell lymphotrophic virus 1 can lead to T-cell leukemia 20–30 years after the infection. The virus is: 1. A nonenveloped, single-stranded, RNA retrovirus 2. An enveloped, double-stranded, RNA retrovirus 3. An enveloped, single-stranded, DNA retrovirus 4. An enveloped, single-stranded, RNA retrovirus Ans. 4. An enveloped, single-stranded, RNA retrovirus USMLE FAVORITE HIV virus •• •• •• •• •• •• Positive sense, single stranded, RNA virus Retro virus Diploid Attacks T helper cells and macrophages Non segmented Found in semen, saliva and blood –– –– –– –– •• •• •• •• •• •• •• •• •• •• •• Contains two copies of ss (+) RNA, RNA dependent DNA Polymerase (Reverse Transcriptase), integrase and protease Subtype A is most prevalent worldwide Subtype C is most prevalent in India Seroconversion takes 4 weeks Heterosexual mode is the mc mode of transmission of HIV Male–female transmission >female-male Accidential needle prick for health worker is 1% RNA-DNA-RNA is the retroviral sequence in host celL p 24 is used for early diagnosis p 24 antigen disappears 6–8 weeks after HIV infection CD 4 cells are attacked CD 4: CD 8 ratio is reversed Macrophages serve as reservoir of infection Window period of AIDS: infection to appearance of antibodies in serum Both ELISA and western blot are negative in window period. 292 •• •• •• •• •• •• •• USMLE Step 1 Platinum Notes Cryptosporiodosis is the mc cause of diarrhea in AIDS Oral ulcer in AIDS is commonly due to candida MC cause of acute meningitis in AIDS: Cryptococcus MC cause of tuberculosis in AIDS in tropical countries: Myc. Tuberculosis Mc Cause of seizures in AIDS: Toxoplasmosis Multifocal tumor of vascular origin in AIDS is: Kaposis sarcoma MC opportunistic infection in AIDS in India is: Tuberculosis. USMLE Case Scenario •• Toxoplasmosis is a protozoan infection acquired by eating undercooked meat or by exposure to cat feces •• Primary toxoplasmosis is usually asymptomatic. In patients with normal immunity, the organism can cause a heterophile-negative, mononucleosis-like syndrome. In patients with AIDS, it causes ring-enhanced focal brain lesions and pneumonia. STRUCTURAL GENES OF HIV VIRUS HIV virus Antigens p 24 p 7p p17 •• •• •• •• Proteins Capsid protein Core nucleocapsid protein Matrix protein Gag •• •• •• •• Pol •• Reverse transcriptase •• Integrase •• Protease •• Produces ds DNA pro virus •• Produces ds DNA integration into host DNA •• Cleaves poly protein Envelop •• gp 120 •• gp 41 •• Surface protein that binds to CD4 on host cell •• Transmembrane protein for cell fusion Regulatory genes of HIV Virus •• Tat: Transactivator protein: Activator of transcription •• Rev: Regulator Protein: Regulator of transport of RNA to cytoplasm •• Nef: Negative factor: Decrease MHC on infected T cells Microbiology 293 Negative sense RNA Viruses Parainfluenza virus •• Croup, common cold, bronchitis Mumps •• Parotitis, pancreatitis, orchitis, memingoencephalitis Measles •• •• •• •• RSV •• Bronchiolitis and pneumonia in infants Rabies virus •• Bites of rabid dogs •• Negri Bodies •• Bullet shaped from Rhabdo viridae Marburg virus •• Acute Hemmorrhagic fever Ebolavirus •• Acute Hemorrhagic fever Influenza virus •• •• •• •• •• Lassa Fever virus •• Hemorrhagic fever in Africa Rubeola Cough, coryza, conjunctivitis, kopliks spots Warthin Finkeldey cells SSPE Segmented Enveloped nucleocapsid Shows minor variation: antigenic drift Major variation: antigenic shift Shows Von Magnus phenomenon (on serial passing progeny with high hemagluttination titer but low infectivity •• Guillain barre and Ryes Syndrome associations USMLE Case Scenario A 3-year-old child develops voluminous watery diarrhea and vomiting. She is brought to the pediatrician by her parents and evaluated. Which of the following viruses is the most likely cause of the child’s diarrhea? 1. Norwalk virus 2. Rotavirus 3. Influenza virus 4. Parainfluenza virus Ans. 2. Rota virus USMLE Case Scenario An enveloped Rhabdovirus produces encephalitis inpersons who have recently traveled outside of the US after a bite of dog. The organism is most likely: 1. Togavirus 2. EB 3. Rabies virus 4. Influenza virus Ans. 3. Rabies virus USMLE Case Scenario The Picornaviruses are positive single-stranded RNA viruses with a naked icosahedral nucleocapsid. This family does not include: 1. Polioviruses 2. Pappiloma viruses 3. Echoviruses 4. Coxsackieviruses Ans. 2. Pappiloma viruses 294 USMLE Step 1 Platinum Notes USMLE Case Scenario Progressive multifocal leukoencephalopathy is a rapidly progressive demyelinating disorder in which the JC virus infects oligodendroglial cells in the brain. The Eosinophilic inclusions represent accumulations of JC virus which is a: 1. Papovavirus 2. Herpes virus 3. Retrovirus3 4. Arena virus Ans. 1. Papova virus USMLE Case Scenario A 44-year-old mother brings her 4-year-old boy into the emergency room of ENT Department because he has developed a harsh, ‘barking’ cough with hoarseness. The virus responsible for this child’s illness belongs to which of the following families? 1. Papovavirus 2. Paramyxovirus 3. Parvovirus 4. Picornavirus Ans. 2. Paramyxovirus (para influenza) USMLE Case Scenario A paralytic disease affecting the ventral horn of the spinal cord and motor cortex, caused by RNA enterovirus is: 1. EBV 2. Poliovirus 3. Rabies virus 4. Influenza virus Ans. 2. Polio virus USMLE Case Scenario A 66-year-old patient from wales presents to a physician because of pain during defecation accompanied by blood in the stool. Physical examination demonstrates a large perianal mass. Pathologic examination of the rectal mass following resection demonstrates a condyloma in which transformation to frank carcinoma has occurred. Which of the following viruses would most likely be associated with these lesions? 1. EBV 2. CMV 3. HSV 4. HPV Ans. 4. HPV The tumor is anal carcinoma arising in a condyloma. Both condyloma and anal carcinoma are related to human papilloma virus (HPV), which is also associated with cervical and penile condylomas and carcinomas. USMLE Case Scenario A Bullet shaped virus spreading along peripheral nerves to the central nervous system causing hydrophobia and copious salivation. Most likely virus is: 1. Togavirus 2. EBV 3. Rabies virus 4. Influenza virus Ans. 3. Rabies virus Microbiology 295 USMLE Case Scenario A 48-year-old female presents with malaise, loss of appetite, nausea, moderate fever, and jaundice. Laboratory tests indicate a marked increase in serum transaminases. Serology for hepatitis viruses is performed and indicates positive results for the presence of HBsAg, HBc IgM antibody, and HCV antibody. Antibody tests for HBsAb and HAV are negative. The results indicate: 1. Hepatitis A virus infection 2. Hepatitis B virus infection 3. Hepatitis C virus infection 4. Hepatitis D virus infections Ans. 2. Hepatitis B virus infection USMLE Case Scenario Dysplasia of the cervix and later carcinomas of the cervix is found to be caused by a virusin a 30-year-old woman with a history of multiple sexual partners. Most likely virus is: 1. EBV 2. CMV 3. HSV 4. HPV Ans. 4. HPV USMLE Case Scenario A 3-month-old infant presents with a 3-day history of fever, cough, and poor feeding. On examination, the baby appears ill and has a temperature of 102° F and a respiratory rate of 32. A chest X-ray film shows bilateral patchy infiltrates in the lungs. Which of the following is the most likely etiologic agent? 1. Influenza virus 2. Parainfluenza virus 3. EBV 4. Respiratory syncytial virus Ans. 4. Respiratory syncytial virus USMLE Case Scenario Pathologist describes a pandemic caused by the ability of the virus of Reoviridae family to undergo dramatic genetic changes of type by reassortment of its segmented RNA genome - a trait called genetic shift. Virus implicated is: 1. Rotavirus 2. Ebola virus 3. Parainfluenza virus 4. EBV Ans. 1. Rota virus USMLE Case Scenario A naked, icosahedral double-stranded circular DNA virus presents with anogenital warts. Most likely virus is: 1. EBV 2. CMV 3. HSV 4. HPV Ans. 4. HPV 296 USMLE Step 1 Platinum Notes USMLE Case Scenario A 14-year-old student presents to the hospital complaining of a sore throat and fever. On examination, he has pharyngitis with cervical lymphadenopathy. Blood tests reveal lymphocytosis and the presence of heterophil antibodies. Which of the following virus is responsible for his illness? 1. Double-stranded, enveloped DNA virus 2. Double-stranded, nonenveloped DNA virus 3. Single-stranded, enveloped RNA virus 4. Single-stranded, nonenveloped DNA virus Ans. 1. Double stranded enveloped DNA virus USMLE Case Scenario Among the choices mentioned below is a member of family Herpesviridae. It is an enveloped virus with an icosahedral nucleocapsid that contains a double-stranded linear DNA genome. 1. CMV 2. Polio 3. HPV 4. Influenza Ans. 1. CMV USMLE Case Scenario A single-stranded +RNA virus, is naked (i.e. nonenveloped) and hence will not be inactivated by lipid solvents such as ether. The live virus vaccine had colonized the intestinal tract of the infant and was still being shed 2 weeks after the earlier oral dose. The virus is: 1. HDV 2. Polio 3. EBV 4. CMV Ans. 2. Polio USMLE Case Scenario A Virus produces neonatal infections and infections in immunocompromised patients such as AIDS patients and most common clinical presentation is producing floaters, visual field deficits, and painless loss of vision. It also produces encephalitis and may produce calcifying lesions in the CNS. Virus most likely is: 1. CMV 2. EBV 3. HSV 4. HHV Ans. 1. CMV USMLE Case Scenario Kaposi Sarcoma is caused by: 1. HHV6 2. HHV7 3. HHV8 4. HHV9 Ans. 3. HHV 8 Double Stranded RNA Viruses Reovirus Rotavirus URTI Mc cause of infantile diarrhea •• Noncultiviable virus •• Detected by antigen in stools Microbiology 297 Rota Virus •• •• •• •• •• •• •• Reoviridae family Double stranded RNA virus Group A mc causative agent Does not grow in cell cultures (noncultiviable) Mc cause of diarrhea in infants Causes destruction of mature enterocytes Detected by antigen in stools Diarrheas are a Feature of •• •• •• •• Rotavirus Adenovirus Calcivirus Enterovirus Hemorrhagic Fever •• African hemorrhagic fever: •• Hemorrhagic fever with renal syndrome: •• Dengue hemorrhagic fever: •• Marburg/ebola virus •• Hantavirus •• Flavivirus ONCOGENIC VIRUSES: (USMLE FAVORITE) Virus Disease Pox disease •• Molluscum contagiosum Hepatitis B and C •• Liver Cancer EBV •• Burkitt’s lymphoma (in malaria infested parts of Africa), and •• Other lymphomas in immunosuppression; •• Nasopharyngeal carcinomas Human papilloma virus •• Warts, genital warts, cervical, vulval, penile, anal and perianal carcinoma HTLV-1 •• Adult T-cell Leukemia (RNA virus) HHV 8 •• Kaposi’s sarcoma Adenovirus, SV40 •• Malignant neoplasms in mice Polyomavirus hominis 1 and 2 •• Are found in the urine of some transplant recipients Human Pappiloma Virus Deep plantar/palmar warts: HPV 1 Common warts/Verruca Vulgaris: HPV 2 Plane warts: HPV 3 Laryngeal Papillomas: HPV 6,11, 30 Anogenital warts (Condyloma accuminata): HPV 6,11 Butchers warts: HPV 7 ‘Koilocytes’ are a feature of HPV infections ‘High oncogenic potential’ is with: HPV16, 18, 31, 33 ‘Low oncogenic potential’ is with: HPV6,11, 42, 43 298 USMLE Step 1 Platinum Notes Viruses and CNS: (USMLE Favorite) •• Acute viral meningitis is most commonly due to enterovirus. •• Fungal meningitis is mostly due to Candida, Aspergillus, Mucor and Cryptococcus. •• Viral Encephalitis shows: –– Perivascular cuffs –– Microglial nodules –– Neuronophagia •• HSV1 particularly effects Temporal lobes, causes hemmorhagic necrosis of temporal lobes •• Aspergillus and Mucor causes vasculitis with hemorrhage •• Cryptococcus invades brain via Virchow Robins spaces with soap bubble lesions •• Toxoplasmosis presents with ring enhancing lesions Kaposis sarcoma •• •• •• •• •• •• •• Kaposis sarcoma is common in homosexuals KS arises from cells linning lymph vessels or blood vessels KS is associated with HIV, immunosuppression, organ transplants On skin Kaposis lesions are red/purple blotches which are asymptomatic or tender GIT, liver, lung lesions can prove dangerous Treatment of HIV with HAART reduces KS as well Associated with HHV 8 virus –– Common sites: Skin, GIT, Lymph nodes, Lungs –– Classic KS as originally described was a relatively indolent disease affecting elderly men from the Mediterranean region, or of Eastern European descent –– Endemic KS was described later in young African people, mainly from sub-Saharan Africa, as a more aggressive disease which infiltrated the skin extensively, especially on the lower limbs. This, it should be noted, is unrelated to HIV infection –– Transplant Related KS had been described, but only rarely until the advent of calcineurin inhibitors (such as ciclosporin, which are inhibitors of T-cell function) for transplant patients. Erythema Infectiosum: (Fifth disease, Slapped cheek disease) •• Erythema infectiosum is caused by parvovirus B19 (human parvovirus), a small, single-stranded DNA virus •• In children the first sign of infection is usually marked erythema of the cheeks or slapped cheek appearance often with relative circumoral pallor •• Then 1–4 days after the slapped cheeks an itchy, erythematous, maculopapular rash develops on the trunk and limbs •• As the rash on the limbs clears it leaves a lacy, reticular pattern. The rash may fluctuate over the next 1–3 weeks and a hot bath, for example, may lead to recrudescence of an evanescent rash •• Complications •• Arthritis or arthralgia is more common in adults, but certainly can occur in children. It usually appears 1–6 days after the rash but there maybe no history of rash at all •• Arthritis is characteristically transient and asymmetrical, affecting wrists, knees, ankles, elbows and fingers, though it may persist for weeks or even months •• Children with sickle cell anemia, thalassemia major, hereditary spherocytosis or other hemolytic anemias, may have severe aplastic crises with hemoglobin levels falling as low as 1–2 g/dl and no reticulocytes •• Infection during pregnancy can result in hydrops fetalis due to fetal anemia, which maybe fatal, but no congenital syndrome has been described in babies of infected mothers who delivered at term •• The diagnosis can be made serologically by demonstrating parvovirus B19-specific IgM on an acute serum sample Treatment •• Arthritis may require salicylates or nonsteroidal antiinflammatory agents •• Children with aplastic crises may require blood transfusion until the red cell aplasia resolves spontaneously after 1–2 weeks. Microbiology 299 Parvoviruses Are small single-stranded DNA viruses, of which only serotype B19 is pathogenic for humans. This virus causes three distinct syndromes: •• A childhood febrile rash known as erythema infectiosum (‘Fifth disease’); •• Aplastic crisis in individuals with chronic hemolytic diseases (sickle cell anemia, thalassemia, etc.); and congenital infections that can present as stillbirth, •• Hydrops fetalis (analogous to severe Rh incompatibility), or severe anemia. Herpesvirus 6 (HHV-6) is the main causative agent for Roseola infantum A common disease of infancy, characterized by fever and the appearance of an erythematous maculopapular rash as the fever defervesces. It is generally benign. Viral Hemorrhagic Fever •• •• •• •• •• •• Lassa fever Rift valley fever Hf with renal syndrome Hantavirus pulmonary syndrome Yellow fever Dengue hemorrhagic fever/dengue shock syndrome Slow Viruses Diseases: (USMLE Favorite) •• Group A –– MaedI –– Visna •• Group B •• Prion diseases –– Caused By prion Protein –– Prions are proteins –– They are infectious –– Most common infectious prion disease in humans –– CJD –– Kuru –– Gerstmann Straussler disease –– Fatal familial insomnia •• Group C –– SSPE –– PML SSPE Subacute sclerosing panencephalitis (SSPE), a rare degenerative central nervous system (CNS) disease characterized by behavioral and intellectual deterioration and convulsions, is a result of a persistent measles virus infection that develops years after the original infection PML JC virus, a human papilloma virus the etiologic agent of progressive multifocal leukoencephalopathy (PML), is an important opportunistic pathogen in patients with AIDS Remember: (USMLE Favorite) Nagleria •• Primary amebic meningoencephalitis Acanthamoeba •• Keratitis •• Granulomatous amebic encephalitis 300 USMLE Step 1 Platinum Notes Entamoeba histolytica •• Amebiasis with flask shaped ulcers Giardia lamblia •• Giardiasis (malabsorption) •• Habitat: duodenum, jejunum •• Falling leaf motility •• Tennis racket shape •• Trophozites and cysts seen in man •• Associated with common variable immunodeficiency •• May cause travelers diarrhea Cryptosporidium •• Diarrhea in immunocompromised Trichomonas vaginalis •• Trichomoniasis (frothy vaginal discharge) Balantidium coli •• Dysentery Malaria •• Plasmodium vivax •• Benign tertian malariae •• Plasmodium ovale •• Benign tertian malariae •• Plasmodium malaria •• Quartan malaria •• Plasmodium falciparum •• Malignant malaria Malarial Parasites Species Identification •• Mauriers clefts: P falciparium •• Schuffners dots: P vivax •• Zeimmans dots: P malariae •• James dots: P ovale •• Urban Malaria is caused by Anopheles Culcifacies •• Type of malaria not seen in India is ovale •• Size of RBC is increased in vivaxmalaria •• The infective agent of malaria is sporozoite •• Gametocytes are seen in PBF of falciparum malaria •• Shizont is not seen in PBF Relapse of malaria is seen in P ovale and P malariae Important Features of P Falciparum Splenic rupture is commonest with P falciparum Parasitemia is highest with P falciparum Most virulent form P falciparum Exoerythrocytic stage is absent in P falciparum Multiple infection of RBC’S is seen in P falciparum Most Virulent plasmodium species is P falciparum Microbiology 301 KALA-AZAR: (USMLE FAVORITE) •• •• •• •• L donovani L tropica L major L braziliens •• •• •• •• Visceral Leishmaniasis Cutaneous Leishmaniasis Cutaneous Leishmaniasis Mucocutaneous Leishmaniasis •• Splenomegaly is a feature •• NNN (Novy, mc Neal, Nicolle) medium used •• Aldehyde test + in 12 weeks KALA-AZAR (Visceral Leishmaniasis; Dumdum Fever) •• Kala-azar occurs in India, China, southern USSR, Africa, the Mediterranean basin, and several South and Central American countries. •• Children and young adults are particularly susceptible. •• The protozoa (L donovani) invade the bloodstream and localize in the reticuloendothelial system, causing fever, pronounced hepatosplenomegaly, emaciation, and pancytopenia. •• The fever is seldom sustained and recurs irregularly. •• Hypergammaglobulinemia is present. •• The parasite maybe found in needle biopsy of the liver, spleen, bone marrow, skin lesions, or lymph nodes or in cultures from these tissues or from blood. •• Pentavalent antimony compounds and pentamidine are the drugs of choice. •• Sodium stibogluconate (sodium antimony gluconate) is given once daily, slowly IV or IM in distilled water. Trypanosoma cruzi •• •• •• •• •• Chagas disease (American Trypanosomiasis) Vector: reduvid bug Romana sign +(Swelling around eyelids) Megacolon, Megaesophagus, Cardiomyopathy are complications Nifurtimox used in treatment Trypanosoma brucei •• •• •• •• Sleeping sickness (African Trypanosomiasis) Tse tse fly transmits it Posterior cervical lymphadenopathy (Winter Bottom sign seen) Suramin and Melarsoprol used in treatment Babesia microti •• Babeiosis •• Seen in immunocompromised/splenectomized patients •• Resides in RBC Toxoplasma gondii •• •• •• •• •• •• •• Toxoplasmosis Cat: definitive host Oocyst found in cat Intracerebral calcifications, chorioretinitis, microcephaly Sabin Feld man test + Pyremethamine + sulfadiazine used in treatment Frenkels test+ USMLE Case Scenario Chagas’ disease is characterized by facial edema and nodules, fever, lymphadenopathy, and hepatosplenomegaly. It affects cardiac muscle most severely. It is most prevalent in Central and South America; with rare cases in the southern US. The causative organism is: 1. Trypanosoma cruzi 2. Trypanosoma brucei 302 USMLE Step 1 Platinum Notes 3. Toxoplasma gondii 4. Babesia microti Ans. 1. Trypanosoma cruzi •• Onchocerca volvolus •• River blindness •• Wucheria bancrofti •• Lymphadenitis •• Elephantiasis Genus Disease produced •• Tenia solium •• Cysticercosis and enteritis •• Tenia saginata •• Enteritis •• Entrobius Vermicularis •• Pruritis ani •• Ascaris lumbricoides •• Enteritis, cholangitis •• Ent. histolytica •• Amebiasis •• Naegleria and Acanthameba •• Meningitis •• Cryptosporidium Parvum •• Cryptosporidiosis •• Giardia lamblia •• Giardiasis •• Toxoplasma gondi •• Intrauterine infection USMLE Case Scenario An organism inhibits the large intestine migrates at night into the perianal region to lay eggs, and can be identified by placing cellophane tape on the perianal skin and then looking at the tape with a microscope. The most likely cause is: Ans. Entrobius vermicularis USMLE Case Scenario A newborn has developed the classic triad of chorioretinitis (at birth), hydrocephalus, and cerebral calcifications. It is found that Humans become infected with it by ingesting cysts in contaminated food or through contact with cat feces Most likely organism is: Ans. Toxoplasma gondii USMLE Case Scenario An organism occurs in the immunocompromised population and may cause severe diarrhea. The organism presents as minute (2–5 mm) intracellular spheres or arc-shaped merozoites under normal mucosa, Most likely organism is: Ans. Cryptosporum parvum Common Names •• Fish Tapeworm: Diphyllobotherium latum •• Beef Tapeworm: Tenia saginata •• Pork Tapeworm: Tenia solium •• Dwarf Tapeworm: H. nana •• Rat Tapeworm: H. diminuta •• Dog Tapeworm: Echinococcus granulosus Microbiology •• Clonorchis sinesis •• Chinese liver fluke •• Fasciola hepatica •• Sheep liver fluke •• Fasciola buski •• Giant intestinal fluke •• Paragonimus westermanii •• Lung fluke •• Echinococcus granulosus •• Hydatid cyst disease •• Echinococcus multilocularis •• Alveolar hydatid 303 USMLE Case Scenario A fluke is producing obstruction of the biliary tract or pancreatic duct and are associated with an increased risk of cholangiocarcinoma. Most likely organism is: Clonorchis sinesis Parasites Causing Autoinfection •• •• •• •• •• •• Tenia solium Strongyloides stercolis Hymenolepsis nana Enterobius vermicularis Cryptosporidium parvum Capillaria philippinesis •• Loa Loa causes Calabar swellings •• Wucheria bancrofti causes Lymphatic Filariasis •• Strongyloides stercolis Larva currens •• Toxocaria canis causes Visceral Larva migrans •• Strongyloides stercolis causes cutaneous larva migrans Filariasis •• •• •• •• Wucheria bancrofti causes Filariasis Habitat is lymph vessels and lymph nodes Man is the definitive host Innoculation is through bite of mosquito •• Infective form is third stage larvae •• Notice the difference in classic Filariasis and occult Filariasis Classic Filariasis Occult Filariasis (Meyer Kouwenaar Syndrome) •• Caused by adult worms •• Caused by microfilariae •• Epitheloid granuloma is basic lesion •• Eosinophilic granuloma is basic lesion •• Lymphatic system involved •• Lymphatic system •• Liver •• Lungs involved •• Microfilaria present in blood •• Microfilaria in tissues •• Complement Fixation test insensitive •• CFT Sensitive 304 USMLE Step 1 Platinum Notes Tenia Solium Cysticercosis in muscles Cysticerci can develop in any voluntary muscle in humans. Invasion of muscle by cysticerci can cause myositis, with fever, eosinophilia, and muscular pseudohypertrophy, which initiate with muscle swelling and later progress to atrophy and fibrosis. In most cases, it is asymptomatic since the cysticerci die and become calcified. Neurocysticercosis Neurocysticercosis presents in many forms, depending on the localization of the cysts and disease activity. Sixty percent of the patients with cysticerci are found to have them in the brain. These cysts increase and slowly leak their antigen into the subarachnoid CSF producing meningitis and can further develop into arachnoiditis, which may lead to obstructive hydrocephalus, cranial nerve involvement, intracranial hypertension, arterial thrombosis and stroke. In intraventricular cysticercosis, the cysts occur in the lateral, third or fourth ventricles which maybe asymptomatic or if they block the flow of CSF, they may cause increased intracranial pressure. Ophthalmic Cysticercosis In some cases, cysticerci maybe found in the globe, subconjunctiva, and extraocular muscles. Depending on the location, they may cause visual difficulties that fluctuate with eye position, retinal edema, hemorrhage, a decreased vision or even a visual loss. Subcutaneous Cysticercosis Subcutaneous cysts are in the form of firm, mobile nodules, occurring mainly on the trunk and extremities. Subcutaneous nodules are sometimes painful Echinococcosis •• It is also known as hydatid disease. (Echinococcus granulosus) •• Hydatid cyst is a parasitic infection of humans by the tapeworm of genus echinococcus •• It is a zoonosis –– Echinococcus granulosus causes Cystic Echinococcuosis –– Echinococcus multilocularis causing Alveolar Echinococcuosis –– Echinococcus vogeli causes Polycystic disease Echinococcus granulosus: The liver is the most common organ effected followed by lungs, muscles, bones and kidneys. Passage of hydatid membrane in emesis is called hydatid emesia. Passage of hydatid membrane in stools is called hydatid enterica. Echinococcosis is caused by larval stages of parasite •• Man is an accidential intermediate host. Other intermediate hosts are sheep and cattle •• The dog is the definitive host. (D-D) •• Serological assay (Weinberg reaction) is specific example of Complement fixation test used in detection •• ELISA is also sensitive •• ARA C 5 is used in diagnosis. Entamoeba Histolytica •• Amebiasis is an infection with the intestinal protozoan Entamoeba histolytica •• About 90% of infections are asymptomatic, and the remaining 10% produce a spectrum of clinical syndromes ranging from dysentery to abscesses of the liver or other organs •• E histolytica is acquired by ingestion of viable cysts from fecally contaminated water, food, or hands •• Both trophozoites and cysts are found in the intestinal lumen, but only trophozoites of E histolytica invade tissue •• Cyst has glycogen mass, chromidial bars, eccentric nucleus •• Liver abscesses are always preceded by intestinal colonization, which maybe asymptomatic •• The most common type of amebic infection is asymptomatic cyst passage •• Amebic Liver Abscess Extraintestinal infection by E histolytica most often involves the liver •• Pleuropulmonary involvement, which is reported in 20 to 30% of patients, is the most frequent complication of amebic liver abscess. Microbiology Microscopic feature 305 Sites of abscess USMLE Case Scenario Patients typically present with diarrhea (often bloody) + right lower quadrant abdominal pain+fever. Amebic abscesses in the liver are a complication due to invasion of the portal venous system by the ameba. •• Primary amebic encephalitis: Naegleria fowleria •• Fulminant amebic meningoencephalitis: Naegleria fowleria •• Granulomatous amebic encephalitis: Balamuthia mandrillaris Paracapillaria Philippinensis •• It has long been known that the nematode Capillaria hepatica can cause a ‘visceral larva migrans-like syndrome’ in people who have eaten meat (e.g. infected liver) or sand containing the eggs of the worm •• These children exhibit such symptoms as fever, eosinophilia, abdominal pain and hepatomegaly, with large numbers of typical eggs being found in the liver on histological examination. •• P philippinensis is a parasite of the small intestine and it is believed to be a zoonotic infection involving birds and freshwater fish. Humans become infected by ingestion of eggs or infected raw fish, the usual intermediate host, and loads within the host may increase as a result of autoinfection •• Diagnosis of capillariasis is based upon histology or finding eggs and larvae in feces •• These eggs are like those of Trichuris, but the polar plugs are inset and the shells are striated or pitted •• Treatment for capillariasis is tiabendazole 25 mg/kg per day for 30 days or longer. Side effects and relapses are, however, common. Mebendazole and albendazole are also reported to be effective for the treatment of capillariasis. Gems Never to be forgotten •• Pneumoniae after exposure to parrots •• Chlamydiae psittaci •• Pregnant women with cats •• Toxoplasmosis gondii •• Muscle pain and eosinophilia •• Trichinosis (Trichinella spiralis) •• Slaughter house worker with fever •• Brucellosis •• Gardener stuck with a thorn •• Sporothrix schenckii •• Aplastic anemia in Sickle cell Disease •• Parvo virus B 19 •• Fungus Ball •• Aspergillus 306 USMLE Step 1 Platinum Notes USMLE Case Scenario A patient (pigeon handler) presents with interstitial pneumonitis accompanied by headache, backache, and a dry, hacking cough. A pale, macular rash is also found on the trunk (Horder’s spots). Likely organism is: 1. Histoplasma 2. Chlamydiae 3. Mycoplasma 4. Aspergillus Ans. 2. Chlamydiae USMLE Case Scenario A nematode infection is caused by taking undercooked Pork with symptoms of diarrhea, periorbital edema, myositis, fever and eosinophilia. Most likely organism is: 1. Tenia solium 2. Tenia saginata 3. Trichinella 4. Fasciola Ans. 3. Trichinella USMLE Case Scenario An organism is found to be a pleomorphic, gram-negative rod that causes a localized skin infection and seems to be a cause of an occupational disease of fishermen, fish handlers, and butchers. Most likely organism is: 1. Erysipelothrix 2. Brucella 3. Salmonella 4. Leptospira Ans. 1. Erysipelothrix NEVER TO BE FORGOTTEN: (USMLE FAVORITE) •• Swollen jaw with sulfur granules •• Actinomyces israelii •• Necrotizing fasciitis •• Sterptococcus pyogenes •• Diaper rash with hyphae and yeast on microscopy •• Candida •• Burnt tissue with blue greenpus, grape like odor •• Pseudomonas aeruginosa •• Denuded superficial area of large skin area: SSS •• Staph aureus •• Pink umblicate warts with central debris •• Molluscum contagiosum •• Virus latent in sensory ganglia with unilateral reactivation •• Varicella zoster virus •• Virus latent in trigeminal ganglia •• Herpes simplex virus 1, VZV •• Virus latent in S2, S3 •• Herpes simplex virus 2 Conjunctivitis on first day of life Chemical conjunctivitis Purulent Conjunctivitis on day 1-4 Gonococcal conjunctivitis Conjunctivitis on 3-10 days with inclusion bodies Chlamydiae trachomatis Follicular conjunctivitis with inturned eye lashes, Corneal scarring Chlamydiae trachomatis Chorioretinitis in immunocompromised Toxoplasma gondii Microbiology •• •• •• •• •• •• Gram-positive cocci in clusters Pear shaped trophozoites Budding yeasts forming germ tubes Yeast within macrophages BLOODY E coli Scotch tape test positive organism •• •• •• •• •• Cholera toxin: Stimulates Gs E coli heat labile toxin: stimulates Gs Pertussis toxin: inhibits Gi Diphtheria Toxin: acts on EF: Shuts down protein synthesis Pseudomonas aeruginosa: acts on EF: Shuts down protein synthesis •• •• •• •• •• •• 307 Staph aureus Giardia lamblia Candida albicans Histoplasma capsulatum E coli 0157: H7 Entrobius vermicularis CAUSATIVE ORGANISMS OF COMMONLY ASKED DISEASES: (USMLE FAVORITE) •• Progressive postoperative Bacterial synergistic gangrene •• Malignant Otitis externa •• Microaerophillic, nonhemolytic Streptococci plus staphylococci •• Pseudomonas •• Scleroma •• Klebsiella rhinoscleromatosis •• Sudoku •• Spirillum minus •• Botryomycosis •• Staph aureus •• Chicleros ulcer •• Leishmania Mexicana •• Espundia •• L Braziliensis •• Favus •• Tricophyton Schonleneii •• Erysipeloid •• Erysipelothrix rhusiopathia Important Causative Agents: (USMLE Favorite) •• •• •• •• •• •• •• •• •• •• •• •• •• Necrotizing fasciitis: Group A streptococci Purpureal sepsis: Group B streptococci Sweaty tennis shoe syndrome: Pseudomonas Fish handlers disease: Erysipelothrix rhusiopathiae Granuloma infantisepticum: Listeria Gay bowel syndrome: Shigella flexiniri Human monocytic ehrilichiosis: E chaffeensis Human granulocytic ehrilichiosis: E equi Rat bite fever: Spirillum minus Medittarenean spotted fever: Ricketssia conorii Cat scratch disease: Bartonella hensla Typhilitis: Pseudomonas aeruginosa Red leg disease: Aeromonas USMLE Case Scenario A gram-negative rod that is a zoonotic agent causingan undulating febrile disease with malaise, lymphadenopathy and hepatosplenomegaly. The normal route of exposure is via ingestion of the organism. Most likely organism is: 1. Borrelia 2. Brucella 3. Legionella3 4. Leptospira Ans. 2. Brucella 308 USMLE Step 1 Platinum Notes USMLE Case Scenario A5-year-old child is bitten by a rat. Three days later, the child develops a rash characterized by discrete erythematous 2–4 mm macules on the lower extremities and face, most obvious on the palms and soles. Most likely organism is: 1. Yersinia Pestis 2. Streptobacillus moniliformis 3. Pasturella 4. Yersinia enterocolitica Ans. 2. Streptobacillus moniliformis USMLE Case Scenario Infection in AIDS Patient from New York is characterized by firm a nodule that often becomes umbilicated. Cause is found to be viral most likely organism is: 1. HSV 2. HPV 3. Poxvirus 4. EBV Ans. 3. Poxvirus USMLE Case Scenario A small, pleomorphic, gram-negative rod that a cause (rabbit fever) with bacteremia, splenomegaly, rash, pneumonia is most likely caused by: 1. Francisella 2. Listeria 3. Leptospira 4. Brucella Ans. 1. Francisella USMLE Case Scenario A gram-negative bacterium causing a local, chronic lymphadenitis, proliferation of blood and lymphatic vessels causing a characteristic ‘mulberry’ lesion in the skin and subcutaneous tissues of the afflicted individual and bacillary angiomatosis is: 1. Brucella 2. Bartonella 3. Legionella 4. Leptospira Ans. 2. Bartonella USMLE Case Scenario A gram-positive spore-forming anaerobic rod causing (a spastic paralysis caused by toxin which blocks the release of the inhibitory neurotransmitters glycine and gamma-aminobutyric acid [GABA]) is most likely: 1. Clostridium tetani 2. Clostridium difficile 3. Clostridium welchi 4. Bacillus anthracus Ans. 1. Clostridium tetani Generalizations asked in USMLE •• First disease: Rubeola, (measles, kopliks spots) •• Second disease: Scarlet fever, (circumoral pallor, pastias lines, strawberry tongue) •• Third disease: Rubella, (Forschmiers spots, posterior cervical lymphadenopathy) Microbiology •• Fourth disease: SSSS, (Nikolskys sign) •• Fifth disease: Erythema infectiosum (parvovirus b 19, slapped cheek appearance) •• Sixth disease: Exanthem subitum, Roseola infantum •• Ankylostoma duodenale: •• Babesia: •• Diphyllobithirum latum: •• Iron deficiency anemia •• Hemolytic anemia •• Megaloblastic anemia Microbiology of Sexually Transmitted/Genital Diseases •• Syphilis: painless ulcer with painless Lymphadenopathy •• Chancroid: (soft chancre) painful ulcer with painful lymphadenopathy. •• LGV: un noticed painless papule with suppurative lymphadenopathy. Groove sign •• Donovaniosis (Granuloma inguinale): painless subcutaneous nodules without lymphadenopathy with pseudobuboes. •• Herpes genitalis: painful papule, with inguinal Lymphadenopathy The chancre of CHANCROID IS ‘PAINFUL’ IN CONTRAST TO SYPHILIS WHICH IS ‘PAINLESS’. Ducreyi makes you cry Never forget the lines about Features of Chancroid: Lesions are multiple in number in the form of ulcers which are painful with undermined and ragged edges Accompanied by Tender and suppurative lymphadenopathy in the form of inguinal buboes. Important Microbiological Tests •• Dick Test •• Scarlet Fever •• Freis Test •• Lymphogranuloma venereum •• Kahns Test •• Syphilis •• Kveims Test •• Sarcoidosis •• Mono spot/ Paul Bunnel Test •• Infectious Mononucleosis •• Rose waaler Test •• Rheumatoid Arthritis •• Sweat Test •• Cystic Fibrosis •• Weil Felix Test •• Rickettsial infection •• Rumpel leed test (Capillary Fragility Test) •• Scurvy USMLE Clinical Case Scenarios Frequent Repititions •• Vomiting 1–6 hours after eating fried rice: Bacillus Cereus •• Vomiting and Diarrhea 1–6 hours after eating contaminated food (Creams): Staph aureus •• Diarrhea after ingestion of raw shell fish: Vibrio parahemolyticus •• Watery Diarrhea with or without vomiting after travel in developing countries: ETEC •• Diarrhea with rapid Fluid loss and Dehydration: V. cholera •• Acute endocarditis: Staph aureus •• Endocarditis in IV Drug abusers: Staph aureus •• Megaloblastic Anemia with history of fish ingestion: Diphyllobothrium latum 309 310 USMLE Step 1 Platinum Notes Vibrio vulnificus is an extremely invasive organism, producing a septicemia in patients after eating raw shellfish, or causing wound infections, cellulitis, fasciitis, and myositis after exposure to seawater or after cleaning shellfish. Patients at high-risk for septicemia include those with liver disease, congestive heart failure, diabetes mellitus, renal failure, hemochromatosis, and immunosuppression. Vibrio diarrhea USMLE Repeated Favorites ‘Sporothrix schenckii’. This organism is responsible for ‘rose gardener’s disease’, known technically as sporotrichosis. The organism enters through skin breaks in the fingers or hands, causing a chancre, papule, or subcutaneous nodule with erythema and fluctuance. Ulcerating lesions appear along lymphatic channels, but the lymph nodes are not commonly infected. Potassium iodide is the treatment for the subcutaneous manifestations. Tularemia, which maybe spread by handling rabbits or rabbit skins, or by bites from ticks that feed on the blood of wild rabbits. The causative organism is Francisella tularensis, a gram-negative coccobacillus. The disease begins as a rupturing pustule followed by an ulcer, with involvement of regional lymph nodes. More serious cases can be complicated by bacteremia, splenomegaly, rash, pneumonia, or endotoxemic shock. Borrelia spp. causes relapsing fever (transmitted by ticks and lice) and Lyme disease (transmitted by ticks). Brucella causes brucellosis after ingestion of contaminated milk or contact with Infected livestock. Leptospira causes leptospirosis and Weil’s disease; the organism is acquired by ingestion of water contaminated with animal urine. Listeria causes listeriosis after contact with contaminated milk, vegetables, or with transplacental transmission. Fungi: (USMLE Favorite) Characteristics Fungi •• Nucleic Acid •• Both •• Nucleus •• Eukaryotic •• Ribosomes •• 80S •• Mitochondria •• Present •• Motality •• Nil •• Reproduction •• Budding Microbiology 311 •• •• •• •• •• •• •• Dimorphic (‘having two forms’) because they are spherical in tissue but grow like molds when cultured at room temperature Histoplasmosis Blastomycosis Sporotrichosis Coccidioidomycosis Paracoccidioidomycosis Penicillin marfenii •• •• •• •• •• •• •• •• •• •• Fungi are Eukaryotic organisms Fungal cell wall contains Chitin.(Chitin is a polysaccharide of long chains of N acetyl glucosamine.) Fungal Cell membrane contains Ergosterol in contrast to human cell membrane which contains cholesteroL STAINED by PAS Most fungi reproduce asexually by forming asexual spore’s conidia Fungi without sexual stage: fungi imperfectii Fungi are culture in Saboubards medium NON Culturable fungus: Rhinosporodium Candida species other than Candida glabrata appear in tissue as both budding yeasts and tubular elements called pseudohyphae Pneumocystis carinii is closer to fungi than to parasites by ribosomal sequences •• Monomorphic, Hyphal fungi with dichotomus branching hyphae at acute angles: Aspergillus fumigates •• Yeasts with pseudohyphae and true hyphae: Candida albicans •• Monomorphic yeast with polysaccharide capsule: Cryptococcus •• Non septate filamentous fungi: Mucor, Rhizopus, Absidia •• Yeast with broadbased bud and double retractile cell wall: Blastomyces Dermatitidis •• Fungus with Endospores and spherules: Coccidomyces immitis •• Filamentous fungi with Tuberculate Macronidia: Histoplasma capsulatum USMLE Case Scenario A disease is seen mainly in the desert parts of the Southwest US. In the lungs, spherules containing endospores are seen. Most likely disease is: 1. Coccidioidomycosis 2. Sporotrichosis 3. Paracoccidioidomycosis 4. Blastomycosis Ans. 1. Coccidioidomycosis USMLE Case Scenario A Disease producing a localized cutaneous infection, following inoculation occurring in association with minor skin trauma during gardening is: 1. Coccidioidomycosis 2. Sporotrichosis 3. Paracoccidioidomycosis 4. Blastomycosis Ans. 2. Sporotrichosis 312 USMLE Step 1 Platinum Notes USMLE Case Scenario A disease is endemic in Latin America, especially in Brazil. The infected cells show a typical ‘pilot’s wheel’ appearance due to multiple yeasts sprouting out of a single parent cell. Most likely the disease is: 1. Coccidioidomycosis 2. Sporotrichosis 3. Blastomycosis 4. Paracoccidioidomycosis Ans. 4. Paracoccidioidomycosis •• Mycotoxicosis: Ingestion of fungal toxins produced in foodmost notably aflatoxin in pea nuts •• Mycetismus: Illness from toxic ingestion of toxic mushrooms •• Fungemia: Sever disseminated fungal infections in immunocompromised patients •• Sick building syndrome: Inhalation of volatile fungal toxins which aggreviates allergies Candida •• Candidiasis, commonly called yeast infection or thrush, also known as ‘Candidosis,’ ‘Moniliasis,’ and Oidiomycosis is a fungal infection (mycosis) of any of the Candida species, of which Candida albicans is the most common •• It is an endogeneous infection •• In immunocompetent persons, candidiasis is usually a very localized infection of the skin or mucosal membranes, including the oral cavity (thrush), the pharynx or esophagus, the gastrointestinal tract, the urinary bladder, or the genitalia (vagina, penis) •• MC fungal infection in neutropenic patients •• Candidiasis is a very common cause of vaginal irritation, or vaginitis, and can also occur on the male genitals •• In immunocompromised patients, Candida infections can affect the esophagus with the potential of becoming systemic, causing a much more serious condition, a fungemia called candidemia •• Shows Reynolds Braude phenomenon- ability to form germ tubes within 2 hours of incubation. •• Candida shows Reynolds Braude Phenomenon (ability to form germ tubes within two hours when incubated in human serum at 37oC). •• Hepatosplenic candidiasis manifests as Bulls Eye Lesion. USMLE Case Scenario A 44-year-old woman in Mexicopresents to her gynecologist because of vaginal itchiness and discharge. Pelvic examination demonstrates abundant white, curdy material in the vagina. Microscopic examination of the material demonstrates fungal hyphae and yeast forms. Fungal Organism is: 1. Aspergillus 2. Trichomonas 3. Tinea 4. Candida Ans. 4. Candida USMLE Case Scenario A lesion appears as creamy, white patches of exudate that can be scraped off an inflamed tongue or buccal mucosa of an AIDS patient from Suburban America. Organisms appear as very large, gram-positive, spherical-to-ovoid organisms with budding daughter cells in Gram-stained preparations. Most likely organism is: 1. EBV 2. HSV 3. Candida 4. CMV Ans. 3. Candida Microbiology 313 USMLE Case Scenario A 33-year-old HIV-positive male from New York complains of pain on swallowing. Physical examination is remarkable for white plaque-like material on his tongue and buccal mucosa, which is scraped and sent to the laboratory. The man is diagnosed with acquired immunodeficiency syndrome (AIDS). With which of the following agents is the man most likely infected? 1. EBV 2. HSV 3. Candida 4. CMV Ans. 3. Candida Types of Dermatophyte Infections Dermatophytes infect: skin, nails, hair Athlete’s foot or tinea pedis T rubrum, T mentagrophytes, E floculossum Jock itch or tinea cruris T rubrum, T mentagrophytes, E floculossum Ringworm of the body or tinea corpora Facial ringworm or tinea faciei Blackdot ringworm or tinea capitis –– MC agent: T tonsurans –– Favus is other manifestation. Caused by T schoneilenni –– Kerion is caused by T mentagrophytes and T verrucosum •• Ringworm of the hands or tinea manuum •• In most cases of tinea manuum, only one hand is involved. Frequently both feet are involved concurrently, Thus the saying ‘one hand, two feet’ Ringworm of the nail, Onychomycosis, or tinea unguium •• •• •• •• •• •• Mycetoma •• •• •• •• •• •• Chronic granulomatous involvement of subcutaneous and deep tissues Commonly effecting foot Usually presents with ulcer on leg, indurated margins and discharging sinuses Destruction of bone occurs Actinomycetoma is caused by bacteria: nocardia, actinomadura, streptomyces, actinomyces Eumycetoma is caused by fungus: madurella, pseudallescheria boydii, philphora Cryptococcus •• •• •• •• Cryptococcus is MonomorphicYeast Has a Polysaccharide capsule The environmental source is soil enriched with pigeon droppings Prediliction for brain •• •• •• •• •• Acute pulmonary infections are common in pigeon breeders Cryptococcal meningitis is dominant in AIDS patients and patients with cancers Latex particle agglutination test for capsular polysaccharide in CSF is rapid and sensitive It is urease positive yeast Microscopy on India ink wet mount is also used for diagnosis ‘Late infections’ (> 6 months after kidney transplantation) include CMV retinitis and a variety of CNS complications. Patients (particularly those whose immunosuppression has been increased) are at risk for ‘subacute meningitis due to Cryptococcus neoformans’. Cryptococcal disease may present in an insidious manner (sometimes as a skin infection before the development of clear CNS findings). 314 USMLE Step 1 Platinum Notes Cryptococcal Meningitis is the mc cause of acute meningitis in AIDS Cryptococcal infections of the lung can be seen in patients with AIDS. Patients with pulmonary cryptococcal disease present with ‘fever, cough, dyspnea, and in some cases, hemoptysis’. A focal or diffuse interstitial infiltrate is seen on chest X-ray in >90% of patients. In addition, one may see lobar disease, cavitary disease, pleural effusions, and hilar or mediastinal adenopathy. ‘Indium In 111-labeled leukocyte scans’ have become useful as an adjunct to other diagnostic procedures in the detection of gastrointestinal and central nervous system (CNS) infections, such as focal encephalitis, cryptococcal meningitis, and cytomegalovirus encephalitis, in acquired immunodeficiency syndrome (AIDS) patients. Coccidioides Immitis •• Grows as a white fluffy mold on most culture media and as a nonbudding spherical form (a spherule) in host tissue or under special conditions •• The organism reproduces in host tissue by forming small endospores within mature spherules •• After rupture of the spherule, the released endospores enlarge, become spherules, and repeat the cycle. The fungus is identified by its appearance and by the formation of thick-walled, barrel-shaped spores, called arthrospores, in the hyphae of the mold form •• Causes: Valley fever/Desert Rheumatism. Histoplasma Capsulatum •• It is a dimorphic fungus •• Hyphae bear both large and small spores, which are used for identification •• H capsulatum grows as small budding yeast in host tissue and on enriched agar, such as blood cysteine glucose, at 37°C •• The fungus is unencapsulated •• Grows in bird/bat enriched soil •• Coculture of isolates with opposite mating types can produce different sporulating structures in which genetic recombination occurs •• When these structures, referred to as a teleomorph or the perfect state, are seen in culture, the name Ajellomyces capsulatus is used •• Causes: Histoplasmosis USMLE Case Scenario A 55-year-old HIV-positive male from Toledo complains of headache and blurred vision. Physical exam reveals papilledema and ataxia. Head CT is normal but CSF obtained by lumbar puncture reveals encapsulated organisms observable with India ink. Which is the organism implicated? 1. Cryptococcus 2. Histoplasmosis 3. Chromoblastomycosis 4. Blastomycosis Ans. 1. Cryptococcus USMLE Case Scenario A 66-year-old farmer from rural area presents with chronic cough. Chest X-ray demonstrates a mass lesion with hilar lymphadenopathy. Biopsy of the mass demonstrates multiple, tiny yeast forms within macrophages. Which of the following is the most likely diagnosis? 1. Histoplasmosis 2. Chromoblastomycosis 3. Blastomycosis 4. Mucormycosis Ans. 1. Histoplasmosis Microbiology 315 Blastomyces Dermatitidis •• It is a dimorphic fungus •• Seen as broad, based, and budding, round yeast like cells with thick wall Causes: •• Blastomycosis –– Have an indolent onset and a chronically progressive course. Fever, cough, weight loss, lassitude, skin lesions, and chest ache are common –– Skin lesions favor exposed areas and enlarge over many weeks from pimples to well-circumscribed, verrucous, crusted, or ulcerated lesions –– Pain and regional lymphadenopathy are minimal large chronic lesions may undergo central healing with scarring and contracture. Mucous membrane lesions resemble squamous cell carcinoma –– Chest X-ray findings are abnormal in two-thirds of patients, with one or more pneumonic or nodular infiltrate –– Remember: Blasts skin, lungs. USMLE Case Scenario A pathogen is found to be present in the respiratory tract of a 36-year-old patient from Honduras as an opportunistic pathogen; Fungus balls are also seen. Patient previously had Tuberculosis. Most likely organism is. 1. Blastomyces dermatitidis 2. Pneumocystis carinii 3. Aspergillus 4. Mycobacterium tuberculosis Ans. 3. Aspergillus Aspergillus: (USMLE Favorite) •• •• •• •• •• •• •• It is the most common cause of aspergillosis, but A flavus, A niger, and several other species can also cause disease Has branching hyphae. (septate) Mc disease caused: otomycosis Aspergillus is a mold with septate hyphae about 2 to 4 mm in diameter Portal of entry is lungs Aspergillus can colonize the damaged bronchial tree, pulmonary cysts, or cavities of patients with underlying lung disease Causes: –– Aspergillomas: Balls of hyphae within cysts or cavities usually in the upper lobe, may reach several centimeters in diameter and maybe visible on chest X-ray. Tissue invasion does not occur –– Allergic bronchopulmonary aspergillosis denotes the condition of patients with pre-existing asthma who have eosinophilia, IgE antibody to Aspergillus and fleeting pulmonary infiltrates from bronchial plugging. Mucormycosis: (USMLE Favorite) •• Species of Rhizopus, Rhizomucor, are the most common causes of mucormycosis •• It is angio invasive •• •• •• •• Zygomycosis is a term that includes mucormycosis and entomophthoromycosis Rhizopus and Rhizomucor species are ubiquitous, appearing on decaying vegetation, dung, and foods of high sugar content Mucormycosis is uncommon and is largely confined to patients with serious pre existing diseases. (Diabetic ketoacidosis) Mucormycosis originating in the paranasal sinuses and nose predominantly affects patients with poorly controlled diabetes mellitus •• Patients who have undergone organ transplantation, who have a hematologic malignancy, or who are receiving long-term deferoxamine therapy are predisposed to mucormycosis of either sinus or lung •• Gastrointestinal mucormycosis occurs in a variety of conditions, including uremia, severe malnutrition, and diarrheal diseases •• Pulmonary mucormycosis manifests as progressive severe pneumonia accompanied by high fever and toxicity. The necrotic center of large infiltrates may cavitate. 316 USMLE Step 1 Platinum Notes USMLE Case Scenario A fungal infection begins in the nasal passages, extends into the paranasal sinuses and spreads through the cribiform plate to the frontal lobes of the brain. Patients typically complain of headache, facial pain and orbital swelling. Most likely cause is: 1. Chromoblastomycosis 2. Aspergillus 3. Mucormycosis 4. Blastomycosis Ans. 3. Mucormycosis USMLE Case Scenario A mold with septate hyphae in immunocompromised patients, aspergillosis presenting with acute pneumonia with cavitation is: 1. Chromoblastomycosis 2. Aspergillus 3. Mucormycosis 4. Blastomycosis Ans. 2. Aspergillus USMLE Case Scenario An 85-year-old diabetic woman, on dialysis for chronic renal failure, develops bilateral orbital and facial pain, headache, and sudden loss of vision in the right eye. When examined 2 days later, she is found to have the right eyelids red and swollen, and she has complete loss of vision and motion on the right eye and partial loss of vision on the left eye. The mucosa of the nasal passages is swollen and necrotic, with a black discoloration. MRI shows soft-tissue swelling of the nasal mucosa, sinuses, and orbital tissues, with no evidence of cavernous sinus thrombosis or retro-orbital cellulitis. Biopsy of the temporal artery is negative for giant cell arteritis. Biopsy of the nasal and sinuses mucosa demonstrates thrombosed vessels and multiple broad nonseptate hyphae with right-angle branches. Which of the following is the most appropriate treatment? 1. Amphotericin B and surgical debridement 2. Corticosteroids 3. Heparin anticoagulation 4. Metronidazole and drainage of the paranasal sinuses 5. Surgical decompression of both orbits Ans. 1. Amphotericin B and surgical debridement Chromoblastomycosis Chronic subcutaneous mycosis, presents as a verrucoid, ulcerated, or crusted skin lesion Cladosporium is causative organism The disease follows the introduction of any of several fungi into subcutaneous tissue by thorns or bits of vegetation The appearance of thick-walled, dark-colored, rounded forms (‘copper pennies’) in histopathologic section is diagnostic. Sclerotic bodies •• Surgical excision is the treatment of choice. •• •• •• •• USMLE Case Scenario A 66-years-old AIDS patient with pneumonia has a bronchoalveolar lavage that demonstrates small, ‘hat-shaped’ structures in alveoli that are about the size of an erythrocyte and stain with silver stains. The microorganism involved is most likely which of the following? 1. Blastomyces dermatitidis 2. Mycobacterium avium 3. Mycobacterium tuberculosis 4. Pneumocystis carinii Ans. 4. Pneumocystis carinii Microbiology 317 USMLE Case Scenario A 44-year-old HIV-positive mancomes to Immunology clinic complaining of dyspnea mild cough and fever. Physical examination is remarkable for oral thrush and a few small, nontender cervical lymphnodes. A chest X-ray film reveals bilateral interstitial infiltrates, and bronchoalveolar lavage reveals small silver-staining cysts. Most likely organism is: 1. Blastomyces dermatitidis 2. Pneumocystis carinii 3. Mycobacterium avium 4. Mycobacterium tuberculosis Ans. 2. Pneumocystis carinii Pneumocystis Carinii: (USMLE Favorite) •• Obligate extracellular fungus •• Present in patients with defects in cell-mediated immunity as with hematologic malignancies, lymphoproliferative diseases, cancer chemotherapy, and AIDS •• Causes interstitial pneumonia •• Traditional stains have included reagents such as methenamine silver, toluidine blue, and cresyl violet, which selectively stain the wall of P carinii cysts, and reagents such as Wright-Giemsa, which stain the nuclei of all developmental stages. Other reagents include nonspecific fluorochrome stains (calcofluor white) and Papanicolaou’s stain. Clinical Case Scenarios of USMLE (Important Guiding Features) •• An organism is found to be a pleomorphic, gram-negative rod that causes a localized skin Erysipelothrix infection and seems to be a cause of an occupational disease of fishermen, fish handlers, and butchers. Most likely disease is caused by: •• A nematode infection is caused by taking undercooked Pork with symptoms of diarrhea, periorbital Trichinella edema, myositis, fever, and eosinophilia. Most likely organism is: •• An organism occurs in the immunocompromised population and may cause severe diarrhea. Cryptosporodiosis The organism presents as minute (2-5 mm) intracellular spheres or arc-shaped merozoites under normal mucosa. Most likely disease is •• A 44-year-old patient presents with facial edema and nodules, fever, lymphadenopathy, and Chagas disease hepatosplenomegaly. The disease also affects cardiac muscle most severely. It is most prevalent in Central and South America; with rare cases in the southern US. The disease is: •• A 35-year-old female says she had a protozoan infection and used to eat undercooked Toxoplasmosis meat and had exposure to cat feces. The organisms can also cause a heterophile-negative, mononucleosis-like syndrome. In patients with AIDS, it causes ring-enhanced focal brain lesions and pneumonia. Most likely the disease is •• An African child develops massive unilateral enlargement of his lower face in the vicinity of Burkitts Lymphoma the mandible. Biopsy demonstrates sheets of medium-sized blast cells with admixed larger macrophages. This type of tumor has been associated with viral infection. Most likely disease is •• A Disease is found to be due to reactivation of epidemic typhus infection caused by Rickettsia Brill Zinsser disease prowazekii. It can occur many years after an infection that was not treated with antibiotics. The most likely disease is: •• A gram-positive coco bacillus is causing Infection during pregnancy that may result in Listerosis sepsis, abortion or premature delivery. Infection in the neonate may produce meningitis. In immunocompromised adults, either meningitis or sepsis may occur. The organism is •• A 3-year-old boy from rural America is brought to the ENT emergency room in extreme Epiglottitis respiratory distress, with a temperature of 104 degrees Fahrenheit. He is drooling and has great difficulty swallowing, and on physical examination, an inspiratory stridoris noted. An immediate lateral X-ray done shows swelling of the epiglottis. He has had no previous vaccinations. Most likely disease is 318 USMLE Step 1 Platinum Notes •• An highly encapsulated organism is found to cause a bronchopneumonia with patchy infiltrates Klebsiella pneumoniae involving one or more lobes with red sputum in a debilitated alcoholic. Most likely disease is: •• A 8-year-old girl is bitten in the leg by a dog. She presents the next day with fever and bone Pasteurella pain localized to her right calf. X-ray reveals a lytic lesion of the left femur. Results of the bone culture are pending. Infecting organism is most likely to be: •• An organism is causing urinary tract infections. It has ability to breakdown urea and is thought to Proteus species. contribute to the development of struvite kidney stones due to the elevation of urine pH by production of ammonia. The said organism is also having swarming motility. The organism is identified •• A 44-year-old man from rural Indian village is brought to a rural hospital with severe Plague bronchopneumonia. He suffered sudden onset of chills, fever, and headache several days ago. Two day later, he complained of chest pain and difficulty breathing, and coughed up bloodtinged sputum. Chest X-ray reveals patchy infiltrates and segmental consolidation. The most likely cause of this man’s pneumonia and the disease itself is due to yersinia. Disease itself is: •• A disease is caused the organism enters through skin breaks in the fingers or hands, causing Sporotrichosis a chancre, papule, or subcutaneous nodule with erythema and fluctuance. Ulcerating lesions appear along lymphatic channels, but the lymph nodes are not commonly infected. Potassium iodide isused for the treatment for the subcutaneous manifestations. The disease is common in gardeners. Most likely disease is: •• A 66-year-old alcoholic man with brain and pulmonary abscess and is treated with antibiotics Clostridium difficile for last two weeks. He develops nausea, vomiting, abdominal pain, and voluminous green diarrhea. The condition is diarrhea due to: •• An organism identified on dark ground microscopy caused testicular involvement with gumma Syphilis formation, endarteritis, and/or a prominent plasma cell infiltrate. Most likely disease is: •• A disease which maybe spread by handling rabbits or rabbit skins, or by bites from ticks that feed Tularemia on the blood of wild rabbits, a gram-negative coccobacillus. The disease begins as a rupturing pustule followed by an ulcer, with involvement of regional lymph nodes. More serious cases can be complicated by bacteremia, splenomegaly, rash, pneumonia, or endotoxemic shock. Most likely disease is: •• A gram-positive spore-forming anaerobic rod causing (a spastic paralysis caused by toxin Tetanus caused by clostridia which blocks the release of the inhibitory neurotransmitters glycine and gamma-aminobutyric tetani acid [GABA]) is most likely: •• A gram-negative rod that is a zoonotic agent causing an undulating febrile disease with Brucellosis malaise, lymphadenopathy and hepatosplenomegaly. The normal route of exposure is via ingestion of the organism. Most likely disease is: Microbiology 319 USMLE Case Scenario A minority of cases of infective endocarditis are caused by a number of normal commensals in the oral cavity, i.e. the ‘HACEK’ group. Hacek Means. 1. Hemophilus, Actinobacillus, Corynebacterium, Eikenella, and Kingella 2. Hemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Klebsiella 3. Hemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella 4. Hemophilus, Actinobacillus, Cardiobacterium, E coli, and Kingella Ans. 3. Hemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella USMLE Case Scenario ADP-ribosylation of an elongation factor is a mechanism of action of: 1. Pseudomonas exotoxins 2. Clostrodial toxin 3. Streptococcal toxin 4. Staphylococcal toxin Ans.1. Pseudomonas exotoxins USMLE Case Scenario An organism is found to be a pleomorphic, gram-negative rod that causes a localized skin infection and seems to be a cause of an occupational disease of fishermen, fish handlers and butchers. Most likely organism is: 1. Erysipelothrix 2. Brucella 3. Salmonella 4. Leptospira Ans. 1. Erysipelothrix USMLE Case Scenario ‘Stalacite’ growth is a feature of: 1. Hemophilus 2. Pasteurella 3. Corynebacterium 4. Mycoplasma 5. Klebsiella 6. Pseudomonas Ans. 2. Pasteurella USMLE Case Scenario A Virus produces neonatal infections and infections in immunocompromised patients such as AIDS patients and most common clinical presentation is producing floaters, visual field deficits, and painless loss of vision. It also produces encephalitis and may produce calcifying lesions in the CNS. Virus most likely is: 1. CMV 2. EBV 3. HSV 4. HHV Ans. 1. CMV 320 USMLE Step 1 Platinum Notes USMLE Case Scenario Staphylococcus aureus is present in mayonnaise. The patient presents with nausea, vomiting, and abdominal pain, followed by diarrhea beginning 1–6 hours after ingestion of the toxin. The toxin is: 1. Not a Preformed enterotoxin 2. Preformed enterotoxin 3. Preformed non enterotoxin 4. Non Preformed non enterotoxin Ans. 2. Preformed enterotoxin USMLE Case Scenario An obligate intracellular parasite that induces endocytosis and resides in the phagosome of infected epithelial cell is: 1. Rickettsia 2. Mycoplasma 3. Mycobacteria 4. Chlamydia Ans. 4. Chlamydia USMLE Case Scenario Lucio phenomenon is a widespread diffuse infiltration of the skin with secondary alopecia of the hair, eyebrows and eyelashes, and generalized sensory loss. The patients are systemically ill with fever, chills, malaise, arthralgias, myalgias, and tender cutaneous lesions that are responsive to steroids but not to thalidomide. Lucio phenomenon is usually associated with: 1. Mycoplasma 2. Chlamydia 3. Mycobacterium avium 4. Mycobacterium africanum 5. Mycobacterium tuberculosis 6. Mycobacterium leprae Ans. 6. Mycobacterium leprae USMLE Case Scenario Overall, 30–40% of all infections contracted in the post renal transplant period are viral. The most common viral infections are by: 1. DNA viruses 2. RNA Viruses 3. Retroviruses 4. Arboviruses Ans. 1. DNA viruses The most common viral infections are DNA viruses of the herpes virus family and include cytomegalovirus (CMV), Epstein-Barr virus, herpes simplex virus, and varicella zoster virus. USMLE Case Scenario An 66-years-old AIDS patient with pneumonia has a bronchoalveolar lavage that demonstrates small, ‘hat- shaped’ structures in alveoli that are about the size of an erythrocyte and stain with silver stains. The microorganism involved is most likely which of the following? 1. Blastomyces dermatitidis 2. Mycobacterium avium 3. Mycobacterium tuberculosis 4. Pneumocystis carinii Ans. 4. Pneumocystis carinii Microbiology 321 USMLE Case Scenario An 85-year-old diabetic woman from Chicago develops orbital and facial pain, headache. When examined 2 days later, she is found to have the right eyelids red and swollen, and she has complete loss of vision and motion on the right eye. The mucosa of the nasal passages is swollen and necrotic, with a black discoloration. Biopsy of the temporal artery is negative for giant cell arteritis. Biopsy of the nasal and sinuses mucosa demonstrates thrombosed vessels and multiple broad nonseptate hyphae with right-angle branches. Most likely cause is: 1. Histoplasmosis 2. Blastomycosis 3. Mucormycosis 4. Aspergellosis Ans. 3. Mucormycosis USMLE Case Scenario A child after playing with a pet injured while playing with a pet has a local abscess. A gram-negative rod that is normal flora of the oral cavity of dogs and cats is found to be causative. Most likely organism is: 1. Pasteurella 2. Pseudomonas 3. Francisella 4. Bartonella Ans. 1. Pasteurella USMLE Case Scenario Visceral larva migrans is due to: 1. Ascariasis 2. Toxocaria 3. Schistosomiasis 4. Clonorchis 5. Trichomonas 6. Plasmodium Ans. 2. Toxocaria USMLE Case Scenario An organism is causing urinary tract infections. It has ability to breakdown urea and is thought to contribute to the development of struvite kidney stones due to the elevation of urine pH by production of ammonia. The said organim is also having swarming motility. The organism is identified as: 1. Brucella 2. Proteus 3. Pseudomonas 4. Anthrax bacillus 5. Clostridia Ans. 2. Proteus USMLE Case Scenario Botulin toxin acts by: 1. ↓Secretion of Ach 2. ↑Synthesis of Ach 3. Muscle nerve block 4. Inhibits Ach release Ans. 4. Inhibits Ach release 322 USMLE Step 1 Platinum Notes USMLE Case Scenario A 33-year-old HIV-positive male from New York complains of pain on swallowing. Physical examination is remarkable for white plaque-like material on his tongue and buccal mucosa, which is scraped and sent to the laboratory. The man is diagnosed with acquired immunodeficiency syndrome (AIDS). With which of the following agents is the man most likely infected? 1. EBV 2. HSV 3. Candida 4. CMV Ans. 3. Candida USMLE Case Scenario A 55-year-old man presents with an episode of shaking chills the previous night. He has now developed right-sided pleuritic chest pain, fever, sweats, malaise, purulent sputum, and mild hemoptysis. On examination, the patient is diaphoretic but alert, with right basilar rales. Chest X-ray films show a right lower lobe infiltrate with blunting of the right costophrenic angle. The causative organism implicated is: 1. Streptococcus agalactiae 2. Streptococcus pneumonia 3. Streptococcus viridians 4. Streptococcus pyogenes Ans. 2. Streptococcus pneumonia USMLE Case Scenario A 22-year-old veterinary surgeon presents with a 2 week history of high fevers, night sweats. He also had dry cough, and myalgia. On examination, the patient had a palpable splenic tip. Blood films for malaria parasites were negative. Liver function tests showed a raised serum alkaline phosphatase, raised serum aspartate aminotransferase concentration, ↑serum bilirubin concentration. Likely cause is: 1. Salmonella 2. Chlamydia 3. Bartonella 4. Francisella 5. Mycoplasma 6. Brucella 7. Legionella Ans. 6. Brucella USMLE Case Scenario Erythema infectiosum is caused by: 1. Parvovirus B19 2. Papova virus 3. Human herpes virus type 8 4. Measles virus Ans. 1. Parvovirus B19 USMLE Case Scenario A Virus produces neonatal infections and infections in immunocompromised patients such as AIDS patients and most common clinical presentation is producing floaters, visual field deficits, and painless loss of vision. It also produces encephalitis and may produce calcifying lesions in the CNS. Virus most likely is: 1. CMV 2. EBV Microbiology 323 3. HSV 4. HHV Ans. 1. CMV USMLE Case Scenario ‘Lipopolysaccharide’ is an important component of: 1. Gram-positive cells 2. Gram-negative cells 3. Neither Gram-positive nor Gram-negative cells 4. Both Gram-positive and Gram-negative cells Ans. 2. Gram-negative cells USMLE Case Scenario Encephalitis typically affects the inferomedial temporal lobes and orbitofrontal gyri. Most likely double stranded DNA virus implicated is: 1. EBV 2. HSV 3. CMV 4. Pox Ans. 2. HSV USMLE Case Scenario Chagas’ disease is characterized by facial edema and nodules, fever, lymphadenopathy, and hepatosplenomegaly. It affects cardiac muscle most severely. It is most prevalent in Central and South America; with rare cases in the southern US. The causative organism is: 1. Trypanosoma cruzi 2. Trypanosoma brucei 3. Toxoplasma gondii 4. Babesia microti Ans. 1. Trypanosoma cruzi USMLE Case Scenario Epidemic keratocojunctivitis is caused by: 1. Coronavirus 2. Epstien-Barr virus 3. Picornavirus 4. Adenovirus Ans. 4. Adenovirus USMLE Case Scenario A pregnant 18-year-old woman came to the clinic with a low-grade fever, malaise and headache. Few days later she presented with a macular rash on her trunk, arms, hands, and feet. Further examination revealed that 1 month previously, she had a painless ulcer on her vagina that healed spontaneously. Most likely diagnosis is: 1. Lyme disease 2. Lymphogranuloma venereum 3. Behcet’s disease 4. Endocarditis 5. Syphilis by treponema Ans. 5. Syphilis by treponema 324 USMLE Step 1 Platinum Notes USMLE Case Scenario Madura foot is caused by: 1. Blastomycosis 2. Nocardia 3. Candida albicans 4. Tenia versicolor Ans. 2. Nocardia USMLE Case Scenario A Bullet shaped virus spreading along peripheral nerves to the central nervous system causing hydrophobia and copious salivation. Most likely virus is: 1. Toga virus 2. EBV 3. Rabies virus 4. Influenza virus Ans. 3. Rabies virus USMLE Case Scenario A 18-year-old, ill-appearing woman comes OPD with a fever. She notes the recent development of nausea, diarrhea, and a rash. Her last menstrual period began 3 days ago. Physical examination is remarkable for blood pressure of 90/40 mm Hg and heart rate of 120 beats per minute. A diffuse erythematous rash with desquamation over feet is noted. Infection with which of the following toxin is the most likely cause of these signs and symptoms? 1. Clostridium perfringens toxin 2. Shigella dysenteriae toxin 3. Staphylococcus aureus toxin 4. Staphylococcus epidermidis toxin Ans. 3. Staphylococcus aureus toxin USMLE Case Scenario A 26-year-old male complains of a severe headache and weakness. His condition rapidly deteriorates over a period of hours. A lumbar puncture is performed and a Gram’s stain of spinal fluid reveals Neisseria meningococcus. The organism is: 1. Gram-negative diplococci 2. Gram-positive cocci 3. Gram-positive bacillus 4. Obligate intracellular organism Ans. 1. Gram-negative diplococci USMLE Case Scenario HTLV-1, or human T-cell lymphotrophic virus 1 can lead to T-cell leukemia 20–30 years after the infection. The virus is: 1. A nonenveloped, single-stranded, RNA retrovirus 2. An enveloped, double-stranded, RNA retrovirus 3. An enveloped, single-stranded, DNA retrovirus 4. An enveloped, single-stranded, RNA retrovirus Ans. 4. An enveloped, single-stranded, RNA retrovirus USMLE Case Scenario A 64-year-old man from New Jersy presents with severe hemoptysis. An organism is isolated and found that it has a tendency to invade pre-existing pulmonary cavities and form a rounded necrotic mass of matted hyphae, fibrin, and inflammatory cells. A filamentous organism with coarse, septate, fragmented hyphae is isolated. Most likely organism is: Microbiology 325 1. Cryptococcus neoformans 2. Candida albicans 3. Blastomyces dermatitidis 4. Paracoccidioides brasiliensis 5. Coccidioidomycosis 6. Aspergillus fumigatus Ans. 6. Aspergillus fumigatus USMLE Case Scenario HTLV-1, or human T-cell lymphotrophic virus 1 can lead to T-cell leukemia 20–30 years after the infection. The virus is: 1. A nonenveloped, single-stranded, RNA retrovirus 2. An enveloped, double-stranded, RNA retrovirus 3. An enveloped, single-stranded, DNA retrovirus 4. An enveloped, single-stranded, RNA retrovirus Ans. 4. An enveloped, single-stranded, RNA retrovirus USMLE Case Scenario A 40-year-old man has been to Malaysia for 6 months. He has an erythematous, serpiginous, pruritic, cutaneous eruption on the medial side of the ankle. What is the diagnosis? 1. Lyme disease 2. Cutaneous larval migrans 3. Leishmaniasis 4. Sarcoidosis 5. Tuberculosis Ans. 2. Cutaneous larval migrans Cutaneous larva migrans is caused by the penetration through intact skin of larval animal hookworms USMLE Case Scenario A 44-year-old man from rural Indian village is brought to a rural hospital with severe bronchopneumonia. He suffered sudden onset of chills, fever, and headache several days ago. Two day later, he complained of chest pain and difficulty breathing, and coughed up blood-tinged sputum. Chest X-ray reveals patchy infiltrates and segmental consolidation. The most likely cause of this man’s pneumonia and the disease itself is due to yersinia. Disease itself is: 1. Leprosy 2. Tuberculosis 3. Listerosis 4. Legionella pneumoniae 5. Tularemia 6. Psittacosis 7. Plague Ans. 7. Plague USMLE Case Scenario The sulfur granules in the wound are diagnostic of: 1. Nocardia 2. Actinomyces 3. Clostridium welchii 4. Aspergillus flavusm Ans. 2. Actinomyces 326 USMLE Step 1 Platinum Notes USMLE Case Scenario An organism inhabits the large intestine migrates at night into the perianal region to lay eggs, and can be identified by placing cellophane tape on the perianal skin and then looking at the tape with a microscope. The most likely cause is: 1. Tenia solium 2. Tenia saginatum 3. H nana 4. F hepatica 5. T vaginalis 6. Enterobius vermicularis Ans. 6. Enterobius vermicularis USMLE Case Scenario A 66-year-old patient from wales presents to a physician because of pain during defecation accompanied by blood in the stool. Physical examination demonstrates a large perianal mass. Pathologic examination of the rectal mass following resection demonstrates a condyloma in which transformation to frank carcinoma has occurred. Which of the following viruses would most likely be associated with these lesions? 1. EBV 2. CMV 3. HSV 4. HPV Ans. 4. HPV USMLE Case Scenario Which virus reactive and involves the eyes? 1. Herpes-Zoster 2. CMV 3. EB virus 4. Enterovirus-70 Ans. 1. Herpes-Zoster USMLE Case Scenario A pathogen is found to be present in the respiratory tract of a 36-year-old patient from Honduras as an opportunistic pathogen; Fungus balls are also seen. Patient previously had Tuberculosis. Most likely organism is: 1. Blastomyces dermatitidis 2. Pneumocystis carinii 3. Aspergillus 4. Mycobacterium tuberculosis Ans. 3. Aspergillus USMLE Case Scenario A 36-year-old female from Washington presents with a 2-day history of fever, chills, chest pain, and cough productive of rusty sputum. Past medical history includes a splenectomy 1 year ago. A chest X-ray film indicates consolidation of the right lower lobe. Blood cultures are positive for and alpha; hemolytic gram-positive diplococcic. Most likely organism is: 1. Pneumococcus 2. Meningococcus 3. Staphylococcus 4. Gonococcus Ans. 1. Pneumococcus Microbiology 327 USMLE Case Scenario A 24-year-old AIDS patient develops chronic abdominal pain, low-grade fever, diarrhea, and malabsorption. Oocysts are demonstrated in the stool. Which of the following organisms is most likely to be the cause of the patients’ diarrhea? 1. Diphyllobothrium latum 2. Entamoeba histolytica 3. Giardia lamblia 4. Isospora belli 5. Microsporidia Ans. 4. Isospora belli USMLE Case Scenario Friable Nasal polyps and subcutaneous nodules are characteristically associated with the infection of: 1. Histoplasma 2. Sporothrix 3. Rhinosporidium 4. Cryptococcus Ans. 3. Rhinosporidium USMLE Case Scenario Gastric ulcers are associated with malignancy, and therefore biopsy should be performed when they are discovered. This association with malignancy is not found with duodenal ulcers. The increased risk for malignancy with gastric ulcers is a good reason to test patients for H pylori and initiate treatment if it is found. H pylori is a: 1. Aerobe 2. Anaerobe 3. Obligate aerobe 4. Microaerophilic Ans. 4. Microaerophilic USMLE Case Scenario A 66-year-old farmer from rural area presents with chronic cough. Chest X-ray demonstrates a mass lesion with hilar lymphadenopathy. Biopsy of the mass demonstrates multiple, tiny yeast forms within macrophages. Which of the following is the most likely diagnosis? 1. Histoplasmosis 2. Chromoblastomycosis 3. Blastomycosis 4. Mucormycosis Ans. 1. Histoplasmosis USMLE Case Scenario A child presents with chronic enteritis, failure to thrive, hypoalbuminemia, and hypokalemia. Other findings include acute right lower quadrant abdominal pain, tenderness, nausea, and vomiting. The infection mimics appendicitis or Crohn’s disease. Most likely organism is: 1. Yersinia enterocolitica 2. Haemophilus aegyptius 3. Borrelia duttonii 4. Haemophilus ducreyi Ans. 1. Yersinia enterocolitica 328 USMLE Step 1 Platinum Notes USMLE Case Scenario Torres bodies are seen in: 1. Kala-Azar 2. Q-fever 3. Yellow fever 4. LGV 5. Malaria 6. Hepatitis 7. Babeiosis Ans. 3. Yellow fever USMLE Case Scenario An organism produces cutaneous disease (malignant pustule or eschar) at the site of inoculation in handlers of animal skins. Most likely organism is: 1. Bacillus anthracus 2. Pseudomonas Aeruginosa 3. Neisseria meningitides 4. Cryptococcus neoformans Ans. 1. Bacillus anthracus USMLE Case Scenario A viral organism was isolated from a painful blister on the lip of a girl. The agent was found to double-stranded, linear DNA and was enveloped. Most likely causative organism is: 1. EBV 2. HSV 3. CMV 4. Pox Ans. 2. HSV USMLE Case Scenario Donovan bodies are: 1. Leukocytes that contain the organism, Calymmatobacterium granulomatis 2. Eosinophils that contain the organism, Calymmatobacterium granulomatis 3. Monocytes that contain the organism, Hemophilus influenza 4. Monocytes that contain the organism, Calymmatobacterium granulomatis Ans. 4. Monocytes that contain the organism, Calymmatobacterium granulomatis USMLE Case Scenario Chagas’ disease is an important cause of cardiac failure in some Latin American countries, and Brazilian cases can be associated with megaesophagus and megacolon. The disease is Chagas’ disease, which is caused by: 1. Bacteria 2. Mycoplasma 3. Protozoa 4. Virus Ans. 3. Protozoa Microbiology 329 USMLE Case Scenario A 55-year-old HIV-positive male from Toledo complains of headache and blurred vision. Physical exam reveals papilledema and ataxia. Head CT is normal but CSF obtained by lumbar puncture reveals encapsulated organisms observable with India ink. Which is the organism implicated? 1. Cryptococcus 2. Histoplasmosis 3. Chromoblastomycosis 4. Blastomycosis Ans. 1. Cryptococcus USMLE Case Scenario A 4 year-old girl with a history of hydrocephalus is brought to the neurologist by her parents with a severe headache and fever. The girl underwent a surgery for a ventricular-peritoneal shunt 2 months ago and the neurologist suspects that an infection has occurred. Organisms would most likely be isolated from the shunt tubing is: 1. Staph aureus 2. Streptococcus 3. Staphylococcus epidermidis 4. Meningococcus Ans. 3. Staphylococcus epidermidis USMLE Case Scenario A disease is seen mainly in the desert parts of the Southwest US. In the lungs, spherules containing endospores are seen. Most likely disease is: 1. Coccidioidomycosis 2. Sporotrichosis 3. Paracoccidioidomycosis 4. Blastomycosis Ans. 1. Coccidioidomycosis USMLE Case Scenario Among the choices mentioned below is a member of family Herpes viridae. It is an enveloped virus with an icosahedral nucleocapsid that contains a double-stranded linear DNA genome. 1. CMV 2. Polio 3. HPV 4. Influenza Ans. 1. CMV USMLE Case Scenario A 33-year-old woman in New Jersy presented with a 1 day history of fever and chills. On examination, she was febrile with a blood pressure of 70/40 mm Hg. Over several hours, a widespread erythrodermic rash developed. The female collapses. Further questioning revealed that the patient had removed a tampon shortly before presentation, as she had just ceased menstruating. 1. Streptoccus Bovis infection 2. Hemolytic uremic syndrome 3. E coli sepsis 4. Fungal infection 5. Toxic shock syndrome 6. Meningococcal septicemia 330 USMLE Step 1 Platinum Notes 7. Staph epidermis infection 8. Pseudomonas induced shock Ans. 5. Toxic shock syndrome Toxic shock syndrome is due to toxin-1 (TSST-1), a protein secreted by S aureus or streptococci, was the first of many toxins associated with the syndrome to be identified. USMLE Case Scenario Pinta is caused by: 1. Treponema pertenue 2. Treponema cerateum 3. Treponema pallidum 4. Treponema endemicum Ans. 2. Treponema cerateum USMLE Case Scenario The organism that is strongly urease positive: 1. Proteus species 2. Klebsiella species 3. Helicobacter pylori 4. Staphylococcus Ans. 1. Proteus species USMLE Case Scenario A 34 years old person has rapidly developing cough, dyspnea, expectoration and blood-tinged sputum. He is febrile, cyanosed, and toxic. Chest examination reveals crepitations and ronchi. The most likely diagnosis is: 1. Legionella 2. Pneumonic plague 3. Septicemic plague 4. Pulmonary tuberculosis Ans. 2. Pneumonic plague USMLE Case Scenario Satellitism is seen in cultures of: 1. Hamophilus 2. Streptococcus 3. Klebsiella 4. Proteus 5. Salmonella Ans. 1. Hamophilus USMLE Case Scenario A patient (pigeon handler) presents with interstitial pneumonitis accompanied by headache, backache and a dry, hacking cough. A pale, macular rash is also found on the trunk (Horder’s spots). Likely organism is: 1. Histoplasma 2. Chlamydiae 3. Mycoplasma 4. Aspergillus Ans. 2. Chlamydiae Microbiology 331 USMLE Case Scenario In a 40-year-old man following tooth extraction developed oral local infection with draining discharge, which on examination showed Gram-positive branching roads and leucocytes. Anaerobic growth was absent. The most likely organism responsible for this is: 1. Fusobacterium 2. Nocardia 3. Bacteroids fragilis 4. Actinomyces Ans. 4. Actinomyces USMLE Case Scenario A-65-year-old man presents to the hospital unwell with diarrhea. He has a BP of 110/70, heart rate 120 and Temp 38°C. A diastolic murmur is heard in aortic area. Which organism is likely to grow in the blood cultures? 1. MRSA 2. Listeria 3. Streptococcus mitis 4. Staphylococcus aureus 5. Streptococcus bovis 6. Escherichia coli 7. Brucella melitensis Ans. 5. Streptococcus bovis usually enters the bloodstream via the gastrointestinal tract. There is also an association with malignancy of the GI tract USMLE Case Scenario In a poultry farm, many chickens developed diarrhea, emaciation and mucopurulent discharge. After about 2 hours the farmer developed fever, chills, headache, and Breathlessness. The most likely diagnosis is: 1. Anthrax b 2. Q fever 3. Relapsing fever 4. Ornithosis Ans. 4. Ornithosis USMLE Case Scenario Fungal meningitis in an immunocompromised individual is most commonly caused by: 1. Candida albicans 2. Cryptococcus neoformans 3. Penicillium 4. Aspergillus Ans. 2. Cryptococcus neoformans USMLE Case Scenario Transplacental transfer of antibodies from immunized mother to her newborn is: 1. Natural active immunity 2. Natural passive immunity 3. Acquired active immunity 4. Acquired passive immunity Ans. 2. Natural passive immunity 332 USMLE Step 1 Platinum Notes USMLE Case Scenario A severely ill 44 years old HIV affected patient from New york has evidence of destruction of myelin at multiple sites in the CNS pointing to a diagnosis of progressive multifocal leukoencephalopathy (PML). PML is caused by: 1. JC virus which is a papovavirus 2. JC virus which is a parvovirus 3. HTLV1 virus which is a Rhabdovirus 4. HTLV2 virus which is a papovavirus Ans. 1. JC virus which is a papovavirus USMLE Case Scenario A farmer developed a swelling in the inguinal region which later ulcerated. What stain can be used to detect bipolar stained organisms? 1. Albert’s stain 2. Waysons stain 3. Ziehl neelsen stain 4. Nigrosin stain Ans. 2. Wayson stain PATHOLOGY Pathology 5 CELL INJURY/CELL DEATH Terminology frequently asked in USMLE •• Hypertrophy: Increased cell and organ size, often in response to increased workload; induced by mechanical stress and by growth factors; occurs in tissues incapable of cell division •• Hyperplasia: Increased cell numbers in response to hormones and other growth factors; occurs in tissues whose cells are able to divide •• Atrophy: Decreased cell and organ size, as a result of decreased nutrient supply or disuse; associated with decreased synthesis and increased proteolytic breakdown of cellular organelles •• Metaplasia: Change in phenotype of differentiated cells, often a response to chronic irritation that makes cells better able to withstand the stress; usually induced by altered differentiation pathway of tissue stem cells; may result in reduced functions or increased propensity for malignant transformation. Different Cell Types: (Commonly asked) •• Cell proliferation is regulated by cyclins that, when complexed with cyclin-dependent kinases, regulate the phosphorylation of proteins involved in cell cycle progression leading to DNA replication and mitosis •• The cell cycle is tightly regulated by stimulators and inhibitors, and contains intrinsic checkpoint controls to prevent replication of abnormal cells •• Tissues are divided into labile, stable and permanent, according to the proliferative capacity of their cells •• Continuously dividing tissues (labile tissues) contain stem cells that differentiate to replenish lost cells and maintain tissue homeostasis High Yield USMLE Points •• •• •• •• •• Labile cells Stable cells Permanent cells Totipotent cells Pleuropotent cells •• •• •• •• •• Regenerate throughout life. (Surface Epithelial Cells, Stem cells, Blood Cells) Replicate at low levels. (Hepatocytes, Proximal tubule Cells) Don’t Replicate (Neurons) They can develop into any cell type, e.g. Germ cells They are primitive cells and can develop into multiple cell types Growth Factors •• Growth Factors, Receptors and Signal Transduction Polypeptide growth factors act in autocrine, paracrine, or endocrine manner •• Growth factors are produced transiently in response to an external stimulus and act by binding to cellular receptors •• Different classes of growth factor receptors include receptors with intrinsic kinase activity, G-protein-coupled receptors and receptors without intrinsic kinase activity •• Growth factors such as EGF and HGF bind to receptors with intrinsic kinase activity, and trigger a cascade of phosphorylating events through MAP kinases, which culminate in transcription factor activation and DNA replication •• Cytokines generally bind to receptors without kinase activity; such receptors interact with cytoplasmic transcription factors that move into the nucleus •• Most growth factors have multiple effects, such as cell migration, differentiation, stimulation of angiogenesis and fibrogenesis in addition to cell proliferation. 336 USMLE Step 1 Platinum Notes Difference in Calcifications: (High Yield Topic) Dystrophic calcification Metastatic calcification •• Occurs in ‘Dying’ tissues •• Occurs in ‘Normal’ tissues •• Serum calcium levels are usually Normal •• Serum calcium levels are usually elevated •• Seen in –– Atherosclerosis –– Damaged heart valves –– Psammoma bodies •• Seen in –– Kidneys –– Lungs –– Gastric mucosa An elevated calcium phosphate product, as in secondary hyperparathyroidism, can lead to nodules of metastatic calcinosis cutis, which tend to be subcutaneous and periarticular. This form is often accompanied by calcification of muscular arteries and subsequent ischemic necrosis (calciphylaxis). Types of Infarcts Red Infarct Pale Infarct •• Hemorraghic infarct •• White Infarct •• Seen in venous occlusion •• Occurs in arterial occlusion •• Area of infarct usually has double blood supply •• Area of infarct usually has single blood supply •• Seen in –– Brain –– Gut –– Liver •• Seen in –– Kidney –– Myocardium –– Spleen Septic Infarctions Occur when bacterial vegetations from a heart valve embolize or when microbes seed an area of necrotic tissue. In these cases the infarct is converted into an abscess, with a correspondingly greater inflammatory response. INFLAMMATION ‘Positive’ Acute Phase Reactants •• CRP •• Mannose binding protein •• Complement factors •• Ferritin •• Cerruloplasmin •• Serum amyloid A •• Haptoglobin •• Alpha 1 antitrypsin •• Alpha 2 macroglobulin ‘Negative’ Acute Phase Reactants •• Albumin •• Transferrin •• Transthyretin •• Transcortin •• Retinol Binding Protein Pathology 337 Types of Necrosis: (Very Important Topic) Coagulation Necrosis Liquefaction Necrosis Fat Necrosis Caseous Necrosis Gangrenous Necrosis Most Common Type (Kerala 96) Seen in Brain Seen in adipose Tissues Combination of Coagulation and Liquefaction Due to Ischemia especially to Lower Limb Severe ischemia Predisposes Due to Hydrolytic enzymes Due to Lipases ‘Cottage cheese’ appearance Examples: •• Thermal injury •• Myocardial infarction •• Tuberculosis Bacterial infections Acute Pancreatic Necrosis Trauma to Breast Retroperitoneal fat Seen in centre of Tuberculous Lesions More of coagulation leads to Dry gangrene More of Liquefaction leads to Wet Gangrene Reversible Cell Injury •• •• •• •• •• •• •• Cellular swelling Loss of microvilli Formation of cytoplasmic blebs ER swelling Ribosomal detachment Myelin figures Clumping of nuclear chromatin Irreversible Cell Injury •• Flocculent, amorphous densities in mitochondria •• Swelling and disruption of lysosomes •• Plasma membrane damage Nuclear changes: •• Pyknosis (nuclear condensation) •• Karryorex his (nuclear fragmentation) •• Karyolysis (nuclear dissolution) Mechanisms of Cell Injury •• ATP depletion: Failure of energy-dependent functions → reversible injury → necrosis Mitochondrial damage: ATP depletion → failure of energy-dependent cellular functions → ultimately, necrosis; under some conditions, leakage of proteins that cause apoptosis •• Influx of calcium: activation of enzymes that damage cellular components and may also trigger apoptosis •• Accumulation of reactive oxygen species: covalent modification of cellular proteins, lipids, nucleic acids •• Increased permeability of cellular membranes: may affect plasma membrane, lysosomal membranes, mitochondrial membranes; typically culminates in necrosis. Accumulation of damaged DNA and misfolded proteins: triggers apoptosis. USMLE Case Scenario Earliest transient change following tissue injury will be: 1. Neutropenia 2. Neutrophilia 3. Monocytosis 4. Lymphocytosis Ans. 2. Neutrophilia 338 USMLE Step 1 Platinum Notes USMLE Case Scenario Oxygen dependent killing is done through: 1. NADPH oxidase 2. Superoxide dismutase 3. Catalase 4. Glutathione peroxidase Ans. 1. NADPH oxidase USMLE Case Scenario Reactive oxygen intermediates are released by: 1. Catalase 2. NADPH oxidase 3. Glutathione peroxidase 4. Superoxide dismutase Ans. 2. NADPH oxidase USMLE Case Scenario The epitheloid cell and multinucleated gaint cells of Granulomatous inflammation are derived from: 1. Basophils 2. Eosinophils 3. CD4-T lymphocytes 4. Monocytes – Macrophages Ans. 4. Monocytes – Macrophages USMLE Case Scenario Degeneration of the basement membrane is mediated by: 1. Oxidases 2. Elastases 3. Hydroxylases 4. Metallo proteinase 5. Protease Ans. 4. Metallo proteinase USMLE Case Scenario Most characteristic feature of acute inflammation is: 1. Vasoconstriction 2. Vascular stasis 3. Vasodilatation and Increased vascular permeability 4. Vasoconstriction and decreased vascular permeability 5. Margination of Leucocytes Ans. 3. Vasodilatation and Increased vascular permeability USMLE Case scenario Most effective bactericidal system within phagocytes is: 1. Lysozyme mediated 2. Lactoferrin mediated 3. Reactive oxygen metabolite mediated 4. Cationic basic protein mediated Ans. 3. Reactive oxygen metabolite mediated Pathology 339 Apoptosis: (USMLE Favorite) •• Regulated mechanism of cell death that serves to eliminate unwanted and irreparably damaged cells, with the least possible host reaction •• Characterized by: enzymatic degradation of proteins and DNA, initiated by caspases; and recognition and removal of dead cells by phagocytes •• Initiated by two major pathways: 1. Mitochondrial (intrinsic) pathway is triggered by loss of survival signals, DNA damage and accumulation of misfolded proteins (ER stress); associated with leakage of pro-apoptotic proteins from mitochondrial membrane into the cytoplasm, where they trigger caspase activation; inhibited by anti-apoptotic members of the Bcl family, which are induced by survival signals including growth factors 2. Death receptor (extrinsic) pathway is responsible for elimination of self-reactive lymphocytes and damage by cytotoxic T-lymphocytes; is initiated by engagement of death receptors (members of the TNF receptor family) by ligands on adjacent cells. Nutshell of Programmed Cell Death •• •• •• •• •• •• •• •• •• Lack of Inflammation Cell shrinkage ‘Condensation of nuclear chromatin’ followed by fragmentation ‘Intranucleosomal cleavage’ of DNA is characteristic Formation of cytoplasmic/Membrane blebs Cytoplasmic chromophilia is a feature ‘Apoptotic’ bodies ‘bcl2’ inhibits Phagocytosis ‘p53’ stimulates phagocytosis Proapoptotic Factors •• •• •• •• •• •• •• Apaf 1 Cytochrome C AIF p53 Caspaces TNFRI FAS (CD 95) •• Apoptosis inhibiting gene is: bcl2 •• Detection of Apoptosis is by: –– DNA fragmentation analysis –– Capsase activity assays –– Annexin V Assay –– Propium Iodide assay USMLE Case Scenario Which of the following organelles plays a pivotal role in Apoptosis: 1. Mitochondria 2. Endoplasmic Reticulum 3. Nucleus 4. Golgi Apparatus Ans. 1. Mitochondria 340 USMLE Step 1 Platinum Notes USMLE Case Scenario Caspases are involved in: 1. Cell division 2. Necrosis 3. Apoptosis 4. Inflammation Ans. 3. Apoptosis USMLE Case Scenario Irreversible cell injury is indicated by: 1. Accumulation of calcium in mitochondria 2. Myelin figures 3. ATP depletion 4. Shifting of ribosomes Ans. 1. Accumulation of calcium in mitochondria USMLE Case Scenario Wound contraction is mediated by: 1. Myofibroblasts 2. Epithelial cells 3. Collagen 4. Elastin Ans. 1. Myofibroblasts USMLE Case Scenario Gene inhibiting apoptosis is: 1. bcl2 2. p53 3. ras 4. n-myc Ans. 1. bcl2 ‘Systemic’ Effects of Inflammation •• Fever: cytokines (TNF, IL-1) stimulate production of prostaglandins in hypothalamus •• Production of acute-phase proteins: C-reactive protein, others; synthesis stimulated by cytokines (IL-6, others) acting on liver cells •• Leukocytosis: cytokines (colony-stimulating factors) stimulate production of leukocytes from precursors in the bone marrow •• In some severe infections, septic shock: fall in blood pressure, disseminated intravascular coagulation, metabolic abnormalities; induced by high levels of TNF. Sepsis, Severe Sepsis, Septic Shock, Systemic Inflammatory Response Syndrome (SIRS) The host’s reaction to invading microbes involves a rapidly amplifying polyphony of signals and responses that may spread beyond the invaded tissue. Fever or hypothermia, tachypnea, and tachycardia often herald the onset of sepsis. The systemic response to microbial invasion. When counter regulatory control mechanisms are overwhelmed, homeostasis may fail, and dysfunction of major organs may supervene (severe sepsis). Pathology 341 Further regulatory imbalance leads to septic shock, which is characterized by hypotension as well as organ dysfunction. As sepsis progresses to septic shock, the risk of dying increases substantially. Sepsis is usually reversible, whereas patients with septic shock often succumb despite aggressive therapy. Systemic inflammatory response syndrome (SIRS): –– Temp > 38ºC or < 36ºC –– HR > 90 bpm –– RR > 20 breaths/min –– WBC > 12000 cells/mm3 or < 4000 cells/mm3 Monocytes-Macrophages: (USMLE Favorite) •• Monocytes arise from precursor cells within bone marrow and circulate with a half-life ranging from 1 to 3 days •• Common locations where tissue macrophages (and certain of their specialized forms) are found are lymph node, spleen, bone marrow, perivascular connective tissue, serous cavities such as the peritoneum, pleura, skin connective tissue, lung (alveolar macrophage), –– Liver (Kupffer cell) –– Bone (osteoclast) –– Central nervous system (microglia) –– And synovium (type A lining cell) Specific Cell Types •• Lymphocytes are the mediators of adaptive immunity and the only cells that produce specific and diverse receptors for antigens •• T (Thymus-derived) lymphocytes express antigen receptors called T cell receptors (TCRs) that recognize peptide fragments of protein antigens that are displayed by MHC molecules on the surface of antigen-presenting cells •• B (Bone marrow-derived) lymphocytes express membrane-bound antibodies that recognize a wide variety of antigens. B cells are activated to become plasma cells, which secrete antibodies •• Natural killer (NK) cells kill cells that are infected by some microbes, or are stressed and damaged beyond repair. NK cells express inhibitory receptors that recognize MHC molecules that are normally expressed on healthy cells, and are thus prevented from killing normal cells •• Antigen-presenting cells (APCs) capture microbes and other antigens, transport them to lymphoid organs, and display them for recognition by lymphocytes. The most efficient APCs are dendritic cells, which live in epithelia and most tissues. The cells of the immune system are organized in tissues, some of which are the sites of production of mature lymphocytes (the generative lymphoid organs, the bone marrow and thymus), and others are the sites of immune responses (the peripheral lymphoid organs, including lymph nodes, spleen, and mucosal lymphoid tissues). Types of immunity 342 USMLE Step 1 Platinum Notes Dendritic/Langerhans Cells •• •• •• •• Dendritic/Langerhans cells are bone marrow-derived They generally lack the standard T, B, NK, and monocyte cell markers but do express CD83 CD 1 is the marker Dendritic cells are referred to as Langerhans cells when they are present in the skin and beneath the mucosal surface. Mediators of Shock Clinical finding Mediator •• Fever •• Interleukin 1 •• Hypotension •• Bradykinin, Nitric Oxide •• Inflammation •• C3a, C5a •• DIC •• Hageman Factor Remember Bradykinin also causes pain, Vasodilation and cough •• CVC Lungs: Brown induration of lungs •• CVC Liver: ‘Nut meg’ liver •• CVC Spleen: ‘Gamma Gandy’ bodies Cytokines Cytokines are soluble proteins produced by a wide variety of hematopoietic and nonhematopoietic cell types Cytokines are involved in the regulation of the growth, development, and activation of immune system cells and in the mediation of the inflammatory response •• Immunoregulatory cytokines involved in the activation, growth, and differentiation of lymphocytes and monocytes, e.g. IL-2, IL-4, IL-10 and transforming growth factor (TGF) •• Proinflammatory cytokines produced predominantly by mononuclear phagocytes in response to infectious agents (e.g. IL1, TNF- and IL-6) and the chemokine family of inflammatory cytokines, within which are included IL-8, monocyte chemotactic protein (MCP)-1, MCP-2, MCP-3, macrophage inflammatory protein and regulation-upon-activation, normal T expressed and secreted (RANTES) •• Cytokines that regulate immature leukocyte growth and differentiation, e.g. IL-3, IL-7, and GM-CSF. Prostaglandins: (USMLE Favorite) LTA4: •• Produced in leucocytes, platelets, mast cells, vascular tissue LTC4, LTD4, LTE4: •• Contraction of smooth muscle •• Bronchoconstriction •• Vasoconstriction •• ↑vascular permeability •• Components of SRSA LTB4: •• ↑Chemotaxis •• Adhesion of WBC •• Release of lysosomal enzymes Thromboxanes: •• Produced mainly in platelets •• Promotes platelet aggregation Pathology 343 •• Vasoconstriction •• Smooth muscle contraction Prostacyclins: •• Produced by endothelium of vessels •• Vasodilation •• Inhibits platelet aggregation •• Cortisol inhibits Phospholipase A2 •• Aspirin, Indomethacin, Phenylbutazone inhibit Both COX 1 and COX 2 •• Coxibs are selective COX 2 inhibitors (Celecoxib) USMLE Case Scenario Which of the following cells play a crucial role in the pathogenesis of alveolar-capillary damage in adult’s respiratory distress syndrome (ARDS)? 1. Basophils 2. CD4-positive lymphocytes 3. CD8-positive lymphocytes 4. Eosinophils 5. Mast cells 6. Neutrophils Ans. 6. Neutrophils Neutrophils release chemokines that attract histiocytes and produce oxygen radicals, prostaglandins, and proteases that damage alveolar epithelium. Formation of hyaline membranes is due to a combination of plasma fluid extravasation and alveolar cell necrosis. Procoagulant States •• •• •• •• •• Factor V (Leidein mutation) Protein C deficiency Protein S deficiency Homocystenemia Antiphospholipid antibody Thrombus Development Depends on the relative contribution of the components of Virchow’s triad: •• Endothelial injury (e.g. by toxins, hypertension, inflammation, or metabolic products) •• Abnormal blood flow — stasis or turbulence (e.g. due to aneurysms, atherosclerotic plaque) •• Hypercoagulability, which can be either primary (e.g. factor V Leiden, increased prothrombin synthesis, antithrombin III deficiency) or secondary (e.g. bed rest, tissue damage, malignancy) Thrombi may propagate, resolve, become organized, or embolize. Thrombosis causes tissue injury by local vascular occlusion or by distal embolization. Anticoagulant Factors •• •• •• •• •• Antithrombin III Protein C Protein S Prostacyclin Nitric oxide 344 USMLE Step 1 Platinum Notes Hyperviscosity •• Multiple myeloma •• Cryoglobinemia •• Myeloproliferative disorders Remember: Virchow’s Triad •• Endothelial injury •• Alteration in blood flow •• Hypercoagulability Stains •• Von kossa: calcium •• Toluidine blue: mast cells •• Alician blue: mucins •• Congo red: amyloid •• Masons trichome: collagen, connective tissue •• Orcein: elastic fibers USMLE Case Scenario Which one of the following stains is specific for Amyloid? 1. Periodic Acid schif (PAS) 2. Alzerian red 3. Congo red 4. Von-Kossa Ans. 3 Congo red Major Histocompatibility Complex The human major histocompatibility complex (MHC), commonly called the human leukocyte antigen (HLA) complex, is a 4-megabase (Mb) region on chromosome 6 Class I MHC •• They are glycoproteins •• Present on surface of all nucleated cells •• Presents antigen to CD 8 positive cells •• Have only one chain encoded by MHC locus •• Antigen binding site on MHC I is proximal end of alpha subunit of one and two Class II MHC •• They are glycoproteins present on the surface of Macrophages, B cells, dendritic cells of spleen and Langerhans cells –– Presents antigen to CD 4 positive cells –– Not Present on surface of nucleated cells –– Have both chains encoded by MHC locus Important HLA Associations: (Frequently asked) •• A3 Hemachromatosis •• B5 Behcets Disease •• B 27 Ankylosing Spondylitis, Rieters Syndrome, Psoriatic Arthritis Pathology •• •• •• •• •• 345 DR 2 Multiple Sclerosis, Narcolepsy DR 3 Dermatitis Herpetiformis, Sjogrens Syndrome, Myasthenia Gravis, Iddm DR 4 Iddm, Rheumatoid Arthritis DR 5 Pernicious Anemia DR 7 Coeliac Disease HLA B-27 associations USMLE Case Scenario Rheumatoid arthritis is characterized by Rheumatoid nodules which develop in 20 to 30 percent of patients, usually on or around joints, on extensor surfaces, or on other areas subjected to mechanical trauma. The most important HLA association is with: 1. HLA-DR2 2. HLA-DR3 3. HLA-DR4 4. HLA B 27 Ans. 3. HLA-DR4 USMLE Case Scenario A 24-year-old man presented to an ophthalmologist with a severe painful left eye for 38 hours. There is redness around the cornea which developed into a iritis. Three days later the right eye also became involved. One week after the onset of the eye symptoms, the patient complained of dysuria. No chlamydia, viruses or bacteria were isolated from this discharge. He was treated with oxytetracycline and his eye signs gradually cleared. At about this time, however, his right first metatarsophalangeal joint became inflamed and, subsequently, several joints were similarly involved. He was found to be HLA-B27-positive. Most likely diagnosis would be: 1. Behcets Disease 2. Ankylosing Spondylitis 3. Reiters Disease 4. Gonococcal arthritis 5. Rheumatoid arthritis 6. Gouty Arthritis Ans. 3. Reiters Disease Natural Killer Cells •• Are part of ‘innate’ immunity •• Are ‘large granular lymphocytes’ •• Lack T cell receptor, surface IgM and IgD 346 •• •• •• •• •• •• •• •• USMLE Step 1 Platinum Notes Express CD 16 and CD 56 The classic NK cells are CD2+, CD3+, CD4+, CD56+, and CD16+ Thymus is not required for their development Activity not enhanced by prior sensitization. NK cells do not require sensitization to express the killer function NK cells constitute 2 to 10% of normal peripheral blood lymphocytes Contain Azurophilic granules Kill virus infected cells and cancer cells Kill by producing perforins, granzymes •• Killing is non specific •• NK cells are not MHC-restricted—they will kill certain autologous, allogeneic, and even xenogeneic tumor cells whether or not these targets express MHC •• NK cells do not use the TCR, CD3 complex to recognize target cells •• Killing is not dependent on foreign antigen presentation. (MHC Independent) Graft Rejection The graft rejection response is initiated mainly by host T cells that recognize the foreign HLA antigens of the graft, either directly (on APCs in the graft) or indirectly (after uptake and presentation by host APCs) Types and mechanisms of rejection: •• Hyperacute rejection. Preformed antidonor antibodies bind to graft endothelium immediately after transplantation, leading to thrombosis, ischemic damage, and rapid graft failure •• Acute cellular rejection. T-cells destroy graft parenchyma by cytotoxicity and DTH reaction •• Acute vascular rejection. T-cells and antibodies damage graft vasculature •• Chronic rejection. Dominated by arteriosclerosis, this type is probably caused by T-cell reaction and secretion of cytokines that induce proliferation of vascular smooth muscle cells, associated with parenchymal fibrosis. Molecular Basis of Carcinogenesis •• •• •• •• •• •• •• Self-sufficiency in growth signals Insensitivity to growth-inhibitory signals Evasion of apoptosis Limitless replicative potential, (i.e. overcoming cellular senescence and avoiding mitotic catastrophe) Development of sustained angiogenesis Ability to invade and metastasize Genomic instability resulting from defects in DNA repair •• Oncogenes that Promote Unregulated Proliferation (Self-sufficiency in Growth Signals) •• Proto-oncogenes: normal cellular genes whose products promote cell proliferation •• Oncogenes: mutant versions of proto-oncogenes that function autonomously without a requirement for normal growthpromoting signals. Insensitivity to Growth-Inhibitory Signals Tumor suppressor genes encode proteins that inhibit cellular proliferation by regulating the cell cycle. Unlike oncogenes, both copies of the gene must be lost for tumor development, leading to loss of heterozygosity at the gene locus. In cases with familial predisposition to develop tumors, the affected individuals inherit one defective (nonfunctional) copy of a tumor suppressor gene and lose the second one through somatic mutation. In sporadic cases both copies are lost through somatic mutations. Pathology 347 USMLE Case Scenario An example of a tumor suppressor gene is: 1. myc 2. fos 3. ras 4. Rb Ans. 4. Rb Oncogenic Organisms HPV has been associated with benign warts, as well as cervical cancer.The oncogenic ability of HPV is related to the expression of two viral oncoproteins, E6 and E7; they bind to RB and p53, respectively, neutralizing their function; they also activate cyclins E6 and E7 from high-risk HPV (that give rise to cancers) have higher affinity for their targets than E6 and E7 from low-risk HPV (that give rise to low-grade tumors). EBV has been implicated in the pathogenesis of Burkitt lymphomas, lymphomas in immunosuppressed individuals with HIV infection or organ transplantation, some forms of Hodgkin lymphoma, and nasopharyngeal carcinoma. All except the nasopharyngeal cancers are B-cell tumors. The oncogenic effects of HBV and HCV are multifactorial, but the dominant effect seems to be immunologically mediated chronic inflammation, hepatocellular injury, stimulation of hepatocyte proliferation, and production of reactive oxygen species that can damage DNA. The HBx protein of HBV and the HCV core protein can activate a variety of signal transduction pathways that may also contribute to carcinogenesis. H pylori infection has been implicated in both gastric adenocarcinoma and MALT lymphoma. The mechanism of H pylori-induced gastric cancers is multifactorial, including immunologically mediated chronic inflammation, stimulation of gastric cell proliferation, and production of reactive oxygen species that damage DNA. H pylori pathogenicity genes, such as CagA, may also contribute by stimulating growth factor pathways. It is thought that H pylori infection leads to polyclonal B-cell proliferations and that eventually a monoclonal B-cell tumor (MALT lymphoma) emerges as a result of accumulation of mutations. Important Translocations: (USMLE Favorite) •• t(8;14) Burkitts Lymphoma •• t(9;22) CML •• t(15;17) AML •• t(11;22) Ewings sarcoma •• t(X;18) Synovial cell Ca USMLE Case Scenario A sarcoma appears like a malignant melanoma, which arises in the soft tissue. It usually is found on the tendons of extremities of young patients. Histologically, the cells can have pigment or clear cytoplasm. It is associated with t(12,22). The sarcoma is: 1. Synovial cell sarcoma 2. Clear Cell sarcoma 3. Leiomyosarcoma 4. Rhabdomyosarcoma Ans. 2. Clear Cell sarcoma Burkitt’s Lympohoma is associated with: 1. t (8:14) 2. t (11:14) 3. t (15:17) 4. t (14:18) Ans. 1. t (8:14) 348 USMLE Step 1 Platinum Notes •• Atrophy: Decreae in cell size/function •• Hypertrophy: Increase in cell size/function •• Hyperplasia: Increase in number of cells in tissues/organs •• Metaplasia: Reversible change of epithelial transformation •• Anaplasia: Hallmark of malignant transformation •• Dysplasia: Reversible abnormal proliferation of cells. Intact basement membrane Premalignant forms of SCC: (USMLE Favorite) •• •• •• •• •• •• •• •• Actinic keratosis, or solar keratoses Actinic cheilitis Bowen’s disease Erythroplasia of Queyrat DLE Xeroderma Pigmentosa UV Radiation –UV B Hypertrophic lichen planus •• Actinic keratoses and cheilitis are hyperkeratotic papules and plaques that occur on sun-exposed areas. While the potential for malignant degeneration is low in any individual lesion, the risk of SCC increases with larger numbers of lesions •• Bowen’s disease presents as a scaling, erythematous plaque, which may develop into invasive SCC in up to 20% of cases. Treatment of premalignant and in situ lesions reduces the subsequent risk of invasive disease. The following oral lesions are Premalignant Lesions •• Leucoplakia •• Erythroplakia •• Chronic hyperplastic candidiasis •• Oral submucous fibrosis •• Syphilitic glossitis •• Sideropenic dysphagia Cancer Type Environmental Risk Factor •• Lung: Smoking, Asbestos, Nickel, Radon, Coal, Arsenic, Chromium, Uranium •• Mesothilioma: Asbestos •• Bladder Ca: Smoking, Aniline dyes, Schistomiasis •• Skin Ca: UV light exposure, coal, Tar, Arsenic •• Liver: Alcohol, Vinyl chloride, Aflatoxins •• Pancreas: Smoking •• Renal Cell Carcinoma: Smoking •• Stomach: Alcohol, Nitrosamines Chemical Carcinogens •• Chemical carcinogens have highly reactive eletrophile groups that directly damage DNA, leading to mutations and eventually cancer •• Direct-acting agents do not require metabolic conversion to become carcinogenic, while indirect-acting agents are not active until converted to an ultimate carcinogen by endogenous metabolic pathways. Pathology 349 •• Hence polymorphisms of endogenous enzymes like cytochrome P-450 may influence carcinogenesis. Following exposure of a cell to a mutagen or an initiator; tumorigenesis can be enhanced by exposure to promoters, which stimulate proliferation of the mutated cells •• Examples of human carcinogens include direct-acting (e.g. alkylating agents used for chemotherapy), indirect-acting (e.g. benzopyrene, azo dyes, and aflatoxin), and promoters/agents that cause pathologic hyperplasias of liver, endometrium. Immune Surveillance Tumor cells can be recognized by the immune system as nonself and destroyed. Antitumor activity is mediated by predominantly cell-mediated mechanisms. Tumor antigens are presented on the cell surface by MHC class I molecules and are recognized by CD8+ CTLs The different classes of tumor antigens include products of mutated proto-oncogenes, tumor suppressor genes, overexpressed or aberrantly expressed proteins, tumor antigens produced by oncogenic viruses, oncofetal antigens, altered glycolipids and glycoproteins, and cell type-specific differentiation antigens. Immunosuppressed patients have an increased risk of cancer. In immunocompetent patients, tumors may avoid the immune system by several mechanisms, including selective outgrowth of antigen—negative variants, loss or reduced expression of histocompatibility antigens, and immunosuppression mediated by secretion of factors (e.g. TGF-β) from the tumor. Hereditary DNA Repair Disorders: (USMLE Favorite) •• Xeroderma pigmentosum: Hypersensitivity to sunlight/UV, resulting in increased skin cancer Incidence and premature aging •• Cockayne syndrome: Hypersensitivity to UV and chemical agents •• Trichothiodystrophy: Sensitive skin, brittle hair and nails •• Werner’s syndrome: Premature aging and retarded growth •• Bloom’s syndrome: Sunlight hypersensitivity, high incidence of malignancies (especially leukemias) •• Ataxia telangiectasia: Sensitivity to ionizing radiation and some chemical agents. All of the above diseases are often called ‘segmental progerias’ (‘accelerated aging diseases’) because their victims appear elderly and suffer from aging-related diseases at an abnormally young age Other diseases associated with reduced DNA repair function include: •• Fanconi’s anemia •• Hereditary breast cancer and •• Hereditary colon cancer Important Tumor Markers •• Alpha fetoprotein •• Hepato cellular carcinoma •• Endodermal sinus tumor •• PSA •• Prostate cancer •• Neuron specific enolase •• Small cell lung cancer, Neuroblastoma •• LDH •• Lymphoma •• Cathecolamines •• Pheochromocytoma 350 USMLE Step 1 Platinum Notes •• Beta 2 microglobulin •• Multiple Myeloma •• Lymphoma Gastrin •• Pancreatic neuroendocrine tumors •• Bladder Tumor Antigen •• Bladder Tumor, UTI, Renal Calculi •• CA 27.29 •• Breast Cancer •• CA 72.4 •• Ovarian and Pancreatic Cancer •• LASA –P (Lipid Associated Sialic Acid) •• Ovarian Cancer •• Keratin •• Ca cervix •• NMP 22 •• Bladder Cancer •• HCG •• Gestational Trophoblastic Disorders •• CA 125 •• Ovarian Cancer •• Placental Alkaline Phosphatase •• Seminoma •• S100 •• Melanoma, Neural Tumors ‘APUD omas’: (CAPITALS) C- Carcinoid tumor A- Adrenal pheochromocytoma P- Pancreatic endocrine tumors I- Islet-cell tumor T- Thyroid medullary carcinoma A- Additional: Ganglioblastoma, neuroblastoma, paragangliomas L- Lung: Small-cell carcinoma S- Skin: Melanoma USMLE Case Scenario Serous papillary cystadenocarcinomas of the ovaries express: 1. CA-125 2. CA-19 3. CEA 4. AFP Ans. 1. CA-125 USMLE Case Scenario A 25-year-old man has a testicular mass, which on orchiectomy shows a malignant tumor with yolk sac differentiation. Which of the following tumor markers would probably be most useful in monitoring the patient for recurrent or metastatic disease? 1. Alpha-fetoprotein 2. Carcinoembryonic antigen (CEA) 3. Prostate-specific antigen (PSA) 4. S-100 Ans. 1. Alpha-fetoprotein Serum alpha-fetoprotein is a fetal serum protein produced by the yolk sac and liver. Increased serum levels in adults are seen in tumors (hepatocellular carcinoma, neuroblastomas and teratoma) and acute hepatitis and colitis. In patients with tumors, serum levels often correlate with tumor size. Resection is usually associated with a fall in serum levels. Serum levels are useful in assessing response to treatment. Pathology Mesenchymal Tumors •• Endothelial tumors •• Melanoma •• Fibrohistiocytic tumors •• Muscle tumors HYPERSENSITIVITY REACTIONS: (USMLE FAVORITE) Type I Hypersensitivity reactions: IgE Mediated •• Theobald phenomenon •• Prusnitz reaction (PK) •• Casonis Test •• Anaphylaxis •• Local: Asthma, Hay fever, Angioedema, Eczema, Urticaria Type II Hypersensitivity reactions: IgG or IgM Mediated •• Graves disease (ALSO TYPE V) •• Goodpasture’s Syndrome •• Myasthenia Gravis •• Blood transfusion reactions •• Immune hemolytic anemia •• Immune Thrombocytopenic purpura Type III Hypersensitivity Reactions: Immune Complex Mediated •• Arthus reaction •• Serum Sickness •• SLE •• Schiks test •• Post Streptococcal Glomerulonephritis Type IV Hypersensitivity Reactions: Delayed Hypersensitivity •• Tuberculin test •• Lepromin Test •• Contact dermatitis •• Pernicious anemia Immune-Complex-Dependent Reactions/Serum Sickness Serum sickness is produced by circulating immune complexes and is characterized by: •• Fever •• Arthritis •• Nephritis •• Neuritis •• Edema, and an Urticarial, papular, or purpuric rash •• Serum sickness was first described following administration of foreign sera, but drugs are now the usual cause 351 352 USMLE Step 1 Platinum Notes •• TYPE III hypersensitivity reaction •• Drugs that produce serum sickness include the Penicillins •• Sulfonamides •• Thiouracils •• Cholecystographic dyes •• Phenytoin, aminosalicylic acid •• Heparin and antilymphocyte globulin •• In classic serum sickness, symptoms develop 6 days or more after exposure to a drug, the latent period representing the time needed to synthesize antibody. The antibodies responsible for immune-complex-dependent drug reactions are largely of the IgG or IgM class Vasculitis, may also be a result of immune complex deposition. Collagen •• Collagen is the main protein of connective tissue in animals and •• The most abundant protein in mammals, making up about 25 to 35% of the whole-body protein content •• In muscle tissue it serves as a major component of Endomysiun. Type I This is the most abundant collagen of the human body It is present in scar tissue, the end product when tissue heals by repair. It is found in •• Tendons •• Skin •• Artery walls •• The endomysium of myofibrils •• Fibrocartilage and the organic part of bones and teeth. Type II •• Hyaline cartilage makes up 50% of all cartilage protein •• Vitreous humor of the eye. Type III This is the collagen of granulation tissue, and is produced quickly by young fibroblasts before the tougher type I collagen is synthesized. Also found in: •• Artery walls •• Skin •• Intestines and the •• Uterus •• Reticular fiber. Type IV Present in •• Basal lamina •• Eye lens •• Filtration system in capillaries and the •• Glomeruli of nephron in the kidney. Amyloidosis: (USMLE Favorite) Amyloidosis is a disorder characterized by the extracellular deposits of misfolded proteins that aggregate to form insoluble fibrils. The deposition of these proteins may result from: excessive production of proteins that are prone to misfolding and aggregation; mutations that produce proteins that cannot fold properly and tend to aggregate; defective or incomplete proteolytic degradation of extracellular proteins Amyloidosis maybe localized or systemic. Pathology Remember the type of Amyloidosis and the Protein type associated Type of Amyloidosis Amyloid protein •• Primary Amyloidosis, Myeloma AL •• Secondary Amyloidosis –– Tuberculosis –– Rheumatoid arthritis –– Hodgkins lymphoma AA •• Familial Medittarean Fever AA •• Hemodialysis associated Amyloidosis Aβ2M •• Cerebral (Alzhiemers) Amyloidosis Aβ •• Cardiac Amyloidosis ATTR •• •• •• •• •• •• •• •• Amyloidosis is deposition of an ‘extracellular protein’ Individual subunits form ‘β pleated sheets.’ Kidney followed by liver is the commonest sites involved Deposits stain ‘red’ with Congo red ‘Apple green birefrigerence’ is seen on Congo red stain under polarized light Amyloid is composed of ‘fibrillary protein, amyloid P Component and Glycosaminoglycans’ Thyroid cancer with amyloid stroma: MTC (Medullary ca thyroid) Rectal biopsy is the best diagnostic method. On light microscopy: Eosinophilic amorphous substance Congo red in ordinary light: Pink color Congo red on polarizing microscope: Yellow green birefringence Electron microscopy: Nonbranching fibrils X-ray crystallography: Crossed β pleated configuration Pathology and Genetics: (USMLE Favorite) The following conditions are inherited as Asked innumerable times in Autosomal Dominant Autosomal Recessive Huntington’s disease Marfans syndrome Adult polycystic kidney disease Familial hypercholestremia Osteogenesis imperfecta Neurofibromatosis Achondroplasia Myotonic dystrophy Von Willebrands disease HNPCC BRCA1, BRCA2 Breast cancer Otosclerosis Tuberous sclerosis MC group of mendelian disorders Cystic fibrosis Ataxia telengectasia Freidrechs ataxia Infantile polycystic kidney disease Wilsons disease Alkaptonuria Hemochromatosis Sickle cell anemia phenyl ketonuria beta thalessemia alpha 1 antitrypsin deficency X-linked recessive Becker Colour blindness Duchenne muscular dystrophy Fabry’s disease G6PD deficiency Hemophilia A, B Hunter’s disease Lesch-Nyhan syndrome Nephrogenic diabetes insipidus Ocular albinism Retinitis pigmentosa Testicular feminization syndrome Wiskott-Aldrich syndrome Color blindness Affects males more 353 354 USMLE Step 1 Platinum Notes Autosomal Dominant Traits Are fully manifest in the presence of a gene in the heterozygous state, i.e. when only one abnormal gene (mutant allele) is present and the corresponding partner allele on the homologous chromosome is normal. The following features are characteristic: •• Each affected individual has an affected parent (unless the condition arose by a new mutation in a germ cell that formed the individual); •• An affected individual usually bears an equal number of affected and unaffected offspring; •• Males and females are affected in equal numbers; •• Each gender can transmit the trait to male and female; •• Normal children of an affected individual have only normal off spring; •• When the trait does not impair viability or reproductive capacity, vertical transmission of the trait occurs through successive generations. Three or more generations of male-to-male transmission argues against X-linkage of a rare gene. Autosomal Recessive Traits Autosomal recessive conditions are clinically apparent only in the homozygous state, i.e. when both alleles at a particular genetic locus are mutant alleles. The following features are characteristic: •• The parents are clinically normal •• Only siblings are affected •• Males and females are affected in equal proportions •• If an affected individual marries a homozygous normal person, none of the children is affected but all are heterozygous carriers •• If an affected individual marries a heterozygous carrier, one half of the children are affected, and the pedigree pattern superficially suggests a dominant trait •• If two individuals who are homozygous for the same mutant gene marry, all of their children are affected •• If both parents are heterozygous at the same genetic locus, one fourth of their children are homozygous affected, on average one fourth are homozygous normal, and one half are heterozygous carriers of the same mutant gene; and •• The less frequent the mutant gene is in the population, the greater the likelihood that the affected individual is the product of consanguineous parents. X-Linked Recessive Traits •• Diseases or traits that result from genes located on the X chromosome are termed X-linked. Because the female has two X chromosomes, she maybe either heterozygous or homozygous for the mutant gene, and the trait may exhibit recessive or dominant expression. The terms X-linked dominant and X-linked recessive refer only to expression of the trait in females. The male has only one X chromosome and therefore is hemizygous for X-linked traits. Males can be expected to express X-linked traits regardless of their recessive or dominant behavior in the female. This accounts for the large numbers of X-linked diseases. •• Males transmit their X chromosome to all of their daughters, making them all obligate carriers of an X-linked disease trait •• Affected males do not transmit an X chromosome to their sons; thus, an important feature of X-linked inheritance is the absence of male-to-male transmission. X-Linked Dominant Traits This mode of inheritance is uncommon. Its characteristic features are as follows: •• Females are affected about twice as often as males; •• Heterozygous females transmit the trait to both genders with a frequency of 50%; •• Hemizygous affected males transmit the trait to all of their daughters and none of their sons; and •• The expression is more variable and generally less severe in heterozygous females than in hemizygous affected males. Examples of X-linked dominant inheritance include the vitamin D-resistant (hypophosphatemic) rickets and pseudohypoparathyroidism. Pathology 355 USMLE Case Scenario The BRCA-1 gene associated with breast cancer and ovarian cancer, is located on: 1. 17q 2. 17 p 3. 22q 4. 18q Ans. 1. 17q •• The NF-1 gene is, associated with neurofibromatosis type I, is on 17q •• The NF-2 gene associated with neurofibromatosis type II, is on 22q •• The p53 gene associated with many cancers, is on 17p •• The DCC oncogene located on the long arm of chromosome 18q USMLE Case Scenario Ophthalmoscopic examination of a 7-year-old child from Washington DC demonstrates a retinal angioma. This finding should raise the possibility of which of the following syndromes? 1. Neurofibromatosis type I 2. Neurofibromatosis type II 3. Tuberous sclerosis 4. von Hippel-Lindau disease Ans. 4. von Hippel-Lindau disease USMLE Case Scenario Subependymal giant cell astrocytoma is a peculiar astrocytic tumor that grows from the walls of the lateral ventricles. It is caused by mutations of TS1 or TS2 genes. It is usually seen in: 1. von Hippel-Lindau syndrome 2. Neurofibromatosis 1 3. Neurofibromatosis 2 4. Tuberous Sclerosis Ans. 4. Tuberous Sclerosis USMLE Case Scenario Kinky hair disease is a disorder where an affected child has peculiar white stubby hair, does not grow, brain degenration is seen and dies by age of two years. A lady is hesitant about having children because her two sisters had sons who had died from kinky hair disease. Her mother’s brother also died of the same condition. Which of the following is the possible mode of inheritence in her family? 1. X-linked recessive 2. X-linked dominant 3. Autosomal recessive 4. Autosomal dominant Ans. 1. X-linked recessive USMLE Case Scenario The chances of having an unaffected baby, when both parents have achondroplasia, are: 1. 0% 2. 25% 3. 50% 4. 100% Ans. 2. 25% 356 USMLE Step 1 Platinum Notes X-Linked Dominant •• Hypophosphatemic type of vitamin D resistant rickets •• Incontenentia pigmentii •• Orofaciodigital syndrome •• Hereditary spherocytosis is AD •• Achondroplasia is AD •• Familial hypercholestrelemia is AD •• Retinoblastoma is AD •• von Villebrands disease is AD •• Homocystinuria is AR Y-Linked Disorders •• Only a few genes are known on the Y chromosome •• One such gene, the sex-region determining Y factor (SRY), or testis-determining factor (TDF), is crucial for normal male development •• Men with oligospermia/azoospermia frequently have microdeletions on the long arm of the Y chromosome that involve one or more of the azoospermia factor (AZF) genes. Trinucleotide Repeat Disorders –– A number of diseases are caused by a mutation that is an expansion of a repetitive sequence of three nucleotides which is genetically unstable –– When repeat length increases from one generation to the next, disease manifestations may worsen or be observed atan earlier age; this phenomenon is referred to as anticipation Conditions Include: •• Huntington’s disease •• Myotonic dystrophy •• Fragile X Syndrome •• Kennedys Syndrome •• Some forms of Spino cerebellar Ataxia Huntington’s disease is transmitted in an autosomal dominant fashion. The age at which the patient becomes symptomatic is variable and has no effect on the probability of transmitting the disease. The defect underlying this degenerative disease is an abnormal expansion of a region of chromosome 4 containing a triplicate repeat (CAG) sequence. Normal individuals have between 6 and 34 copies of this CAG section; patients with Huntington’s disease may have from 37 to more than 100 repeats. Once expanded beyond 40 copies, the repeats are unstable and may further increase as they are passed on from one generation to the next. An increased number of repeats leads to a phenomenon known as anticipation, by which successive generations have earlier disease onset. Fragile X-Syndrome: (USMLE Favorite) Pathologic amplification of trinucleotide repeats causes loss-of-function (fragile X-syndrome) or gain-of-function mutations (Huntington disease). Most such mutations produce neurodegenerative disorders. Fragile X-syndrome results from loss of FMR1 gene function and is characterized by mental retardation, macroorchidism, and abnormal facial features. In the normal population there are about 29 CGG repeats in the FMR1 gene. Carrier males and females carry permutations with 52 to 200 CGG repeats that can expand to 4000 repeats (full mutations) during oogenesis. When full mutations are transmitted to progeny, fragile X-syndrome occurs. Pathology 357 Genomic Imprinting Imprinting involves transcriptional silencing of the paternal or maternal copies of certain genes during gametogenesis. For such genes only one functional copy exists in the individual. Loss of the functional allele (not imprinted) by deletions gives rise to diseases Prader-Willi syndrome results from deletion of paternal chromosome 15q12 and is characterized by mental retardation, short stature, hypotonia, obesity and hypogonadism Angelman syndrome results from deletion of maternal chromosome 15q12 and is characterized by mental retardation, ataxia, seizures and inappropriate laughter. Mitochondrial DNA/Mitochondriopathies: (USMLE Favorite) •• Mutation rate about ten times greater than nuclear DNA •• This is because there are no introns and a mutation invariably strikes a coding sequence (axon) •• Tissues with greatest ATP requirement (CNS, Skeletal muscle, Heart muscle, Kidney, Liver) are most affected •• Mitochondrial DNA is maternally inherited because mitochondria from sperms do not enter the fertilized egg •• Mitochondrial DNA is Closed and circular and 16.5 kb in length •• MELAS (Mitochondrial Encephalopathy, Lactic Acidosis and Stroke like episodes) are attributed to Mitochondrial mutations. Other diseases associated with mt DNA are: •• Leber’s Hereditary Optic Neuropathy •• MELAS (mitochondrial encephalopathy with lactic acidosis and stroke like episodes) •• Myopathy •• MERRF Syndrome: (myoclonic epilepsy and ragged red fibers.) •• Cardiomyopathy •• Strokes •• Lactic acidosis •• External Ophthalmoplegia •• Optic atrophy •• NARP (Neuropathy, ataxia and retinitis pigmentosa) •• Pearsons syndrome •• Sensorineural deafness •• Diabetes mellitus Gene Frequency The distribution of a mutant gene in the general population maybe calculated on the basis of the Hardy-Weinberg equation. If the frequency of a particular gene A is p, then that of its alternative allele is (1 – p) = q. Three genotypes are found in the population: •• Those who are homozygous AA •• Those who are heterozygous Aa and •• Those who are homozygous aa •• In a randomly mating population, the frequencies of these genotypes are in the proportion p2 (AA), 2 pq (Aa), and q2 (aa) •• An important consequence of this distribution is that irrespective of the initial frequency of the genes A and a in the population, the proportion of the three genotypes tends to remain constant in succeeding generations, provided that there is no difference in biologic fitness of any of the genotypes. If viability or fertility among the three genotypes is unequal, if individuals migrate into or out of the population, or if mating is not random, the frequency calculations require considerable correction. In small populations major changes in gene frequency can occur on the basis of chance alone •• If the frequency of a recessive disease in a particular population is known, the frequency of heterozygous carriers and of the abnormal gene can be calculated. Thus for a recessively inherited disease aa (q2) with a frequency of 1 per 10,000 (e.g. albinism), the frequency of the gene a (q) is 1 per 100, and that of heterozygous carriers is 2´ p ´q = 2´ 99/100´ 1/100 = approximately 1 in 50 358 USMLE Step 1 Platinum Notes ‘Commonly’ asked Terminology: (USMLE Favorite) •• ‘Allelic Heterogeneity’refers to the fact that different mutations in the same genetic locus can cause an identical or similar phenotype. For example, many different mutations of the b-globin locus can cause b-thalassemia. •• ‘Phenotypic Heterogeneity’occurs when more than one phenotype is caused by allelic mutations (e.g. different mutations in the same gene). e.g. Similarly, identical mutations in the FGFR2 gene can result in very distinct phenotypes: Crouzon syndrome (craniofacial synostosis), or Pfeiffer syndrome (acrocephalo polysyndactyly). •• ‘Locus or Nonallelic Heterogeneity’ and Phenocopies: Refers to the situation in which a similar disease phenotype results from mutations at different genetic loci. For example, osteogenesis imperfecta can arise from mutations in two different procollagen genes (COL1A1 or COL1A2) that are located on different chromosomes. •• ‘Variable Expressivity’ and Incomplete Penetrance: The same genetic mutation causes a phenotypic spectrum illustrating the phenomenon of variable expressivity. MEN-1 illustrates several of these features. Families with this autosomal dominant disorder develop tumors of the parathyroid gland, endocrine pancreas, and the pituitary gland. However, the pattern of tumors in the different glands, the age at which tumors develop, and the types of hormones produced vary among affected individuals, even within a given family. •• Penetrance: It is the probability of expressing the phenotype given a defined genotype; it can be complete or incomplete. For example, hypertrophic obstructive cardiomyopathy (HOCM) caused by mutations in the myosin heavy chain b gene is a dominant disorder with clinical features in only a subset of patients who carry the mutation. Patients who have the mutation but no evidence of the disease can still transmit the disorder to subsequent generations. In this situation, the disorder is said to be nonpenetrant or incompletely penetrant. USMLE Case Scenario Differential expression of same gene depending on parent of origin is referred to as: 1. Genomic imprinting 2. Mosaicism 3. Anticipation 4. Nonpenetrance Ans. 1. Genomic imprinting USMLE Case Scenario Males are more commonly affected than females in: 1. Autosomal Dominant 2. Autosomal Recessive 3. X- Linked Dominant 4. X- Linked recessive Ans. 4. X- Linked recessive Cluster Designation (CD) Markers •• •• •• •• •• CD 3 CD 10 CD 19 CD 20, 21, 22 CD 16 and CD 56 •• •• •• •• •• Pan T-cell marker Immature B-cell marker Pan B-cell marker B-cell markers NK-cells USMLE Case Scenario Which of the following markers is specific for Gastrointestinal stromal tumors (GIST): 1. CD 117 2. CD 34 Pathology 359 3. CD 23 4. S – 100 Ans. 1. CD 117 USMLE Case Scenario Which of the following are characteristic markers for Hodgkin’s Lymphoma? 1. CD15 and CD30 2. CD15 and CD45 3. CD30 and CD68 4. CD15 and CD3 Ans. 1. CD15 and CD30 USMLE Case Scenario Which of the following is a marker for Langerhans cell histiocytosis: 1. CD 1a 2. CD 10 3. CD 30 4. CD 56 Ans. 1. CD 1a Chromosomal Involvements: (USMLE Favorite) •• Chromosome 1 Neuroblastoma •• Chromosome 2 Cystinuria •• Chromosome 3 RCC •• Chromosome 4 Huntingtons Chorea •• Chromosome 5 FAP, Cri Du Chat •• Chromosome 6 HLA/MHC Antigens •• Chromosome 7 Cystic Fibrosis •• Chromosome 8 Osteopetrosis •• Chromosome 9 Freidreichs Ataxia •• Chromosome 11 Wilms Tumor •• Chromosome 13 Retinoblastoma •• The c-Ki-ras and the c-myc genes are the oncogenes most frequently altered in colorectal cancer •• Antigen presenting cells (APC) gene, a tumor suppressor gene located on chromosome 5q, is a inactivated by a point mutation in FAP •• The p53 gene is also implicated in colorectal cancer. It checks the integrity of the genome prior to mitosis •• BRCA1 gene is associated with familial breast cancer. USMLE Case Scenario Familial polyposis coli is a rare condition inherited as autosomal dominant, with equal sex incidence. Hundreds of adenomas develop throughout the colon and rectum. The gene responsible for FAP is: 1. On the short arm of chromosome 5 2. On the long arm of chromosome 5 3. On the short arm of chromosome 15 4. On the long arm of chromosome 15 Ans. 1. On the short arm of chromosome 5 360 USMLE Step 1 Platinum Notes USMLE Case Scenario Cowden syndrome is due to: 1. Mutations of a gene on chromosome 9 2. Mutations of a gene on chromosome 10 3. Mutations of a gene on chromosome 11 4. Mutations of a gene on chromosome 12 Ans. 2. Mutations of a gene on chromosome 10 Remember •• •• •• •• •• •• •• •• Gene for Major Histocompatibility is carried on chromosome 6 Gene for Folate carrier protein is carried on chromosome 21 Cystic fibrosis transmembrane conductance regulator gene is carried onchromosome 7 Short arm of chromosome is p arm Long arm of chromosome is q arm Genes regulating morphogenesis: homeobox genes (HOX) APC gene is located on chromosome 5 BRCA 1 gene is located on chromosome 17 ‘Important Points’ about Antibodies Immunoglobulin IgM •• The first Ab formed after primary immunization (exposure to new Ag) •• Exists in a monomeric or pentameric form and protects the intravascular space from disease. •• The large IgM molecules readily activate complement and serve as opsonizers and agglutinators to assist the phagocytic system to eliminate many kinds of microorganisms •• Fixes complement •• Isohemagglutinins and many Abs to gram-negative organisms are IgM. Pathology 361 IgG •• The most prevalent type of Ab is found in plasma and extravascular spaces; it is produced when IgM titers begin to decrease after primary immunization. •• IgG is the major Ig produced after reimmunization (the memory immune response or secondary immune response). •• IgG is the prime mediator of the memory response and protects the tissues from bacteria, viruses and toxins. •• It is the only Ig that crosses the placenta. •• IgG subclasses neutralize bacterial toxins, activate complement and enhance phagocytosis by opsonization. •• Commercial gamma globulin is almost entirely IgG, with small amounts of other Igs. •• IgA (secretory Ab) •• It is found in mucous secretions (saliva, tears, respiratory, GU and GI tracts, and colostrum), where it provides an early antibacterial and antiviral defense. •• Secretory IgA is synthesized in the subepithelial regions of the GI and respiratory tracts and is present in combination with locally produced secretory component (SC). IgD •• It is not known to have much biologic activity. Present in serum in extremely low concentrations, it appears on the surface of developing B cells and maybe important in their growth and development. IgE •• (Reaginic, skin-sensitizing, or anaphylactic Ab), like IgA, is found primarily in respiratory and GI mucous secretions. •• In serum, IgE is present in very low concentrations •• IgE is elevated in atopic diseases (e.g. allergic asthma, hay fever and atopic dermatitis), parasitic diseases, far-advanced Hodgkin’s disease, and IgE-monoclonal myeloma •• IgE may also have a beneficial role in the defense against parasites. •• IgE -mediates reagenic hypersensitivity IgG •• IgG: This is major serum immunoglobulin •• IgG: It is only maternal immunoglobulin that is normally transported across the placenta and provides natural passive immunity in newborn •• IgA: It is the second most abundant class of immunoglobulin seen in body fluids such as colostrums, saliva and tears •• IgM: It is called ‘millionaire’ molecule. It is not transported across the placenta hence presence of IgM in the fetus or newborn indicates diagnosis of congenital infection such as syphilis, rubella, HIV and toxoplasmosis •• IgM: Antibodies are short lived; hence their presence in serum indicates recent infection •• IgE: Greatly elevated in atopic (Type I allergy) conditions such as asthma, hay fever, eczema, and also in children having high load of intestinal parasites. Interferons IFN-alpha •• Produced by leucocytes •• Antiviral action •• Useful in hepatitis B and C, Kaposi’s sarcoma, metastatic renal cell cancer, hairy cell leukemia IFN-beta •• Produced by fibroblasts •• Antiviral action •• Reduces the frequency of exacerbations in patients with relapsing-remitting MS 362 USMLE Step 1 Platinum Notes IFN-gamma •• Produced by T-lymphocytes and NK-cells •• Weaker antiviral action, more of a role in immunomodulation particularly macrophage activation •• Maybe useful in Chronic granulomatous disease. Interleukins: (USMLE Favorite) •• IL1 causes Fever •• IL2T cell stimulation •• IL3 Bone Marrow stimulation •• IL4IgE Stimulation •• IL5IgA Stimulation Functions of Different Complement Components •• Opsonization (C3b) •• Chemotaxis (C5a) •• Anaphylotoxin (C3a, C4a, C5a) •• Cytolysis (insertion of C5b, 6,7,8,9 into the cell membrane) •• Enhancement of antibody production (C3b) Oncogenes •• Oncogenes are regulatory genes •• Activity is abnormally increased after a genetic alteration •• Oncogene activation may occur after –– Chromosomal translocation –– Gene amplification –– Mutation within coding sequence of oncogene •• Oncogenes act in a dominant fashion •• Examples of oncogenes include: •• Ras on chromosome 11 — mediates signal transduction •• ErbB2 on chromosome 7 — growth factor receptor •• Src on chromosome 20 — tyrosine kinase •• Myc on chromosome 8 — transcription factor. Tumor Suppressor Genes •• •• •• •• •• Code for inhibitory proteins Normal function is to prevent cell growth In cancer, suppressor function is lost Most tumor suppressor genes are recessive Inactivation of tumor suppressor genes can occur by –– Gene mutation causing loss of gene product –– Prevention of binding of a gene product to its target site –– Inactivation by other proteins Pathology 363 •• Examples of tumor suppressor genes include –– Rb on chromosome 13 — control of cell cycle –– p53 on chromosome 17 — DNA repair and apoptosis –– Bcl2 on chromosome 18 — apoptosis –– APC on chromosome 5 — regulation of co-transcriptional activators •• Mutation of tumor suppressor genes is seen in many familial cancers –– Rb — childhood retinoblastoma –– p53 — Li-Fraumeni syndrome –– APC — familial colon cancer –– BRCA1/2 — familial breast cancer Tumor Suppressor Genes: (Nutshell) Tumor suppressor gene •• VHL •• WT 1 and 2 •• Rb •• P53 (Guardian of genome) •• BRCA1 •• BRCA2 •• APC •• DCC •• NF1 and NF2 Tumors •• von Hippel-Lindau disease •• Wilms tumor •• Retinoblastoma, Osteosarcoma •• Lung, colon, breat Ca •• Hereditary breast and ovarian Ca •• Hereditary breast Ca •• Adenomatous polyps and colon Ca •• Colon Ca •• Neurofibromas Protein 53: (USMLE Favorite) •• p53 also known as protein 53 or tumor protein 53 is a transcription factor which in humans is encoded by the TP53 gene. •• p53 is important in multicellular organisms, where it regulates the cell cycle and thus functions as a tumor suppressor that is involved in preventing cancer •• Acts at G1 S Phase. •• As such, p53 has been described as •• ‘The guardian of the genome,’ •• ‘The guardian angel gene,’ and the •• ‘Master watchman,’ referring to its role in conserving stability by preventing genome mutation. •• The name p53 is in reference to its apparent molecular mass: it runs as a 53 kilodalton (kDa) protein on SDS-PAGE. •• In humans, p53 is encoded by the TP53 gene (guardian of the cell) located on the short arm of chromosome 17 (17p13.1). •• p53 has many anti-cancer mechanisms: •• It can activate DNA repair proteins when DNA has sustained damage. •• It can induce growth arrest by holding the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle.) •• It can initiate apoptosis, the programmed cell death, if the DNA damage proves to be irreparable. Oncogenes: (USMLE Favorite) •• RAS: –– K-RAS: colon, lung, pancreatic tumors –– N-RAS: melanoma, AML –– H-RAS: Bladder, kidney tumors 364 USMLE Step 1 Platinum Notes •• ABL •• MYC –– C-MYC: Burkitts lymphoma –– N-MYC: Neuroblastoma –– L-MYC: Small cell lung cancer –– WNT 1 –– ERB –B2 –– FOS –– JUN –– AKTI, AKT2 –– BRAF Immunology: (USMLE Favorite) Primary immunodeficiency disorders maybe classified according to which component of the immune system they affect: Neutrophil disorders •• Chronic granulomatous disease •• Chediak-Higashi syndrome •• Leukocyte adhesion deficiency B-cell disorders •• Common variable immunodeficiency •• Bruton’s congenital agammaglobulinemia •• IgA deficiency T-cell disorders •• Di George syndrome (Thymic and Parathroid aplasia) Combined B-and T-cell disorders •• Severe combined immunodeficiency •• Ataxic telangiectasia •• Wiskott-Aldrich syndrome Job’s Syndrome/Hyperimmunoglobulin E-recurrent Infection Syndrome •• The hyperimmunoglobulin E-recurrent infection (HIE) syndrome or Job’s syndrome •• It is a rare multisystem disease in which the immune system, bone, teeth, lung and skin are affected. ‘Abnormal chemotaxis’ is a variable feature •• The ‘cold abscesses’ have been considered a reflection of impaired chemotaxis with too few phagocytes arriving too late, perhaps due to a lymphocyte factor inhibiting chemotaxis •• Serum IgE elevated. Other immunoglobulins normal. ABNORMAL NEUTROPHIL FUNCTION Disorders of Adhesion (Leukocyte adhesion deficiency (LAD)) •• Two types of leukocyte adhesion deficiency (LAD) have been described •• Both are autosomal recessive traits and result in the inability of neutrophils to exit the circulation to sites of infection, leading to leukocytosis and increased susceptibility to infection Neutrophils (and monocytes) from patients with LAD 1 adhere poorly to endothelial cells and protein-coated surfaces and exhibit defective spreading, aggregation and chemotaxis •• LAD 1 Patients have recurrent bacterial and fungal infections involving skin, oral and genital mucosa, and respiratory and intestinal tracts; persistent leukocytosis (neutrophil counts of 15,000 to 20,000/uL) because cells do not marginate; and in severe cases •• A history of delayed separation of the umbilical stump •• Infections, especially of the skin, may become necrotic with progressively enlarging borders Pathology 365 •• Slow healing and development of dysplastic scars •• The most common bacteria are Staphylococcus aureus and enteric gram-negative bacteria •• LAD 2 is caused by an abnormality of CD15, the ligand on neutrophils that interacts with selectins on endothelial cells. Disorders of Neutrophil Granules •• The most common neutrophil defect is Myeloperoxidase deficiency, a primary granule defect inherited as an autosomal recessive trait •• Microbicidal activity of neutrophils is delayed but not absent •• Myeloperoxidase deficiency may make other acquired host defense defects more serious •• An acquired form of myeloperoxidase deficiency occurs in myelomonocytic leukemia and acute myeloid leukemia. Chediak-Higashi Syndrome (CHS) •• Autosomal recessive inheritance due to defects in the lysosomal transport protein LYST, encoded by the gene CHS1 at 1q42. This protein is required for normal packaging and disbursement of granules •• Neutrophils (and all cells containing lysosomes) from patients with CHS characteristically have large granules Patients with CHS have an increased number of infections resulting from many agents •• CHS neutrophils and monocytes have impaired chemotaxis and abnormal rates of microbial killing due to slow rates of fusion of the lysosomal granules with phagosomes •• NK cell function is also impaired •• Specific granule deficiency is a rare autosomal recessive disease in which the production of secondary granules and their contents, as well as primary granule component defensins, is defective •• The defect in bacterial killing leads to severe bacterial infections. Chronic Granulomatous Disease •• Disorders of granulocyte and monocyte oxidative metabolism •• There is defective neutrophil oxidative metabolism •• Most often CGD is inherited as an X-linked recessive trait; 30% of patients inherit the disease in an autosomal recessive pattern •• Leukocytes from patients with CGD have severely diminished hydrogen peroxide production •• Patients with CGD characteristically have increased numbers of infections due to catalase-positive microorganisms (organisms that destroy their own hydrogen peroxide) •• When patients with CGD become infected, they often have extensive inflammatory reactions, and lymph node suppuration is common despite the administration of appropriate antibiotics. •• Persistent Neutrophilia with cell counts of 30,000 to 50,000/microliter or higher is called ‘Leukemoid reaction’ •• In leukemoid reaction the circulating neutrophils are mature and not clonally derived. Cyclic Neutropenia: •• It is decrease in neutrophils counts at intervals of 3 weeks (13–45) days with normal periods in between •• Patients develop overwhelming infections •• It is inherited as Autosomal Dominant trait •• It is due to Neutrophil elastase gene defect. ‘Hereditary neutropenias’: Are rare and may manifest in early childhood as a profound constant neutropenia or agranulocytosis Congenital forms of neutropenia include: •• Kostmann’s syndrome (neutrophil count <100/uL), which is often fatal; more benign chronic idiopathic neutropenia (neutrophil count of 300 to 1500/uL); 366 USMLE Step 1 Platinum Notes •• Cartilage-hair hypoplasia syndrome; Shwachman’s syndrome associated with pancreatic insufficiency; myelokathexis, a congenital disorder characterized by neutrophil degeneration, hypersegmentation, and myeloid hyperplasia in the marrow associated with decreased expression of bcl-XL in myeloid precursors and accelerated apoptosis •• Neutropenias associated with other immune defects (X-linked agammaglobulinemia, ataxia telangiectasia, IgA deficiency) •• The presence of immunoglobulin directed toward neutrophils is seen in Felty’s syndrome: a triad of rheumatoid arthritis, splenomegaly and Neutropenia. Vessel Disorders: (USMLE Favorite) Large Vessel Arteritis •• Giant cell arteritis •• Takayasus arteritis Medium Sized Vessel Arteritis •• Poly arteritis nodosa •• Kawasaki disease Small Sized Vessel Arteritis •• •• •• •• •• Essential cryoglobinemia Churg strauss syndrome HSP Microscopic poly angitis Wegners Granulomatosis Takayasus Arteritis •• Also called as ‘Pulseless Disease’ or ‘Aortic Arch Syndrome’ •• It is a vasculitis common in Asia especially in young and middle aged females, affecting medium to large size arteries including Aorta and its branches •• Characterized by granulomatous Inflammation leading to arterial thrombosis, stenosis or aneurysm •• Clinical features are: –– Loss of pulse in upper extremities. (Radial Pulse not felt) –– Systemic features: fever, weight loss, arthalgias, fatigue –– Anemia and increased ESR –– Visual loss or field defects, retinal hemorrhages –– Neurological abnormalities like Headache, plus Chest Pain, Hypertension Polymyositis/Dermatomyositis A systemic connective tissue disease characterized by inflammatory and degenerative changes in the muscles (polymyositis) and frequently also in the skin (dermatomyositis), leading to symmetric weakness and some degree of muscle atrophy, principally of the limb girdles. USMLE Case Scenario A 32-year-old woman with a past history of ulcerative colitis (quiescent for the last 7 years), presented with a dry cough. Increasing dyspnea, myalgia and arthralgia. A clinical diagnosis of fibrosing alveolitis was made and confirmed by transbronchial biopsy. She had a severe proximal myopathy. Serum creatine kinase was found to be very high and a muscle biopsy showed necrosis and a cellular infiltrate. She had a circulating autoantibody to Jo1 antigen Ans. Diagnosis is: Polymyositis Pathology 367 Reiter’s Syndrome (RS) •• Arthritis associated with nonbacterial urethritis or cervicitis, conjunctivitis and mucocutaneous lesions •• RS is classified with the seronegative spondyloarthropathies •• Joint involvement generally is asymmetric and polyarticular, occurring in the large joints of the lower extremities as well as the toes. Back pain may occur, usually with more severe disease •• Enthesopathy (inflammation at tendinous insertion into bone) is common in RS and other seronegative arthritides, e.g. plantar fasciitis, digital periostitis, Achilles tendinitis •• Mucocutaneous lesions—small, painless superficial ulcers—are commonly seen on the oral mucosa, tongue, and glans penis (balanitis circinata) •• Patients may also develop hyperkeratotic skin lesions of the palms and soles and around the nails (keratoderma blennorrhagica) •• Cardiovascular involvement with aortitis, aortic insufficiency and conduction defects occurs rarely. Temporal Arteritis (Giant Cell Arteritis; Cranial Arteritis) A chronic inflammatory disease of large blood vessels, particularly those with a prominent elastica, occurring primarily in the elderly •• Giant cell arteritis most often involves arteries of the carotid system, particularly the cranial arteries •• Segments of the aorta, its branches, the coronary arteries, and the peripheral arteries may also be affected •• The disease has a predilection for arteries containing elastic tissue; it is rarely seen in veins •• The histologic reaction is a granulomatous inflammation of the intima and inner part of the media Presentations are diverse, depending on the distribution of the arteritis, but typically include: –– Severe headache (especially temporal and occipital) –– Scalp tenderness –– Visual disturbances (amaurosis fugax, diplopia, scotomata, ptosis and vision blurring) –– Claudication of the masseter, temporalis and tongue muscles are characteristic Blindness due to ischemic optic neuropathy probably occurs in < = 20% of patients but is infrequent after high dose corticosteroid treatment. On physical examination, there maybe swelling and tenderness with nodularity over the temporal arteries and bruits over the large vessels ESR is usually markedly elevated (often > 100 mm/h, Westergren) during the active phase, but is normal in about 1% of patients Normochromic and normocytic anemia is often present and, at times, profound. Alkaline phosphatase maybe elevated. Other nonspecific findings include ‘polyclonal hyperglobulinemia and leukocytosis.’ High Yield USMLE •• Wegners granulomatosis: necrotizing lesions in upper respiratory tract and kidney •• Henon scholein purpura: IgA deposits with vasculitis •• Churg strauss syndrome: asthma plus blood eosinophilia •• Kawasakis disease: in children •• Takayasus arteritis: in young patients •• Giant cell arteritis: in older patients USMLE Case Scenario Giant cell arteritis involves the cranial arteries (branches of the carotid system). Biopsying 2 cm lengths of each temporal artery are indicated because the process can be patchy. Biopsy can reveal. 1. Granulomatous inflammation 2. Fibrinoid necrosis 3. Hyperplastic necrosis 4. Leukocytoclastic vasculitis Ans. 1. Granulomatous inflammation 368 USMLE Step 1 Platinum Notes USMLE Case Scenario A 48-year-old male from Ohio presents with sinus pain and drainage, bloody nasal discharge and nasal mucosal ulceration. On laboratory examination, the man is found to have hematuria, and red blood cell casts. A biopsy of the upper airway tissue reveals granulomatous inflammation with necrosis. Blood tests show the presence of antineutrophil cytoplasmic antibodies (c-ANCA). Most likely diagnosis is: 1. Goodpasture’s syndrome 2. Noninfectious granulomatous disease 3. Wegener’s granulomatosis 4. Bergers Disease Ans. 3. Wegener’s granulomatosis Atherosclerosis Complicated lesions indicate advanced atherosclerotic disease. They arise in atherosclerotic plaques, and render them more susceptible to sudden occlusion and acute infarction of the supplied tissues. Commonly, the plaque ulcerates or ruptures, and the exposed surfaces, being highly thrombogenic, precipitate thrombus formation Thrombi are typified by the lines of Zahn, alternating layers of platelets and fibrin (the pale lines) and layers of blood (the dark lines). Beyond thrombus formation, other features of a complicated plaque include hemorrhage into the lesion itself, and microembolism by cholesterol crystals or calcified debris. Furthermore, the weakened media underlying the plaque may develop an aneurysmal dilatation. In general, the clinical significance of atherosclerosis is related to the consequences of complicated lesions. Aneurysms Pseudoaneurysm also known as false aneurysm is usually as a result of trauma to all the three layers of the artery resulting in hematoma •• This hematoma must communicate with artery to be considered as a pseudoaneurysm •• Pseudoaneurysm differs from true aneurysm in that it does not contain any vessel wall •• Penetrating trauma is the most common cause of pseudoaneurysm. Other Causes are •• Marfans syndrome •• Fibromuscular Dysplasia •• Vasculitis Pulsatile mass is the most common manifestation. Locations of Pseudoaneurysms Femoral artery Left Ventricular Pseudoaneurysm Abdominal Aorta Pseudoaneurysm Carotid Pseudoaneurysm Important Points about Aneurysms •• •• •• •• •• •• •• The most common type of ‘true aneurysm’ is fusiform type The most common site of arterial aneurysm is Infrarenal part of Abdominal Aorta Popliteal Aneurysms are the most common Peripheral aneurysms The most common site for dissecting aneurysms is Ascending Aorta ‘Cirsoid aneurysms’ are common in superficial temporal artery Atherosclerosis is the mc cause of Abdominal aneurysms Atherosclerosis is the mc cause of any aneurysm. Pathology 369 Types of aneurysms: •• Berry aneurysm: occurs in circle of willis •• Microaneurysms: seen in Diabetes and Hypertension •• Mycotic aneurysms: are seen in bacterial infections •• Aortic dissecting Aneurysms: Due to degeneration of tunica media •• Occur in Marfans Syndrome and Hypertension •• Syphilitic aneurysms or Luetic aneurysms: involve ascending Aorta •• Tree bark calcification is seen in syphilis. Developmental or Berry, Aneurysms Occur in cerebral vessels. These are small, spherical dilatations typically in the circle of Willis; when ruptured, they can causes fatal intracerebral hemorrhage. Arteriovenous fistulas Are abnormal, typically small, direct connections between arteries and veins that bypass the intervening capillaries. They occur most commonly as developmental defects but can also result from rupture of an arterial aneurysm into the adjacent vein, from penetrating injuries that pierce arteries and veins or from inflammatory necrosis of adjacent vessels; intentionally created arteriovenous fistulas are used to provide vascular access for chronic hemodialysis. When arteriovenous fistulas are large or extensive, they can become clinically significant by shunting blood from the arterial to the venous circulations. This forces the heart to pump additional volume, and highoutput cardiac failure can ensue. Fibromuscular dysplasia It is a focal irregular thickening of the walls of medium and large muscular arteries, including renal, carotid, splanchnic and vertebral vessels. The cause is developmental. Segments of the vessel wall are focally thickened by some combination of irregular medial and intimal hyperplasia and fibrosis; this results in luminal stenosis and in the renal arteries maybe a cause of renovascular hypertension. Aortic Dissection •• In the vast majority of spontaneous dissections, the intimal tear marking the point of origin of the dissection is found in the ascending aorta, usually within 10 cm of the aortic valve •• The dissection can extend along the aorta retrograde toward the heart as well as distally, sometimes all the way into the iliac and femoral arteries. The dissecting hematoma spreads characteristically along the laminar planes of the aorta, usually approximately between the middle and outer thirds •• It often ruptures out through the adventitia, causing massive hemorrhage. In some instances, the dissecting hematoma reenters the lumen of the aorta, producing a second distal intimal tear and a new vascular channel within the media of the aortic wall (and resulting in a ‘double-barreled aorta’ with a false channel). This averts a fatal extra-aortic hemorrhage. In the course of time, false channels may become endothelialized and can be recognized as chronic dissections. Abnormal structural proteins produce inborn errors such as •• •• •• •• Marfan syndrome (fibrillin) Osteogenesis imperfecta (collagen type I) Spondyloepiphyseal dysplasia (collagen type II), and Sack syndrome (collagen type III) Marfan Syndrome: (USMLE Favorite) It is characterized by skeletal, ocular and cardiovascular abnormalities. Typically, Marfan patients are tall with very long legs and tapering fingers. Laxity of joints is present, so that the thumb can be extended back to the wrist. Chest and spinal column deformities maybe present as well. The most frequent cardiovascular anomalies are incompetence of the aortic valve, aortic dissection and mitral valve prolapse (‘floppy valve’). The latter may give rise to mitral regurgitation with the typical auscultatory phenomenon of a systolic click followed by a murmur. The most characteristic ocular change is ectopia lentis, i.e. dislocation of the lens. Most deaths are due to rupture of aortic dissections. The gene mutated in Marfan syndrome encodes fibrillin, a 350-kD protein that serves as scaffolding for the deposition of elastin and formation of elastic fibers. 370 USMLE Step 1 Platinum Notes USMLE Case Scenario It is seen that vasa vasorum of the aorta undergoes obliterative endarteritis, leading to atrophy of the muscularis and elastic tissues of the aorta and dilatation. Linear calcifications are often seen in the ascending aorta by X-ray. The intimal wrinkling is seen. The disease most likely represents: 1. Marfan’s syndrome 2. Syphilis infection 3. Aortic dissection 4. Takayasu’s arteritis Ans. 2. Syphilis Infection (The intimal wrinkling or ‘tree barking’ is also a common feature.) USMLE Case Scenario A 35-year-old tall male from New Jersey has Marfan syndrome, an autosomal dominant disorder with features of subluxated lens of the eye, mitral valve prolapsed. The defect lies in: 1. Gene on chromosome 15 encoding fibrillin 2. Gene on chromosome 16 encoding fibrillin 3. Gene on chromosome 17 encoding fibrillin 4. Gene on chromosome 18 encoding fibrillin Ans. 1. Gene on chromosome 15 encoding fibrillin Rheumatic Heart Disease •• •• •• •• •• •• •• •• •• •• •• Preceded by streptococcal pharyngitis Aschoff bodies are a feature Anitschkow cells/caterpillar cells are seen Pancarditis Bread and butter pericarditis Vegitation along line of closure of valves Sub endocardial Mc Callums patches present Mc cause of mitral stenosis ASLO titers used in diagnosis Tricuspid valve is least commonly involved MC cause of MS is rheumatic fever •• Mc Callums Patch •• Lesions of Mural endocardium •• Deposition of Aschoff Bodies occurs here •• Site of Thrombus formation •• Aschoff Bodies •• Present in Perivascular connective tissue •• Feature of Rheumatic heart disease •• Anitschkow myocytes •• Modified cardiac mesenchymal cells with caterpillar nuclei, ↑cytoplasm. •• Aschoff cells •• Multinucleated giant cells USMLE Case Scenario Aschoff’s nodules are seen in: 1. Subacute bacterial endocarditis 2. Libman-Sacks endocarditis 3. Rheumatic carditis 4. Nonbacterial Thrombotic endocarditis Ans. 3. Rheumatic carditis Pathology 371 Myocarditis Can be caused by a variety of conditions such as a virus, sarcoidosis and immune diseases (such as systemic lupus, etc.), pregnancy, and others. The most common cause of myocarditis is infection of the heart muscle by a virus. Coxsackievirus B is the most common culprit in the United States. Viruses capable of causing myocarditis include. Coxsackievirus types A and B (especially type B) •• Adenovirus (most commonly types 2 and 5) •• Cytomegalovirus •• Echovirus •• Epstein-Barr virus •• Hepatitis C virus •• Herpes virus •• Human immunodeficiency virus •• Influenza and parainfluenza •• Measles •• Mumps, associated with endocardial fibroelastosis (EFE) •• Parvovirus B19 •• Poliomyelitis virus •• Rubella •• Varicella HIV infection: About 10 percent of people with HIV develop myocarditis Bacterial infection: Rarely, myocarditis occurs as a complication of endocarditis, an infection of the heart valves and the lining inside the heart’s chambers caused by bacteria. Some common bacteria responsible for myocarditis include Staphylococcus aureus, enterococci and Corynebacterium diphtheriae Chagas’ disease: This infection, caused by the protozoan Trypanosoma cruzi, is transmitted by an insect bite. In the United States, myocarditis caused by Chagas’ disease is most common among travelers or immigrants from Central and South America. In up to one-third of people with Chagas’ disease, a form of chronic myocarditis develops many years after the initial infection. This chronic myocarditis leads to significant destruction of heart muscle with progressive heart failure Lyme myocarditis: Lyme disease, an infection caused by the tick-borne bacterium Borrelia burgdorferi, causes myocarditis or other heart problems in about 10 percent of patients Giant cell myocarditis: This rare form of myocarditis takes its name from large, abnormal giant cells that are found when a piece of the affected heart muscle is examined under a microscope. Giant-cell myocarditis is most common among patients suffering from thymoma, systemic lupus erythematosus (SLE or lupus), or thyrotoxicosis Other agents: Myocarditis also can be caused by: Alcohol, radiation, chemicals (hydrocarbons and arsenic) and drugs, including doxorubicin Adriamycin, cyclophosphamide emetine, chloroquine and sulfonamides ‘Diphtheria causes myocarditis by virtue of it exotoxin. The flabby, stretched out heart muscle is characteristic of diphtheria. Because of flabby nature of heart muscle; the myocardial pumping activity is significantly reduced as a result if which congestive heart failure occurs within three weeks of illness.’ Myxoma •• •• •• •• •• •• Myxomas are the most common type of primary cardiac tumor in all age groups Female predilection Most myxomas are sporadic NAME syndrome (nevi, atrial myxoma, myxoid neurofibroma and ephelides) LAMB syndrome (lentigines, atrial myxoma and blue nevi) Carney complex 372 USMLE Step 1 Platinum Notes •• Pathologically, myxomas are gelatinous structures consisting of myxoma cells imbedded in a stroma rich in glycosaminoglycans •• The majority are solitary and located in the atria •• Myxomas commonly present with obstructive, embolic, or constitutional signs and symptoms. USMLE Case Scenario A 68-year-old woman who is normotensive presents to hercardiac physician after several episodes of syncope. Physical examination is remarkable for alow-pitched ‘plopping’ sound during mid-systole. Two-dimensional echocardiography demonstrates aball-valve type obstruction of the mitral valve. Which of the following would most likely be observed if the cause of the obstruction were biopsied? 1. Benign glandular tissue 2. Myxomatous degeneration of valves 3. Dense calcification in tricuspid area 4. Densely packed smooth muscle 5. Densely packed striated muscle 6. Malignant glandular tissue 7. Scattered mesenchymal cells in a myxoid background Ans. 7. Scattered mesenchymal cells in a myxoid background Atrial myxoma may intermittently obstruct the mitral valve. Histologically, these tumors are composed of scattered mesenchymal cells in a prominent myxoid background. Myocardial Infarction •• •• •• •• •• •• •• LAD is the mc artery involved Enzyme elevated in first two hours is CPK MB Waviness of fibers is the earliest change Coagulation necrosis and neutrophilic infiltration is seen within 1–3 days Granulation tissue is seen within 1 week Scarring in MI is completed by 3 months Troponin T is a marker of MI. •• Hyaline arteriosclerosis: benign hypertension •• Hyperplastic arteriosclerosis: malignant hypertension •• MC Primary tumor of heart myxoma •• Libman sacks endocarditis is found in SLE •• Dresselers syndrome is autoimmune. Respiratory Pathology •• •• •• •• •• •• •• Pores of Kohn are present in Alveoli Charcoat layden crystals: Feature of asthma Curschmanns spirals: Feature of asthma Creola bodies: Feature of asthma Reid index is used for Chronic bronchitis Blue bloaters: Chronic bronchitis Pink puffers: Emphysema. ARDS In the acute phase of ARDS the lungs are dark red, firm, airless and heavy Microscopically, there is capillary congestion, necrosis of alveolar epithelial cells, interstitial and intra-alveolar edema and hemorrhage, and (particularly with sepsis) caollections of neutrophils in capillaries The most characteristic finding is the presence of hyaline membranes, particularly lining the distended alveolar ducts Such membranes consist of fibrin-rich edema fluid admixed with remnants of necrotic epithelial cells. Pathology 373 Emphysema •• Emphysema is defined anatomically as a permanent and destructive enlargement of airspaces distal to the terminal bronchioles without obvious fibrosis and with loss of normal architecture •• α1 antitrypsin (α1AT) deficency is associated with panacinar emphysema •• Smoking is a cause of emphysema. The diagnosis and classification of emphysema depend largely on the macroscopic appearance of the lung Panacinar emphysema, when well developed, produces pale, voluminous lungs that often obscure the heart when the anterior chest wall is removed at autopsy With advanced disease, adjacent alveoli become confluent creating large airs paces. In addition to alveolar loss, the number of alveolar capillaries is diminished. Chronic Bronchitis: (USMLE Favorite) Grossly, the mucosal lining of the larger airways is usually hyperemic and swollen by edema fluid It is often covered by a layer of mucinous or mucopurulent secretions The smaller bronchi and bronchioles may also be filled with similar secretions. Histologically, the diagnostic feature of chronic bronchitis in the trachea and larger bronchi is enlargement of the mucus-secreting glands The magnitude of the increase in size is assessed by the ratio of the thickness of the submucosal gland layer to that of the bronchial wall (Reid index; normally 0.4) Chronic bronchiolitis (small airway disease), characterized by: •• Goblet cell metaplasia •• Mucus plugging •• Inflammation, and •• Fibrosis Asthma •• Grossly, the lungs are overdistended because of overinflation, and there maybe small areas of atelectasis. The most striking macroscopic finding is occlusion of bronchi and bronchioles by thick, tenacious mucus plugs. Histologically, the mucus plugs contain whorls of shed epithelium (Curschmann spirals) •• Numerous eosinophils and Charcot-Leyden crystals (collections of crystalloids made-up of eosinophil proteins) are also present. Bronchiectasis: (USMLE Favorite) •• When tumors or aspiration of foreign bodies lead to bronchiectasis, involvement maybe sharply localized to a single segment of the lungs •• In the full-blown active case, an intense acute and chronic inflammatory exudate within the walls of the bronchi and bronchioles and the desquamation of lining epithelium cause extensive areas of ulceration. In the usual case, a mixed flora can be cultured from the involved bronchi, including staphylococci, streptococci, pneumococci, enteric organisms, anaerobic and microaerophilic bacteria, and (particularly in children) Hemophilus influenzae and Pseudomonas aeruginosa. Pulmonary Anthracosis It is coal-induced pulmonary lesion in coal miners, urban dwellers and tobacco smokers. Inhaled carbon pigment is engulfed by alveolar or interstitial macrophages, which then accumulate in the connective tissue along the lymphatics, including the pleural lymphatics or in lymph nodes. Coal Worker’s Pneumoconiosis (Cwp) •• Coal dust is associated with CWP •• Much of the symptomatology associated with simple CWP appears to be similar and additive to the effects of cigarette smoking on the development of chronic bronchitis and obstructive lung disease 374 USMLE Step 1 Platinum Notes •• With prolonged exposure, small, rounded, regular opacities, 1 to 5 mm in diameter (nodular pattern). Calcification is generally not seen •• Complicated CWP is manifested by the appearance on the chest radiograph of nodules ranging from 1 cm in diameter to the size of an entire lobe, generally confined to the upper half of the lungs •• Particle size of 1–5 micrometer is dangerous dor pneumoconiosis. Caplan’s Syndrome: (USMLE Favorite) First described in coal miners but subsequently found in patients with a variety of •• Pneumoconioses •• Seropositive Rheumatoid arthritis with •• Characteristic progressive massive fibrosis Simple CWP It is characterized by coal macules and the somewhat larger coal nodule •• The coal macule consists of dust-laden macrophages; in addition the nodule contains small amounts of a delicate network of collagen fibers •• Although these lesions are scattered throughout the lung, the upper lobes and upper zones of the lower lobes are more heavily involved. Complicated CWP (PMF) •• Occurs on a background of simple CWP by coalescence of coal nodules and generally requires many years to develop •• It is characterized by intensely blackened scars larger than 2 cm, sometimes up to 10 cm in greatest diameter •• They are usually multiple. •• •• •• •• Beryllium may produce an acute pneumonitis or, far more commonly, a chronic interstitial pneumonitis. (BERYLLIOSIS) Radiodense dusts include iron and iron oxides from welding or silver finishing (Siderosis) Tin oxide used in metallurgy, color stabilization, printing, and the manufacture of porcelain, glass, and fabric (Stannosis) And barium sulfate used as a catalyst for organic reactions, drilling mud components, and electroplating (Baritosis). Silicosis: (USMLE Favorite) •• •• •• •• •• Mc occupational disorder Crystalline form most common cause Upper lobes involved ‘Eggshell’ pattern Patients with silicosis are at greater risk of acquiring Mycobacterium tuberculosis infections (silicotuberculosis) and atypical mycobacterial infections. •• Silicotic nodules are characterized grossly in their early stages by tiny, barely palpable, discrete, pale-to-blackened nodules in the upper zones of the lungs •• Microscopically, the silicotic nodule demonstrates concentrically arranged hyalinized collagen fibers surrounding an amorphous center •• The ‘whorled’ appearance of the collagen fibers is quite distinctive for sometimes, thin sheets of calcification occur in the lymph nodes and are appreciated radiographically as ‘eggshell’ calcification (e.g. calcium surrounding a zone lacking calcification). Asbestosis: (USMLE Favorite) •• Asbestos is a generic term for several different mineral silicates, including chrysolite, amosite, anthophyllite and crocidolite •• Asbestosis is a diffuse interstitial fibrosing disease of the lung •• Physiologic studies reveal a restrictive pattern with a decrease in lung volumes Pathology 375 •• Lower lobes affected commonly •• Asbestos bodies •• Ferruginous bodies •• Laryngeal and colonic cancers associated •• Mesotheliomas, both pleural and peritoneal, are also associated with asbestos exposure •• Intense fibrosis is a pathological feature of mesotheliomas. •• It is marked by diffuse pulmonary interstitial fibrosis •• These changes are indistinguishable from those resulting from other causes of diffuse interstitial fibrosis, except for the presence of asbestos bodies, which are seen as golden brown, fusiform or beaded rods with a translucent center. They consist of asbestos fibers coated with an iron-containing proteinaceous material •• Asbestosis begins in the lower lobes and subpleurally, but the middle and upper lobes of the lungs become affected as fibrosis progresses. Pleural plaques are the most common manifestation of asbestos exposure and are well-circumscribed plaques of dense collagen. Sarcoidosis: (USMLE Favorite) •• •• •• •• •• •• Noncaseating granulomas with bilateral hilar lymphadenopathy Berylium inhalation mimicks sarcoidosis It is an end stage lung disease Epitheloid cells with no caseation Seen Sarcoidosis does not involves brain Kveim test is used for sarcoidosis –– Schaumann bodies (conchlike structures) –– Asteroid bodies (stellate-like structures), and –– Residual bodies (refractile calcium-containing inclusions) •• Two syndromes have been identified in the acute group –– Lofgren’s syndrome includes the complex of Erythema nodosum and X-ray findings of bilateral hilar adenopathy, often accompanied by joint symptoms, including arthritis at the ankles, knees, wrists, or elbows –– The Heerfordt-Waldenstrom syndrome describes individuals with fever, parotid enlargement, anterior uveitis and facial nerve palsy. •• Feature is the noncaseating epithelioid granuloma •• This is a discrete, compact collection of epithelioid cells rimmed by an outer zone of largely CD4 + T-cells. The epithelioid cells are derived from macrophages and are characterized by abundant eosinophilic cytoplasm and vesicular nuclei. Two other microscopic features are sometimes seen in the granulomas: (1) Schaumann bodies: laminated concretions composed of calcium and proteins; and (2) Asteroid bodies: stellate inclusions enclosed within giant cells •• Intrathoracic hilar and paratracheal lymph nodes are enlarged 75 to 90% of patients, while a third present with peripheral lymphadenopathy. The nodes are characteristically painless and have a firm, rubbery texture •• Erythema nodosum, the hallmark of acute sarcoidosis, consists of raised, red, tender nodules on the anterior aspects of the legs. In contrast, discrete painless subcutaneous nodules can also occur in sarcoidosis, and these usually reveal abundant noncaseating granulomas. Another characteristic skin lesion of sarcoidosis consists of indurated plaques associated with a violaceous discoloration in the region of the nose, cheeks and lips (lupus pernio) •• Involvement of the eye and lacrimal glands occurs in about one-fifth to one-half of patients. The ocular involvement takes the form of iritis or iridocyclitis and maybe unilateral or bilateral. The posterior uveal tract is also affected with resultant choroiditis, retinitis and optic nerve involvement. These ocular lesions are frequently accompanied by inflammation in the lacrimal glands, with suppression of lacrimation (sicca syndrome) •• Unilateral or bilateral parotitis with painful enlargement of the parotid glands occurs in less than 10% of the individuals with sarcoidosis; some go onto develop xerostomia (dry mouth). Combined uveoparotid involvement is designated Mikulicz syndrome. 376 USMLE Step 1 Platinum Notes Acute Pneumonias S pneumoniae (pneumococcus) is the most common cause of community-acquired acute pneumonia, and the distribution of inflammation is usually lobar Morphologically, lobar pneumonias evolve through four stages: congestion, red hepatization, gray hepatization and resolution Other common causes of acute pneumonias in the community include H influenzae and M catarrhalis (both associated with acute exacerbations of COPD) •• S aureus (usually secondary to viral respiratory infections) •• K pneumoniae (observed in chronic alcoholics) •• P aeruginosa (seen in individuals with cystic fibrosis, in burn patients and in neutropenics) and L pneumophila, seen particularly in individuals who have undergone organ transplants. Lung Abscess: (USMLE Favorite) •• Abscesses vary in diameter from a few millimeters to large cavities of 5 to 6 cm •• The localization and number of abscesses depend on their mode of development •• Pulmonary abscesses resulting from aspiration of infective material are much more common on the right side (more vertical airways) than on the left and most are single •• On the right side, they tend to occur in the posterior segment of the upper lobe and in the apical segments of the lower lobe, because these locations reflect the probable course of aspirated material when the patient is recumbent •• Abscesses that develop in the course of pneumonia or bronchiectasis are commonly multiple, basal and diffusely scattered. Septic emboli and abscesses arising from hematogenous seeding are commonly multiple and may affect any region of the lungs. Tuberculosis: (USMLE Favorite) The initial lesion is usually a small focus of consolidation, less than 2 cm in diameter, within 1 to 2 cm of the apical pleura. Localized, apical, secondary pulmonary tuberculosis may heal with fibrosis either spontaneously or after therapy, or the disease may progress and extend along several different pathways: Progressive pulmonary tuberculosis may ensue. The apical lesion enlarges with expansion of the area of caseation. Erosion into a bronchus evacuates the caseous center, creating a ragged, irregular cavity lined by caseous material that is poorly walled off by fibrous tissue Erosion of blood vessels results in hemoptysis. If the treatment is inadequate, or if host defenses are impaired, the infection may spread by direct expansion, via dissemination through airways, lymphatic channels, or the vascular system. •• Miliary pulmonary disease occurs when organisms drain through lymphatics into the lymphatic ducts, which empty into the venous return to the right side of the heart and thence into the pulmonary arteries •• Miliary lesions may expand and coalesce to yield almost total consolidation of large regions or even whole lobes of the lung. With progressive pulmonary tuberculosis, the pleural cavity is invariably involved and serous pleural effusions, tuberculous empyema, or obliterative fibrous pleuritis may develop •• Endobronchial, endotracheal and laryngeal tuberculosis may develop when infective material is spread either through lymphatic channels or from expectorated infectious material. The mucosal lining maybe studded with minute granulomatous lesions, sometimes apparent only on microscopic examination •• Systemic miliary tuberculosis ensues when infective foci in the lungs seed the pulmonary venous return to the heart; the organisms subsequently disseminate through the systemic arterial system. Almost every organ in the body maybe seeded. Lesions resemble those in the lung. Miliary tuberculosis is most prominent in the liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopian tubes and epididymis •• Isolated-organ tuberculosis may appear in any one of the organs or tissues seeded hematogenously and maybe the presenting manifestation of tuberculosis. Organs typically involved include the : – Meninges (tuberculous meningitis) – Kidneys (renal tuberculosis) – Adrenals (formerly an important cause of Addison disease) – Bones (osteomyelitis), and –– Fallopian tubes (salpingitis) –– When the vertebrae are affected, the disease is referred to as Pott disease. Pathology 377 •• Paraspinal ‘cold’ abscesses in persons with this disorder may track along the tissue planes to present as an abdominal or pelvic mass •• Lymphadenitis is the most frequent form of extrapulmonary tuberculosis, usually occurring in the cervical region (‘scrofula’). In HIV-negative individuals, lymphadenopathy tends to be unifocal, and most individuals do not have evidence of ongoing extranodal disease •• Intestinal tuberculosis is more often a complication of protracted advanced secondary tuberculosis, secondary to the swallowing of coughed-up infective material. Typically, the organisms are trapped in mucosal lymphoid aggregates of the small and large bowel, which then undergo inflammatory enlargement with ulceration of the overlying mucosa, particularly in the ileum. Malignant Mesotheliomas: (USMLE Favorite) •• Are often preceded by extensive pleural fibrosis and plaque formation •• These tumors begin in a localized area and in the course of time spread widely, either by contiguous growth or by diffusely seeding the pleural surfaces •• The neoplasm may directly invade the thoracic wall or the subpleural lung tissue. Normal mesothelial cells are biphasic, giving rise to pleural lining cells as well as the underlying fibrous tissue. USMLE Case Scenario (PAS)-positive cytoplasmic granules in hepatocytes are seen in: 1. Wilson’s disease 2. Hepatitis B 3. Alpha1-antitrypsin deficiency 4. Alcoholic hepatitis Ans. 3. Alpha1-antitrypsin deficiency USMLE Case Scenario A 34-year-old male from Africa in New York Chest clinic as a pathology characterized by noncaseating granulomata in lungs. The disease was discovered incidentally when chest X-ray reveals bilateral hilar adenopathy. Definitive diagnosis is based on biopsy, which reveals noncaseating granulomata that are negative for fungi or acid-fast bacilli. The disease most likely is: 1. Cat scratch disease 2. Sarcoidosis 3. Scleroderma 4. Systemic lupus erythematosus Ans. 2. Sarcoidosis 378 USMLE Step 1 Platinum Notes USMLE Case Scenario A 38-year-old man from Washington complained of breathlessness on examination, he had no clubbing and no abnormal chest signs. A chest X-ray showed fine, diffuse radiological shadows, predominantly in the mid zones, and bilateral hilar lymphadenopathy. Lung function tests were normal and a Mantoux test was negative. ACE levels and calcium levels are increased. A clinical diagnosis suggests: 1. Pneumonia 2. Tuberculosis 3. Sarcoidosis 4. Cat scratch disease 5. Coal workers lung 6. Caplans syndrome Ans. 3. Sarcoidosis USMLE Case Scenario A disease occurs with prolonged exposure to dust during glass production which can progress to respiratory failure and death, and is associated with increased risk for tuberculosis. Classic X-ray findings include calcified lymph nodes that produce an ‘eggshell’ pattern. Pleural involvement creates dense fibrous plaques and adhesions that may obliterate the pleural cavities. Most likely disease is: 1. Byssinosis 2. Berylliosis 3. Silicosis 4. Anthracosis Ans. 3. Silicosis USMLE Case Scenario A 35-year-old occupational worker presents to his primary care physician complaining of dyspnea and chronic dry cough. Chest X-ray reveals pulmonary hyperinflation with ‘honeycombing’ and calcified parietal pleural plaques. The most likely diagnosis is: 1. Anthracosis 2. Asbestosis 3. Histoplasmosis 4. Tuberculosis 5. Berylliosis 6. Byssinosis 7. Silicosis Ans. 2. Asbestosis GIT PATHOLOGY Esophagus The metaplasia of esophageal squamous epithelium to columnar epithelium (Barrett’s esophagus) is a complication of severe reflux esophagitis, and it is a risk factor for esophageal adenocarcinoma Barrett’s epithelium progresses through a dysplastic stage before developing into adenocarcinoma The etiology of squamous cell esophageal cancer is related to •• Excess alcohol consumption and/or cigarette smoking •• Ingestion of nitrites, smoked opiates and fungal toxins in pickled vegetables, as well as mucosal damage caused by such physical insults as long-term exposure to extremely hot tea, the ingestion of lye, radiation-induced strictures, and chronic achalasia •• The presence of an esophageal web in association with glossitis and iron deficiency (i.e. Plummer-Vinson or Paterson-Kelly syndrome) and congenital hyperkeratosis and pitting of the palms and soles (i.e. tylosis palmaris et plantaris) have each been linked with squamous cell esophageal cancer •• Dietary deficiencies of molybdenum, zinc and vitamin A •• Viral Esophagitis Herpes simplex virus (HSV) type 1 occasionally causes esophagitis in immunocompetent individuals, but either HSV type 1 or HSV type 2 may afflict patients who are immunosuppressed. Pathology 379 •• Herpetic vesicles on the nose and lips may provide a clue to the diagnosis. Barium swallow is inadequate to detect early lesions and cannot reliably distinguish HSV infection from other types of infections. Endoscopy shows vesicles and small, discrete, punched-out superficial ulcerations with or without a fibrinous exudate. In later stages, a diffuse erosive esophagitis develops from enlargement and coalescence of the ulcers. Mucosal cells from a biopsy sample taken at the edge of an ulcer or from a cytologic smear show ballooning degeneration, ground-glass changes in the nuclei with eosinophilic intranuclear inclusions (Cowdry type A), and giant cell formation on routine stains Viruses causing esophagitis: •• HSV1 •• HSV2 •• Varicella zoster •• CMV •• HIV Varicella-zoster virus (VZV) sometimes produces esophagitis in children with chickenpox and adults with herpes zoster. Esophageal VZV also can be the source of disseminated VZV infection without skin involvement. In an immunocompromised host, VZV esophagitis causes vesicles and confluent ulcers and usually resolves spontaneously, but it may cause necrotizing esophagitis in a severely compromised host. •• Cytomegalovirus (CMV) infections occur only in immunocompromised patients. CMV is usually activated from a latent stage or maybe acquired from blood product transfusions •• CMV lesions initially appear as serpiginous ulcers in an otherwise normal mucosa •• These may coalesce to form giant ulcers, particularly in the distal esophagus. Barrett’s Esophagus: (USMLE Favorite) May occur in a small number of patients who have gastroesophageal reflux disease (GERD). This condition is a metaplasia of the normal squamous mucosa of the esophagus to a columnar (glandular) type of epithelium, and is usually seen as a response to repeated acid exposure to the distal esophagus. Tobacco and alcohol use are also thought to contribute to the process. The significance of Barrett’s esophagus is that it may lead to the development of low-grade dysplasia, high-grade dysplasia, or esophageal adenocarcinoma. H pylori •• H pylori colonization induces chronic superficial gastritis, which includes both mononuclear and polymorphonuclear cell infiltration of the mucosa •• Progression to atrophy when H pylori is present •• Most H pylori-colonized persons do not develop clinical sequelae •• The two major disease-associated H pylori virulence factors are a vacuolating cytotoxin, VacA, and a group of genes termed the cag pathogenicity island (cag PaI) •• H pylori colonization diminishes the number of somatostatin-producing cells; somatostatin-mediated inhibition of gastrin release leads to hypergastrinemia. 380 USMLE Step 1 Platinum Notes Gastric Carcinoma •• Gastric carcinoma is classified on the basis of depth of invasion, macroscopic growth pattern and histologic subtype. The morphologic feature having the greatest impact on clinical outcome is the depth of invasion •• Early gastric carcinoma is defined as a lesion confined to the mucosa and submucosa, regardless of the presence or absence of perigastric lymph node metastases •• Advanced gastric carcinoma is a neoplasm that has extended below the submucosa into the muscular wall and has perhaps spread more widely. Gastric mucosal dysplasia is the presumed precursor lesion of early gastric cancer, which then in turn progresses to ‘advanced’ lesions. •• Sometimes a broad region of the gastric wall, or the entire stomach, is extensively infiltrated by malignancy. The rigid and thickened stomach is termed a leather bottle stomach, or linitis plastical •• The diffuse variant is composed of gastric-type mucous cells that generally do not form glands but rather permeate the mucosa and wall as scattered individual ‘signet-ring’ cells or small clusters in an ‘infiltrative’ growth pattern •• For obscure reasons, the earliest lymph node metastasis may sometimes involve a supraclavicular lymph node (Virchow node) •• Another somewhat unusual mode of intraperitoneal spread in females is to both the ovaries, giving rise to the so-called Krukenberg tumor. Gastrointestinal stromal tumor (GIST): (USMLE Favorite) •• Arise from interstitial cells of Cajal •• Stain positive for antibodies with: CD 117, CD 34 •• Increased tyrosine kinase activity Most (50–80%) GISTs arise because of a mutation in a gene called c-kit. This gene encodes a transmembrane receptor for a growth factor termed scf (stem cell factor). The c-kit/CD117 receptor is expressed on ICCs and a large number of other cells, mainly bone marrow cells, mast cells, melanocytes and several others. In the gut, however, a mass staining positive for CD117 is likely to be a GIST, arising from ICC cells The c-kit molecule comprises a long extracellular domain, a transcellular segment, and an intracellular part. Mutations generally occur in the DNA encoding the intracellular part (exon 11), which acts as a tyrosine kinase to activate other enzymes. Mutations make c-kit function independent of activation by scf, leading to a high cell division rate and possibly genomic instability. It is likely that additional mutations are ‘required’ for a cell with a c-kit mutation to develop into a GIST, but the c-kit mutation is probably the first step of this process. The tyrosine kinase function of c-kit is vital in the therapy for GISTs Carneys triad: Gastric GIST+Para ganglioma+pulmonary chondroma. Intestinal Polyposis and Associations: (This table has been repeated in surgery for revision) •• Bessauds-Hillmand-Augier Syndrome: Sexual infantilism associated with intestinal polyposis. •• Carter-Horsley-Hughes Syndrome. Diffuse polyposis of the small and large intestine. –– Cowden’s Disease or Multiple Hamartoma Syndrome –– Hamartomatous, juvenile, lipomatous, or inflammatory polyps are present mainly in the stomach and colon but are also present in the small intestine. Benign and malignant breast and thyroid disease are also found in these patients, as well as mucocutaneous lesions, trichilemmomas, acral keratoses and oral papillomas. •• Cronkhite-Canada Syndrome. This syndrome is characterized by: –– Generalized gastrointestinal polyposis and –– ‘Ectodermal defects,’ such as alopecia, excessive skin pigmentations and nail atrophy –– In the intestinal polyps, dilated cystic glands are found in an edematous lamina propria. Loss of protein from the gut, along with calcium, magnesium and potassium deficiencies, may occur. •• Familial Polyposis of the Colon. This syndrome is customarily associated with polyps of the colon, but cases of generalized polyposis have been recorded, with associated malignancy •• Gardner’s Syndrome. This syndrome is generally characterized by rectal and colonic polyposis, but generalized Polyposis has been recorded. These polyps are involved in the development of adenocarcinoma. The syndrome also includes: Pathology –– –– –– –– –– –– –– 381 Cysts of the skin Osteomas Fibrous and fatty tumors of the skin and mesentery Follicular odontomas Dentigerous cysts and Changes in the bony structures of the jaws This syndrome is familial and is transmitted as an autosomal dominant trait •• Gordon’s Disease. This is a protein-losing gastroenteropathy, usually manifested as Menetrier’s disease, which involves: –– Mucosal hypertrophy –– Hyperplasia of the superficial epithelium –– Degeneration in the glandular layer, and –– Hypoproteinemia due to leakage of proteins through the mucous membranes. A diffuse gastrointestinal polyposis associated with protein loss has also been reported. •• Juvenile Polyposis. Juvenile polyposis is most commonly found in the colon and rectum, but isolated examples of generalized gastrointestinal polyposis have been reported with and without family history or other congenital abnormalities. –– –– –– –– Muir-Torre Syndrome. This syndrome was described to include Sebaceous adenomas Epidermoid cysts, fibromas, desmoids, lipomas, fibrosarcomas and Leiomyomas with visceral cancers •• Peutz-Jeghers Syndrome. This syndrome is characterized by hamartomatous polyps of the gastrointestinal tract (stomach, small bowel, colon) that are associated with mucocutaneous pigmentation (lips, oral mucosa, fingers, forearm, toes, umbilical area). The skin pigmentation may fade after puberty, but that of the mucous membrane is retained. •• Rendu-Osler-Weber Disease. This disease is described as telangiectasia of the nasopharynx or gastrointestinal tract. •• Turcot’s Syndrome. Malignant brain tumors are associated with inherited intestinal adenomatous polyposis. •• von Recklinghausen’s Disease. Generalized neurofibromatosis with café au lait skin pigmentation may also include neurofibromas of the gastrointestinal tract. PATHOLOGY OF INTESTINAL DISEASES Celiac sprue •• Is gluten sensitive enteropathy or nontropical sprue –– Hypersensitivity to gluten/gliadin occurs with loss of villi and Malabsorption –– –– –– –– Genetic predisposition: HLA B8 DR 3 DQ2 –– Pathology –– Loss of villi –– Increased intraepithelial lymphocytes –– Increased plasma cells in lamina propria –– Presentation: Malabsorption, abdominal distension, bloating, diarrhea, steatorrhea, weight loss –– Association with ‘dermatitis herpetiformis’. Tropical Sprue Malabsorptive disease in tropical regions with unknown etiology Similar features to celiac sprue and responds to antibiotics, Vitamin B12, Folate. 382 USMLE Step 1 Platinum Notes Whipple Disease Malabsorptive disease caused by Trophermyma whippeli •• PAS positive, rod shaped bacilli fill lamina propria •• Treatment is with antibiotics. USMLE Case Scenario A 44-year-old female developed loose stools and generalized but vague abdominal pain. On questioning, she had felt tired for 3 years and had lost about five kg in weight during the preceding 7 months despite a good appetite. Laboratory investigations showed a macrocytic anemia only. The blood film showed many Howell-Jolly bodies. Bone marrow examination revealed active erythropoiesis with early megaloblastic features. Her serum was positive for IgA antibodies to endomysium and she had high levels of IgA and IgG antibodies to gliadin. The pathologists report on doing jejunal biopsy showed stunted villi, and subtotal villous atrophy with marked increase in intraepithelial lymphocytes and chronic inflammation in the lamina propria. The patient should be started on: 1. A high carbohydrate diet 2. A low iron diet with high gluten content 3. A high calorie diet 4. A gluten-free diet 5. Total parentral nutrition (TPN) 6. Intravenous iron only Ans. 4. A gluten-free diet INFLAMMATORY BOWEL DISEASES Crohn Disease There is gross involvement of the small intestine alone in about 30% of cases, of small intestine and colon in 40%, and of the colon alone in about 30%. Crohn disease may involve the duodenum, stomach, esophagus and even mouth, but these sites are distinctly uncommon When fully developed, Crohn disease is characterized by: •• Sharply delimited and typically transmural involvement of the bowel by an inflammatory process with mucosal damage •• The presence of noncaseating granulomas in 40 to 60% of cases, and •• Fissuring with formation of fistulae. Ulcerative Colitis •• Involves the rectum and sigmoid and may involve the entire colon •• Presentation with an even higher proximal extension (pancolitis) occurs much less frequently. Colonic involvement is continuous from the distal colon, so that skip lesions are not encountered. Active disease denotes ongoing inflammatory destruction of the mucosa, with macroscopic hyperemia, edema and granularity with friability and easy bleeding. Ulcerative colitis Crohn’s disease •• Involves rectum always •• Pipe stem colon •• Involves ileum mostly •• May cause ‘pancolitis’ •• Diffuse involvement •• Nondiffuse involvement •• Called ‘regional enteritis’ •• Retrograde spread to ileum is backwash ileitis •• Disease of continuity •• Skip lesions •• Pseudopolyps present •• Pseudopolyps absent •• Limited to mucosa and submucosa •• Transmural inflammation •• Noncaseating granulomas not seen •• Noncaseating granulomas seen Pathology Ulcerative colitis Crohn’s disease •• Creeping fat not seen •• Creeping fat seen •• Strictures, ulcerations, fistula less frequent •• Strictures, ulcerations, fistula frequent •• Toxic megacolon occurs •• Rare •• Malignant transformation +++ •• Malignant transformation + 383 USMLE Case Scenario A 52-year-old man from Nebraska presents to Gastro clinic with a complaint of nonbloody diarrhea and right lower quadrant pain with a palpable mass and tenderness. He states that this ‘flare-up’ is one of the worst he has ever experienced. Radiographic examination reveals evidence of ulceration, stricturing, and fistula development of the colon and small bowel. The most likely diagnosis is: Ans. Crohn’s disease USMLE Case Scenario A 33-year-old business class woman was admitted with a 3 weeks history of increasing bloody diarrhea and abdominal pain; she had lost 5 kg in weight. She smoked 25 cigarettes a day. On examination, she was having tenderness over the right iliac fossa, sigmoidoscopy showed a red, granular mucosa with mucopus and contact bleeding. Ulceration of the surface epithelium, noncaseating granulomas and skip lesions. Most likely cause is: 1. Ischemic colitis 2. Gluten enteropathy 3. Crohn’s disease 4. Ulcerative colitis 5. Pseudomembranous colitis Ans. 3. Crohn’s disease Typhoid Ulcer •• •• •• •• Ulceration of Peyer’s patches It is a longitudinal ulcer Perforates Stricture formation is rare. •• Mallory bodies are composed of eosinophilic intracytoplasmic inclusions are seen in: –– Alcoholism –– Primary Biliary Cirrhosis –– Wilson’s Disease 384 USMLE Step 1 Platinum Notes •• Mallory Hyaline is absent in: –– Hepatitis –– Secondary Biliary Cirrhosis –– Fibrosis •• Ito cells are a source of collagen in Cirrhosis of liver •• Nutmeg Liver is due to Chronic passive congestion Hepatitis: (You should not attempt examinations without knowing this table) Acute infection: HBsAg+, IgM anti HBc+ Resolved infection: HBsAg–, IgG anti HBc+ Vaccination: HBsAg–, anti HBs+ Inactive carrier: –– HBsAg + greater than 6 months –– HBeAg–, anti–HBe+ –– HBV DNA < 105copies/ml –– Normal liver enzymes •• Chronic Hepatitis: –– HBV DNA > 105copies/ml –– ↑Liver enzymes –– Necro inflammation on liver biopsy. •• •• •• •• Features of Acute Hepatitis: (USMLE Favorite) •• •• •• •• •• •• •• •• •• Zonal necrosis Bridging hepatic necrosis Hepatic cell necrosis ↑liver size ↑liver redness Kupffer cell hypertrophy and hyperplasia Lobular disarray Focal necrotic spot Councilman/apoptotic bodies are seen in acute hepatitis. Features of Chronic Hepatitis: (USMLE Favorite) Chronic Active Hepatitis: •• Piecemeal necrosis •• Bridging necrosis •• Rosette and Pseudolobule formation •• Ground glass appearance of Hepatocytes •• Councilman Bodies •• Kupffer cell Hyperplasia. Chronic Persistent Hepatitis: •• No piecemeal necrosis •• Mononuclear infiltrate confined to portal tract •• Septae into parenchyma. Pathology 385 HEPATITIS C The Characteristic Lesion is: •• Paucity of inflammation •• Increase in activation of sinusoidal lining •• Lymphoid aggregates •• Bile duct damage in portal tracts •• Most common cause of post-transfusion hepatitis •• Causes chronic hepatitis. USMLE Case Scenario A 44-year-old lady had nephrotic syndrome. On further investigations warm sample of ladys blood serum contained a mixed cryoglobulin, A skin biopsy showed scattered deposits of IgM, IgG and C3 in dermal blood vessels. The final diagnosis was mixed cryoglobulinemia. It is seen in association with: 1. Perihepatitis by chlamydia 2. Hepatitis A infection 3. Chronic Hepatitis C infection 4. Lichen planus 5. Psoriasis Ans. 3. Chronic Hepatitis C infection HEPATITIS D •• •• •• •• HDV is ‘Defective’ because it does not have genes for its proteins HDV can replicate in cells only infected with HBV HDV uses surface antigen of HBV (HBsAg) as it envelop protein HBV is a helper virus for HDV. •• •• •• •• •• HDV is an enveloped virus HDV is an RNA virus Genome of HDV is small and encodes only one protein the delta antigen HDV genome is a Ribozyme i.e. has ability to self-cleave and self-ligate Infection with hepatitis D can be prevented by vaccinating susceptible persons with hepatitis B vaccine •• Most common cause of sporadiac cases of hepatitis in adults: Hep E •• Worst prognosis in pregnancy: Hep E •• Most common route of spread of Hep E is fecooral PRIMARY LIVER CARCINOMAS Hepatocellular Cancer Hepatocelluler Cancer is the most common. They, may appear grossly as: •• A unifocal, usually massive •• A multifocal tumor made of nodules of variable size; or •• A diffusely infiltrative cancer, permeating widely and sometimes involving the entire liver, blending imperceptibly into the cirrhotic liver background The main etiologic agents for hepatocellular carcinoma are: •• Hepatitis B and C •• Alcoholic cirrhosis 386 USMLE Step 1 Platinum Notes •• Hemochromatosis and •• Tyrosinemia Hepatocellular carcinomas maybe unifocal or multifocal tend to invade blood vessels, and recapitulate normal liver architecture to varying degrees Histologically, HCCs range from well differentiated lesions that reproduce hepatocytes arranged in cords, trabeculae or glandular patterns to poorly differentiated lesions, often composed of large multinucleate anaplastic tumor giant cells. Fibrolamellar Carcinoma A distinctive clinicopathologic variant of HCC is the fibrolamellar carcinoma, which occurs in young male and female adults (20– 40 years of age) with equal incidence has no association with cirrhosis or other risk factors (It usually consists of a single large, hard ‘scirrhous’ tumor with fibrous bands coursing through it, vaguely resembling focal nodular hyperplasia. The liver is the most common site of metastatic cancers from primary tumors of the colon, lung and breast. •• Angiosarcoma liver: Vinyl chloride, Aflatoxin, Thorotrast •• Peliosis hepatitis: Steroids, Danazol •• Hepatic vein thrombosis: OCP, cytotoxic drugs •• Veno-occlusive disease: Pyrrolizidine alkaloids, cytotoxic drugs. Causes of Splenomegaly: (USMLE Favorite) Massive Splenomegaly (weight more than 1000 gm) –– Chronic myeloproliferative disorders (chronic myeloid leukemia, myeloid metaplasia with myelofibrosis) –– Chronic lymphocytic leukemia –– Hairy cell leukemia –– Lymphomas –– Malaria –– Gaucher disease –– Primary tumors of the spleen Moderate splenomegaly (weight 500–1000 gm) –– Chronic congestive splenomegaly (portal hypertension or splenic vein obstruction) –– Acute leukemias –– Hereditary spherocytosis –– Thalassemia major –– Autoimmune hemolytic anemia –– Amyloidosis –– Niemann-Pick disease –– Langerhans histiocytosis –– Chronic splenitis (especially with infective endocarditis) –– Tuberculosis, sarcoidosis, typhoid –– Metastatic carcinoma or sarcoma Mild splenomegaly (weight < 500 gm) –– Acute splenitis –– Acute splenic congestion –– Infectious mononucleosis –– Miscellaneous acute febrile disorders, including septicemia, SLE and intraabdominal infections Pathology 387 RENAL SYSTEM ‘Pathology detected on Macroscopic appearance of Kidneys’ Renomegaly: •• Diabetic nephropathy •• Amyloidosis •• Scleroderma •• Polycystic kidney •• Acute Glomerulonephritis Contracted Kidney: •• Chronic Glomerulonephritis •• Chronic Pyelonephritis •• Benign Nephrosclerosis (B/L) Flea Bitten Kidney: •• Acute Post streptococcal Glomerulonephritis •• RPGN •• HUS •• TTP •• HSP •• SABE •• Malignant Hypertension USMLE Case Scenario Kidney biopsy from a child with hemolytic uremic syndrome characteristically most likely presents features of: 1. Thrombotic microangiopathy 2. Proliferative glomerulonephritis 3. Focal segmental glomerulosclerosis 4. Minimal change disease Ans. 1. Thrombotic microangiopathy Nephritic syndrome Nephrotic syndrome •• Hematuria •• Severe proteinuria •• Hypertension •• Hypoalbuminemia •• Oliguria •• Hyperlipidemia •• Proteinuria Glomerulopathies: (USMLE Favorite) •• The most frequent cause of nephrotic syndrome in children is minimal change disease (lipoid nephrosis) •• It is characterized by an absence of findings by light microscopy and •• Fusion of epithelial foot processes by electron microscopy •• •• •• •• •• Dense deposits are seen in type II membranoproliferative glomerulonephritis Mesangial deposits are a prominent feature of IgA nephropathy and are seen to a lesser degree in several other glomerulonephritides Subendothelial deposits are seen in type I membranoproliferative glomerulonephritis Diffuse involvement is seen in PSGN Anti GBM antibodies are seen in Goodpasture’s syndrome Focal segmental glomerulosclerosis is a feature of HIV associated nephropathy Collapsing variety of FSGS has worst prognosis Hypertrophy and necrosis of epithelium are a feature. 388 USMLE Step 1 Platinum Notes USMLE Case Scenario A 34-year-old man from New Orleans presents with hemoptysis and hematuria. This is a classic case of Goodpasture’s syndrome. Under immunofluorescence; there are linear deposits of IgG on alveolar and glomerular basement membranes. Renal biopsy shows inflammation of the glomeruli. X-ray shows focal pulmonary infiltrates. The most likely cause is: 1. Wegener’s granulomatosis 2. Poststreptococcal glomerulonephritis 3. Berger’s disease 4. Goodpasture’s syndrome Ans. 4. Goodpasture’s syndrome •• •• •• •• •• •• •• Subepithelial humps: PSGN Subepithelial spikes with M spike: Membranous GN Subendothelial deposits: Lupus nephritis Spike and dome pattern: Membranous glomeruolonephritis Lumpy bumpy deposits: RPGN Tram track appearance: Membranoproliferative GN Crescents: Epithelial cells + fibrin + macrophage Causes of Low Complement •• •• •• •• •• •• •• •• •• •• Poststreptococcal GN (NONPERSISTENT) Lupus nephritis Cryoglobinemia Bacterial endocarditis Shunt nephritis MP GN Cresentric GN Idiopathic Proliferative GN Sepsis Cryoglobulinemia Alport’s Syndrome: (USMLE Favorite) •• •• •• •• •• •• Hereditary Nephritis Nerve Deafness Eye disorders (Lens Dislocation, Corneal Dystrophy, Posterior cataracts) Foamy cells in interstitium Thinning of Basement membrane <100 nm Mutation in alpha 5 chain of collagen type IV Xanthogranulomatous Pyelonephritis •• Rare type of chronic pyelonephritis •• Accumulation of foamy macrophages, plasma cells, lymphocytes. Analgesic Nephropathy •• •• •• •• Chronic disease due to excessive use of analgesics Pathological; lesions: Papillary Necrosis with Chronic Tubulointerstitial nephritis But most common cause of renal papillary necrosis is Diabetes mellitus Diabetes mellitus, Analgesics, sickle cell disease cause necrotizing pappilitis Pathology 389 POLYCYSTIC KIDNEYS Autosomal Dominant Polycystic Kidney Disease: (USMLE Favorite) •• ADPKD-1 accounts for 90% of cases, and the gene has been localized to the short arm of chromosome 16 •• ADPKD-2 has been mapped to the long arm of chromosome 4 The protein products of the two genes form the ‘Polycystin complex’, which may regulate cell-cell or cell-matrix interactions Pathology: •• The kidneys are grossly enlarged, with multiple cysts studding the surface of the kidney •• The cysts contain straw-colored fluid that may become hemorrhagic •• The cysts are spherical, vary in size from a few millimeters to centimeters, and are distributed evenly throughout the cortex and medulla •• The remaining renal parenchyma reveals varying degrees of tubular atrophy, interstitial fibrosis and nephrosclerosis •• Colonic diverticulae •• Cysts in other organs •• Berry aneurysm •• Mitral valve prolapsed + Aortic Regurgitation. Autosomal Recessive Polycystic Kidney Disease The gene for ARPKD has been localized to chromosome 6 Hepatic cysts with hepatic fibrosis. 390 USMLE Step 1 Platinum Notes Tuberous Sclerosis: (USMLE Favorite) Patients with this multisystem disease most commonly present with skin lesions and benign tumors of the central nervous system) •• Renal involvement is common •• Angiomyolipomas are the most frequent abnormality and are usually bilateral •• Renal cysts maybe present as well and can give an appearance similar to that of ADPKD Histologically, the cysts are unique The cyst lining cells are large with an eosinophilic staining cytoplasm and may form hyperplastic nodules that can fill the cyst space. Von Hippel-Lindau Disease This autosomal dominant disease is characterized by •• Hemangioblastomas of the retina and the central nervous system •• Renal cysts occur in the majority of cases and are usually bilateral •• The VHL gene is a tumor-suppressor gene and has been localized to chromosome 3. It is the same gene that is mutated in sporadic renal cell carcinoma, which maybe found in up to 25% of patients with von Hippel-Lindau disease and is frequently multifocal. Medullary: (Sponge Kidney) Medullary sponge kidney (MSK) is a congenital disorder Although some cases have apparent autosomal dominant inheritance, most are sporadic Males and females are affected equally The pathologic lesion is cystic dilation of the inner medullary and papillary collecting ducts, with collecting diameters ranging from 1 to 5 mm •• Bilateral renal involvement is present in 70% of cases, but not all papillae are equally affected •• The dilated ducts are lined by cuboidal epithelium with areas of pseudostratified and stratified squamous epithelium •• Calculi are frequently found in the dilated collecting ducts. •• •• •• •• Juvenile Nephrophthisis/Medullary Cystic Disease •• Juvenile nephrophthisis (JN) and medullary cystic disease (MCD) have similar pathologic findings but differ in inheritance pattern and age of onset •• JN is inherited as an autosomal recessive disease •• MCD is an autosomal dominant disease •• In both conditions •• The kidneys tend to be small, with cysts throughout the medulla •• The cortex and papilla rarely have cysts •• The cysts originate in the collecting ducts, distal convoluted tubules and loops of Henle and range in size from 1 to 10 mm •• Sclerotic glomeruli, tubule atrophy and interstitial fibrosis are frequent findings on biopsy. Juvenile Nephronophthisis Medullary Cystic Disease •• Patients with JN present during childhood with symptoms •• of polyuria, growth retardation, anemia and progressive renal insufficiency •• Most patients develop ESRD prior to the age of 20; MCD presents in the third or fourth decade, though some cases maybe diagnosed in the elderly population. Presenting symptoms in MCD are the same as in JN except for growth retardation. •• JN accounts for 2 to 10% of renal failure in children •• MCD does not have extrarenal abnormalities. Severe salt wasting can be seen •• Hepatic fibrosis and cerebellar ataxia has been reported in association with JN •• Other features of tubule damage are often found, including hyperkalemia and hyperchloremic metabolic acidosis. Proteinuria •• JN with retinal degeneration is termed the Senior-Loken is mild, and hematuria is rare. syndrome. Pathology 391 Renal Cancer Renal cell neoplasia represents a heterogeneous group of tumors with distinct histopathologic, genetic and clinical features ranging from benign to high-grade malignant Categories include: –– Clear cell carcinoma (MC) –– Papillary –– Chromophobic tumors –– Oncocytomas –– Collecting or Bellini duct tumors •• Clear cell tumors are characterized by tumor cells with clear cytoplasm and consistently show a deletion of 3p •• Papillary tumors tend to be bilateral and multifocal. Trisomy 7 and/or 17 is most frequent genetic markers •• Chromophobic tumors are characterized by multiple chromosomal losses but do not exhibit 3p deletions •• Oncocytomas have a characteristic morphology including a deeply eosinophilic cytoplasm, do not exhibit 3p deletions or trisomy 7 or 17, and are considered benign neoplasms •• Bellini duct carcinomas are very rare and are thought to arise from the collecting ducts within the renal medulla. They tend to afflict younger patients and are very aggressive tumors. Wegners Granulomatosis •• Necrotizing vasculitis of small arteries and veins together with granuloma formation that can be either Intravascular or extravascular •• Lung involvement: bilateral nodular cavitary infiltrates, demonstrate necrotizing granulomatous vasculitis •• The renal biopsy lesion is that of a pauci-immune necrotizing and crescentic GN •• Lung, nose, kidneys involved •• Anti-GBM disease commonly presents with hematuria, nephritic urinary sediment, subnephrotic proteinuria •• Rapidly progressive renal failure over weeks, with or without pulmonary hemorrhage When pulmonary hemorrhage occurs, it usually predates nephritis by weeks or months Hemoptysis can vary from fluffy pulmonary infiltrates on Chest X-ray and mild dyspnea on exertion to life-threatening pulmonary hemorrhage •• Renal biopsy is the gold standard for diagnosis of anti-GBM nephritis •• The typical morphologic pattern on light Microscopy is diffuse proliferative glomerulonephritis, with focal necrotizing lesions and crescents in >50% of Glomeruli (crescentic glomerulonephritis) •• Immunofluorescence microscopy reveals linear ribbon-like deposition of IgG along the GBM USMLE Case Scenario A 62-year-old from Wales presently in US develops oliguria and peripheral edema over a period of weeks. Urinalysis reveals hematuria and proteinuria; examination of the urinary sediment reveals red cell casts. Renal biopsy shows many glomerular crescents. This presentation is most suggestive of which of the following conditions? 1. Rapidly progressive glomerulonephritis 2. Diabetic nephropathy 3. Hypertensive nephropathy 4. Lupus nephritis Ans. 1. Rapidly progressive glomerulonephritis Catheter-Associated UTIs •• Bacteriuria develops in at least 10 to 15% of hospitalized patients with indwelling urethral catheters •• E coli, Proteus, Pseudomonas, Klebsiella, Serratia, staphylococci, enterococci and Candida usually cause these infections •• Infection occurs when bacteria reach the bladder by one of two routes: by migrating through the column of urine in the catheter lumen (intraluminal route) or by moving up the mucous sheath outside the catheter (periurethral route). 392 USMLE Step 1 Platinum Notes •• Clinically, most catheter-associated infections cause minimal symptoms and no fever and often resolve after withdrawal of the catheter •• Catheter-associated UTIs can sometimes be prevented in patients catheterized for 2 weeks by use of a sterile closed collecting system, by attention to aseptic technique during insertion and care of the catheter and by measures to minimize crossinfection. Other preventive approaches, including –– Short courses of systemic antimicrobial therapy –– Topical application of periurethral antimicrobial ointments –– Use of preconnected catheter-drainage tube units –– Use of catheters impregnated with antimicrobial agents and –– Addition of antimicrobial drugs to the drainage bag •• Bilateral renal cell carcinomas can be a feature of von Hippel-Lindau disease •• Kimlstein wilson lesions: feature of diabetic nephropathy. Thyroid Pathology Primary hyperthyroidism: TSH ↑, T4↑ Secondary hyperthyroidism: TSH ↑ Hypothyroidism: TSH ↑ Hashimotos Thyroiditis Mc type Mc cause of hypothyroidism Mc in females •• Anti-TSH receptor antibodies •• Anti-thyroglobulin antibodies •• Anti-thyroid peroxidase antibodies •• Hurthle cells seen Grossly, the thyroid is usually diffusely and symmetrically enlarged, although more localized enlargement maybe seen in some cases The capsule is intact, and the gland is well demarcated from adjacent structures. The cut surface is pale, gray-tan, firm and somewhat friable. Microscopic examination reveals widespread infiltration of the parenchyma by a mononuclear inflammatory infiltrate containing small lymphocytes, plasma cells and well-developed germinal centers The thyroid follicles are atrophic and are lined in many areas by epithelial cells distinguished by the presence of abundant eosinophilic, granular cytoplasm, termed Hürthle, or oxyphil, cells Less commonly, the thyroid is small and atrophic as a result of more extensive fibrosis (fibrosing variant). Subacute Granulomatous (De Quervain) Thyroiditis: (USMLE Favorite) •• Subacute granulomatous thyroiditis, also known as de Quervain thyroiditis, is much less common than is Hashimoto disease •• De Quervain thyroiditis is most common between the ages of 30 and 50 and, like other forms of thyroiditis, occurs more frequently in women than in men •• Subacute thyroiditis is believed to be caused by a viral infection or a postviral inflammatory process •• The gland is firm, with an intact capsule, and maybe unilaterally or bilaterally enlarged •• Histologically, there is disruption of thyroid follicles, with extravasation of colloid leading to a polymorphonuclear infiltrate, which is replaced overtime by lymphocytes, plasma cells and macrophages. Riedel Thyroiditis •• It is a rare disorder of unknown etiology, is characterized by extensive fibrosis involving the thyroid and contiguous neck structures •• The presence of a hard and fixed thyroid mass clinically simulates a thyroid neoplasm •• It maybe associated with idiopathic fibrosis in other sites in the body, such as the retroperitoneum •• The presence of circulating antithyroid antibodies in most patients suggests an autoimmune etiology. Pathology 393 Hyperthyroidism The measurement of serum TSH concentration using sensitive assays provides the most useful single screening test for hyperthyroidism, because TSH levels are decreased even at the earliest stages. Hyperthyroidism results predominantly from increased circulating levels of T3 (T3 toxicosis). In these cases free T4 levels maybe decreased, and direct measurement of serum T3 maybe useful Remember: Once the diagnosis of thyrotoxicosis has been confirmed by a combination of TSH and free thyroid hormone assays, measurement of radioactive iodine uptake by the thyroid gland is often valuable in determining the etiology There maybe diffusely increased uptake in the whole gland (Graves disease), increased uptake in a solitary nodule (toxic adenoma), or •• Decreased uptake (thyroiditis). USMLE Case Scenario A 33-year-old nervous and anxious woman presented with a 3-month history of increased sweating and palpitations with weight loss of 7 kg. On examination, she had a diffuse, nontender, smooth enlargement of her thyroid, over which a bruit could be heard. She had a fine tremor of her fingers and a resting pulse rate of 159/minute. On investigation, she had serum T3 of 5.5 nmol/l (NR 0.8–2.4) and a T4 of 59 nmol/l (NR 9–23). Measurement of her thyroid-stimulating hormone showed that this was low normal, 0.4 mU/l (NR 0.4–5 mU/l). Circulating antibodies to thyroid peroxidase were detected by agglutination. Most likely cause is: 1. Hashimotos disease 2. Wolf chaikkoff effect 3. Pendred syndrome 4. Autoimmune thyrotoxicosis 5. De quervians disease Ans. 4. Autoimmune thyrotoxicosis USMLE Case Scenario A 44 year-old woman from a hilly area presented with a large, painless swelling in her neck. Thyroid function tests showed that she was euthyroid; however, her serum contained high titre antibodies to thyroid peroxidase. Most likely cause is: 1. Hashimoto’s thyroiditis 2. Wolf chaikkoff effect 3. Pendred syndrome 4. Autoimmune thyrotoxicosis 5. De quervians disease Ans. 1. Hashimoto’s thyroiditis Malignant Solitary Thyroid Nodule •• •• •• •• •• Male Young Solitary nodule Cold on radioactive scan Radiation exposure to head and neck Pappilary Ca Thyroid •• •• •• •• •• •• Mc type Spread by lymphatics Psommoma bodies seen Orphan annie eyed nuclei seen Develops in throglossal tract Associated with dystrophic calcification 394 USMLE Step 1 Platinum Notes •• Least malignant The nuclei of papillary carcinoma cells contain very finely dispersed chromatin, which imparts an optically clear appearance, giving rise to the designation ‘ground-glass’ or ‘Orphan Annie eye’ nuclei. A papillary architecture is present in many cases Concentrically calcified structures termed psammoma bodies are often present within the papillae. Follicular Ca Thyroid: (USMLE Favorite) •• Second mc tumor of thyroid •• Hematogeneous spread •• Diagnosis by biopsy not FNAC •• Hurhle cell ca is a variant Microscopically, most follicular carcinomas are composed of fairly uniform cells forming small follicles, reminiscent of normal thyroid. Medullary Ca Thyroid: (USMLE Favorite) •• •• •• •• •• Arises from parafollicular cells C cells Secrete calcitonin Associated with MEN II Amyloid stroma RET proto oncogene involved Anaplastic Ca Worst Prognosis Thyroid Neoplasms •• Most thyroid neoplasms present as solitary thyroid nodules; only 1% of all thyroid nodules are neoplastic •• Follicular adenomas are the most common benign neoplasms, while papillary carcinoma is the most common malignancy •• Multiple genetic pathways are involved in thyroid carcinogenesis. Some of the genetic abnormalities that are fairly unique to thyroid cancers include –– PAX8-PPARγ1 fusion (in follicular carcinoma) –– Chromosomal rearrangements involving the RET oncogene (papillary cancers) –– Mutations of RET (medullary carcinomas) •• Follicular adenomas and carcinomas are both composed of well-differentiated follicular epithelial cells, and are distinguished by evidence of capsular and/or vascular invasion in the latter. Pathology 395 •• Papillary carcinomas are recognized based on nuclear features (ground-glass nuclei, pseudo-inclusions) even in the absence of papillae •• Psammoma bodies are a characteristic feature of papillary cancers; these neoplasms typically metastasize via lymphatics but their prognosis is excellent •• Medullary cancers are nonepithelial neoplasms arising from the parafollicular C cells and can occur in either sporadic (80%) or familial (20%) settings Amyloid deposits are a characteristic histologic finding •• Anaplastic carcinomas are thought to arise by dedifferentiation of more differentiated neoplasms. They are highly aggressive, uniformly lethal cancers. USMLE Case Scenario MEN II and MEN III are associated with: 1. C-myc 2. erb-B2 3. L-myc 4. Ret Ans. 4. Ret USMLE Case Scenario Which of the following gene defect is associated with development of medullary carcinoma of thyroid? 1. Ret Proto Oncogene 2. FAP gene 3. Rb gene 4. BRCA 1 gene Ans. 1. Ret Proto Oncogene USMLE Case Scenario The correct sequence of cell cycle is: 1. G0-G1-S-G2-M 2. G0-G1-G2-S-M 3. G0-M-G2-S-G1 4. G0-G1-S-M-G2 Ans. 1.G0-G1-S-G2-M Struma Ovarii •• It is composed of mature thyroid tissue •• Usually a teratoma •• May present with hyperthyroidism. Pheochromocytoma Sweating, tachycardia, palpitations, hypertension are features MC site: adrenal glands •• Bilaterality: 10% •• Extra-adrenal: 10% •• Malignant: 10% •• Children: 10% •• Familial: 10% 396 USMLE Step 1 Platinum Notes Immunomarkers: •• Chromogranin •• Synaptophysin •• S 100 Associations: •• MEN I •• MEN II •• MEN III •• Sturge weber syndrome •• von Hippel-Lindau syndrome •• Neurofibromatosis •• Pheochromocytomas range from small, circumscribed lesions confined to the adrenal to large, hemorrhagic masses weighing several kilograms •• On cut surface, smaller pheochromocytomas are yellow-tan, well-defined lesions that compress the adjacent adrenal larger lesions tend to be hemorrhagic, necrotic, and cystic and typically efface the adrenal gland •• Incubation of the fresh tissue with potassium dichromate solutions turns the tumor a dark brown color •• Microscopically, pheochromocytomas are composed of polygonal to spindle-shaped chromaffin cells and their supporting cells, compartmentalized into small nests, or ‘Zellballen,’ by a rich vascular network. USMLE Case Scenario Pheochromocytoma intermittently secretes epinephrine and other vasoactive amines, producing episodes of elevated blood pressure accompanied by headache. This is the tumor to associate with the rule of the 10’s: 1. It is 10% nonmalignant 2. It is 10% unilateral 3. 10% adrenal 4. 10% are familial Ans. 4. 10% are familial USMLE Case Scenario A disease is associated with multiple telangiectasias which are usually small. The most likely disease is: 1. von Hippel-Lindau disease 2. Osler-Weber-Rendu disease 3. Milroy’s disease 4. Buerger’s disease Ans. 2. Osler-Weber-Rendu disease USMLE Case Scenario A boy presents with a purple, flat vascular ectasia on the head and along distribution of the trigeminal nerve, mental retardation, seizures, and hemiplegia. The most likely disease is: 1. Milroy’s disease 2. Osler-Weber-Rendu disease 3. Sturge-Weber syndrome 4. von Hippel-Lindau disease Ans. 3. Sturge-Weber syndrome Pathology 397 Hematology •• Uremia •• G6PD deficiency •• Hemet cells •• Burr cells are seen •• Bite cells •• Hemolytic Uremic Syndrome •• Cirrhosis •• Spur cells are seen •• Iron depletion •• Seen in Iron deficiency anemia, polycythemia vera •• Thalassemia minor •• Decreased osmolysis, microcytic hypochromic anemia, increased HbA2 •• Sickle cell anemia •• Tactoids and sickling seen •• Acquired spherocytosis •• Schistocytes present, Coombs positive •• Hereditary spherocytosis •• Coombs negative •• Aplastic anemia •• Platelets maximum affected and last to recover, Pancytopenia present •• Pernicious anemia and Folate deficiency •• Anisocytosis, poikilocytosis, fragmented RBC, neutrophil lobes increased, anemia platelets normal. Absolute reticulocyte count low. •• Sideroblastic Anemia •• Ring Sideroblasts present (These are Iron granules in mitochondria around the nucleus) Microcytic, hypochromis RBC Macrocytic hypo or normochromic RBC •• Polycythemia vera •• Increased RBCs, platelets and Leukocytes Splenomegaly Present •• Myeloid metaplastia and Myelofibrosis •• Giant Platelets Macrocytic Anemia ‘Tear Drop’poikilocytes Leukoerythroblastic picture •• Megakaryocytosis marrow seen in •• Idiopathic Thrombocytopenic purpura Myeloid Metaplasia Polycythemia vera Postsplenectomy Changes •• •• •• •• •• •• Anisocytosis, poikilocytosis Macrocytosis Howell jolly bodies Heinz bodies Target cells Pappenheimer bodies. •• •• •• •• •• Burr cell is seen in uremia Acanthocytes are seen in abetalipoproteinemia Macroploycytes are seen in megaloblastic anemia Hypersegmented neutrophils are seen in megaloblastic anemia Spurr cells are seen in chronic liver disease. 398 USMLE Step 1 Platinum Notes •• Sickle cell anemia is due to structurally abnormal Hb •• Sickle cell anemia is due to replacement of glutamate by valine •• Hereditary spherocytosis is due to spectrin deficiency •• Proteins defective in hereditary spherocytosis are ankyrin, paladin, anion transport protein •• Hereditary spherocytosis is Autosomal dominant. Recognizing the Hematological Diseases by •• Subleukemic Leukemia •• Abnormal cells present White cell count normal or decreased •• Aleukemic Leukemia •• No abnormal cells WBC Count usually decreased below normal Diagnosis from marrow aspiration •• Hairy cell Leukemia (B-CELL) •• Neutropenia, Splenomegaly, hairy cells seen •• Acute nonlymphocytic Leukemia Lymphoblasts •• Total count usually more than 1,00,000 Macrocytic Normochromic Myeloblasts Anemia Severe Thrombocytopenia PAS Positive, Sudan black positive stains with Romanowski stain •• CML •• All series of cells seen Myeloblasts greater than 10 •• Increased Basophils, eosonophils, thrombocytes •• CLL (B-Cell disease) •• Small lymphocytes increased Blasts are rare Auto immune hemolytic anemia present •• Prolymphocytic Leukemia •• Large lymphocytes with prominent nucleolus •• Eosinophilic Leukemia •• Eosinophils increased •• Burkit’s lymphoma •• ‘Starry sky’ appearance in Lymphnode biopsy Causes of Aplastic Anemia •• •• •• •• •• •• •• Drugs (Chloramphenicol) Viruses PNH Pregnancy Idiopathic Fanconis anemia Schwaman Diamond Syndrome Pan Cytopenia with Hypocellular Marrow •• Acquired aplastic anemia •• Fanconis anemia •• A leukemic leukemia Pathology 399 Pan Cytopenia with Hypercellular Marrow •• •• •• •• •• •• Myelodysplastic syndrome PNH Megaloblastic anemia Myelofibrosis Hairy cell leukemia Myelophthisis Splenomegaly is absent in aplastic anemia BMT (bone marrow transplant) is the most effective treatment USMLE Case Scenario Microcytic, hypochromic anemia with reduced mental and physical performance is due to: 1. Iron deficiency 2. Copper deficiency 3. Calcium deficiency Ans. 1. Iron deficiency LEUKEMIA Acute myeloid leukemia •• Heredity: Certain syndromes with somatic cell chromosome aneuploidy, e.g. Down (chromosome 21 trisomy), Klinefelter (XXY and variants), and Patau (chromosome 13 trisomy), are associated with an increased incidence of AML. Inherited diseases with excessive chromatin fragility, e.g. –– Fanconi anemia –– Bloom syndrome –– Ataxia telangiectasia and –– Kostmann syndrome are also associated with AML •• Radiation Survivors of the atomic bomb explosions in Japan had an increased incidence of myeloid leukemias that peaked 5 to 7 years after exposure. Therapeutic radiation alone seems to add little risk of AML but can increase the risk in people exposed to alkylating agents •• Chemical and Other Exposures Exposure to benzene, which is used as a solvent in the chemical, plastic, rubber and pharmaceutical industries, is associated with an increased incidence of AML. Smoking and exposure to petroleum products, paint, embalming fluids, ethylene oxide, herbicides and pesticides, have also been associated with an increased risk of AML •• Drugs Anticancer drugs are the leading cause of treatment-associated AML. Alkylating agents, Topoisomerase II inhibitors, Chloramphenicol, phenylbutazone and less commonly, chloroquine and methoxy psoralen can result in bone marrow failure that may evolve into AML •• Chloroma occurs in AML •• Auer rods seen •• Nonspecific esterase is positive •• Nonspecific esterase is NOT positive IN M 6 Type only •• AML with gum infiltration is M4 •• DIC is seen in APML •• t (15: 17) is seen in APML •• MC type is pre B-cell ALL •• By definition, in AML myeloid blasts or promyelocytes make-up more than 20% of the bone marrow cellularity •• Myeloblasts (precursors of granulocytes) have delicate nuclear chromatin; three to five nucleoli; and fine, azurophilic granules in the cytoplasm •• Distinctive red-staining rodlike structures (Auer rods) maybe present in myeloblasts or more differentiated cells; they are particularly prevalent in the progranulocytes found in acute promyelocytic leukemia. 400 USMLE Step 1 Platinum Notes Chronic Myeloid Leukemia (CML) •• The diagnosis of CML is established by identifying a clonal expansion of a hematopoietic stem cell possessing a reciprocal translocation between chromosomes 9 and 22 •• This translocation results in the head-to-tail fusion of the breakpoint cluster region (BCR) gene on chromosome 22q11 with the ABL (named after the abelson murine leukemia virus) gene located on chromosome 9q34. •• Basophilic leukocytosis occurs •• Untreated, the disease is characterized by the inevitable transition from a chronic phase to an accelerated phase and onto blast crisis Chronic Lymphoid Leukemia (CLL): (USMLE Favorite) •• It is the most prevalent form of leukemia in western countries –– It occurs most frequently in older adults and is exceedingly rare in children –– CML principally affects adults between 25 and 60 years of age and accounts for 15 to 20% of all cases of leukemia –– The peak incidence is in the fourth and fifth decades of life –– CLL is more common in men than in women and more common in whites than in blacks –– The onset of CML is usually slow, and the initial symptoms are often nonspecific (e.g. easy fatigability, weakness, and weight loss) –– Sometimes the first symptom is a dragging sensation in the abdomen, caused by the extreme splenomegaly that is characteristic of this condition. Acute Lymphoid Leukemias (ALL): (USMLE Favorite) Acute lymphoid leukemias (ALLs) are predominantly cancers of children and young adults •• The L3 or Burkitt’s leukemia occurring in children in developing countries seems to be associated with infection by the EpsteinBarr virus (EBV) in infancy •• Childhood ALL occurs more often in higher socioeconomic subgroups •• Children with trisomy 21 (Down’s syndrome) have an increased risk for childhood acute lymphoblastic leukemia as well as acute myeloid leukemia •• Exposure to high-energy radiation in early childhood increases the risk of developing T-cell acute lymphoblastic leukemia. FAB Classification of ALL •• L 1 •• L 2 •• L 3 Lymphoblasts with uniform, round nuclei and scant cytoplasm More variability of lymphoblasts; nuclei maybe irregular with more cytoplasm than L 1 Lymphoblasts have finer nuclear chromatin and blue-to-deep-blue cytoplasm with cytoplasmic vacuolization FAB Classification of AML •• •• •• •• •• •• •• M1 M2 M3 M4 M5 M6 M7 Undifferentiated myeloblastic; no cytoplasmic granulation Differentiated myeloblastic; a few to many cells may have sparse granulation Promyelocytic; granulation typical of promyelocytic morphology Myelomonoblastic; mixed myeloblastic and monocytoid morphology Monoblastic; pure monoblastic morphology ‘Erythroleukemic;’ predominantly immature erythroblastic morphology, sometimes megaloblastic appearance Megakaryoblastic; cells have shaggy borders that may show some budding. B-Cell Neoplasms •• •• •• •• •• •• CLL Hairy cell leukemia Promyelocytic leukemia NHL Mantle cell lymphomas Burkitts lymphoma Pathology 401 Mantle Cell Lymphoma: (USMLE Favorite) •• Tumor of mature B-cells that usually presents with advanced disease involving lymph nodes, bone marrow, and extranodal sites such as the gut •• Associated with t (11; 14) translocations that result in over-expression of cyclin D1, a regulator of cell cycle progression. Hairy Cell Leukemia •• B-cell neoplasm is distinguished by the presence of leukemic cells that have fine, hairlike cytoplasmic projections •• The tumor cells express pan-B-cell markers, including CD19 and CD20, surface immunoglobulin, and characteristically, CD11c and CD103 •• Occurs mainly in older males, and its manifestations result largely from infiltration of bone marrow and spleen •• Splenomegaly is often massive, is the most common and sometimes the only abnormal physical finding •• Pancytopenia, resulting from marrow infiltration and splenic sequestration, is seen in more than half the cases •• Hepatomegaly is less common and not as marked, and lymphadenopathy is distinctly rare. Burkitt Lymphoma •• Very aggressive tumor of mature B-cells that usually arises at extranodal sites •• It is uniformly associated with translocations involving the c-MYC protooncogene •• It is often associated with latent infection by Epstein-Barr virus (EBV). T-Cell Neoplasms •• Mediastinal lymphatic leukemia •• Adult T-cell leukemia MISCELLANEOUS NEOPLASMS Mycosis Fungoides and Sezary Syndrome •• These are composed of neoplastic CD4+ T-cells that home to the skin; as a result, they are often referred to as cutaneous T-cell lymphomas •• Usually presents as a nonspecific erythrodermic rash, which overtime tends to progress through a plaque phase to a tumor phase •• Histologically, there is infiltration of the epidermis and upper dermis by neoplastic T-cells, which often have a cerebriform nucleus characterized by marked infolding of the nuclear membrane •• Sezary syndrome is a clinical variant characterized by the presence of (1) a generalized exfoliative erythroderma and (2) tumor cells (Sézary cells) in the peripheral blood. Infectious Mononucleosis •• It is the cause of ‘heterophile-positive’ infectious mononucleosis (IM), which is •• Characterized by: –– Fever –– Sore throat –– Lymphadenopathy, and –– Atypical lymphocytosis •• The EBV receptor (CD21), present on the surface of B-cells and epithelial cells, is also the receptor for the C3d component of complement •• Lymphadenopathy most often affects the posterior cervical nodes but maybe generalized. Enlarged lymph nodes are frequently tender and symmetric but are not fixed in place. Pharyngitis, often the most prominent sign, can be accompanied by enlargement of the tonsils with an exudate resembling that of streptococcal pharyngitis •• A morbilliform or papular rash, usually on the arms or trunk, develops in about 5% of cases. Most patients treated with ampicillin develop a macular rash 402 •• •• •• •• •• •• USMLE Step 1 Platinum Notes Erythema nodosum and erythema multiforme Downey cell Atypical lymphocytes Paul Bunnel test+ Monospot Test + Called Kissing Disease. Other Diseases Associated with EBV Infection The X-linked lymphoproliferative syndrome (Duncan’s disease) is a recessive disorder of young boys who have a normal response to childhood infections but develop fatal lymphoproliferative disorders after infection with EBV •• Oral hairy leukoplakia •• Chronic fatigue syndrome •• Burkitt’s lymphoma •• Anaplastic nasopharyngeal carcinoma EBV has been associated with Hodgkin’s disease, especially the mixed-cellularity type •• Tonsillar carcinoma •• Angioimmunoblastic lymphadenopathy •• Angiocentric nasal NK/T-cell immunoproliferative lesions •• T-cell lymphoma •• Thymoma •• Gastric carcinoma, and •• CNS lymphoma from patients with no underlying immunodeficiency. PLASMA CELL DYSCRASIASIS: (USMLE FAVORITE) Multiple Myeloma •• Multiple myeloma: –– Mc symptomatic monoclonal gammopathy •• Russel bodies •• Flame cells •• Mott cells •• Dutcher bodies –– Pathological fractures with hypercalcemia with M spike with Bence jones proteins –– IL 6 associated with poor prognosis –– Bence Jones proteins are light chains –– ↑ Ca –– ↑ uric acid –– urea↑ Pathology 403 Multiple myeloma presents most often as multifocal destructive bone lesions throughout the skeletal system The bone resorption results from the secretion of cytokines (e.g. IL-1β, tumor necrosis factor, IL-6) by myeloma cells These cytokines stimulate production of another cytokine called RANK-ligand, which promotes the differentiation and activation of osteoclasts. Plasma cell lesions often lead to pathologic fractures, which occur most frequently in the vertebral column. The bone lesions usually appear radiographically as punched-out defects Microscopic examination of the marrow reveals an increased number of plasma cells With progressive disease, plasma cell infiltrations of soft tissues can be encountered in the spleen, liver, kidneys, lungs and lymph nodes. Renal involvement, generally called myeloma nephrosis, is a distinctive feature of multiple myeloma. Proteinaceous casts are prominent in the distal convoluted tubules and collecting ducts. Most of these casts are made-up of Bence-Jones proteins, but they may also contain complete immunoglobulins, Tamm-Horsfall protein and albumin Metastatic calcification as a result of bone resorption and hypercalcemia maybe encountered. •• Waldenstroms macroglobunemia: Hyperviscocity with ↑IgM •• Heavy chain disease •• Immune associated amyloidosis •• Monoclonal gamma pathy of undetermined significance (MGUS). Manifestations of myeloma WALDENSTROMS MACROGLOBULINEMIA USMLE Case Scenario A 88-year-old woman presented with a 7 month history of weakness, malaise, exertional dyspnoea and abdominal discomfort. She had experienced two epistaxis but did not have headaches, visual disturbances, weight loss, bone pain or recurrent infections. On examination she was pale, with moderate axillary and cervical lymphadenopathy. Her liver and spleen were enlarged by 5 cm On investigation, she had an ESR of 112 mm/h and hemoglobin of 108 g/l. The total serum protein was increased to 130 g/l. Protein electrophoresis and immunoelectrophoresis showed a dense paraprotein in the gamma region which proved to be an IgM of kappa type. ↑ IgM was noted. Electrophoresis of concentrated urine showed no free monoclonal light chains and there were no bone lesions on X-rays of her chest and skull Diagnosis would be most Likely NOT Myeloma BUT Waldenströms macroglobulinemia. USMLE Case Scenario A patient reports to a physician. His details are: A 77-year-old man residing in a suburban area of Mexico presented with Lumbago. He was mildly anemic but had no lymphadenopathy and no fever. There was no hepatosplenomegaly and no abdominal masses. On investigation, his hemoglobin was low (99 g/l). He had a normal differential white-cell count and a normal platelet count but his ESR was 96.6 mm/h. Total serum proteins were raised at 88.9 g/l (NR 65–75 g/l) and this resulted on the rouleaux seen on the blood film.His serum albumin, creatinine and urea were normal. He had a raised serum calcium level (3.2 mmol/l), a normal alkaline phosphatase. Serum protein electrophoresis revealed a monoclonal band in the gamma region. Skull X-ray Revealed Osteolytic Lesions. He was having bone pains before the diagnostic evaluation Likely Diagnosis is: Myeloma 404 USMLE Step 1 Platinum Notes Gamma Heavy Chain Disease: (Franklin’s Disease) •• Characterized by: lymphadenopathy, fever, anemia, malaise, hepatosplenomegaly and weakness •• Most distinctive symptom is palatal edema, resulting from node involvement of Waldeyer’s ring, and this may progress to produce respiratory compromise •• The diagnosis depends on the demonstration of an anomalous serum M component [often < 20 g/L (< 2 g/dL)] that reacts with anti-IgG but not anti-light chain reagents •• The M component is typically present in both serum and urine •• The patients may have thrombocytopenia, eosinophilia, and nondiagnostic bone marrow. Alpha Heavy Chain Disease: (Seligmann’s Disease) •• This is the most common of the heavy chain diseases •• It is closely related to a malignancy known as Mediterranean lymphoma, a disease that affects young people in parts of the world where intestinal parasites are common, such as the Mediterranean, Asia and South America •• The disease is characterized by an infiltration of the lamina propria of the small intestine with lymphoplasmacytoid cells that secrete truncated alpha chains •• The patients present with chronic diarrhea, weight loss, and malabsorption and have extensive mesenteric and para-aortic adenopathy. Respiratory tract involvement occurs rarely. Mu Heavy Chain Disease •• The secretion of isolated mu heavy chains into the serum appears to occur in a very rare subset of patients with chronic lymphocytic leukemia •• The only features that may distinguish patients with mu heavy chain disease are the presence of vacuoles in the malignant lymphocytes and the excretion of kappa light chains in the urine •• The tumor cells seem to have a defect in the assembly of light and heavy chains, because they appear to contain both in their cytoplasm. Types of plasma cell disorders Mantle Cell Lymphoma •• Makes up ~ 6% of all non-Hodgkin’s lymphomas •• These lymphomas have a characteristic chromosomal translocation, t(11;14) •• The tumor is a B-cell lymphoma •• Mantle cell lymphoma and small lymphocytic lymphoma share a characteristic expression of CD5 Present CD 20, CD 43 also •• Mantle cell lymphoma usually has a slightly indented nucleus •• Express bcl 1 protein called cyclin D •• The most common presentation of mantle cell lymphoma is with palpable lymphadenopathy, frequently accompanied by systemic symptoms. Pathology 405 Hairy Cell Leukemia: (USMLE Favorite) It is a rare disease that presents predominantly in older males B-cell neoplasm Typical presentation involves pancytopenia, although occasional patients will have a leukemic presentation Splenomegaly is usual The malignant cells appear to have ‘hairy’ projections on light and electron microscopy The cells are tartrate-resistant acid phosphatase positive (TRAP)+ Bone marrow is typically not able to be aspirated, and biopsy shows a pattern of fibrosis with diffuse infiltration by the malignant cells •• Patients with this disorder are prone to unusual infections including infection by Mycobacterium avium intracellulare, and vasculitic syndromes have been described •• Hairy cell leukemia is responsive to chemotherapy with interferon, pentostatin, or •• Cladribine being the usually preferred treatment. (DOC) •• •• •• •• •• •• •• Immunophenotyping USMLE Case Scenario A 44-year-old man was found to have an enlarged spleen on examination confirmed by USG Scan. Further Investigation showed normal hemoglobin, raised white-cell count (14.2 x 109/l). On the blood film these cells were mainly small mononuclear cells resembling lymphocytes, but had a ‘hairy’ appearance, had B-cell markers on their surface. The cells stain positively for tartrate-resistant acid phosphatase. (TRAP +) Most likely diagnosis is: Hairy cell leukemia Castleman’s Disease: (USMLE Favorite) •• Which can present with localized or disseminated lymphadenopathy; some patients have systemic symptoms –– The disseminated form is often accompanied by anemia and polyclonal hypergammaglobulinemia, and the condition seems to be related to an overproduction of interleukin 6, possibly produced by human herpesvirus 8. Rosai-Dorfman’s Disease: (USMLE Favorite) •• Sinus histiocytosis with massive lymphadenopathy (usually presents with bulky lymphadenopathy in children or young adults. The disease is usually nonprogressive and self-limited, but patients can manifest autoimmune hemolytic anemia. Mycosis Fungoides: (USMLE Favorite) •• Is also known as cutaneous T-cell lymphoma –– Mycosis fungoides is an indolent lymphoma with patients often having several years of eczematous or dermatitic skin lesions. The skin lesions progress from patch stage to plaque stage to cutaneous tumors. •• A particular syndrome in patients with this lymphoma involves erythroderma and circulating tumor cells. This is known as Sezary’s syndrome. 406 USMLE Step 1 Platinum Notes USMLE Case Scenario A 58-year-old man after repeated visits to a dermatologist is referred to a physician. He presented severe keratosis on the soles of his feet and the palms of his hands. On examination, he had characteristic exfoliative dermatitis with lymphadenopathy in the axilla and inguinal region. Investigation showed he had a ↑white-cell count (17 × 109/l). A blood film shows a considerable increase in the number of small cleaved lymphocytes, 90% of which were T-lymphocytes. Electron microscopy of buffy coat cells confirmed that the nuclei of these cells had multiple clefts. Most likely diagnosis is: 1. Mantle cell lymphoma 2. Glandular fever 3. Littoral cell angioma 4. Portal hypertension 5. Acute Leukemia 6. Sezary Syndrome 7. Follicular cell lymphoma 8. Hairy cell Leukemia 9. CML Ans. 6. Sezary Syndrome Hodgkin’s Disease: (USMLE Favorite) •• •• •• •• •• •• •• •• •• Bimodal age distribution. (late 20 and after 50 years) The commonest presentation of Hodgkins Lymphoma is painless enlargement of Lymph nodes Prognosis is directly proportional to number of RS cells and inversely proportional to number of lymphocytes Spread is to contigious to adjacent lymph nodes Extranodal spread is uncommon Malignant cell is Reed Stenberg Cell. (Owl eyed, bilobed nucleus with prominent nucleoli) RS cells are positive for CD 15 and CD 30. (except Lymphocyte Predominant) CNS involvement is uncommon. The feature for Hodgkin lymphoma is the Reed-Stenberg (RS) cell. This is a large cell (15–45 μm in diameter) with an enlarged multilobated nucleus, exceptionally prominent nucleoli, and abundant, usually slightly eosinophilic, cytoplasm •• Particularly characteristic are cells with two mirror-image nuclei or nuclear lobes, each containing a large (inclusion-like) acidophilic nucleolus surrounded by a distinctive clear zone; together they impart an owl-eye appearance. The nuclear membrane is distinct. •• As we will see, such ‘classic’ RS cells are common in the mixed-cellularity subtype, uncommon in the nodular sclerosis subtype and rare in the lymphocyte-predominance subtype; in these latter two subtypes, other characteristic RS cell variants predominate. •• •• •• •• Starry sky appearance: Burkitts Lymphoma Lacunar cells are seen in nodular sclerosis type of lymphoma Stomach is the mc site for extranodal NHL Hilar lymphadenopathy is a feature of nodular sclerosis type. Nodular Sclerosing HL •• •• •• •• Most common type Most common type in females Mediastinal involvement common Lacunar cell present. Antiphospholipid Syndrome: (USMLE Favorite) Arterial thromboses, recurrent fetal loss and thrombocytopenia •• It may occur as primary disorder or secondary to other conditions, most commonly systemic lupus erythematous (SLE) •• A key point for the exam is to appreciate that antiphospholipid syndrome causes a paradoxical rise in the APTT. This is due to an ex-vivo reaction of the lupus anticoagulant autoantibodies with phospholipids involved in the coagulation cascade. Pathology 407 Features: can be assymptomatic •• Venous/arterial thrombosis NOT BLEEDING •• Recurrent fetal loss (2nd trimester abortions) •• Live do reticularis •• Thrombocytopenia •• Prolonged APTT, Normal PT •• Other features: Preeclampsia •• Pulmonary hypertension. USMLE Case Scenario Lacunar cells are seen in: 1. Nodular sclerosing variant of Hodgkin’s disease 2. Burkitt’s lymphoma 3. Mixed cellularity Hodgkin’s 4. Normal Lymph nodes Ans. 1. Nodular sclerosing variant of Hodgkin’s disease Remember: (USMLE Favorites, Commonly asked) •• Faggot cell: It is a term used for cells normally found in the hypergranular form of acute promyelocytic leukemia. This term is applied to these blast cells because of the presence of numerous Auer rods in the cytoplasm. The accumulation of these Auer rods gives the appearance of a bundle of sticks, from which the cells are given their name. They are also seen in AML type M3 •• Dohle bodies: Irregular grayish or greenish inclusions in the peripheral cytoplasm of neutrophils. They are nuclear remnants that are often seen in association with toxic granules and vacuoles. They maybe present in association with burns, trauma, acute or systemic infections, and maybe present with exposure to cytotoxic agents, (i.e. chemotherapy). They may also be seen during a normal pregnancy •• Toxic Granulation: Large dark blue granules in the cytoplasm, associated with severe infection, chemical poisoning, and other toxic states •• Auer Bodies (Auer Rods): Unique, pink or red rod-shaped inclusions that are seen in very immature granulocytes (‘blasts’) in patients with acute non-lymphocytic leukemias (i.e. Acute Myeloid Leukemia; AML) •• Pelger-Huet Anamoly: Hereditary anomaly where neutrophils appear with fewer than two lobes. The nucleus is often in the shape of a peanut or dumbbell, or may consist of two lobes connected with an obvious filament •• Pseudo-Pelger-Huet anomaly: An acquired or pseudo-Pelger-Huet anomaly is seen in myelodysplastic disorders and following drug therapy, and may accompany leukemia and certain infections •• Alder-Reilly granules: Large, dark leukocyte granules that stain purple. They are indicative of mucopolysaccharidosis (an inherited enzyme deficiency disorder, Hurler’s and Hunter’s syndromes). CNS Pathology •• Macrophage of Brain is Microglia •• Complex granular corpuscles are produced by Microglia •• Cell not participating in repair after brain infarction is Fibroblast Bacterial Meningitis is Due to: (USMLE Favorite) •• •• •• •• In Neonates: Group B streptococci, E. Coli Infants: H Influenza Youg Adults: Nisseria meningitides Elderly: Strep Pneumoniae 408 USMLE Step 1 Platinum Notes ‘Bacterial Meningitis Score’ = determined that patients had a very low risk for bacterial meningitis if all of the following were absent: •• Positive CSF gram stain •• CSF absolute neutrophil count (ANC) of ≥ 1000 •• CSF protein of ≥ 80 mg/dL •• A circulating ANC of ≥ 10,000 cells/microliter (mcL) or a seizure as part of the presentation •• CSF findings in Tubercular meningitis: increased protein decreased sugar, increased lymphocytes •• CSF findings in pyogenic meningitis: increased protein, decreased sugar. •• In acute meningitis, an exudate is evident within the leptomeninges over the surface of the brain. The meningeal vessels are engorged and prominent •• From the areas of greatest accumulation, tracts of pus can be followed along blood vessels on the brain surface •• When the meningitis is fulminant, the inflammatory cells infiltrate the walls of the leptomeningeal veins and may spread into the substance of the brain (focal cerebritis), or the inflammation may extend to the ventricles, producing ventriculitis. •• Features of viral encephalitis: –– Perivascular cuffing –– Microglial nodules –– Neuron loss –– Neuronophagia •• Viral Meningitis (Aseptic) is most commonly due to Enteroviruses •• HSV Virus usually affects Temporal Lobes •• Negri bodies in Hippocampus in Rabies. Tuberculous Meningitis •• Usually presents with generalized symptoms of headache, malaise, mental confusion and vomiting •• There is only a moderate increase in cellularity of the CSF (pleiocytosis) made-up of mononuclear cells, or a mixture of polymorphonuclear and mononuclear cells; the protein level is elevated •• May also result in a well-circumscribed intraparenchymal mass (tuberculoma), which maybe associated with meningitis •• Chronic tuberculous meningitis is a cause of arachnoid fibrosis, which may produce hydrocephalus •• There maybe discrete white granules scattered over the leptomeninges •• The infection may spread through the CSF to the choroid plexuses and ependymal surface •• On microscopic examination there are mixtures of lymphocytes, plasma cells and macrophages. Florid cases show wellformed granulomas, often with caseous necrosis and giant cells, similar to the lesions of tuberculosis elsewhere in the body. Similar findings are observed in tuberculomas within the brain. Neurosyphilis: (USMLE Favorite) •• Neurosyphilis is a tertiary stage of syphilis •• The major manifestation is meningeal, called meningovascular neurosyphilis •• Tabes dorsalis is another form of neurosyphilis, resulting from ‘damage to the sensory nerves in the dorsal roots’ producing impaired joint position sense and resultant ataxia (locomotor ataxia); loss of pain sensation, leading to skin and joint damage (Charcot joints) •• Other sensory disturbances, particularly characteristic ‘lightning pains’ and absence of deep tendon reflexes •• Cerebral gummas (mass lesions rich in plasma cells) may also occur in relation to meninges and extend into the brain. HIV •• Cerebral involvement: AIDS dementia complex •• Multinucleate giant cells •• Vacuolar myelopathy. Pathology 409 Progressive Multifocal Leukoencephalopathy: (USMLE Favorite) •• It is due to Polyoma JC Virus, a polyomavirus •• The virus preferentially infects oligodendrocytes, so demyelination is its principal pathologic effect •• The disease occurs almost invariably in immunosuppressed individuals in various clinical settings, including chronic lymphoproliferative or myeloproliferative illnesses, immunosuppressive therapy and AIDS •• Patients develop focal and relentlessly progressive neurologic symptoms and signs, and imaging studies show extensive, often multifocal, ring-enhancing lesions in the hemispheric or cerebellar white matter •• Demyelination and Astrogliosis are a feature •• The lesions consist of patches of irregular, ill-defined destruction of the white matter that enlarge as the disease progresses. Each lesion is an area of demyelination, in the center of which are scattered lipid-laden macrophages and a reduced number of axons. At the edge of the lesion are greatly enlarged oligodendrocyte nuclei whose chromatin is replaced by glassy amphophilic viral inclusion. Prion Disease: (USMLE Favorite) •• This group of diseases includes sporadic, familial, iatrogenic and variant forms of Creutzfeldt-Jakob disease (CJD) •• Several animal diseases from this group are also known, including scrapie in sheep and goats and bovine spongiform encephalopathy in cattle (‘mad cow’ disease) •• All these disorders are associated with abnormal forms of a normal cellular protein, termed prion protein (PrPc) •• The abnormal form of this protein can act as an infectious agent, since it propagates itself and injures the cells in which it is present •• Most cases of prion disease are either sporadic or associated with mutations in the gene that encodes PrPc •• The unique pathogenesis of prion diseases is related to changes in the conformation of PrP from its native PrPc form to an abnormal configuration called either PrPsc (for scrapie) or PrPres (for protease resistant) •• In the abnormal conformation, the prion protein becomes resistant to protease digestion. Once formed, PrPsc can then initiate comparable transformation of other PrPc molecules. The infectious nature of PrPsc protein comes from this ability to propagate the pathologic conformational change. Creutz Feldt Jackobson Disease: (USMLE Favorite) •• •• •• •• Manifests clinically as a rapidly progressive dementia Most common infectious prion disease in humans On light microscopy, the pathologic hallmarks of CJD are spongiform degeneration and astrogliosis The lack of an inflammatory response in CJD and other prion diseases is an important pathologic feature of these degenerative disorders •• Spongiform degeneration is characterized by many 1- to 5-um vacuoles in the neuropil between nerve cell bodies •• In (New variant) nvCJD, a characteristic feature is the presence of ‘florid plaques.’ These are composed of a central core of PrP amyloid surrounded by vacuoles in a pattern suggesting petals on a flower. Cerebral Toxoplasmosis: (USMLE Favorite) •• Cerebral toxoplasmosis-infection with the protozoan Toxoplasma gondii •• Seen in AIDS Patients •• Computed tomography and magnetic resonance imaging studies can show multiple ring-enhancing lesions; however, this radiographic appearance is not pathognomonic •• Acute lesions consist of central foci of necrosis with variable petechiae surrounded by acute and chronic inflammation, macrophage infiltration and vascular proliferation. Both free tachyzoites and encysted bradyzoites maybe found at the periphery of the necrotic foci. Cysticercosis: (USMLE Favorite) •• Cysticercosis is the consequence of an end-stage infection by the tapeworm Tenia solium •• These cysts can be found throughout the body, although they are common within the brain and subarachnoid space •• They typically present as a mass lesion and can cause seizures. Symptoms can intensify when the organism dies within the cyst, as happens after therapy •• The organism is encysted within a smooth lining; around the cyst, there is often a marked degree of gliosis. 410 USMLE Step 1 Platinum Notes Diffuse Axonal Injury •• Deep white matter lesion consists of widespread acute disruption, or ‘shearing,’ of axons at the time of impact •• Pathologically there are small areas of tissue disruption in the corpus callosum and dorsolateral pons •• The presence of widespread axonal damage of both hemispheres, a state called Diffuse axonal injury, has been proposed as the explanation of persistent coma or vegetative state, but small ischemic-hemorrhagic lesions in the midbrain and low diencephalon are as often the cause •• Only severe shearing lesions that contain blood are visualized by CT, usually in the corpus callosum and centrum semi ovale however, within days of the injury •• MRI scan demonstrates such lesions throughout the white matter, especially with the use of gradient echo MRI sequences. CNS TUMORS: (GEMS ABOUT TUMORS) (NEVER FORGET) High Yield USMLE Points Astrocytoma Oligodendroglioma Ependymoma •• •• •• •• •• •• •• •• •• Origin from oligodendrocytes •• Fried Egg Appearance •• Chicken wire pattern of capillaries •• Slow growing •• •• •• •• Schwanomma Cranipharyngioma •• •• •• •• •• •• •• •• From Odontogenic epithelium •• Affects young/children •• Calcium deposits seen Origin from astrocytes Most common primary brain tumor in adults GFAP Positive Glioblastoma multi forme is grade IV astrocytoma Crosses midline (Butterfly Glioma) Pseudopallisading Necrosis Common in white matter Meningoma •• •• •• •• •• Most common benign brain tumor Origin from arachnoid cells Whorled pattern Psommoma bodies Good prognosis From schwann cells Eighth cranial nerve At CP angle Antoni A and Antoni B areas Verocay Bodies S 100 positivity Bilateral → NF 2 Medulloblastomas: (USMLE Favorite) •• •• •• •• •• •• Are primitive neuroectodermal tumors (PNET) Arise in cerebellar vermis (midline) Responsive to radiotherapy These highly cellular malignant tumors are thought to arise from neural precursor cells They are the most frequent malignant brain tumor of children These tumors frequently disseminate along CSF pathways. Remember •• Mc primary brain tumor: glioma •• Mc brain tumor in adults: astrocytoma •• Mc type of glial tumor: astrocytoma •• Mc site of brain tumors in children: infratentorial (cerebellar) •• Mc site of brain tumor in neonates: supratentorial •• Mc posterior fossa tumor in children: cerebellar astrocytoma •• Second mc posterior fossa tumor in children. Medulloblastoma Usually in ventricular system Ependymal rosettes Perivascular pseudorossettes Often causes hydrocephalus Pathology 411 Features not to be forgotten •• •• •• •• •• •• Pseudorosettes: Neuroblastoma Enamel like structures: Craniopharyngioma Glial fibrillary proteins: Astrocytoma Verocay bodies: Schwannoma Butterfly tumor: Glioblastoma multi forme Fried egg appearance: Oligiodendroglioma USMLE Case Scenario A 45-year-old male from Kansas develops a gelatinous, well-circumscribed mass in her right cerebral hemisphere. Biopsy of the mass reveals neoplastic cells with ‘fried egg’ morphology. Which of the following tumors does these patients most likely have? 1. Choroid plexus papilloma 2. Ependymoma 3. Glioblastoma multiforme 4. Oligodendroglioma 5. Medulloblastoma 6. Hemangioma Ans. 4. Oligodendroglioma USMLE Case Scenario Rosenthal fibers are corkscrew-shaped, intensely eosinophilic structures deriving from accumulation of and alpha; and beta;crystalline within astrocytic processes. They are usually found in: 1. Ependymoma 2. Glioblastoma multiforme 3. Medulloblastoma 4. Pilocytic astrocytoma Ans. 4. Pilocytic astrocytoma High Yield USMLE Pointson Commonly asked Diseases Alzhiemers disease Picks Disease Lewy Body Disease Parkinsonism •• Neurofibrillary tangles are intracytoplasmic filamentous inclusions found in Alzheimer disease and, to a lesser extent, in normal aging brains •• Granulovacuolar degeneration •• Hirano Bodies: They are Specific protein deposits associated with AGE (Advance Glycosylation End products) localized within soma of neurons •• Amyloid Plaques: They represent fragmented accumulations of proteins which are normally broken down but accumulate in Alzheimer’s disease •• Alzhiemers Cells (Special cells) •• Neurofibrillary tangles: are insoluble twisted fibrils composed of Tau proteins Swollen or ballooned neurons contain silverstaining cytoplasmic inclusions referred to as Pick bodies •• Walnut brain •• Knife blade atrophy •• Balloning degeneration Lewy bodies are intraneuronal cytoplasmic inclusions that stain with periodic acid-Schiff and ubiquitin. They contain epitopes recognized by antibodies against phosphorylated and nonphosphorylated neurofilament proteins, ubiquitin, and a presynaptic protein called α synuclein Lewy bodies are filamentous inclusions that appear brightly eosinophilic on hematoxylin and eosin stain and accumulate in the cytoplasm of dopaminergic neurons in the substantia nigra in Parkinson disease. 412 USMLE Step 1 Platinum Notes Marinesco bodies are also present in the dopaminergic neurons of substantia nigra. They are intranuclear. These inclusions are found occasionally in normal brains, and their significance is unknown. USMLE Case Scenario Intracytoplasmic spherules composed of paired helical filaments stained with silver stains are seen infrontallobe with severe neuronal loss and astrocytosis. The condition most likely is: 1. HSV Encephalitis 2. Picks disease 3. Alzhiemers disease 4. Parkinsons disease Ans. 2. Picks Disease (Pick’s bodies) USMLE Case Scenario Methyl phenyl tetrahydropyridine is taken by a 25-year-old male from Calfornia complaining of uncontrollable shaking in his hands. Most likely pathology he might have as a result of above mentioned features is: 1. Lewy bodies 2. Picks bodies 3. Negri bodies 4. Neurofibrillary tangles Ans. 1. Lewy bodies The patient has Parkinsonism induced methyl phenyl tetrahydropyridine (MPTP), a meperidine analog. USMLE Case Scenario Degenerated neurofilaments seen in patients with Alzheimer’s disease are: 1. Hirano bodies 2. Lipofuscin granules 3. Neurofibrillary tangles 4. Amyloid plaques Ans. 3. Neurofibrillary tangles USMLE Case Scenario A dementing disorder is characterized clinically by progressive loss of memory, parkinsonism, and visual/auditory hallucinations, and pathologically by round intracytoplasmic neuronal inclusions in the substantia nigra and neocortex. The clinical features are suggestive of: 1. HIV encephalitis 2. Lewy body disease 3. Shy dragger syndrome 4. Parkinsonism Ans. 2. Lewy body disease Abnormal Protein Aggregates •• •• •• •• •• •• Alzhiemers disease: A beta, tau Picks disease: tau Parkinsons disease, multiple systems atrophy: alpha synuclein Huntigtons disease: huntingtin Spinocerebellar ataxia: ataxin Prion disease: prion protein Pathology 413 Berry Aneurysm •• •• •• •• •• Thin walled Saccular out pouching of Tunica intima and adventitia Most frequent cause of SAH Most frequent site: Anterior circle of willis Least frequent site: posterior circulation Association with: –– Marfans syndrome –– Ehler danhlos Syndrome –– Adult Polycystic Kidney Disease. Multiple Sclerosis Multiple sclerosis (MS) is characterized by •• A relapsing-remitting or progressive course and •• A pathologic triad of CNS inflammation, demyelination and gliosis (scarring) MS derives its name from the multiple scarred areas visible on macroscopic examination of the brain. These lesions, termed plaques, are sharply demarcated gray or pink areas easily distinguished from surrounding white matter •• MS is a white matter disease; abnormalities on the surface of the brain are usually restricted to those regions where myelinated fiber tracts course superficially (brain stem and spinal cord). Affected areas show multiple, well-circumscribed, slightly depressed, glassy, gray-tan, irregularly shaped lesions, termed plaques •• The acute MS lesion, rarely found at autopsy, consists of perivenular cuffing by inflammatory mononuclear cells, predominantly T-lymphocytes and macrophages, which also infiltrate white matter tissue and appear to orchestrate demyelination. At sites of inflammation, the blood-brain barrier is disrupted but the vessel wall itself is preserved, distinguishing the MS lesion from vasculitis •• The correspondence between number and size of plaques (‘Plaque burden’) and the severity of clinical symptoms is imprecise •• Axonal loss and cavitation are particularly prominent in the subtype of MS known as ‘Neuromyelitis Optica’ or ‘Devic’s syndrome’. CSF analysis in Multiple Sclerosis: USMLE asks presentations with Lab values •• IgG concentration↑ •• Albumin concentration↑ •• IgG/albumin ratio↑ •• IgG index↑ •• Isoelectric focusing Oligoclonal bands present USMLE Case Scenario A 44-year-old woman concerned about her disease reports and presents with unusual feelings like tingling, numbness and clumsiness of both hands for 2 week. Earlier she had experienced paraesthesia in the feet. On neurological examination, she had absent abdominal reflexes with brisk tendon jerks and bilateral extensor plantar responses. Blood investigations were normal, including hemoglobin, white-cell count and differential, erythrocyte sedimentation rate, vitamin B12 and folate levels and syphilis serology. Oligoclonal IgG bands were found in CSF. The most likely diagnosis is: 414 USMLE Step 1 Platinum Notes 1. SAH 2. Gullian Barre Syndrome 3. Multiple sclerosis 4. Subacute degeneration of cord 5. Hysteria 6. Empty sella syndrome Ans. 3. Multiple Sclerosis BREAST PATHOLOGY: (USMLE FAVORITE) High Yield USMLE Points •• •• •• •• •• •• •• •• •• •• •• •• •• •• Mc disorder of breast Mc tumor of breast Mc carcinoma of breast Mc bilateral tumor Mc involved Lymph nodes are Mc cause of breast discharge Mc cause of bloody discharge Mc site of metastasis of breast Ca Mc site of breast Ca FIRST INVESTIGATION FOR BREAST LUMP BEST INVESTIGATION FOR BREAST LUMP BRCA 1 gene is located on chromosome BRCA 2 gene is located on chromosome Marker for breast cancer •• •• •• •• •• •• •• •• •• •• •• •• •• •• Fibroadenosis Fibroadenoma Ductal/Schirrous carcinoma Lobular carcinoma of breast Axillary group Duct ectasia Duct pappiloma Bone Upper outer quadrant FNAC BIOPSY 17 13 CA 15-3 Risk Factors for Breast Cancer •• •• •• •• •• •• •• •• •• •• •• •• •• Race: White females Age: elderly Family history + Relatives (true) Nonbreastfeeding mothers ↑Fatty food intake Nulliparity BRCA1 and BRCA2 mutations Cancer in other breast Mammary dysplasia/Atypical hyperplasia/Sclerosing adenosis Early menarche Late menopause Late first pregnancy Epithelial hyperplasia: (USMLE Favorite) •• Histologically, there is an almost infinite spectrum of proliferative alterations. The ducts, ductules, or lobules maybe filled with orderly cuboidal cells, within which small gland patterns can be discerned (called fenestrations) •• Sometimes the proliferating epithelium projects in multiple small papillary excrescences into the ductal lumen (ductal papillomatosis). The degree of hyperplasia, manifested in part by the number of layers of intraductal epithelial proliferation, can be mild, moderate, or severe •• In some instances the hyperplastic cells become monomorphic with complex architectural patterns •• Atypical lobular hyperplasia is the term used to describe hyperplasias that cytologically resemble lobular carcinoma in situ. Atypical lobular hyperplasia is associated with an increased risk of invasive carcinoma. Pathology 415 Fibrocystic Changes •• Classified as nonproliferative cystic lesions or proliferative lesions •• Proliferative lesions include epithelial proliferations of ducts and lobules, with or without features of atypia, and adenosis, the proliferation of terminal ducts, sometimes associated with fibrosis (sclerosing adenosis) •• Atypical hyperplasia of ductular or lobular epithelium is associated with a five-fold increase in the risk of developing carcinoma; when associated with a family history of breast carcinoma, the risk is 10-fold. Abscesses •• Staphylococcal infections induce single or multiple abscesses accompanied by the typical clinical acute inflammatory changes •• They are usually small, but when sufficiently large they may heal with residual foci of scarring that are palpable as localized areas of induration •• Streptococcal infections generally spread throughout the entire breast, causing pain, marked swelling and breast tenderness. Galactocele: (USMLE Favorite) It is a milk-filled cyst Round, well circumscribed and easily movable within the breast Usually occurs after the cessation of lactation or when feeding frequency has been curtailed significantly Inspissated milk within a large lactiferous duct is responsible The tumor is usually located in the central portion of the breast or under the nipple Needle aspiration produces thick, creamy material that maybe tinged dark-green or brown. Although it appears purulent, the fluid is sterile •• The treatment is needle aspiration. Withdrawal of thick milky secretion confirms the diagnosis •• Operation is reserved for those cysts that cannot be aspirated or that become super infected. •• •• •• •• •• •• MAMMARY DUCT ECTASIA: (PERIDUCTAL OR PLASMA CELL MASTITIS) (USMLE Favorite) •• It is a nonbacterial chronic inflammation of the breast associated with inspissation of breast secretions in the main excretory ducts •• Ductal dilation with ductal rupture leads to reactive changes in the surrounding breast substance •• It is an uncommon condition, usually encountered in women in their 40s and 50s who have borne children •• Usually the inflammatory changes are confined to an area drained by one or several of the major excretory ducts of the nipple. Fibroadenoma •• It is by the most common benign neoplasm of the female breast •• Increase in estrogen activity is thought to contribute to its development, and indeed similar lesions may appear with fibrocystic changes (fibroadenomatoid changes) •• Fibroadenomas usually appear in young women •• The peak incidence is in the third decade of life •• The fibroadenoma occurs as a discrete, usually solitary, freely movable nodule, 1 to 10 cm in diameter Intraductal Papilloma •• It is a neoplastic papillary growth within a duct •• Most lesions are solitary, found within the principal lactiferous ducts or sinuses •• They present clinically as a result of (1) the appearance of serous or bloody nipple discharge (2) the presence of a small subareolar tumor a few millimeters in diameter, or (3) rarely, nipple retraction 416 USMLE Step 1 Platinum Notes Breast cancers are classified into those that have not penetrated the limiting basement membrane (noninvasive) and those that have (invasive). The chief forms of carcinoma of the breast are classified as follows: Noninvasive •• Ductal carcinoma in situ (DCIS; intraductal carcinoma) •• Lobular carcinoma in situ (LCIS) Invasive (infiltrating) •• Invasive ductal carcinoma (‘not otherwise specified’) •• Invasive lobular carcinoma •• Medullary carcinoma •• Colloid carcinoma (mucinous carcinoma) •• Tubular carcinoma •• Other types Of these, invasive ductal carcinoma is by far the most common. Because it usually has an abundant fibrous stroma, it is also referred to as scirrhous carcinoma. NONINVASIVE (IN SITU) CARCINOMA (INCLUDING PAGET DISEASE) (USMLE Favorite) •• There are two types of noninvasive breast carcinoma: DCIS and LCIS •• Morphologic studies have shown that both usually arise from the ‘Terminal duct lobular unit’ •• DCIS tends to fill, distort and unfold involved lobules and thus appears to involve duct like spaces •• LCIS usually expands but does not alter the underlying lobular architecture •• Both are confined by a basement membrane and do not invade into stroma or lymphovascular channels •• DCIS has a wide variety of histologic appearances •• Architectural patterns are often mixed and include. •• •• •• •• •• •• Solid Comedo Cribriform Papillary Micropapillary and Clinging types Paget Disease of the Nipple: (USMLE Favorite) •• It is caused by the extension of DCIS up to the lactiferous ducts and into the contiguous skin of the nipple •• The malignant cells disrupt the normal epidermal barrier, which allows extracellular fluid to be extruded onto the surface •• The clinical appearance is usually of a unilateral crusting exudate over the nipple and areolar skin. In about half of cases, an underlying invasive carcinoma will also be present •• Prognosis is based on the underlying carcinoma and is not worsened by the presence of Paget disease. LCIS, like the low-nuclear-grade DCIS and unlike high-nuclear-grade DCIS, has a uniform appearance. Carcinomas of ‘no special type’ or ‘not otherwise specified’ are synonyms for ductal carcinomas. •• The majority (70 to 80%) of cancers fall into this group •• This type of cancer is usually associated with DCIS, but rarely LCIS is present •• Most ductal carcinomas produce a desmoplastic response, which replaces normal breast fat (resulting in a mammographic density) and forms a hard, palpable mass (Advanced cancers may cause dimpling of the skin, retraction of the nipple, or fixation to the chest wall. About two-thirds express estrogen or progestagen receptors, and about one-third overexpress HER2/NEU. Pathology 417 Inflammatory Carcinoma: (USMLE Favorite) •• It is defined by the clinical presentation of an enlarged, swollen, erythematous breast, usually without a palpable mass •• The underlying carcinoma is generally poorly differentiated and diffusely invades the breast parenchyma. The blockage of numerous dermal lymphatic spaces by carcinoma results in the clinical appearance •• True inflammation is minimal or absent •• Most of these tumors have distant metastases, and the prognosis is extremely poor. Invasive Lobular Carcinoma •• •• •• •• Consists of cells morphologically identical to the cells of LCIS Two-thirds of the cases are associated with adjacent LCIS The cells invade individually into stroma and are often aligned in strands or chains More frequently than ductal carcinomas, metastasize to cerebrospinal fluid, serosal surfaces, gastrointestinal tract, ovary and uterus, and bone marrow •• Lobular carcinomas are also more frequently multicentric and bilateral (10 to 20%) •• Almost all of these carcinomas express hormone receptors, but HER2/NEU overexpression is very rare or absent. Medullary Carcinoma •• It is a rare subtype •• Occur with increased frequency in women with BRCA1 mutations •• These carcinomas uniformly lack hormone receptors and do not overexpress HER2/NEU Colloid: (Mucinous) Carcinoma •• It is a rare subtype •• Tumor cells produce abundant quantities of extracellular mucin that dissects into the surrounding stroma •• Grossly the tumors are usually soft and gelatinous. Most express hormone receptors and rare examples may overexpress HER2/ NEU. Tubular Carcinomas: (USMLE Favorite) •• Rarely present as palpable masses but account for 10% of invasive carcinomas smaller than 1 cm found with mammographic screening •• They usually present as irregular mammographic densities •• Microscopically, the carcinomas consist of well-formed tubules with low-grade nuclei •• Lymph node metastases are rare and prognosis is excellent •• Virtually all tubular carcinomas express hormone receptors, but overexpression of HER2/NEU is highly unusual Phyllodes Tumor: (USMLE Favorite) •• •• •• •• •• •• •• •• •• •• •• Serocystic disease of Broide or Cystosarcoma Phyllodes Name is misnomer as it is rarely cystic or rarely develops into sarcoma Phyllodes: Leaf. It is a benign breast tumor. It is a stromal breast tumor They presents as a large, massive tumor with uneven bosselated surface They are however mobile and resemble fibroadenoma They account for less than 1% of all breast neoplasms This is predominantly a tumor of adult women, with very few examples reported in adolescents Patients typically present with a firm, palpable mass These tumors are very fast growing, and can increase in size in just a few weeks Occurrence is most common between the ages of 40 and 50, prior to the menopause The common treatment for phyllodes is wide local excision. Other than surgery, there is no cure for phyllodes, as chemotherapy and radiation therapy are not effective. 418 USMLE Step 1 Platinum Notes FEATURES COMMON TO ALL INVASIVE CANCER: (USMLE FAVORITE) These Include •• Tendency to become adherent to the pectoral muscles or deep fascia of the chest wall, with consequent fixation of the lesion •• As well as adherence to the overlying skin, with retraction or dimpling of the skin or nipple. The latter is an important sign, because it maybe the first indication of a lesion, observed by the woman herself during self-examination •• Involvement of the lymphatic pathways may cause localized lymphedema. In these cases the skin becomes thickened around exaggerated hair follicles, a change known as peau d’orange. Ovarian Tumors Primary Epithelial Tumors 80% Nonepithelial Tumors •• Mucinous Cystadenoma or Cystadenocarcinoma •• Serous Cystadenoma or Cystadenocarcinoma •• Endometrioma or Endometriod Carcinoma •• Clear cell carcinoma •• Brenner Tumor •• •• •• •• •• Fibroma Dysgerminoma Teratoma Gonadoblastoma Yolk-sac tumor Hormone-Producing Tumors •• Estrogen-producing –– Granulosa cell tumor –– Thecoma •• Androgen-producing –– Sertoli-Leydig cell tumor –– (Arrhenoblastoma) –– Hilar cell tumor –– Lipoid cell tumor (Ovoblastoma, Musculinovoblastoma, Adrenal-like tumor) •• OTHERS –– Carcinoid (Seratonin-producing) –– Thyroid tumor (Struma Ovarii) –– Choriocarcinoma of the ovary High Yield USMLE Points •• •• •• •• •• •• •• •• •• Call Exner Bodies Renkies Crystals Signet ring cells Schiller Duval bodies Psommoma bodies Meigs syndrome Pseudomeigs syndrome Walthard cell nest Rokintansky bodies •• •• •• •• •• •• •• •• •• Granulosa cell tumor Hilus cell tumor Krukenbergs tumor Endodermal sinus tumor Pappillary Serous tumors Fibroma ovary Brenner cell tumor Brenner tumor Teratoma Remember •• Rupture of mucinous tumors may result in mucinous deposits in the peritoneum; however, these typically do not result in longterm growth of tumor in the peritoneum. Implantation of mucinous tumor cells in the peritoneum with production of copious amounts of mucin is called pseudomyxoma peritonei •• They are caused by metastasis from the gastrointestinal tract, primarily the appendix •• Metastasis of mucinous tumor of the gastrointestinal tract to the ovaries (the so-called Krukenberg tumor) may also mimic an ovarian primary tumor. Testicular Cancer: (USMLE Favorite) •• Primary germ cell tumors (GCTs) of the testis constitute 95% of all testicular neoplasms. Infrequently, GCTs arise from an extragonadal site, including the: –– Mediastinum –– Retroperitoneum and very rarely –– Pineal gland. (Remember the sites) Pathology •• •• •• •• •• •• •• •• •• 419 Cryptorchidism is associated with a several fold higher risk of GCT Abdominal cryptorchid testes are at a higher risk than inguinal cryptorchid testes Orchiopexy should be performed before puberty, if possible Testicular feminization syndromes increase the risk of testicular GCT and Klinefelter’s syndrome is associated with mediastinal GCT An isochromosome of the short arm of chromosome 12 is pathognomonic for GCT A painless testicular mass is pathognomonic for a testicular malignancy Commonest testicular malignancy is: Seminoma Most malignant testicular cancer is: Choriocarcinoma. Seminoma •• •• •• •• •• Has a median age in the fourth decade Generally follows a more indolent clinical course Seminomas are radiosensitive Seminomas metastasize by lymphatics Seminomas correspond to dysgerminomas of ovary They are histologically identical to ovarian dysgerminomas and to germinomas occurring in the central nervous system and other extragonadal sites. Seminomas are large, soft, well-demarcated, usually homogeneous, gray-white tumors that bulge from the cut surface of the affected testis. Microscopically, seminomas are composed of large, uniform cells with distinct cell borders, clear, glycogen-rich cytoplasm, and round nuclei with conspicuous nucleoli. The cells are often arrayed in small lobules with intervening fibrous septa. A lymphocytic infiltrate is usually present and may, on occasion, overshadow the neoplastic cells. Neoplasms of the Peripheral Nervous System and Familial Tumor Syndromes Neoplasms of the peripheral nervous system may originate from •• Schwann cells •• Perineurial cells and •• Fibroblasts •• They include •• Schwannoma •• Neurofibroma and •• Malignant peripheral nerve sheat tumor. Familial Tumor Syndromes Include •• Neurofibromatosis •• Tuberous sclerosis and •• von Hippel-Lindau disease Miscellaneous Hot Topics Asked in Previous Examinations Neurofibromatosis Type 1 (von Recklinghausen’s Disease) NEUROFIBROMATOSIS NF1 •• Cutaneous neurofibromas, pigmented lesions of the skin called cafe au lait spots, freckling in nonsun exposed areas such as the axilla, hamartomas of the iris termed Lisch nodules, and pseudoarthrosis of the tibia •• Neurofibromas are benign peripheral nerve tumors composed of proliferating Schwann cells and fibroblasts. They present as multiple, palpable, rubbery, cutaneous tumors •• Mutation of the NF1 gene on chromosome 17 causes von Recklinghausen’s disease •• The NF1 gene is a tumor suppressor gene; it encodes a protein, neurofibromin, which modulates signal transduction through the ras GTPase pathway. 420 USMLE Step 1 Platinum Notes •• Patients with NF1 are at increased risk of developing nervous system neoplasms, including plexiform neurofibromas, optic gliomas, ependymomas, meningiomas, astrocytomas and pheochromocytomas •• Neurofibromas may undergo secondary malignant degeneration and become sarcomas •• Optic nerve glioma is the one of the mc tumor associated with NF1. Neurofibromatosis Type 2 NF2 (USMLE Favorite) •• It is characterized by the development of bilateral vestibular schwannomas in 90% of individuals who inherit the gene •• Patients with NF2 also have a predisposition for the development of meningiomas, gliomas and schwannomas of cranial and spinal nerves •• In addition, a characteristic type of cataract, juvenile posterior subcapsular lenticular opacity, occurs in NF2. Multiple cafe au lait spots and peripheral neurofibromas occur rarely •• In patients with NF2, vestibular schwannomas usually present with progressive unilateral deafness early in the third decade of life •• Bilateral vestibular schwannomas are generally detectable by MRI •• The NF2 gene on chromosome 22q codes for a protein called neurofibromin 2, schwannomin, or merlin. Tuberous Sclerosis (Bourneville’s Disease) (USMLE Favorite) •• Is characterized by cutaneous lesions, seizures and mental retardation •• The cutaneous lesions include –– Adenoma sebaceum (facial angiofibromas) –– Ash leaf-shaped hypopigmented macules (best seen under ultraviolet illumination with a Wood’s lamp) –– Shagreen patches (yellowish thickenings of the skin over the lumbosacral region of the back) and –– Depigmented nevi •• On neuroimaging studies, the presence of subependymal nodules, which maybe calcified, is characteristic •• Patients inheriting the tuberous sclerosis gene are at increased risk of developing ependymomas and childhood astrocytomas, of which 90% are subependymal giant cell astrocytomas •• Rhabdomyomas of the myocardium and angiomyomas of the kidney, liver, adrenals and pancreas may also occur Subependymal giant cell astrocytoma is a peculiar astrocytic tumor that grows from the walls of the lateral ventricles. It is pathognomonic of tuberous sclerosis, which is caused by mutations of TS1 or TS2 genes. Tuberous sclerosis manifests with multiple hamartomatous lesions in the skin, CNS, and visceral organs. Cortical tubers are malformed (hamartomatous) nodules of the cortex, probably resulting from faulty cortical development. USMLE Favorite Pathology 421 VON HIPPEL-LINDAU SYNDROME (USMLE Favorite) •• This syndrome consists of retinal, cerebellar and spinal hemangioblastomas, which are slowly growing cystic tumors –– Hypernephroma –– Renal cell carcinoma –– Pheochromocytoma, and –– Cysts of the kidneys, pancreas, epididymis, or liver may also occur •• Erythropoietin production by hemangioblastomas may result in polycythemia •• The von Hippel-Lindau (VHL) is a tumor suppressor gene on chromosome 3p. Sturge Weber Syndrome: (USMLE Favorite) •• •• •• •• •• Port wine stain Cavernous hemangioma Seizures Hemiatrophy of cerebral cortex Rail road calcifications of cerebral cortex. Appendegeal Tumors •• •• •• •• •• •• •• •• •• Adenexal or Appendegeal tumors arise from cutaneous appendages They may serve as markers for internal malignancies They are mostly in the form of solitary or multiple nodules/papules Eccrine porcoma is seen on palms and soles Cylindroma or turban tumor is seen on forehead and scalp Syringomas are seen in vicinity of lower eyelids Trichoepitheliomas and Tricolemmoma arise from hair follicles and are seen on face, scalp, neck and upper trunk Sebaceous adenoma arises from sebaceous glands Brookes tumor from hair follicles. •• Benign fibrous histiocytoma on the other hand is a benign dermal neoplasm. •• Most common presentation is a dermatofibroma. •• They are most common in adults with indolent behaviour and appear as tan to brown firm papules. USMLE Case Scenario A 3-year-old child with mental retardation, seizures and facial angiofibromas develops repeated episodes of syncope. Echocardiogram reveals a mass in the left ventricle producing intermittent obstruction. Pathologic examination of the resected mass demonstrates a cardiac rhabdomyoma. Which of the following lesions would this patient most likely also have? 1. Acoustic neuromas 2. Berry aneurysm 3. Cortical tubers 4. Neurofibromas Ans. 3. Cortical tubers (The disease is tuberous sclerosis) USMLE Case Scenario Ophthalmoscopic examination of a 7-year-old child from Washington DC demonstrates a retinal angioma. This finding should raise the possibility of which of the following syndromes? 1. Neurofibromatosis type I 2. Neurofibromatosis type II 422 USMLE Step 1 Platinum Notes 3. Tuberous sclerosis 4. von Hippel-Lindau disease Ans. 4. von Hippel-Lindau disease USMLE Case Scenario A 22-year-old male from New York presents with adenoma sebaceum of the skin and cortical tubers. The person is most probably having: 1. Neurofibromatosis type I 2. Neurofibromatosis type II 3. Tuberous sclerosis 4. von Hippel-Lindau disease Ans. 3. Tuberous sclerosis Important Pathological Eponyms Related to Fruits/Vegetables •• •• •• •• •• •• •• •• •• •• •• •• •• Potato Nodes: Sarcoidosis Potato Tumor: Chemodectoma Potato/oyster ovary: PCOD Strawberry Cervix: Trichomonas Vaginalis Strawberry tongue: Scarlet fever Strawberry hemangioma: Nevus vasculosus Barley colored fluid cyst: Spermatocele Aple jelly nodules: Lupus Vulgaris Apple core lesion: Ca Colon Raspberry tumor: Umbilical adenoma Raspberry thorn sign: Crohns disease Peau de Orange appearance of breast: Breast Cancer Orange Tonsils : Tangiers disease Antibodies and Diseases: (USMLE Favorite) Antibody Target Disease •• Nicotinic acetyl choline receptor •• Myasthenia Gravis •• Intrinsic factor •• Pernicious Anemia •• Proiteinase 3 (ANCA) •• Wegners Granulomatosis •• Alpha 3 chain of Collagen Type IV •• Good Pasteurs Syndrome •• Thyroid Peroxidase •• Hashimotos Thyroiditis •• ANA: SLE •• Anti-Smith, anti ds DNA: Specific for SLE •• Anti-Histone: Drug induced SLE •• Anticentromere: CREST Syndrome •• Anti-Scl-70: Scleroderma •• Anti-SSA, Anti-SSB: Sjogrens syndrome •• Anti-Jo-1: Polymyositis •• Antimitochondrial: Primary Biliary Cirrhosis •• Antiglidian, Antitransglutaminase: Celiac disease Pathology 423 •• Anti-GIL: Hemolytic transfusion reactions •• Anti-sacchromyces cervessiae: Crohns disease •• Anti-epithelial cell: Pemphigus vulgaris •• Anti-IgG: Rheumatoid Arthritis Anti-Ri is the least common of the paraneoplastic autoantibodies. Detection of Anti-Ri antibody in serum or spinal fluid identifies an otherwise unexplained neurological disorder as autoimmune and paraneoplastic. A positive result prompts a search for an underlying occult malignancy. Anti-Ri antibodies are detected most commonly in postmenopausal women who usually present with signs of midbrain, brainstem, cerebellar and/or spinal cord dysfunction. Ocular opsoclonus-myoclonus maybe a prominent symptom. Most patients have a primary carcinoma of the breast. Lung and gynecological cancer are less frequently associated with this syndrome. Treatment of the cancer can lead to decreased antibody titer and improvement of the neurological disorder. A negative result does not rule out cancer Anti-Hu is one of several antibodies detected in the serum of patients with neurologic paraneoplastic syndromes. Anti-Hu antibody causes either a syndrome of encephalomyelitis or sensory neuropathy. The underlying cancer is usually small cell cancer of the lung Anti-Yo polyclonal IgG autoantibody directed against Purkinje’s cells and associated with paraneoplastic cerebellar degeneration in oat cell carcinoma of the lung and cancer of the breast or ovary. Also called anti-Purkinje cell antibody. USMLE Case Scenario A 32-year-old female is reported with a past history of ulcerative colitis has a severe proximal myopathy. Serum creatine kinase is found to be very high and a muscle biopsy shows necrosis and a cellular infiltrate. She had a circulating autoantibody to Jo-1 antigen. Diagnosis is: Ans. Polymyositis USMLE Case Scenario CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal motility syndrome, sclerodactyly and telangiectasia) which is also called limited scleroderma. This would be associated with: 1. Anti-Ro 2. Anti-SS-B 3. Decreased ESR 4. Anti-centromere antibody Ans. 4. Anti-centromere antibody HIV Infection •• HIV is an RNA virus whose hallmark is the reverse transcription of its genomic RNA to DNA by the enzyme reverse transcriptase •• Window period is time between infection and detection of antibodies against HIV •• HIV is transmitted by: –– Homosexual –– Heterosexual contact –– Blood and blood products –– Infected mothers to infants either intrapartum, perinatally, or via breast milk •• HIV can be transmitted to individuals who receive HIV-tainted blood transfusions, blood products, or transplanted tissue •• The hallmark of HIV disease is a profound immunodeficiency progressive quantitative and qualitative deficiency of the subset of T-lymphocytes referred to as helper T-cells, or inducer T-cells. AIDS related neoplasms are: •• Kaposis sarcoma •• B-cell non-hodgkins lymphoma •• Primary lymphoma of brain 424 USMLE Step 1 Platinum Notes Important points in HIV Pathology: (USMLE Favorite) •• AIDS is caused by HIV •• A human retrovirus belonging to the lentivirus family •• HIV-1 is the more common type associated with AIDS in the United States, Europe and Central Africa, whereas HIV-2 causes a similar disease principally in West Africa •• The viral particle is covered by a lipid bilayer derived from the host cell and studded with viral glycoproteins gp41 and gp120 •• Like most retroviruses, the HIV-1 virion is spherical and contains an electron-dense, cone-shaped core surrounded by a lipid envelope derived from the host cell membrane •• The virus core contains: –– Major capsid protein p24 –– Nucleocapsid protein p7/p9 –– Two copies of genomic RNA and –– Three viral enzymes (protease, reverse transcriptase and integrase) •• p24 is the most readily detected viral antigen and is therefore the target for the antibodies used to diagnose HIV infection in blood screening •• The viral core is surrounded by a matrix protein called p17, lying beneath the virion envelope •• The viral envelope itself is studded by two viral glycoproteins (gp120 and gp41), critical for HIV infection of cells •• The HIV-1 proviral genome contains the gag, pol and env genes, which code for various viral proteins •• In addition to these three standard retroviral genes, HIV contains several other genes (given three-letter names such as tat, rev, vif, nef, vpr and vpu) that regulate the synthesis and assembly of infectious viral particles •• The product of the tat (transactivator) gene, e.g. is critical for virus replication •• The nef protein activates intracellular kinase activity (affecting T-cell activation, viral replication and viral infectivity) and reduces surface expression of CD4 and MHC molecules on infected cells •• The two major targets of HIV infection are the immune system and the CNS. The life cycle of the virus is best understood in terms of its interactions with the immune system •• The entry of HIV into cells requires the CD4 molecule, which acts as a high-affinity receptor for the virus. This explains the tropism of the virus for CD4 + T-cells and its ability to infect other CD4 + cells, particularly macrophages and DCs •• However, binding to CD4 is not sufficient for infection; the HIV envelope gp-120 must also bind to other cell surface molecules (coreceptors) to facilitate cell entry. Two cell surface chemokine receptors, CCR5 and CXCR4, serve this role. Kaposis Sarcoma •• Kaposis sarcoma is common in homosexuals •• Kaposis sarcoma (KS) is asociated with HHV 8 virus •• KS arises from cells linning lymph vessels or blood vessels. KS actually arises as a cancer of lymphatic endothelium •• KS is associated with HIV, immunosuppression, organ transplants •• On skin Kaposis lesions are red/purple blotches which are asymptomatic or tender •• GIT, liver, lung lesions are dangerous •• Treatment of HIV with HAART reduces KS as well •• Common sites: Skin, GIT, Lymph nodes, Lungs Pathologically KS lesions contain tumor cells with a characteristic abnormal elongated shape, called ‘spindle cells’ The tumor is highly vascular, containing abnormally dense and irregular blood vessels, which leak red blood cells into the surrounding tissue and give the tumor its dark color. Inflammation around the tumor may produce swelling and pain •• Although KS maybe suspected from the appearance of lesions and the patient’s risk factors, a definite diagnosis can only be made by biopsy and microscopic examination, which will show the presence of spindle cells •• Detection of the ‘KSHV protein LANA’ in tumor cells confirms the diagnosis. Pathology 425 USMLE Case Scenario A 45-year-old man came to see an immunologist who has noted several 1 to 2 cm reddish purple, nodular lesions present on the skin of his right arm which have increased in size and number over the past 3 months. The lesions do not itch and are not painful. He has had a watery diarrhea for the past month. On physical examination he has generalized lymphadenopathy and oral thrush. Which of the following infections is most likely to be related to the appearance of these skin lesions? 1. Candida albicans 2. Human herpesvirus 8 3. Mycobacterium tuberculosis 4. Pseudomonas aeruginosa 5. Pneumocystis jiroveci Ans. 2. Human herpesvirus 8 Histiocytosis X •• This condition is rare •• Cells involved are Langerhans’ cells •• Cells contain Birbeck granules •• Cells express CDI markers Letterer–Siwe disease •• Discrete yellow–brown papules develop on the scalp, face, upper trunk and flexures, with a distribution mimicking seborrheic eczema. Purpura and crusting of the lesion may become evident. In some children mucous membranes are also involved, with gingivitis and oral and genital ulceration •• Signs of systemic involvement become manifest, with hepatosplenomegaly, lymphadenopathy and anemia. Chest X-ray shows miliary shadowing and bone scans may show osteolytic areas Hand–Schuller–Christian disease •• This is a more benign form of histiocytosis X, which usually presents within the first 5 years of life and follows a chronic nonfatal course. The usual manifestations are radiological bone defects, exophthalmos and diabetes insipidus Eosinophilic granuloma •• This is the most benign form of histiocytosis X. It commonly presents within the first 5 years of life, and skin involvement is rare. When it does occur, yellowish or brownish papules are found on the scalp and trunk in a distribution similar to the other forms of histiocytosis X •• Solitary lesion is commonest in skull •• Spontaneous resolution usually occurs. Pathological Conditions Related to Term X: (USMLE Favorite) Cardiac syndrome X: occurs when a patient has all of the symptoms of angina pectoris without coronary artery disease or spasm. These spasms can occur either at rest or with exertion. Cardiac syndrome X, the triad of •• Angina pectoris •• A positive exercise electrocardiogram for myocardial ischemia and •• Angiographically smooth coronary arteries The main cause of this syndrome is coronary microvascular dysfunction, as indicated by an abnormal response of coronary microcirculation to both vasoconstrictor and vasodilatory stimuli (microvascular angina). Syndrome X: It is a term used to describe a constellation of metabolic derangements that includes •• Insulin resistance •• Hypertension •• Dyslipidemia •• Central or visceral obesity •• Endothelial dysfunction and •• Accelerated cardiovascular disease 426 USMLE Step 1 Platinum Notes X-Linked agammaglobulinemia •• Males with this syndrome often begin to have recurrent bacterial infections late in the first year of life, when maternally derived immunoglobulins have disappeared •• Affected individuals have very few immunoglobulin-bearing B-lymphocytes in their circulation and lack primary and secondary lymphoid follicles •• Mutations of Bruton’s tyrosine kinase (Btk) gene are responsible for X-linked agammaglobulinemia •• Sinopulmonary bacterial infections constitute the most frequent clinical problem •• Treatment with intravenous immunoglobulin. Fragile X Syndrome: (USMLE Favorite) •• It is now recognized as the second commonest cause of mental handicap in males after Downs syndrome •• Fragile X males have –– A large forehead –– Large head –– Long nose –– Prominent chin and –– Long ears •• Fragile X males tend to be larger at birth •• Macro-orchidism is present.The size of the testes maybe considerably enlarged •• There is a slight increase in the frequency of mitral valve prolapse, aortic root dilatation and hernias. More striking clinically is the soft skin and joint hypermobility, which maybe helpful diagnostically. The range of intellectual handicap in fragile X males varies but most are moderately to severely retarded. THE X-LINKED LYMPHOPROLIFERATIVE SYNDROME (DUNCAN’S DISEASE): (USMLE Favorite) •• It is aX LINKED recessive disorder of young boys who have a normal response to childhood infections but develop fatal lympho proliferative disorders after infection with EBV. Enzyme Markers used in Pathology: (USMLE Favorite) Serum Enzyme •• Aminotransferases •• •• •• •• •• •• Amylase ↓Cerulloplasmin CPK LDH Lipase Alkaline Phosphatase Diagnostic Use •• Viral Hepatitis (AST>ALT) •• Alcoholic Hepatitis (ALT>AST) •• Acute Pancreatitis •• Wilsons Disease •• Muscular Dystrophies, MI •• MI (LDH 1>LDH2) •• Acute Pancreatitis •• Pagets disease (of bone) •• Obstructive Liver Disease Chromosomal Disorders: (USMLE Favorite) Chromosome 14: •• Krabbes disease •• Niemann pick disease •• Multiple myeloma •• Alpha 1 antitrypsin deficiency •• Familial HOCM •• Congenital hypothyroidism Pathology 427 Chromosome 15: •• Albinism •• Angelman syndrome •• Prader willi syndrome •• Tay Sachs disease •• Xeroderma pigmentosum •• Marfans syndrome •• Bloom syndrome Chromosome 16: •• ADPKD •• Alpha thalassemia •• Pseudoxanthoma elasticum Chromosome 17: •• p53 gene •• Neurofibromatosis 1 •• BRCA 1gene •• Medulloblastoma •• Ovarian tumor Chromosome 18: •• De Gruchy syndrome •• Bipolar disorder Chromosome 19: •• Myotonia dystrophica •• Malignant hyperthermia •• Familial hypercholesterolemia •• Peutz jeghers syndrome Chromosome 20: •• Severe combined immunodeficiency disease (SCID) Chromosome 21: •• Amyloidosis •• Homocystinuria •• Down syndrome Chromosome 22: •• Meningioma •• Acoustic neuroma •• Neurofibromatosis 2 •• Di George syndrome •• Velocardiofacial syndrome USMLE Case Scenario A disease is characterized by osteolysis, producing patchwork areas of bone resorption with bizarre, large osteoclasts. In the middle stage of the disease, secondary osteoblastic activity compensates with new bone formation, producing the mosaic pattern. A mosaic pattern is a feature. The Pathology represents: 1. Rickets 2. Osteomalacia 3. Osteodystrophy 4. Pagets Disease Ans. 4. Pagets Disease 428 USMLE Step 1 Platinum Notes Remember: (How to Identify Tricky Questions) •• Burkitts lymphoma Starry skin pattern •• Mycosis fungoides Pautriers abscess •• Hairy cell leukemia TRAP Positive •• Histiocytosis X Birbeck granules •• Multiple Myeloma Lytic bony lesions •• Waldenstroms Macroglobunemia Nonlytic lesions Pathologically Important Bodies: (Viral) •• Guarneri bodies •• Vaccinia •• Bollinger bodies •• Fowlpox •• Paschen bodies •• Smallpox •• Torres Bodies •• Yellow fever •• Cowdry Type A •• Herpesvirus •• Cowdry Type B •• Adeno virus, Poliovirus Some Other Important Bodies are •• HP (Halber staedtler) bodies •• Trachoma •• Levinthal Colle Bodies •• Psittacosis •• Moosers bodies •• Endemic Typhus •• Miyagawa bodies •• Chlamydia Trachomatis •• Asteroid Bodies •• Sarcoidosis •• Babes Ernest Bodies •• Diphtheria •• Verocay Bodies •• Neurilemmoma •• Civatte Bodies •• Lichen Planus •• Donavan Bodies •• Kala azar •• Hassal bodies •• Thymus •• Zebra bodies •• Metachromatic leukodystrophy •• Winkler bodies •• Syphilis •• Ross bodies •• Syphilis •• Moot bodies •• Multiple myeloma •• Creola bodies •• Asthma •• Citron bodies •• Clostridium septicum Psammoma Bodies •• •• •• •• Papillary adenocarcinoma of Thyroid Serous Papillary cystadenocarcinoma of ovary Meningiomas Malignant Mesothelioma Pathology 429 SRBCTS: (SMALL ROUND BLUE CELL TUMORS) Are characterized by sheets of cells with rounded, small nuclei. They include: •• •• •• •• •• •• •• •• Neuroblastoma Ewings sarcoma Rhabdomyosarcoma Burkitts lymphoma Lymphobalstic lymphoma Wilms tumor Retinoblastoma Medulloblastoma USMLE Case Scenario A 58-year-old woman who is a bit nervous presents to a physician in Detriot with a 3-year history of headaches, generalized tonic-clonic seizures and bilateral leg weakness. Skull X-ray shows areas of hyperostosis of the calvarium. Biopsy of the responsible lesion shows a whorling pattern of the cells. Which of the following is the most likely diagnosis? 1. Medulloblastomas 2. Arachnoid cyst 3. Glioblastoma multiforme 4. Meningioma 5. Neurosarcoid 6. Metastatic breast cancer 7. Oligodendroglioma Ans. 4. Meningioma The most likely diagnosis is an intracranial meningioma. USMLE Case Scenario Embryonal rhabdomyosarcoma is the most common form of rhabdomyosarcoma. The tumor is composed predominantly of small, round cells resembling cells found in developing muscle. The most common site for embryonal rhabdomyosarcoma is: 1. Head and neck 2. Kidneys 3. Liver 4. Lungs Ans. 1. Head and neck Types of ‘Erythemas’ •• •• •• •• •• •• •• •• •• •• Erythema chronicum migrans. Lymes Disease Erythema Ab Agne: Reticulate pigmentation due to long-term heat exposure. Erythema Gyratum Repens: Internal malignancies Erythema Nodosum: Multisystemic disorders, e.g. sarcoidosis Erythema multiforme: Mucosal involvement with viral, bacterial, rickettsial diseases with target lesions Erythema toxicum neonatorum: This is a transient condition of unknown etiology occurring in up to 70% of neonates. The onset is from birth to 14 days but most cases start between day 1 and day 4. The commonest lesions are erythematous macules and papules but in some cases pustules appear Erythema marginatum: Present in acute rheumatic fever, pink/red nonpruritic rash on trunk and upper limbs in associsation with carditis Erythema necrolyticum migrans Glucagonoma Erythema infectiosum Parvo virus Erythema arthriticum epidemicum Haver hill fever, streptobacillus monoliformis. 430 USMLE Step 1 Platinum Notes USMLE Case Scenario A 45-year-old abruptly develops an intensely itchy rash. He reports to a dermatology clinic. Physical examination demonstrates multiple erythematous patches of the distal arms and legs. Some of the patches show central clearing with surrounding erythematous rings. Which of the following is the most likely diagnosis? 1. Erythema nodosum 2. Erythema chronicum migrans 3. Erythema migrans chronicum 4. Erythema multiforme Ans. 4. Erythema multiforme Pathological Types of Common Cancers •• •• •• •• •• •• •• Mc type of Stomach Ca: Adeno carcinoma Mc type of Lung Ca: Adeno Carcinoma Mc type of Pancreatic Ca: Ductal cell Adeno carcinoma Mc type of Breast Ca: Intra ductal Adeno carcinoma Mc type of Endometrial Ca: Adenocarcinoma Mc type of cervical Ca: Squamous cell cancer Mc type of vulval Ca: Squamous cell cancer IMPORTANT CLINICAL SCENARIOS: (USMLE FAVORITES) Repeated often USMLE Case Scenario Klinefilters Disease •• Males who are –– Sexually under developled with rudimentary testes and prostate glands –– Sparse pubic and facial hair –– Long arms and legs, and large hands and feet are likely to have the chromosome complement of: Klinefelters disease. USMLE Case Scenario Verrucous Carcinoma •• A 72-year-old male from Texas who has been –– Chewing tobacco for the past 50 years presents with a six months history of a large, fungating, soft papillary lesions in the oral cavity –– The lesion has penetrated into the mandible. Lymph nodes are not palpable –– Two biopsies taken from the lesion proper show benign appearing papillomatosis with hyperkeratosis and acanthosis infiltrating the subjacent tissues The most likely diagnosis is Verrucous Carcinoma USMLE Case Scenario Clear Cell Sarcoma •• A sarcoma appears –– Like a malignant melanoma, which arises in the soft Tissue –– It usually is found on the tendons of extremities of young Patients –– Histologically, the cells can have pigment or clear cytoplasm. It is associated with t (12,22) The sarcoma is Clear Cell sarcoma Pathology 431 USMLE Case Scenario Pagets Disease •• A disease is characterized by osteolysis, producing patchwork areas of –– Bone resorption with bizarre, large osteoclasts –– In the middle stage of the disease, secondary osteoblastic activity compensates with new bone formation, producing the mosaic pattern –– Inlate Paget’s, the bones are dense and osteosclerotic. A mosaic pattern is a feature The Pathology represents Pagets Disease USMLE Case Scenario Picks Disease •• Intracytoplasmic spherules composed of –– Paired helical filaments stained with silver stains are seen in frontallobe with –– Severe neuronal loss and astrocytosis The condition most likely is Picks Disease (Pick’s bodies) USMLE Case Scenario Hairy Cell Leukemia •• An elderly 77-year-old man comes to oncology clinic with: –– Anemia and multiple infections –– Physical examination is remarkable for marked hepatosplenomegaly –– Blood counts demonstrates pancytopenia –– Peripheral smear by a hematologist demonstrates rare, distinctive –– Neoplastic white cells covered by fine, hairlike projections Most likely disease is Hairy cell leukemia USMLE Case Scenario Crohn’s Disease •• A 52-year-old man presents to Gastro clinic with a complaint of: –– Nonbloody diarrhea and right lower quadrant pain with a palpable mass and tenderness –– He states that this ‘flare-up’ is one of the worst he has ever experienced –– Radiographic examination reveals evidence of ulceration, stricturing, and fistula development of the colon and small bowel The most likely diagnosis is Crohn’s disease USMLE Case Scenario Silicosis •• A disease occurs with: –– Prolonged exposure to dust during glass production which can progress to respiratory failure and death, and is associated with increased risk for tuberculosis –– Classic X-ray findings include calcified lymph nodes that produce an ‘eggshell’ pattern. Pleural involvement creates dense fibrous plaques and adhesions that may obliterate the pleural cavities Most likely disease is Silicosis 432 USMLE Step 1 Platinum Notes USMLE Case Scenario Syphilis •• It is seen that vasa vasorum of the aorta undergoes obliterative end arteritis: –– Leading to atrophy of the muscularis and elastic tissues of the aorta and dilatation –– Linear calcifications are often seen in the ascending aorta by X-ray –– The intimal wrinkling is seen The disease most likely represents: Syphilis infection. (The intimal wrinkling or ‘tree barking’ is also a common feature.) USMLE Case Scenario Sturge-Weber Syndrome •• A 13-year-old boy presents with a –– Purple, flat vascular ectasia on the head and along distribution of the trigeminal nerve, mental retardation –– Seizures and –– Hemiplegia The most likely disease is Sturge-Weber syndrome USMLE Case Scenario Wegener’s Granulomatosis •• A patient presents with: –– Respiratory symptoms, i.e. cough hemoptysis and glomerulonephritis –– His C-ANCA levles in serum were found to be raised The most lkely diagnosis is Wegener’s granulomatosis. USMLE Case Scenario Pituitary Adenoma •• A 35-year-old female from New Orleans presented –– With one year history of menstrual irregularity and galactorrhea –– She also had off-and-on headache –– Her examination revealed bitemporal superior quadrantopia –– Her fundus examination showed primary optic atropy The most likely diagnosis in this case Pituitary macroadenoma USMLE Case Scenario Acute Lymphoblastic Leukemia •• A four-year-old boy was admitted with a history of abdominal pain and fever for two months, maculopapular rash for ten days and dry cough, dyspnea and wheezing for three days. On examination, liver and spleen were enlarged 4 cm and 3 cm respectively below the costal margins. His hemoglobin was 10.0 g/dl, platelet count 37 × 5 109/L and total leukocyte count 70 × 109/L, which included 80% eosinophils. Bone marrow examination revealed a cellular marrow comprising 45% blasts and 34% Eosinophils and eosinophilic precursors. The blasts stained negative for myeloperoxidase and nonspecific esterase and were positive for CD19, CD10, CD22 and CD20 The most likely diagnosis acutelymphoblastic leukemia with hyper eosinophilic syndrome Pathology 433 USMLE Case Scenario Hairy Cell Leukemia •• CD19 positive, CD22 positive, CD103 positive monoclonal B-cells with bright kappa positivity were found to comprise 60% of the peripheral blood lymphoid cells on flow cytometric analysis in a 55-year-old man with massive splenomegaly and a total leucocyte count of 3.3 × 109/L The most likely diagnosis is Hairy cell leukemia USMLE Case Scenario Syphilis •• A 30-year-old male from suburban area with a history of sexual exposure comes with a painless indurated ulcer over the penis with everted margins The diagnosis is Syphilis USMLE Case Scenario Craniopharyngioma •• A 6-year-old boy has been complaining of –– Headache, ignoring to see the objects on the sides for four months. On examination, he is not mentally retarded, his grades at school are good, and visual acuity is diminished in both the eyes. Visual charting showed significant field defect –– CT scan of the head showed suprasellar mass with calcification The most probable diagnosis Craniopharyngioma USMLE Case Scenario Tuberculosis •• A 25-year-old man presented with fever and cough for two months –– CT chest showed bilateral upper lobe fibrosis and mediastinal enlarged necrotic nodes with peripheral rim enhancement The most likely diagnosis Tuberculosis USMLE Case Scenario Polyarteritis Nodosa •• A 30-year-old male patient presents with complaints of –– Weakness in right upper and both lower limbs for last 4 months –– He developed digital infarcts involving 2nd and 3rd fingers on right side and 5th finger on left side. On examination, BP was 160/140 mm Hg, all peripheral pulses were palpable and there was asymmetrical neuropathy –– Investigations showed Hb 12 gm%, TLC 12,000 per cu. mm, Platelets 4,30,000 and ESR 49 mm. Urine examination showed Proteinuria and RBC-10–15/hpf with no casts. The most likely diagnosis Polyarteritis nodosa USMLE Case Scenario Caplan’s Syndrome •• A 45-year-old coal mine worker presents with –– Cutaneous nodules, joint pain and occasional cough with dyspnea –– His chest radiograph shows multiple small (1–4 cm) nodules in bilateral lung fields –– Some of the nodules show cavitation and specks of calcification Most likely these features are diagnostic of Caplan’s syndrome 434 USMLE Step 1 Platinum Notes USMLE Case Scenario Crohn’s Disease •• Two identical specimen of the intestine obtained following colectomy shows on examination hemorrhagic cobblestone appearance one of them however, shows longitudinal grooving. it is likely to be a specimen of: Ans. Crohn’s disease USMLE Case Scenario Adenoid Cystic Carcinoma •• Salivary gland tumors having propensity for perineural spread and tendency for recurence along the nerve is most likely: Adenoid cystic carcinoma USMLE Case Scenario Alpha-1 Antitrypsin Deficiency •• Liver biopsy in an adolescent with cirrhosis revealed hepatocytes containing round to oval ‘PAS distase resistant’ globular inclusions. The most likely cause of cirrhosis in this patient is Alpha-1 antitrypsin deficiency. USMLE Case Scenario Clostridium Difficile •• In a case of diarrhea with histopathological feature of intestinal mucosal clefts studded with copious thick secretions and inflammatory cells, characteristic of pseudomembranous colitis, the likely cause is: Clostridium difficile. USMLE Case Scenario Good Pasteur’s Syndrome •• A person presents with hemoptysis and hematuria with antibasement membrane antibodies Diagnosis is Good Pasteur’s syndrome USMLE Case Scenario Seminoma •• Testicular tumors having an increased elevation of placental alkaline phosphatase in the serum as well as a positive immunohistochemical staining for placental alkaline phosphatase Seminoma USMLE Case Scenario CML: (Chronic Myeloid Leukemia) •• A 60-year-old man from Cardiff presently working in New York presented with fatigue, weight loss and heaviness in left hypochondrium for 6 months The hemogram showed –– Hb 10 gm/dL –– TLC 5 lakhs/mm3 –– Platelet count 4 lakhs/mm3 –– DLC; neutrophil 55%, lymphocytes 4%, monocytes 2%, basophils 6% –– metamyelocytes 10%, myelocytes 18%, promyelocytes 2% and blasta 3% The most likely diagnosis is CML Pathology 435 USMLE Case Scenario Multiple Myeloma •• A renal biopsy from a 66-year-old woman from Washington DC with –– Progressive renal failure for the past 3 years shows glomerular and vascular deposition of pink amorphous material –– It shows apple-green birefringence under polarized light after Congo red staining –– These deposits are positive for lambda light chains Likely diagnosis is Multiple myeloma USMLE Case Scenario Pulmonary Thromboembolism •• On sectioning of an organ at the time of autopsy, a pathologist in New York Central Hospital reports –– A focal, wedge-shaped firm area is seen accompanied by extensive hemorrhage, with a red appearance –– The lesion has a base on the surface of the organ This findings is typically of Lung with pulmonary thromboembolism USMLE Case Scenario Sarcoidosis •• A young lady from Ohio presented with –– Bilateral nodular lesions on shins –– She was also found to have bilateral hilar lymphadenopathy on chest X-ray –– Mantoux test reveals indurations of 5 mms –– Skin biopsy would reveals Noncaseating Granuloma Likely diagnosis is Sarcoidosis. 436 USMLE Step 1 Platinum Notes USMLE Case Scenario A 68-year-old woman who is normotensive presents to her cardiac physician after several episodes of syncope. Physical examination is remarkable for a low-pitched ‘plopping’ sound during mid-systole. Two-dimensional echocardiography demonstrates a ball-valve type obstruction of the mitral valve. Which of the following would most likely be observed if the cause of the obstruction were biopsied? 1. Benign glandular tissue 2. Myxomatous degeneration of valves 3. Dense calcification in tricuspid area 4. Densely packed smooth muscle 5. Densely packed striated muscle 6. Malignant glandular tissue 7. Scattered mesenchymal cells in a myxoid background Ans. 7. Scattered mesenchymal cells in a myxoid background Atrial myxoma may intermittently obstruct the mitral valve. Histologically, these tumors are composed of scattered mesenchymal cells in a prominent myxoid background. USMLE Case Scenario A 8-year-old girl has chickenpox. A week after the onset of the rash, she begins vomiting and becomes lethargic and comatose. Laboratory examination is significant for elevated liver enzymes and ammonia. Which of the following is the most likely diagnosis? 1. Crigler-Najjar syndrome 2. Dubin-Johnson syndrome 3. Gilbert syndrome 4. Reye syndrome Ans. 4. Reye Syndrome USMLE Case Scenario Condition resulting from incomplete separation of the cerebral hemisphere along the midline, leading, in its extreme form, to a single midline ventricular cavity enclosed within the forebrain. Associated facial anomalies, often associated with trisomy 13 is: 1. Dandy-Walker malformation 2. Holoprosencephaly 3. Arnold-Chiari malformation 4. Myelomeningocele Ans. 2. Holoprosencephaly USMLE Case Scenario Lacunar cells are seen in: 1. Nodular sclerosing variant of Hodgkin’s disease 2. Burkitt’s lymphoma 3. Mixed cellularity Hodgkin’s 4. Normal Lymph nodes Ans. 1. Nodular sclerosing variant of Hodgkin’s disease USMLE Case Scenario A sarcoma appears like a malignant melanoma, which arises in the soft tissue. It usually is found on the tendons of extremities of young patients. Histologically, the cells can have pigment or clear cytoplasm. It is associated with t(12, 22). The sarcoma is: 1. Synovial cell sarcoma 2. Clear Cell sarcoma Pathology 437 3. Leiomyosarcoma 4. Rhabdomyosarcoma Ans. 2. Clear Cell sarcoma USMLE Case Scenario A 24-year-old man presented to an ophthalmologist with a severe painful left eye for 38 hours. There is redness around the cornea which developed into a iritis. Three days later the right eye also became involved. One week after the onset of the eye symptoms, the patient complained of dysuria. No chlamydia, viruses or bacteria were isolated from this discharge. He was treated with oxytetracycline and his eye signs gradually cleared. At about this time, however, his right first metatarsophalangeal joint became inflamed and, subsequently, several joints were similarly involved. He was found to be HLA-B27-positive. Most likely diagnosis would be: 1. Behcets Disease 2. Ankylosing Spondylitis 3. Reiters Disease 4. Gonococcal arthritis 5. Rheumatoid arthritis 6. Gouty Arthritis Ans. 3. Reiters Disease USMLE Case Scenario A 45-year-old male from Kansas develops a gelatinous, well-circumscribed mass in her right cerebral hemisphere. Biopsy of the mass reveals neoplastic cells with ‘fried egg’ morphology. Which of the following tumors does this patient most likely have? 1. Choroid plexus papilloma 2. Ependymoma 3. Glioblastoma multiforme 4. Oligodendroglioma Ans. 4. Oligodendroglioma USMLE Case Scenario A 44-year-old woman who takes alcohol heavily has the sudden onset of severe abdominal pain with diffuse tenderness in all abdominal quadrants, with marked guarding and muscular rigidity. An abdominal CT scan reveals peritoneal fluid collections and decreased attenuation along with enlargement of the pancreas. A diagnosis of pancreatitis is made. Which of the following cellular changes is most likely to accompany these findings? 1. Coagulative necrosis 2. Dry gangrene 3. Fat necrosis 4. Apoptosis (Programmed Cell Death) 5. Liquefactive necrosis 6. Wet gangrene 7. Hemorrhagic necrosis Ans. 3. Fat Necrosis The enzymes released from the pancreas with acute pancreatitis damage the surrounding fat and cause of fat necrosis. USMLE Case Scenario Rosenthal fibers are corkscrew-shaped, intensely eosinophilic structures deriving from accumulation of alpha and beta crystalline within astrocytic processes. They are usually found in: 1. Ependymoma 2. Glioblastoma multiforme 3. Medulloblastoma 4. Pilocytic astrocytoma Ans. 4. Pilocytic astrocytoma 438 USMLE Step 1 Platinum Notes USMLE Case Scenario A 44-year-old patient on chemotherapy for small cell carcinoma lung presents to a physician because of a markedly inflamed and painful great toe. Physical examination additionally demonstrates small nodules on the patient’s external ear. Aspiration of the metatarsal-phalangeal joint of the affected toe demonstrates needle-shaped, negatively birefringent crystals. Which of the following are the crystals most likely composed of? 1. Bile pigments 2. Calcium pyrophosphate 3. Cystine 4. Monosodium urate Ans. 4. Monosodium urate USMLE Case Scenario A 34-year-old man from New Orleans presents with hemoptysis and hematuria. This is a classic case of Goodpasture’s syndrome. Under immunofluorescence, there are linear deposits of IgG on alveolar and glomerular basement membranes. Renal biopsy shows inflammation of the glomeruli. X-ray shows focal pulmonary infiltrates. The most likely cause is: 1. Wegners granulomatosis 2. Poststreptococcal glomerulonephritis 3. Berger’s disease 4. Goodpasture’s syndrome Ans. 4. Goodpasture’s syndrome USMLE Case Scenario A 22-year-old tall man from Honduras presents with gynecomastia and testicular atrophy has a testicular biopsy that shows sparse, completely hyalinized seminiferous tubules with Leydig cells present in large clumps between the hyalinized tubules. Which of the following genetic disorders should be suspected? 1. 45, XO 2. 47, XXY 3. Trisomy 18 4. Trisomy 21 Ans. 2. 47, XXY USMLE Case Scenario A 48-year-old male from Ohio presents with sinus pain and drainage, bloody nasal discharge and nasal mucosal ulceration. On laboratory examination, the man is found to have hematuria and red blood cell casts. A biopsy of the upper airway tissue reveals granulomatous inflammation with necrosis. Blood tests show the presence of antineutrophil cytoplasmic antibodies (c-ANCA). Most likely diagnosis is: 1. Goodpasture’s syndrome 2. Noninfectious granulomatous disease 3. Wegener’s granulomatosis 4. Berger’s Disease Ans. 3. Wegener’s granulomatosis USMLE Case Scenario A 45-year-old abruptly develops an intensely itchy rash. Physical examination demonstrates multiple erythematous patches of the distal arms and legs. Some of the patches show central clearing with surrounding erythematous rings. Which of the following is the most likely diagnosis? 1. Erythema nodosum 2. Erythema chronicum migrans 3. Erythema migrans chronicum 4. Erythema multiforme Ans. 4. Erythema multiforme Pathology 439 USMLE Case Scenario Gandy-Gamma nodules are thought to be the result of organization of old hemorrhages. Seen in: 1. Hepatic cirrhosis 2. Hodgkin’s disease 3. Rheumatoid arthritis 4. Sickle cell anemia Ans. 1. Hepatic cirrhosis USMLE Case Scenario It is seen that meninges and spinal cord herniate through a bony vertebral defect. These defects most commonly occur in the lumbosacral region typically resulting in motor and sensory deficits in the lower extremities, and bowel and bladder dysfunction. Deficency of which factor leads to the defect: 1. Ascorbate 2. Folate 3. Pyruvate 4. Glutamate Ans. 2. Folate USMLE Case Scenario Pheochromocytoma intermittently secretes epinephrine and other vasoactive amines, producing episodes of elevated blood pressure accompanied by headache. This is the tumor to associate with the rule of the 10’s: 1. It is 10% nonmalignant 2. It is 10% unilateral 3. 10% adrenal 4. 10% are familial Ans. 4. 10% are familial USMLE Case Scenario The defect in sickle cell anemia is amino acid substitution/s but the globin chain is still made. The gene may less commonly be present in some Mediterranean and Eastern Arabian populations. There is enough fetal hemoglobin at birth to prevent sickling with sickle cell disease. Sickle cell disease represents: 1. Missense mutations involve a change in many amino acids 2. Missense mutations involve a change in a single amino acid (valine for glutamic acid) 3. Missense mutations involve a change in a single amino acid (glutamic acid for valine) 4. Nonsense mutations involve a change in a single amino acid (valine for glutamic acid) 5. Nonsense mutations involve a change in a single amino acid (glutamic acid for valine) Ans. 2. Missense mutations involve a change in a single amino acid (valine for glutamic acid) USMLE Case Scenario Ophthalmoscopic examination of a 7-year-old child from Washington DC demonstrates a retinal angioma. This finding should raise the possibility of which of the following syndromes? 1. Neurofibromatosis type I 2. Neurofibromatosis type II 3. Tuberous sclerosis 4. von Hippel-Lindau disease Ans. 4. von Hippel-Lindau disease 440 USMLE Step 1 Platinum Notes USMLE Case Scenario A 22-year-old male from New York presents with adenoma sebaceum of the skin and cortical tubers. The person is most probably having: 1. Neurofibromatosis type I 2. Neurofibromatosis type II 3. Tuberous sclerosis 4. von Hippel-Lindau disease Ans. 3. Tuberous sclerosis USMLE Case Scenario A 3-year-old child with mental retardation, seizures and facial angiofibromas develops repeated episodes of syncope. Echocardiogram reveals a mass in the left ventricle producing intermittent obstruction. Pathologic examination of the resected mass demonstrates a cardiac rhabdomyoma. Which of the following lesions would this patient most likely also have? 1. Acoustic neuromas 2. Berry aneurysm 3. Cortical tubers 4. Neurofibromas Ans. 3. Cortical tubers. The disease is tuberous sclerosis USMLE Case Scenario A disease is characterized by osteolysis, producing patchwork areas of bone resorption with bizarre, large osteoclasts. In the middle stage of the disease, secondary osteoblastic activity compensates with new bone formation, producing the mosaic pattern. In late Paget’s, the bones are dense and osteosclerotic. A mosaic pattern is a feature. The Pathology represents: 1. Rickets 2. Osteomalacia 3. Osteodystrophy 4. Paget’s Disease Ans. 4. Paget’s Disease USMLE Case Scenario Cowden syndrome is due to : 1. Mutations of a gene on chromosome 9 2. Mutations of a gene on chromosome 10 3. Mutations of a gene on chromosome 11 4. Mutations of a gene on chromosome 12 Ans. 2. Mutations of a gene on chromosome 10 USMLE Case Scenario An elderly 77-year-old man comes to oncology clinic with anemia and multiple infections. Physical examination is remarkable for marked hepatosplenomegaly. A blood count demonstrates pancytopenia. Peripheral smear by a hematologist demonstrates rare, distinctive, neoplastic white cells covered by fine, hairlike projections. Which of the following characteristics would likely be associated with these cells? 1. Elevated CEA levels 2. Elevated leukocyte alkaline phosphatase 3. Philadelphia chromosome 4. Positive tartrate-resistant acid phosphatase Ans. 4. Positive tartrate-resistant acid phosphatase Pathology 441 USMLE Case Scenario A pathologist from Mexico reports the presence of koilocytes in a cervical biopsy from a 22-year-old woman. Which of the following conditions does this patient most likely have? 1. Chlamydia infection 2. Gonococcal infection 3. Herpes simplex virus infection 4. Human papilloma virus infection Ans. 4. Human papilloma virus infection USMLE Case Scenario With CML there is a marked increase in the WBC count with many immature myelocytic forms, but not many blasts. In CML 1. The erythrocyte alkaline phosphatase is low 2. The erythrocyte alkaline phosphatase is high 3. The leukocyte alkaline phosphatase is low 4. The leukocyte alkaline phosphatase is high Ans. 3. The leukocyte alkaline phosphatase is low USMLE Case Scenario A 25-year-old man has a testicular mass, which on orchiectomy shows a malignant tumor with yolk sac differentiation. Which of the following tumor markers would probably be most useful in monitoring the patient for recurrent or metastatic disease? 1. Alpha-fetoprotein 2. Carcinoembryonic antigen (CEA) 3. Prostate-specific antigen (PSA) 4. S-100 Ans. 1. Alpha-fetoprotein USMLE Case Scenario A 45-year-old abruptly develops an intensely itchy rash. Physical examination demonstrates multiple erythematous patches of the distal arms and legs. Some of the patches show central clearing with surrounding erythematous rings. Which of the following is the most likely diagnosis? 1. Erythema nodosum 2. Erythema chronicum migrans 3. Erythema migrans chronicum 4. Erythema multiforme Ans. 4. Erythema multiforme USMLE Case Scenario A 42-year-old female presents to New York Central Hospital with painful oral ulcers. Physical examination demonstrates widespread erosions of her mucous membranes. Dermatological examination reveals a friable mucosa. Biopsy of perilesional mucosa demonstrates acantholysis; Direct immunofluorescence demonstrates an intraepidermal band of IgG and C3. The most likely diagnosis is: 1. Bullous pemphigoid 2. Dermatitis herpetiformis 3. Herpes simplex I 4. Pemphigus vulgaris Ans. 4. Pemphigus vulgaris 442 USMLE Step 1 Platinum Notes USMLE Case Scenario Cells similar to fibroblasts are seen growing in a storiform (‘pinwheel’) pattern. This pattern of cells is characteristic of: 1. Leiomyosarcoma 2. Basal cell carcinoma 3. Keratocanthoma 4. Dermatofibrosarcoma Ans. 4. Dermatofibrosarcoma USMLE Case Scenario A 58–year-old woman who is a bit nervous presents with a 3-year history of headaches, generalized tonic-clonic seizures, and bilateral leg weakness. Skull X-ray films reveal hyperostosis of the calvarium. Biopsy of the responsible lesion shows a whorling pattern of the cells. Which of the following is the most likely diagnosis? 1. Medulloblastomsa 2. Arachnoid cyst 3. Glioblastoma multiforme 4. Meningioma 5. Neurosarcoid 6. Metastatic breast cancer 7. Oligodendroglioma Ans. 4. Meningioma USMLE Case Scenario A 44-year-old male presents to the dermatologist with pain in the joints along with silvery, scaling plaques on his elbows and knees. The most likely diagnosis is 1. Acne vulgaris 2. Pemphigus vulgaris 3. Psoriasis vulgaris 4. Pemphigoid Ans. 3. Psoriasis vulgaris USMLE Case Scenario A 33-year-old female bar worker presents in a hospital in Ohio with a red, scaling, ‘herald patch’ approximately 3 cm in diameter. It is followed within days by eruption in a ‘short-sleeve turtleneck’ distribution and crops of small, pink, oval patches in a ‘fir tree configuration’ on the flexural lines. The most likely disease is: 1. Pityriasis alba 2. Pityriasis rosea 3. Pemphigus vegetans 4. Pemphigus vulgaris Ans. 2. Pityriasis rosea USMLE Case Scenario A 34-year-old male from Africa in New York Chest clinic has a pathology characterized by noncaseating granulomata in lungs. The disease was discovered incidentally when chest X-ray reveals bilateral hilar adenopathy. Definitive diagnosis is based on biopsy, which reveals non-caseating granulomata that are negative for fungi or acid-fast bacilli. The disease most likely is: 1. Cat Scratch Disease 2. Sarcoidosis 3. Scleroderma 4. Systemic lupus erythematosus Ans. 2. Sarcoidosis Pathology 443 USMLE Case Scenario Embryonal rhabdomyosarcoma is the most common form of rhabdomyosarcoma. The tumor is composed predominantly of small, round cells resembling cells found in developing muscle. The most common site for Embryonal rhabdomyosarcoma is: 1. Head and neck 2. Kidneys 3. Liver 4. Lungs Ans. 1. Head and neck USMLE Case Scenario A biopsy of this mass demonstrates pleomorphic spindle cells that are cytokeratin negative, CD 45 negative and vimentin positive. Which of the following neoplasms is he most likely to have? 1. Wilms tumor 2. Teratoma 3. Leiomyosarcoma 4. Rhabdomyosarcoma 5. Neuroblastoma 6. Ewing sarcoma 7. Malignant lymphoma Ans. 4. Rhabdomyosarcoma USMLE Case Scenario A 38-year-old downtown drug addict known to be infected with HIV for the past 8 years has abdominal pain for the past 3 days. On Physical examination there is abdominal distension with diffuse tenderness and absent bowel sounds. An abdominal CT scan reveals a mass lesion involving the small intestine after surgical excision shows an encircling mass 8.5 cm long and 3.5 cm infiltrating the bowel. Most likely diagnosis is: 1. Metastatic disease 2. Hodgkin lymphoma 3. High-grade B-cell lymphoma 4. AML 5. CML 6. Carcinoid 7. Adenocarcinoma Ans. 3. High-grade B-cell lymphoma USMLE Case Scenario An elderly 77-year-old man comes to oncology clinic with anemia and multiple infections. Physical examination is remarkable for marked hepatosplenomegaly. Blood counts demonstrate pancytopenia. Peripheral smear by a hematologist demonstrates rare, distinctive, neoplastic white cells covered by fine, hairlike projections. Which of the following characteristics would likely be associated with these cells? 1. Elevated CEA levels 2. Elevated leukocyte alkaline phosphatase 3. Philadelphia chromosome 4. Positive tartrate-resistant acid phosphatase Ans. 4. Positive tartrate-resistant acid phosphatase USMLE Case Scenario A 48-year-old woman who has had multiple sexual partners for the past 30 years has an abnormal Pap smear with cytologic changes suggesting human papillomavirus infection. Without treatment, she is most likely to develop which of the following lesions? 1. Squamous cell carcinoma 444 USMLE Step 1 Platinum Notes 2. Non-Hodgkin’s lymphoma 3. Kaposi’s sarcoma 4. Adenocarcinoma 5. Leiomyoma Ans. 1. Squamous cell carcinoma USMLE Case Scenario Hypophosphatemic rickets is a condition causing abnormal regulation of vitamin D3 metabolism and defects in renal tubular phosphate transport. Symptoms include growth retardation, osteomalacia, and rickets.It is a/an: 1. Is an X-linked recessive condition 2. Is an X-linked dominant condition 3. Is an autosomal dominant condition 4. Is an autosomalco dominant condition Ans. 2. Is an X-linked dominant condition USMLE Case Scenario Hereditary hemochromatosis results from increased iron absorbtion with markedly increased iron stores. The iron accumulation in tissues results in manifestations such as 1. Hepatomegaly, skin hypopigmentation, diabetes insipidus and hypogonadism 2. Hepatomegaly, skin hyperpigmentation, diabetes insipidus and hypogonadism 3. Hepatomegaly, skin hyperpigmentation, diabetes mellitus and hypogonadism 4. Hepatomegaly, skin hypopigmentation, diabetes mellitus and hypergonadism Ans. 3. Hepatomegaly, skin hyperpigmentation, diabetes mellitus and hypogonadism USMLE Case Scenario Rheumatoid arthritis is characterized by Rheumatoid nodules which develop in 20 to 30 percent of patients, usually on or around joints, on extensor surfaces, or on other areas subjected to mechanical trauma. The most important HLA association is with: 1. HLA-DR2 2. HLA-DR3 3. HLA-DR4 4. HLA B 27 Ans. 3. HLA-DR4 USMLE Case Scenario Cervical intraepithelial neoplasia (CIN) is associated with human papilloma virus (HPV) infection, particularly types 16 or 18. These papillomaviruses produce 1. E6 and E7 proteins 2. EBNA proteins 3. E1A and E1B proteins 4. Tumor Proteins Ans. 1. E6 and E7 proteins USMLE Case Scenario A patient has a pleural effusion. Which of the following conditions may lead to development of an exudate within the pleural cavity? 1. Tubercular effusion 2. Cirrhosis of the liver 3. Congestive heart failure 4. Nephrotic syndrome Pathology 445 5. Protein-losing enteropathy Ans. 1. Tubercular Effusion An exudate results from leakage of protein-rich fluid from the plasma into the interstitium. It is usually the result of increased vascular permeability caused by inflammation. USMLE Case Scenario Mutagenic effects on bacterial cells in culture is tested by: 1. Rotheras test 2. Lachman Test 3. Ames test 4. Nitroblue tetrazolium test 5. Watson-Schwartz test 6. Widal test Ans. 3. Ames test. It measures damage to DNA and correlates well with carcinogenicity in vitro USMLE Case Scenario A 2-year-old boy was admitted to a pediatric hospital with a 7-day history of high fever, lymphadenopathy, conjunctivitis and an erythematous exfoliative rash affecting his trunk and extremities. On the basis of the characteristic clinical picture, a clinical diagnosis of Kawasaki’s disease (also known as acute mucocutaneous lymph node syndrome). It is best described as: 1. An acute vasculitic disorder of infants affecting small and medium-sized blood vessels 2. An acute vasculitic disorder of infants affecting medium and large sized blood vessels, was made 3. A chronic nonvasculitic disorder of infants affecting small and medium-sized blood vessels was made 4. A chronic nonvasculitic disorder of infants affecting medium and large sized blood vessels, was made Ans. 1. An acute vasculitic disorder of infants affecting small and medium-sized blood vessels USMLE Case Scenario TTP, as is the pentad of: 1. Fever, mental changes, renal failure, thrombocytosis and microangiopathic hemolytic anemia 2. Fever, mental changes, renal failure, thrombocytosis and microangiopathic nonhemolytic anemia 3. Fever, mental changes, renal failure, thrombocytopenia and microangiopathic hemolytic anemia 4. Fever, mental changes, renal failure, thrombocytopenia and macroangiopathic nonhemolytic anemia Ans. 3. Fever, mental changes, renal failure, thrombocytopenia and microangiopathic hemolytic anemia USMLE Case Scenario Intracytoplasmic spherules composed of paired helical filaments stained with silver stains are seen infrontal lobe with severe neuronal loss and astrocytosis. The condition most likely is: 1. HSV Encephalitis 2. Pick’s disease 3. Alzheimer’s disease 4. Parkinson’s disease Ans. 2. Pick’s Disease (Pick’s bodies) USMLE Case Scenario Subependymal giant cell astrocytoma is a peculiar astrocytic tumor that grows from the walls of the lateral ventricles. It is caused by mutations of TS1 or TS2 genes. It is usually seen in: 1. von Hippel-Lindau syndrome 2. Neurofibromatosis 1 3. Neurofibromatosis 2 4. Tuberous Sclerosis Ans. 4. Tuberous Sclerosis 446 USMLE Step 1 Platinum Notes USMLE Case Scenario Microcytic, hypochromic anemia with reduced mental and physical performance is due to: 1. Iron deficiency 2. Copper deficiency 3. Calcium deficiency 4. Calcium deficiency Ans. 1. Iron deficiency Giant cell arteritis involves the cranial arteries (branches of the carotid system) USMLE Case Scenario Biopsying 2 cm lengths of each temporal artery are indicated because the process can be patchy. Biopsy can reveal 1. Granulomatous inflammation 2. Fibrinoid necrosis 3. Hyperplastic necrosis 4. Leukocytoclastic vasculitis Ans. 1. Granulomatous inflammation USMLE Case Scenario A dementing disorder characterized clinically by progressive loss of memory, Parkinsonism, and visual/auditory hallucinations, and pathologically by round intracytoplasmic neuronal inclusions in the substantia nigra and neocortex. The clinical features are suggestive of: 1. HIV encephalitis 2. Lewy body disease 3. Shy dragger syndrome 4. Parkinsonism Ans. 2. Lewy body disease USMLE Case Scenario A 32-year-old female presents to her physician with fatigue, pruritus and steatorrhea. Blood tests demonstrate an elevated alkaline phosphatase. Patient has hypercholesterolemia and xanthomas. The most likely disease is: 1. Primary biliary cirrhosis 2. Alcoholic hepatitis 3. Bacterial Cholangitis 4. Carolis disease Ans. 1. Primary biliary cirrhosis USMLE Case Scenario A 45-year-old man has easy fatiguibility for the past 12 months. On physical examination there are no abnormal findings. Laboratory studies show his Hg is 9.5, Hct 26.9%, MCV 139 fL, platelet count 240,000/microliter, and WBC count 7200/ microliter. Which of the following morphologic findings is most likely to be present on examination of his peripheral blood smear? 1. Tactoids 2. Hypersegmented RBCs 3. Hypersegmented neutrophils 4. Nucleated red blood cells 5. Blasts 6. Hypochromic, microcytic RBC’s 7. Spherocytes Pathology 447 8. Elliptocytes Ans. 3. Hypersegmented neutrophils The increased MCV points to a macrocytic anemia such as a megaloblastic anemia that can also have hypersegmented PMN’s from reduced numbers of nuclear divisions. USMLE Case Scenario Auer rods are formed of the cytoplasmic granules of the myeloid blasts of AML and are a typical finding with 1. ALL 2. AML 3. CML 4. CLL 5. Hodgkin’s disease 6. Non-hodgkin’s disease Ans. 2. AML USMLE Case Scenario Serous papillary cystadenocarcinomas of the ovaries express: 1. CA-125 2. CA-19 3. CEA 4. AFP Ans. 1. CA-125 USMLE Case Scenario A Syndrome is characterized by Pancreatic neoplasm (insulinoma), Pituitary, and Parathyroid involvement. The syndrome is: 1. Polyglandular Type 1 2. Polyglangular Type 2 3. Wermer 4. Sipple Ans. 3. Wermer USMLE Case Scenario Degenerated neurofilaments seen in patients with Alzheimer’s disease are: 1. Hirano bodies 2. Lipofuscin granules 3. Neurofibrillary tangles 4. Amyloid plaques Ans. 3. Neurofibrillary tangles USMLE Case Scenario Methyl phenyl tetrahydropyridine is taken by a 25-year-old male from California complaining of uncontrollable shaking in his hands. Most likely pathology he might have as a result of above mentioned features is: 1. Lewy bodies 2. Picks bodies 3. Negri bodies 4. Neurofibrillary tangles Ans. 1. Lewy Bodies The patient has parkinsonism induced methyl phenyl tetrahydropyridine (MPTP), a meperidine analog 448 USMLE Step 1 Platinum Notes USMLE Case Scenario A disease is associated with multiple telangiectasias which are usually small. The most likely disease is: 1. von Hippel-Lindau disease 2. Osler-Weber-Rendu disease 3. Milroy’s disease 4. Buerger’s disease Ans. 2. Osler-Weber-Rendu Disease USMLE Case Scenario A boy presents with a purple, flat vascular ectasia on the head and along distribution of the trigeminal nerve, mental retardation, seizures and hemiplegia. The most likely disease is: 1. Milroy’s disease 2. Osler-Weber-Rendu disease 3. Sturge-Weber syndrome 4. von Hippel-Lindau disease Ans. 3. Sturge-Weber syndrome USMLE Case Scenario A disease occurs with prolonged exposure to dust during glass production which can progress to respiratory failure and death, and is associated with increased risk for tuberculosis. Classic X-ray findings include calcified lymph nodes that produce an ‘eggshell’ pattern. Pleural involvement creates dense fibrous plaques and adhesions that may obliterate the pleural cavities. Most likely disease is: 1. Byssinosis 2. Berylliosis 3. Silicosis 4. Anthracosis Ans. 3. Silicosis USMLE Case Scenario It is seen that vasa vasorum of the aorta undergoes obliterative endarteritis, leading to atrophy of the muscularis and elastic tissues of the aorta and dilatation. Linear calcifications are often seen in the ascending aorta by X-ray. The intimal wrinkling is seen. The disease most likely represents: 1. Marfan’s syndrome 2. Syphilis infection 3. Aortic dissection 4. Takayasu’s arteritis Ans. 2. Syphilis infection (The intimal wrinkling or ‘tree barking’ is also a common feature) USMLE Case Scenario A patient is brought to the emergency room following a seizure. Electrolytes show SIADH. CT-Scand emonstrates a lung mass. Which of the following forms of lung cancer is most likely to cause the described electrolyte imbalance? 1. Adenocarcinoma 2. Bronchioloalveolar carcinoma 3. Large cell carcinoma 4. Small cell carcinoma Ans. 4. Small cell carcinoma Pathology 449 USMLE Case Scenario The BRCA-1 gene associated with breast cancer and ovarian cancer, is located on: 1. 17 q 2. 17 p 3. 22 q 4. 18 q Ans. 1. 17 q •• The NF-1 gene is associated with neurofibromatosis type I is on 17q •• The NF-2 gene associated with neurofibromatosis type II is on 22q •• The p53 gene associated with many cancers, is on 17p •• The DCC oncogene located on the long arm of chromosome 18q. USMLE Case Scenario A 35-year-old tall male from New Jersy has Marfan syndrome, an autosomal dominant disorder with features of subluxated lens of the eye, mitral valve prolapsed. The defect lies in: 1. Gene on chromosome 15 encoding fibrillin 2. Gene on chromosome 16 encoding fibrillin 3. Gene on chromosome 17 encoding fibrillin 4. Gene on chromosome 18 encoding fibrillin Ans. 1. Gene on chromosome 15 encoding fibrillin USMLE Case Scenario MEN II and MEN III are associated with 1. C-myc 2. Erb-B2 3. L-myc 4. Ret Ans. 4. Ret USMLE Case Scenario A 62-year-old from Wales presently in US develops oliguria and peripheral edema over a period of weeks. Urinalysis reveals hematuria and proteinuria; examination of the urinary sediment reveals red cell casts. Renal biopsy shows many glomerular crescents. This presentation is most suggestive of which of the following conditions? 1. Rapidly progressive glomerulonephritis 2. Diabetic nephropathy 3. Hypertensive nephropathy 4. Lupus nephritis Ans. 1. Rapidly progressive glomerulonephritis USMLE Case Scenario Touton giant cells are found in: 1. Xanthomas 2. Dermatofibromas 3. Actinic keratosis 4. Benign nevocellular nevus Ans. 1. Xanthoma 450 USMLE Step 1 Platinum Notes USMLE Case Scenario A 72-year-old man from Chicago with an 76 pack year history of smoking experiences an episode of hemoptysis. On physical examination he has puffiness of the face, some pedal edema. A chest radiograph reveals a 5.5 cm right upper lobe lung mass.A fine needle aspirate of this mass yields cells consistent with oat cell carcinoma. A bone scan shows no metastases. Immunohistochemical staining of the tumor cells is likely to be positive for which of the following hormones? 1. Parathormone 2. Erythropoietin 3. ACTH 4. Insulin 5. Vimentin 6. Keratin 7. Gastrin Ans. 3. ACTH USMLE Case Scenario In a Teritary level Labit is observed that chronic, increased exposure to ionizing radiation results in damage to cellular DNA. As a consequence, a protein is now absent that would arrest the cell in the G1 phase of the cell cycle. Subsequent to this, the cell is transformed to acquire the property of unregulated growth. The absent protein is most likely the product of which of the following genes? 1. RAS 2. VHL 3. p53 4. MYC 5. ABL Ans. 3. p53 USMLE Case Scenario A 55-year-old man from Chicago complains of pain in his left thigh for five months. On physical examination his thigh is increased in size, compared to the right. A plain film radiograph reveals the presence of a 15 cm solid mass that does not appear to arise from bone, but it does have infiltrative margins. A biopsy of this mass is taken and on microscopic examination the mass is composed of highly pleomorphic spindle cells. Which of the following markers is most likely to be demonstrated in the cells of this mass? 1. Cytokeratin 2. Factor VIII 3. Alpha fetoprotein 4. Lambda light chain 5. Vimentin 6. Parathormone 7. Erythropoietin 8. ACTH 9. Insulin Ans. 5. Vimentin USMLE Case Scenario PAS-positive cytoplasmic granules in hepatocytes are seen in: 1. Wilson’s disease 2. Hepatitis B 3. Alpha1-antitrypsin deficiency 4. Alcoholic hepatitis Ans. 3. Alpha1-antitrypsin deficiency PHARMACOLOGY Pharmacology 6 Important Terminology in Basic Pharmacology •• •• •• •• •• •• Affinity Intrinsic activity (efficacy) Agonist Antagonist Partial agonist Inverse agonist Ability of a drug to combine with receptor Ability of drug to activate receptor Have affinity and maximal efficacy Have affinity and no maximal efficacy Have affinity and sub maximal efficacy Have affinity and opposite efficacy Important Terminology (USMLE Favorite) •• Clearance, a measure of the body’s ability to eliminate drug; Clearance is a measure of the rate at which the organs that eliminate drug from the body remove drug from the blood •• Volume of distribution, an indication of the extent to which the drug is distributed outside of the blood compartment •• Bioavailability, the fraction of the administered dose that reaches the systemic circulation •• Steady state is achieved when the rate of drug elimination equals the rate of drug delivery into the systemic circulation, which, if bioavailability is complete, corresponds to the rate at which the drug dose is administered: •• Therapeutic index: The ratio of the toxic dose to the therapeutic dose. LD50/ED50 If absorption is too rapid, then the resulting high concentration may cause adverse effects not observed with a more slowly available formulation. At the other extreme, slow absorption is deliberately designed into ‘slow-release’ or ‘sustained-release’ drug formulations in order to maintain plasma concentrations essentially constant during the dosage interval, because the drug’s rate of elimination is offset by an equivalent rate of absorption controlled by formulation factors •• Half-Life: Half-life (t1/2) is the time that it takes for the plasma concentration or amount of drug in the body to decline by 50% •• Drug Potency: Relative concentrations of two or more drugs that elicit same effect. Refers to amount of drug needed to produce a certain response •• Drug Efficacy: Maximal effect that a particular drug may elicit •• More important than potency in determining choice of drug •• Therapeutic window phenomenon: Optimal therapeutic response of drug is exerted only over a narrow range of plasma drug concentration, e.g. TCA, clonidine, glipize. ‘Therapeutic and toxic effect’ 454 USMLE Step 1 Platinum Notes Pharmacokinetics: It is quantitative study of drug movement in through and out of the body what the body does to a drug •• Pharmacodynamics: It is what the drug dose to a body •• Pharmacogenetics: Study of genetic basis for variability in drug response •• Pharmacogenomics: Use of genetic information to guide choice of drug and dose on individual basis •• Pharmacovigilance: Science and activities related to detection, assessment, understanding and prevention of adverse effects of drug or other drug related problems. DRUG METABOLISM Occurs in two phases •• Phase I: –– Oxidation –– Reduction –– Hydrolysis –– Cyclization, Decyclization –– MFO (Mixed Function Oxidases) in Liver participate. •• Phase II: Conjugation with –– Glucronide –– Sulfate –– Glutathione, Acetylation, Methylation –– Conjugation does not occur in metabolism of xenobiotics. Factors Governing Volume of Distribution of a Drug Lipid: water coefficient of drug pKa: value of a drug Degree of Plasma protein binding Degree of blood flow Affinity for different tissues Fat: Lean body mass ratio Diseases like CHF, Uremia, Cirrhosis Pregnancy Never Forget •• •• •• •• •• •• •• Plasma protein binding occurs with many drugs Highly plasma protein bound drugs are restricted mainly to vascular compartment Displacement of protein bound drug↑ plasma levels of drug Have lower volumes of distribution Bound fraction is not available for action In hypoalbuminemia binding maybe reduced and high concentration of free drug maybe available Binding sites are nonspecific and one drug can displace other. List of ‘Prodrugs’ •• Enalapril: Enalaprilate •• Sulfasalazine: 5 Aminosalisylic acid •• Fluorouracil: Fluorouracil monophosphate Pharmacology 455 •• Dipivefrine: Epinephrine •• Predsnisone: Prednisolone •• Levodopa: Dopamine Other Prodrugs •• Methyl dopa •• Terfenadine •• Zidovudine •• Sulindac •• Cyclophosphamide •• Bacampacillin •• Fluorouracil, mercaptopurine •• Ticlopidine, Clopidregel Drug Kinetics (USMLE Favorite) 1. Drugs with zero order kinetics: Phenytoin, aspirin, ethanol, theophylline, propafenone, warfarin, tolbutamide 2. Drugs with First-order kinetics, the time required to achieve steady-state levels can be predicted from the Half-life, because accumulation is a first-order process with a half-life identical to that for elimination. Thus, accumulation reaches 90% of steadystate levels at the end of three to four half-lives. A pharmacologist is examining a new drug with potential antipsychotic properties. He begins by analyzing the pharmacokinetic properties of the drug. Studies of the drug’s rate of elimination reveal the data below. The kinetics of drug are: This drug is exhibiting zero-order kinetics, also known as saturation kinetics. Drug kinetics This means that a constant amount of drug is eliminated per unit time, regardless of the plasma concentration This is in contrast to first-order kinetics, which implies that a constant fraction of drug is eliminated per unit time, so that drug elimination is dependent on the plasma concentration Drugs with zero-order kinetics and first-order kinetics can be distinguished from each other by examining a graph depicting the time course of the disappearance of the drug from the plasma •• With zero-order kinetics, the drug concentration falls linearly •• With first-order kinetics, the drug declines in an exponential fashion. Therefore, when the Y-axis is plasma concentration (Linear concentration scale), the curve shows exponential decay; when the Y-axis is the logarithm of the plasma concentration (logarithmic concentration scale), a straight line is observed. Very few drugs actually exhibit zero-order kinetics; notable examples are: 456 USMLE Step 1 Platinum Notes –– Ethanol –– Phenytoin and –– Salicylate In Zero Order Reaction •• •• •• •• A ‘constant amount’ of drug is eliminated per unit time Rate of elimination is independent of plasma concentration Drugs with zero order elimination have no fixed half life. (t ½ is variable) Phenytoin, Ethanol and Salicylates show zero order kinetics. In First Order Reaction •• •• •• •• A Constant fraction of drug is eliminated per unit time Rate of elimination is directly dependent on plasma concentration Drugs with first order elimination have fixed half life. (t ½ is constant) Most drugs show first order kinetics. Zero order: Elimination rate constant t½ variable First order: Elimination rate variable t½ Constant ‘Some drugs follow first order kinetics but at higher doses follow zero order kinetics This is actually known as ‘Pseudo zero order’. Phenytoin, Tolbutamide, Warfarin and Theophylline follows both zero as well as first order kinetics.’ Important Points: (USMLE Favorite) •• In 1st t1/2E  50% drug eliminated •• In 2nd t1/2  75% drug eliminated •• In 3rd t1/2  87.5% drug eliminated •• In 4th t1/2  93.7% drug eliminated •• In 5th t1/2  97% drug eliminated •• Loading dose is governed by volume of distribution •• Maintainance dose is governed by clearance of drug and half life (t ½) •• •• •• •• •• •• •• Acidic drugs ionize more at alkaline pH Basic drugs ionize more at acidic pH Unionized drugs are lipid soluble and diffusible Ionized drugs are lipid insoluble and non diffusible Ionized drugs are excreted mainly by kidney Acidic drugs are absorbed in stomach. (are unionized in acidic medium and hence difusable) Basic drugs are absorbed from intestine. (Proximal) Ionized drugs poorly pass across placenta Ionized drugs poorly pass across blood brain barrier Ionized drugs poorly pass across renal tubules (Easily excreted). Pharmacology Microsomal Enzyme Inducers: (USMLE Favorite) •• Barbiturates •• Carbamazepine, clofibrate •• DDT •• Ethanol •• Griseofulvin •• Phenytoin, phenobarbitone •• Primidone Rifampicin, ritonavir Phenobarbitone Smoking, chronic alcohol intake Microsomal Enzyme Inhibitors: (USMLE Favorite) •• •• •• •• •• •• •• •• •• •• Quinolones Erythromycin Quinidine Grape fruit juice Cimetidine Allopurinol Ketocanazole Omeprazole Sulfonamides MAO inhibitors SIDE EFFECTS OF DRUGS ON IMPORTANT ORGANS Features Related to Nephrotoxicity: (USMLE Favorite) •• •• •• •• •• Most nephrotoxic cephalosporine: cephaloridine Most nephrotoxic aminoglycoside: gentamycin Least nephrotoxic antitubercular: rifampicin Least nephrotoxic aminoglycoside: tobramycin Tetracycline safe in renal failure: doxycycline Features Related to Hepatotoxicity: (USMLE Favorite) Causing ‘Hepatitis’ –– Halothane –– MAO inhibitors –– Anticonvulsants –– Methyldopa –– Rimapicin, isoniazid, pyrazinamide Causing ‘Intrahepatic Cholestasis’ –– Phenothiazines –– TCA –– NSAIDS –– Erythromycin, carbencillin, sulfonamides 457 458 USMLE Step 1 Platinum Notes Hepatotoxins •• Tetracycline •• CCL4 •• Paracetamol •• Methotrexate •• Alfatoxin Features related to Cardiotoxicity: (USMLE Favorite) •• •• •• •• •• Doxarubicin Daunorubicin Vincristine Halothane Alcohol Drugs causing Pulmonary Fibrosis •• •• •• •• •• •• •• Busulfan Bleomycin Methotrexate Nitrofurantoin Sulfasalazine Practolol Amiodarone Drugs with ‘Low Safety Margin’ •• •• •• •• •• •• Digoxin Anticonvulsants Antiarrythmics TCA (Tricyclic antidepressants) Lithium Aminoglycosides ↑Age Related Changes in Body which Effect Drug Action •• •• •• •• •• •• •• •• Body fat ↑ Volume of distribution↑ Total body water↓ Lean body mass↓ Baroreceptor sensitivity↓ Renal function↓ Serum albumin↓ Hepatic blood flow↓ The Cytochrome P-450 Mixed-Function Oxidase System: (USMLE Favorite) It is located on smooth endoplasmic reticulum in liver cells. This system is involved in the detoxification of some drugs and other exogenous compounds (barbiturates, carcinogenic hydrocarbons, steroids, carbon tetrachloride, alcohol, insecticides), and its growth can be stimulated by exposure (particularly chronic exposure) to these agents. As a consequence, cells adapted to one drug can more rapidly metabolize the other drugs and compounds handled by the P-450 system. Pharmacology Drugs Produced by DNA Recombinant Technology •• Human insulin •• Growth hormone •• Interferons •• Interleukins •• Monoclonal antibodies •• Vaccines Pharmacology of Autonomic Nervous System: High Yield Basic Points •• •• •• •• •• Neurotransmitter in all preganglionic nerves is acetyl choline Neurotransmitter in all ganglia is acetyl choline Neurotransmitter in all postganglionic parasympathetic nerves is acetyl choline Neurotransmitter in almost all postganglionic sympathetic nerves is noradrenaline except renal Mesenteric beds and sweat glands Botulinium inhibits Acetylcholine release. Ach use is not possible because it is rapidly degraded. Muscarinic Receptor Agonists •• Contraction of sphincter puppilae: Miosis •• Contraction of ciliary muscle: Accommodation •• Heart: ↓ heart rate↓ conduction velocity •• Lungs: Bronchoconstriction •• GIT: ↑motility, cramps •• Urinary bladder: Contraction •• Glands: Secretion •• Blood vessels: Dilatation 459 460 USMLE Step 1 Platinum Notes Uses •• •• •• •• Ach Bethanechol Methanechol Pilocarpine •• •• •• •• No clinical use Treatment of ileus, urinary retention Diagnosis of bronchial hyperreactivity Treatment of glaucoma, xerostomia Acetyl Cholinesterase Inhibitors •• Edrophonium: Diagnosis of myasthenia gravis •• Physostigmine: Tertiary amine antidote in atropine poisoning –– –– –– –– Neostigmine/Pyridostigmine: Treatment of ileus Urinary retention Reversal of NM blockade •• Donepezil: Treatment of Alzhiemers disease •• Organophosphates: Used as insectiscides OP Poisoning: (Important For USMLE) A 33-year-old farmer is rushed to a Peripheral Hospital after accidental exposure to parathion. He is in severe respiratory distress and is bradycardia. Which of the following drugs can be given to increase the activity of his acetylcholinesterase. Pralidoxime: PAM is an acetylcholinesterase (AChE) reactivating agent It is only useful for counteracting AChE inhibitors which act by phosphorylating the enzyme (organophosphates). Pralidoxime can remove the phosphate group from AChE, thus regenerating the enzyme. This must be done in a timely fashion because normally after the phosphate group is bound to the enzyme, it undergoes a chemical reaction known as ‘aging.’ Once this bond ages, pralidoxime will nolonger be effective Atropine is a nonselective muscarinic antagonist. Although atropine would be an appropriate agent for this patient, it acts by preventing the excess ACh from stimulating muscarinic receptors rather than altering the activity of AChE. Features of OP Poisoning: (DUMBBELSS) •• •• •• •• •• •• •• •• •• •• Diarrhea Urination Pin point pupils Miosis Bradycardia Bronchoconstriction Excitation of muscles and CNS (Nicotinic) Lacrimation Salivation Sweating Atropine is used in OP Poisoning. (Antidote) Atropine is also used for amantia (mushroom) poisoning Pralidoxime is used in conjuction and reactivates cholinesterase. Uses of Atropine Atropine is used in OP Poisoning Atropine is used as Mydriatic Pharmacology 461 Atropine is used in Mushroom poisoning Atropine is used in Preanesthetic medication Atropine is used in treating Bradyarrhythmias Nicotinic Receptor Antagonists Ganglion blockers: Hexamethonium and Mecamylamine •• Reduce autonomic tone •• Prevent baroreceptor reflex changes in heart rate a 1 agonists: Uses •• Phenyl epherine: Nasal decongestant, Mydriatic •• Methoxamine: Paroxysmal atrial tachycardia a 2 agonists: •• Clonidine and methyl dopa: used in hypertension βagonists •• Isoproterenol: β1 = β2, used in bronchospasm, heart block, bradyarrhythmias •• Dobutamine: β1 > β2 Selective β 2 agonists: •• Salmeterol, albuterol, terbutaline: Used in asthma •• Ritodrine: Used in premature labor Receptors on Which Important Drugs Act (USMLE Favorite) •• Isoprenaline •• β1, β2 •• Diastolic BP↓, HR↑ •• Noradrenaline •• Adrenaline •• a1, a2, β1 •• a1, a2, β1, β2 •• Systolic BP↑, Diastolic BP↑, HR↓ •• Systolic BP↑, Diastolic BP↓, HR↑ •• Dopamine a 1 blockers: •• Prazosin •• Doxazosin •• Terazosin •• Tamsolusin a 2 blockers: Yohimbine Mirtazapine (antidepressant) •• D1, D2, a1, a2, β1 •• Improves renal perfusion USMLE Case Scenario A 76-year-old patient is presenting with hypertension and signs and symptoms of benign prostatic hyperplasia (BPH) such as nocturia, high post-void residual volume, urinary retentionTerazosin is given. Terazosin is: an alpha-adrenergic antagonist that selectively blocks alpha-1 receptors in vascular smooth muscle producing relaxation. It is indicated for the treatment of both hypertension and BPH. Beta Blockers β 1 blockers: •• Acebutolol 462 USMLE Step 1 Platinum Notes •• Atenolol •• Metoprolol Combined β1 β2 blockers: •• Labetalol •• Carvedilol •• Dilevalol Timolol •• Used mainly for glaucoma •• No miosis No accommodative spasm •• •• •• •• •• Timolol can cause AV Block Bradycardia Hypotension Asthma Contraindicated in asthma, heart block SEROTONIN: 5HT 5HT Agonists •• 5HT1AAgonist: Antianxiety •• Buspirone, ipsapirone, gepirone •• 5HT1BAgonist: Migrane •• Sumitriptan •• 5HT4Agonist: ↑gastric motility •• Cisapride 5HT Antagonists •• 5HT2AAntagonist •• Cyproheptadine, ketansarein •• 5HT2A/2 CAntagonist •• Clozapine •• 5HT3Antagonist •• Ondansetron, granisetron, tropisetron USMLE Case Scenario A 77-year-old patient from Chicago goes to his family doctor complaining of persistent and severe headaches with aura. His physician diagnoses migraine headache and prescribes sumatriptan. What is the mechanism of action of this drug? Sumatriptan is a serotonin agonist that is used to abort migraine headaches. Antimigrane Drugs (High Yield for USMLE) •• •• •• •• Triptans act on 5HT1B receptors. (agonists) Sumatriptan is shortest acting triptan Frovatriptan is longest acting triptan Rizatriptan is fastest acting triptan –– DOC for acute migrane: aspirin, paracetamol –– DOC for acute severe migrane: sumatriptan Drugs used in prophylaxis of migrane: •• Beta blockers: propranolol Pharmacology •• •• •• •• •• TCA: amytriptiline Calcium channel blockers (flunarazine) Valproic acid, cyproheptadine Methysergide Papaverin Prostaglandins •• •• •• •• Cytoprotective for stomach Dilate renal vasculature Contract uterus Maintain ductus arteriosus PGE 1 •• Misoprostol: treatment of NSAID induced ulcer maintains ductus arteriosus •• Alprostadil: used in male impotence PGE 2 •• Dinoprostone: used in cervical ripening, abortifacient PGF 2a •• Carboprost: Abortifacient •• Latanoprost: Treatment of glaucoma PGI 2 •• Prostacyclin: Vasodilator, platelet stabilizer PGE 2 and PGF 2 •• Mediate dysmenorrheal Thrombaxanes •• Platelet aggregator Drugs used for Glaucoma Acetazolamide is a carbonic anhydrase inhibitor used firstly as IV followed by Oral dose Mannitol is also used as an IV Solution Topical drugs to be used are: •• Topical Pilocarpine 2 % •• Topical Timolol •• Topical Dorzolamide •• Topical Brinzolamide Anti glaucoma drugs •• Binatoprost •• Travoprost •• Iravoprost •• Unoprostone 463 464 USMLE Step 1 Platinum Notes USMLE Case Scenario A 66-year-old man presents to the ophthamology department in Ohio with acute onset of severe ocular pain accompanied by blurred vision that is associated with halos around lights. On examination, the left eye is red and hard; the cornea is described as having a steamy appearance, and mydriasis is noted. The most appropriate agent for the treatment of this patient’s acute signs and symptoms is: Acetazolamide (IV) Acetazolamide is a carbonic anhydrase inhibitor used firstly as IV followed by Oral dose. Aspirin •• Irreversible COX Inhibitor •• Antiplatelet •• Analgesia •• Antipyretic •• Anti-inflammatory –– Aspirin has an anti thrombotic effect –– It inhibits TXA2 synthesis in platelets by irreversible acetylation and inhibition of COX 1 –– Platelets are annucleate and cannot overcome this inhibition but endothelial cells are nucleate and can overcome this acetylation by regenerating more enzyme. (These points are gems, so try to remember not just for exams) –– This is a therapeutic effect finding use of aspirin in prophylaxis for stroke and MI management. Causes respiratory alkalosis and metabolic acidosis in high doses GIT ulceration, bleeding, salicylism: tinnitus vertigo Bronchoconstriction Reyes syndrome ↑BT Other NSAIDS Nonselective COX 2 inhibitors: •• Ibuprofen •• Naproxen •• Indomethacin •• Ketorolac •• Sulindac Selective COX 2 inhibitors: •• Celecoxib •• Etorocoxib •• Valdecoxib •• Lumiracoxib •• Rofecoxib Preferential COX 2 inhibitors: •• Nimesulide •• Meloxicam •• Nabumetone Pharmacology 465 Acetaminophen No antiplatelet action No Reyes syndrome No bronchospasm Lesser GIT effects •• Increased doses cause hepatotoxicity due to depletion of glutathione •• N acetyl cysteine is used in acetaminophen toxicity Diuretics Sites of Action Thiazides •• Chlorthiazide Distal tubule •• Hydrochlorthiazide Distal tubule •• Chlorthalidone Distal tubule •• Indapamide Distal tubule •• Metolazone Proximal and distal tubules Loop diuretics •• Frusemide Loop of Henle •• Bumatenide Loop of Henle •• Ethacrynic acid Loop of Henle Carbonic anhydrase inhibitors •• Acetazolamide Proximal tubule Potassium sparing diuretics •• Spironolactone Distal tubule and collecting duct •• Triamterene Distal tubule and collecting duct •• Amiloride Distal tubule and collecting duct Thiazides •• Chlorthalidone •• Indapamide •• Chlorothiazide •• Inhibit Na+/Cl– transporter in DCT. (Compare with loop diuretics below) •• With K+ sparing diuretics are first choice treatment of essential hypertension •• Thiazides are drugs used for ‘idiopathic Hypercalciuria.’ (Dents Disease) ‘But not’ Hypercalcemia Uses: •• CHF •• Hypertension •• Nephrogenic Diabetes Insipidus Side effects/Cause: •• Hyperglycemia •• Hyperurecemia •• Hypercalcemia Kindly understand the point: Thiazides are used in treatment of hypercalciuria but themselves causes hypercalcemia and renal stones. 466 USMLE Step 1 Platinum Notes Loop Diuretics Furoremide is basically a diuretic which acts rapidly. (High ceiling, loop diuretics) is a sulphamoyl derivative (Furosemide, bumetanide, toresamide, ethacrynic acid.) Furosemide acts on thick ascending limb of loop of Henle Inhibit Na+/K+/2Cl– transporter. (compare with thiazides above) Can be used in renal failure It is also used for: Acute Hypercalcemia Second drug of choice after morphine for Acute Pulmonary edema Uses: Heart Failure Pulmonary edema Acute Renal Failure Hypertension Anion Overdose Side effects: •• Hyperuricemia •• Hypocalcemia •• Hyperlipidemia •• Hyperglycemia •• Acute saline depletion Ethacrynic acid among the group is more ototoxic. Spironolactone and Eplerenone USMLE Case Scenario A 55-year-old male presents to Medical OPD with a chief complaint of a substantial increase in the size of his breasts over the past few months. Three months ago he was diagnosed with hypertension, and placed on antihypertensive medication. Medications most likely prescribed was Spironolactone. Spironolactone antagonizes the sodium retaining effect of aldosterone and is used to treat Cirrhotic edema Nephrotic syndrome CHF and Hyperaldosteronism •• It also acts as a diuretic. (Pottasium sparing) •• Caneronone is its active metabolite. •• Spironolactone reduces potassium loss and in combination with other potassium sparing diuretics, fatal hyperkalemia can occur. Side effects are: •• Rashes •• Abdominal pain •• Amenorrhea •• Gynecomastia Pharmacology Triamterene and Amiloride Pottasium sparing diuretics Saluretic effect is greater than thiazides Block Na+ channels in collecting duct Amiloride is more potent. Acetazolamide Carbonic anhydrase inhibitors (CA) •• Acetazolamide •• Dorazolamide •• Brinzolamide CA is present in renal tubular cells, gastric mucosa, exocrine pancreas, brain, RBC and ciliary body of eye Uses: •• •• •• •• Glaucoma Acute mountain sickness Epilepsy Not given in ‘sulfonamide sensitivity’ Mannitol •• •• •• •• •• Primary site of action of Mannitol is proximal tubule Mannitol increases blood viscosity and increases perfusion Mannitol is not metabolized Mannitol is given parentally On oral administration mannitol causes Osmotic diarrhea. Uses: •• Reduce ICT (Intra Cranial Tension) •• Reduce IOT (Intra Ocular Tension) •• Increase Urine volume in Renal Compromise •• Should not be given in ATN, anuria, pulmonary edema Toxicity: •• Extracellular volume Expansion •• Dehydration and Hypernatremia. Raised ICT: Treatment •• IV mannitol •• Furosemide •• •• •• •• Hyperventilation Fluid restriction Osmotic agents Corticosteroids (dexamethasone) for vasogenic edema Antidiuretics Vasopressin Lypressin Terlipressin 467 468 USMLE Step 1 Platinum Notes Desmopressin •• Given intranasally •• ‘DOC for Diabetes insipidus’ •• Lithium •• Demeclocycline ‘DOC for SIADH’ Desmopressin •• Desmopressin (DDAVP) is a synthetic replacement for vasopressin, the hormone that reduces urine production during sleep. It maybe taken nasally, intravenously, or as a pill •• Clinical uses Bedwetting •• Desmopressin is frequently used for treatment of bedwetting. It is usually in the form of Desmopressin acetate, DDAVP. The drug replaces the antidiuretic hormone for a single night with no cumulative effect Coagulation disorders •• Desmopressin can be used to promote the release of von Willebrand factor and factor VIII in patients with coagulation disorders such as type I von Willebrand disease, mild hemophilia A, and thrombocytopenia. It is not effective in the treatment of hemophilia B or severe hemophilia A Diabetes Insipidus •• Desmopressin is also used to replace missing ADH in central diabetes. ANTIDIABETIC DRUGS Metformin •• ↑Glycolysis •• ↓Gluconeogenesis •• Diarrhea and metallic taste in mouth are adverse features –– It is particularly used in obese patients –– It does not cause weight gain –– –– –– –– Lactic acidosis is a feared complication of Metformin use Metformin should not be used in Renal impairment Causes Malabsorption of Vit B12 Metformin is a biguanide Acarbose and Miglitol are alpha glucosidase inhibitor Decreases progression of impaired glucose tolerance to overt disease. Along with (metformin, orlistat reduces fibrinogen levels also are euglycemics. Do not cause hypoglycemia Side effects are: GIT Discomfort, Flatulence and Diarrhea. Also known as starch inhibitor –– Potential Hepatotoxicity has been demonstrated. Hypoglycemia occurs with sulfonylureas (Tolbutamide) and can be severe, prolonged for days and fatal especially in elderly and in heart failure. ‘Thiazolidinediones’ Thiazolidinediones or TZDs act by binding to PPARs (peroxisome proliferator-activated receptors), a group of receptor molecules inside the cell nucleus, specifically PPAR γ (gamma) The ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, the receptor migrates to the DNA, activating transcription of a number of specific genes. By activating PPAR γ: •• Insulin resistance is decreased •• Insulin sensitivity↑ Pharmacology 469 •• Adipocyte differentiation is modified •• VEGF-induced angiogenesis is inhibited •• Leptin levels decrease (leading to an increased appetite) •• Levels of certain interleukins (e.g. IL-6) fall •• Adiponectin levels rise. Chemically, the members of this class are derivatives of the parent compound thiazolidinedione, and include: •• Rosiglitazone •• Pioglitazone •• Troglitazone, which was withdrawn from the market due to an increased incidence of drug-induced hepatitis •• Rivoglitazone •• Ciglitazone Piaglitazone and rosiglitazone are antihyperglycemics which bind to PPAR (Peroxisome Proliferator Activating Receptors) increase insulin sensitivity, increase insulin receptor numbers and decrease hepatic gluconeogenesis. Side effects Hypoglycemia, weight gain, edema Repaglinide and Nateglinide •• Stimulate insulin release from Pancreatic Beta cells •• Used in Type II DM as an adjunct just before meals •• Have rapid onset, short duration. Glucagon like Peptide-Exenatide •• It is an incretin released from small intestine •• Glucagon like peptide. (GLP 1 analouge) •• Augments insulin secretion •• Degraded by enzyme dipeptidyl peptidase DPP4 •• Sitagliptin inhibits DPP4 and hence augments action of exenatide •• It is a full agonist and used as a combination Pramlinitide •• Synthetic amylin analogue: •• Reduces glucagon secretion from alpha cells of pancreas •• Useful in both type 1 and type 2 DM Glucomannan •• •• •• •• •• •• •• Powdered extract from konjar Promoted as a dietary fiber for diabetics Dietary adjunct for diabetes ↓Appetite, ↓Serum lipids ↓Blood sugar ↓Constipation 470 USMLE Step 1 Platinum Notes Insulin •• t ½ of insulin in blood is: 5 minutes •• Insulin causes potassium entry into cell •• Insulin has 51 amino acids. Human insulin differs from pork insulin by 1 amino acid •• Humulin is human insulin Insulin types •• Rapid acting •• Insulin aspartate •• Lisproinsulin •• Insulin glusuline •• Short acting •• Semilentene •• Soluble insulin (SSS) •• Intermediate acting •• Insulin zinc suspension •• Isophane insulin •• Long acting •• Protamine zinc insulin •• Insulin glargine Rapid → Slow Lispro > Regular > NPH> Lente > Ultralente > Glargine Types of insulin Factors effecting insulin release USMLE Case Scenario An overweight 48-year-old male from Texas presents with complaints of increased thirst and frequent urination. Laboratory examination reveals a blood glucose level of 192 mg/dL. The patient’s past medical history is unremarkable, except for an anaphylactic reaction that occurred one year ago when he was given trimethoprim-sulfamethoxazole for a sinus infection. Based on this information, which of the following agents should be prescribed? 1. Chlorpropamide 2. Glipizide 3. Glucagon 4. Metformin 5. Propranolol Ans. 4. Metformin The patient’s presentation strongly suggests Type 2 diabetes mellitus (NIDDM), which usually begins in middle or late life. Obesity makes Metformin DOC. USMLE Case Scenario An obese patient presented in casualty in an unconscious state. His blood sugar measured 400 mg%, urine tested positive for sugar and ketones; drug most useful in management is: 1. Glibenclamide 2. Troglitazone 3. Insulin 4. Chlorpropamide Ans. 3. Insulin Pharmacology 471 Diabetes Insipidus Thiazides paradoxically exert an antidiuretic effect in diabetes insipidus DRUGS USED IN DI: •• Vasopressin (Neurogenic DI) •• Amiloride (Lithium induced DI) •• Indomethacin •• Chlorpropamide •• Carbamazepine •• Clofibrate Corticoids •• •• •• •• Maximum mineralocorticoid activity: Aldosterone Maximum glucocorticoid activity: Dexamethasone Glucocorticoids with maximum mineralocorticoid activity: Hydrocortisone Glucocorticoids with minimum glucocorticoid activity: Hydrocortisone Antiandrogens •• •• •• •• •• •• Flutamide Biclutamide Finasteride Dutasteride Danazol Cyproterone (Androgen receptor blocker) Important Table •• Flutamide: Used in metastatic prostate cancer •• Has fast action in case of BHP •• Biclutamide: Longer acting and more potent analogue of flutamide •• Finasteride: Selective 5 α reductase type 1 inhibitor –– Uses BHP, hirusitism –– Male pattern baldness •• Dutasteride: 5 α reductase type 1 and type 2 inhibitor. Longer acting •• Cyproterone: Used in PCOD, Precocious puberty •• Clompihene is antiestrogen Tamoxifen (USMLE Favorite) Tamoxifen is an ‘oral selective estrogen receptor modulator’ ↓FSH It is used for the ‘treatment of early and advanced breast cancer’ in both pre- and post-menopausal women It is also ‘approved by the FDA’ for the ‘reduction of the incidence of breast cancer’ in women at high-risk of developing the disease. It has been further approved for the reduction of contralateral (in the opposite breast) breast cancer •• It has ‘benefit throughout the whole spectrum of breast cancer’: In the treatment of noninvasive ductal carcinoma in situ (DCIS) it has been shown to be effective as adjuvant to surgery and radiotherapy. In early breast cancer adjuvant treatment with tamoxifen has been shown to significantly reduce the risk of disease recurrence and death, and reduce the risk of new primary tumors developing in the contralateral breast. •• •• •• •• 472 USMLE Step 1 Platinum Notes •• These benefits appear to ‘apply to both node-negative and node-positive disease’ and irrespective of the menopausal status of the patient. Five years of treatment with tamoxifen is currently recommended in the adjuvant setting •• Tamoxifen is a well-established endocrine treatment for advanced breast cancer, providing effective palliative treatment in hormone-responsive breast cancer ‘at all stages of the disease and irrespective of the age of the patient’ •• Given orally once daily, it is relatively well tolerated, most side effects being of an antioestrogenic nature – hot flushes, tachycardia •• However, as a partial agonist the drug also displays some estrogenic properties. Whilst these can confer some benefits in postmenopausal women, such as protection against osteoporosis and cardiovascular disease, they can also have detrimental effects in a small number of women, notably an increase in the risk of ‘endometrial hyperplasia and carcinoma’. •• Exemastine, latrazole are other hormonal agents used for breast cancer. •• Latrazole is an aromatase inhibitor. Tamoxifen is known to act as an estrogen agonist at the level of the endometrium. Numerous studies have shown that women on tamoxifen develop changes in the endometrium including polyps, hyperplasia, and cancer. Hyperplasia runs a continuum from cystic glandular hyperplasia to atypical hyperplasia. Patients with atypical hyperplasia are at significantly increased risk for the eventual development of endometrial cancer. Thus, in a patient who is taking tamoxifen for breast cancer prevention and develops atypical endometrial hyperplasia, the tamoxifen should be stopped. If there is a need to continue the tamoxifen, then hysterectomy should be considered. Antiasthmatics Theophylline and Doxophylline Mechanism of Action: Inhibits phosphodiesterase 4 and increases cAMP concentration Blocks adenosine receptors Releases calcium from Sarcoplasm BETA 2 Agonist Mucociliary movement stimulator Important points about metabolism: •• It has low therapeutic index •• At high doses kinetics changes from First order to zero order •• Erythromycin inhibits metabolism of Theophylline (Increases Theophylline levels) •• Crosses placenta and is secreted in milk •• Smoking, phenytoin, rifampicin, phenobarbitone ↓ plasma levels of Theophylline •• Erythromycin, ciprofloxacin, cimetidine, allopurinol ↑ plasma levels of theophylline Sodium Cromoglycate •• •• •• •• Inhibits mast cell degranulation Ineffective in acute attack Used for prophylaxis Not absorbed orally, given as aerosol Montelukast •• Montelukast is a LTRA (Leukotriene receptor antagonist) used in maintenance therapy of asthma and relief of seasonal allergies •• It is not useful in acute attacks. It is usually administered orally •• Montelukast is a CysLT1 antagonist; that is it blocks the action of leukotriene D4 on the cysteinyl leukotriene receptor CysLT1 in the lungs and bronchial tubes by binding to it. This reduces the bronchoconstriction otherwise caused by the leukotriene, and results in less inflammation •• Because of its method of operation, it is not useful for the treatment of acute asthma attacks. Again because of its very specific focus of operation, it does not interact with other allergy medications such as theophylline. Pharmacology 473 Side effects •• Side effects include gastrointestinal disturbances, hypersensitivity reactions, sleep disorders and increased bleeding tendency, aside from many other generic adverse reactions. Its use is associated with a higher incidence of Churg-Strauss syndrome •• Another leukotriene receptor antagonist is zafirlukast taken once daily •• 5 lipo oxygenase inhibitor is Zileuton. Beta 2 Sympathomimetic Bronchodilators •• •• •• •• Salbutamol, Terbutaline: Short acting: Used in acute attacks Salmeterol, bambuterol, formoterol: Long acting: used for prophylaxis Most effective bronchodilators No anti-inflammatory effects Side Effects: •• Hypokalemia •• Hyperglycemia •• Tolerance, tachyphylaxis Ipratropium and Tiotropium •• Anticholinergic bronchodilators •• Bronchodilators of choice in COPD/COAD Steroids •• •• •• •• •• •• Are anti-inflammatory ↑Lipocortin levels Block phospholipid breakdown Not bronchodilators Have no role in acute attacks or status asthamaticus Reduce airway inflammation –– Beclomethasone –– Budesonide –– Fluticasone –– Flunisolide –– Triamicinolone –– Ciclesonide are commonly used steroids. Effects of antiasthamatics 474 USMLE Step 1 Platinum Notes Newer Drugs •• Omalizumab –– Humanized IgE antibody –– Reduces frequency of Asthma exacerbations •• Ciclesonide: –– Inhalational steroid –– Prodrug •• Cilomilast, Roflumilast –– PGE 4 inhibitors Ist Generation Antihistaminics Terfenadine is the drug listed that does not cross the blood-brain barrier and therefore does not cause sedation (a bad thing for someone flying an airplane). Other drugs from the same class include astemizole and loratadine. •• Diphenhydramine •• Dimenhydrinate •• Promethazine •• Hydroxyzine •• Meclizine •• Pheniramine •• Chlorpheniramine •• Cyclazine Second Generation Antihistaminics •• Terfenadine •• Astemizole •• Loratidine •• Cetrizine •• Fexofenadine •• Rupatidine •• Azelastine •• Acrivastin Drugs Acting on GIT Prokinetics are: •• Metoclop aramide •• Domperidone •• Cisapride •• Mozapride •• Primary indication is Gastroesophageal Reflux Disease (GERD) •• Antiulcer drugs •• Ranitidine •• Roxatidine •• Famotidine Pharmacology 475 •• Omeprazole •• Esmoperazole •• Rabeperazole •• Pentoprazole •• Proton pump inhibitor –– Are long acting –– Are long lasting –– Have high first pass metabolism •• Sucralfate: Ulcer protectant •• H pylori gastritis responds to: Omeprazole, clarithromycin, amoxicillin, metronidazole therapies, bismuth •• Triple therapy: (Lansoprazole, clarithromycin and amoxicillin) •• Triple therapy: (Bismuth subsalicylate, tetracycline, and metronidazole). Sucralfate It is a drug that is not presently in widespread use because it is incompatible with H2 antagonists such as cimetidine, ranitidine, famotidine and nizatidine. Sucralfate is aluminum sucrose sulfate, a sulfated disaccharide, which polymerizes and binds to ulcerated tissue. It forms a protective coating against acid, pepsin and bile, giving the tissue a chance to heal. Unfortunately, a low gastric pH is required for polymerization, meaning that sucralfate is incompatible with drugs that reduce gastric acidity, such as H2 blockers and antacids. ANTIBIOTICS Mechanism of Action of Antibiotics Inhibition of Cell wall Synthesis •• Inhibition of cross linking (Transpeptidase): Pencillins, Cephalosporins, Vancomycin, Imipinem, Aztreonam •• Inhibition of Peptidoglycan synthesis: Cycloserine, Bacitracin •• Inhibition of β glucan synthesis: Caspofungin Inhibitors of Protein Synthesis •• Aminoglycosides, Tetracyclines bind to 30S Ribosomal subunit •• Chloramphenicol, erythromycin, clindamycin bind to 50S Ribosomal subunit Inhibition of Nucleic Acid Synthesis •• Rifampin blocks RNA Synthesis RNA polymerase •• Quinolones inhibit DNA Synthesis DNA gyrase (Topoisomerase) •• Sulfonamides and trimethoprim inhibit Nucleotide synthesis of tetrahydrofolic acid. Alteration of Cell Membrane •• Antibacterial Polymyxin •• Antifungal Azoles (Ketoconazole, Flucoriazole, Itracanazole) inhibit ergosterol synthesis •• Amphoterecin disrupts fungal cell membrane by binding to ergosterol. Metronidazole acts as an electronic sink taking away electrons that organisms need for survival 476 USMLE Step 1 Platinum Notes Actions of drugs Drugs Inhibiting Cell Wall Synthesis: (USMLE Favorite) •• •• •• •• •• Penicillins Cephalosporins Cycloserine Vancomycin Bacitracin Drugs Acting on Cell Membrane: (USMLE Favorite) •• •• •• •• Amphotercin Nystatin Polymyxin Colistin Drugs Interfering with Metabolism •• •• •• •• Trimethoprim Sulfonamides Ethambutol, Pyrimethamine PAS Mechanism of Action of Antimicrobials •• Aminoglycoside, Tetracyclines Block protein synthesis at the 30S ribosomal Subunit •• Chloramphenicol Blocks protein synthesis at the 50S ribosomal subunit Pharmacology •• Clindamycin Blocks protein synthesis at the 50S ribosomal subunit •• Macrolides Block protein synthesis at the 50S ribosomal subunit •• Penicillin along with the cephalosporins, imipenem and actreonam, penicillin inhibits peptidoglycan cross-linking •• Quinolones Block DNA topoisomerases •• Rifampicin Blocks mRNA synthesis •• Sulfonamides Block nucleotide synthesis •• Vancomycin Blocks peptidoglycan synthesis Drugs effecting folate metabolism Types of drugs •• Bacteriostatic drugs: –– Erythromycin –– Clindamycin –– Chloramphenicol –– Streptomycin –– Tetracycline –– Trimethoprim •• Bacteriocidal drugs: –– Penicillin –– Cephalosporin –– Aminoglycosides –– Metronidazole Mechanism of Action Outlined Aminoglycosides and tetracyclines bind to 30S Ribosomal subunit Chloramphenicol, erythromycin, clindamycin bind to 50S Ribosomal subunit Chloramphenicol inhibits bacterial protein synthesis by blocking peptidyl transferase •• •• •• •• Isoniazid inhibits synthesis of mycolic acid Metronidazole acts as an electronic sink taking away electrons that organisms need for survival Rifampicin blocks RNA polymerase Quinolones inhibit DNA gyrase (topoisomerase) 477 478 •• •• •• •• •• USMLE Step 1 Platinum Notes Sulfonamides and trimethoprim inhibit synthesis of tetrahydrofolic acid Azoles (Ketoconazole, fluconazole, Itracanazole) inhibit ergosterol synthesis Amphoterecin disrupts fungal cell membrane by binding to ergosterol Vancomycin inhibits transpeptidases Capsofungin blocks synthesis of β glucan Penicillinase-resistant penicillins are able to resist degradation by staphylococcal penicillinase Methicillin, (Acid labile) Nafcillin Oxacillin Cloxacillin Dicloxacillin Flucloxacillin CEPHALOSPORINS Ist Gen: effective against gram+ ve organisms Cefazolin Cephalothin Cephapirin Cephalexin Cefadroxil Cephradine 2nd Gen: effective against gram-organisms Cefamandole, Cefuroxime, Cefoxitin, Cefotetan, Cefmetazole, Cefaclor, Cefprozil, Cefpodoxime, Loracarbef 3rd Gen: Effective against gram-enterobacteriacea Cefotaxime Ceftriaxone Ceftizoxime Ceftazidime Cefoperazone 4th Gen Cefepime Cefpirome Cefepime •• The fourth-generation cephalosporin cefepime is more resistant to hydrolysis by beta-lactamases than are the thirdgeneration cephalosporins is stable against plasmid-encoded beta-lactamase and is also relatively resistant to the inducible chromosomally encoded beta-lactamases •• Penetrates rapidly into gram-negative bacteria •• Targets multiple essential penicillin-binding proteins •• Cefoxitine is effective against anaerobes •• Cephaperazone has antipseudomonal activity •• Cefepime is inactive against, methicillin-resistant staphylococci, penicillin-resistant pneumococci, most strains of Clostridium difficile, and most strains of enterococci such as Enterococcus faecalis. Quinupristin and Dalfopristin (USMLE Favorite) •• Quinupristin and dalfopristin are used in treatment of vancomycin-resistant Enterococcus faecium (VREF) •• Bind 50 S ribosome •• Dalfopristin inhibits the early phase of protein synthesis in the bacterial ribosome and quinupristin inhibits the late phase of protein synthesis •• Quinupristin and dalfopristin are bacteriostatic against Enterococcus faecium and bacteriocidal against strains of methicillinsusceptible and methicillin-resistant staphylococci. Pharmacology 479 •• Quinupristin and dalfopristin combination, a streptogamin antibacterial agent for intravenous administration, is a sterile lyophilized formulation of two semisynthetic pristinamycin derivatives •• Quinupristin is derived from pristinamycin I •• Dalfopristin is derived from pristinamycin IIA ‘Drugs and Protein Synthesis’ Linezolid interferes with formation of Initiation complex Dalforpristin interferes with Amino Acid Incorporation Quinipristine interferes with Amino Acid Incorporation Chloramphenicol interferes with formation of Peptide bonds Macrolides interfere with translocation Sites of action Carbapenams •• •• •• •• Imipenem Meropenem Faropenem Ertapenem –– Effective against gram–, gram-, anaerobic pathogenic bacteria –– Beta lactamase resistant –– Imipenem is inhibited by dehydropeptidase and hence given along with cilastatin. Aztreonam •• It is a monobactam •• No activity against gram+ and anaerobes •• Can be safely used in patients allergic to pencillin and related group of drugs because of lack of cross reactivity. Linezoild It is a synthetic antibiotic used for the treatment of serious infections caused by multi-resistant Gram-positive bacteria, including •• Streptococci •• Vancomycin-resistant enterococci (VRE) •• Methicillin-resistant staphylococcus aureus (MRSA) •• Linezolid is a protein synthesis inhibitor: •• Unlike most other protein synthesis inhibitors, which inhibit elongation, linezolid appears to work on the first step of protein synthesis, i.e. ‘initiation’ •• Linezolid binds to the 23S portion of the 50S subunit (the center of peptidyl transferase activity) •• Linezolid is effective against all clinically important Gram-positive bacteria, notably Enterococcus faecium and Enterococcus faecalis (including vancomycin-resistant enterococci), Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus, MRSA), Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes •• It has almost no effect on Gram-negative bacteria. 480 USMLE Step 1 Platinum Notes Macrolides Three important macrolides are: Erythromycin Azithromycin and Chlarithromycin –– Azithromycin is effective against Chlamydia, Mycoplasma, Ureaplasma, Legionella. Mycobacterium avium intercellulare –– Azithromycin is excreted by kidneys –– Azithromycin does not inhibit cytochrome P450 (IS NOT AN ENZYME INHIBITOR) –– Azithromycin is safe in pregnancy Clarithromycin is most effective against H Pylori Macrolides stimulate motilin receptors and cause GIT distress Erythromycin estolate causes cholestatic jaundice Erythromycin is used in penicillin allergics In meningitis and pencillin allergy Chloramphenicol is used. Telithromycin •• •• •• •• •• •• •• It is the first ketolide antibiotic to enter clinical use It is used to treat mild to moderate respiratory infections Telithromycin is a semi-synthetic erythromycin derivative Telithromycin prevents bacteria from growing, by interfering with their protein synthesis Telithromycin binds to the subunit 50S of the bacterial ribosome, and blocks the progression of the growing polypeptide chain Telithromycin has over 10 times higher affinity to the subunit 50S than erythromycin Telithromycin is metabolized mainly in the liver, the main elimination route being the bile, a small portion is also excreted into the urine. GLYCOPEPTIDES ANTIBIOTICS: VANCOMYCIN, TEICOPLANIN Vancomycin: (USMLE Favorite) •• Inhibits bacterial cell wall •• Ototoxicity, nephrotoxicity, Red man syndrome •• It is DOC for MRSA infection and used for pseudomembranous colitis Teicoplanin: (USMLE Favorite) •• Teicoplanin is an antibiotic used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including MRSA. Methicillin-resistant Staphylococcus aureus and Enterococcus faecalis. •• It is a glycopeptide antibiotic extracted from Actinoplanes teichomyceticus, with a similar spectrum of activity to vancomycin •• Its mechanism of action is to inhibit bacterial cell wall synthesis. Clindamycin: (USMLE Favorite) •• •• •• •• •• Lincosamide antibiotic Inhibits protein synthesis Binds to 50S ribosomal subunit Implicated in pseudomembranous colitis DOC for streptococcal necrotizing fasciitis USMLE Case Scenario Following the treatment of an oral abscess with clindamycin, a patient develops a greenish, foul-smelling watery diarrhea with left lower quadrant pain. Other signs and symptoms include fever, leukocytosis, and lethargy. If the toxin produced by Clostridium difficile is detected in the stool, the patient would most appropriately be treated with Metronidazole. Pharmacology 481 Antibiotic-induced colitis (pseudomembranous colitis) is characterized by severe persistent greenish, foul-smelling diarrhea and severe abdominal cramps, as well as fever, leukocytosis, and lethargy. This condition is caused by the toxin produced by Clostridium difficile. This disorder is after clindamycin therapy. Tetracyclines •• Group I: Tetracycline, oxytetracycline, Chlortetracycline •• Group II: Demeclocycline •• Group III: Minocycline, Doxycycline are bacteriostatic •• Tetracyclines bind to 30S Ribosomal subunit Doxycycline: All tetracyclines are ‘nephrotoxic’ except Doxycycline Doxycycline is metabolized and excreted via liver in bile. Doxycycline is not excreted via kidneys and hence is not nephrotoxic. All tetracyclines except doxycycline ‘accumulate’ in renal failure All tetracyclines except doxycycline ‘enhance’ renal failure. Contraindicated in pregnancy, lactation •• Outdated tetracyclines cause Fanconis syndrome •• Doxycycline causes photodermatitis •• Are teratogenic •• Cause super infections •• Cause tooth discoloration •• Minocycline causes pigmentation Uses •• Doxycycline is indicated for use in the treatment of chronic adult periodontitis in order to increase clinical attachment, reduce probing depth, and reduce bleeding upon probing •• Endocervical, rectal, or urethral infection, uncomplicated, caused by Chlamydia trachomatis •• Epididymo-orchitis caused by C trachomatis or Neisseria gonorrheae or •• Nongonococcal urethritis caused by C trachomatis or Ureaplasma urealyticum •• Gonococcal infections, uncomplicated (except anorectal infections in men) •• Lyme disease •• Malaria prophylaxis •• Syphilis (early), for penicillin-allergic patients •• Syphilis (of > 1 year’s duration), for penicillin-allergic patients Chloramphenicol •• •• •• •• Binds 50S subunit Bacteriostatic Blocks elongation of peptide chain Undergoes extensive enterohepatic circulation •• Causes aplastic anemia •• Causes grey baby syndrome 482 USMLE Step 1 Platinum Notes Aminoglycosides •• •• •• •• •• •• •• •• •• Bactericidal Inhibit translation Active against gram–bacilli Ineffective against anaerobes Used synergestic with pencillins Distributed only extra cellularly Netlimicin is least ototoxic Framycetin, sisomycin are aminoglycosides Streptomycin is used in treatment of plague/tularemia •• Teratogenic •• Ototoxic •• Vestibulotoxic •• Nephrotoxic •• Cause neuromuscular blokade •• •• •• •• Ototoxicity is due to damage to stereocilia Should not be used in myasthenia gravis Resistance is due to enzyme production Amikacin is one of the most resistant to bacterial inactivating enzymes. Quinolones Ist generation: –– Norfloxacin, ciprofloxacin, ofloxacin, pefloxacin 2 nd generation: –– lomefloxacin, levofloxacin, sparfloxacin, gatifloxacin, moxifloxacin –– Pefloxacin: Attains high CSF concentration –– Levofloxacin: Highest oral bioavailability –– Pefloxacin: Highest first pass metabolism –– Sparfloxacin: Longest acting, phototoxic –– Moxifloxacin: Most potent, active against gram-positive organisms are contraindicated in children •• Cause arthopathy in children •• Temafloxin: Causes immune hemolytic anemia •• Trovafloxacin: Hepatotoxic Chemoprophylactic Agents of Choice •• •• •• •• •• •• •• •• •• Cholera Plague P carnii Whooping cough Diphtheria TB MAC Malaria Rheumatic fever •• •• •• •• •• •• •• •• •• Tetracycline Tetracycline Cotrimaxozole Erythromycin Erythromycin INH Clarithromycin, azithromycin Chloroquine Benzathine pencillin Pharmacology PARASITOLOGY Antimalarials Treatment of •• Chloroquine sensitive malaria: chloroquine •• Chloroquine resistant malaria: mefloquine •• Mefloquine resistant malaria: sulfadoxine+pyremethamine Quinine •• It is the DOC for cerebral malaria •• Causes hypoglycemia •• Can be given safely in pregnancy along with chloroquine Primaquine •• It is the only antimalarial active in exoerythrocytic stage •• Primaquine is ineffective against p falciparum •• Primaquine is effective for radical cure of pl vivax •• Can cause G6PD deficiency Halofantrine It is effective against Chloroquine resistant p falciparum and p vivax Causes prolonged QT •• Artemensin derivatives •• (artesunate, artemether, arteheter) are fastest acting erythrocytic schizontocides •• Lumefantrine is an antimalarial •• Pyronaridine is an antimalarial Chloroquine Chloroquine is an antimalarial drug Chloroquine is also an immunosuppressant drug Chloroquine is lysomotrophic (accumulates in lysosomes) It is widely distributed in adipose tissue It also has –– Antitumor –– Antiviral –– DMARD Properties It is used in treatment of SLE, Rheumatoid arthritis Chloroquine is known to cause lots of side effects •• •• •• •• •• Occular manifestations: •• Keratopathy •• Retinal toxicity •• Blurred vision •• Corneal deposits •• Central serous retinopathy •• Pigmentary bulls eye retinopathy •• Optic atrophy –– Myopathy –– Retinopathy Antifungal Drugs Antifungal •• •• •• •• Amphotericin B Griseofulvin Ketoconazole Flucytosine Mechanism of Action •• •• •• •• Affinity for ergosterol, forms micropores in fungal cell membrane Interferes with mitosis, disorients microtubules Inhibits fungal lanosterol 14-demethylase, impairing ergosterol synthesis Inhibits thymidilate synthetase (after being converted to active form;5-fluorouracil) 483 484 USMLE Step 1 Platinum Notes •• Polyenes- amphotericin b, nystatin, hamycin, natamycin •• Heterocyclic benzofuran- griseofulvin •• Azole, miconazole, clotrimazole, ketoconazole. Aspergillosis (treatment) Itraconazole is indicated in the treatment of aspergillosis caused by Aspergillus species in patients who are intolerant of or refractory to amphotericin B therapy Blastomycosis (treatment) Itraconazole is indicated for the treatment of pulmonary and extrapulmonary blastomycosis caused by Blastomyces dermatiditis in immunocompromised and nonimmunocompromised patients Candidiasis (prophylaxis) Fluconazole is indicated for the prophylaxis of candidiasis in patients undergoing bone marrow transplant who receive cytotoxic chemotherapy and/or radiation therapy. Amphotericin Polyene derivative Derived from streptomyces nodosus Fungicidal as well as fungistatic High affinity for ergosterol Given IV with glucose solution Given as lipid bound preparations –– Amphotericin B lipid complex –– Amphotericin B colloid suspension –– Liposomal Amphotericin Decreases toxicity –– It is not mixed with saline •• Causes hypokalemia •• •• •• •• •• •• Parenteral Amphotericin •• •• •• •• •• •• •• •• •• •• •• •• Parenteral amphotericin B is indicated in the treatment of aspergillosis caused by Aspergillus fumigates Parenteral amphotericin B is indicated in the treatment of disseminated candidiasis caused by Candida species Parenteral amphotericin B is indicated in the treatment of coccidioidomycosis caused by Coccidioides immitis Parenteral amphotericin B is indicated in the treatment of cryptococcosis caused by Cryptococcus neoformans Parenteral amphotericin B is indicated in the treatment of fungal endocarditis Parenteral and intraocular administration of amphotericin B are used in the treatment of candidal endophthalmitis Parenteral amphotericin B is indicated in the treatment of histoplasmosis caused by Histoplasma capsulatum Parenteral amphotericin B is indicated, with or without concurrent administration of flucytosine, in the treatment and suppression of cryptococcal meningitis caused by Cryptococcus neoformans Parenteral amphotericin B is also indicated in the treatment of fungal meningitis caused by organisms such as Coccidioides immitis, Candida species, Sporothrix schenckii, and Aspergillus species Parenteral amphotericin B is indicated in the treatment of mucormycosis (phycomycosis) caused by Mucor, Rhizopus, Absidia, Entomophthora, and Basidiobolus organisms Parenteral amphotericin B is indicated in the treatment of fungal septicemia Parenteral amphotericin B is indicated in the treatment of disseminated sporotrichosis caused by Sporothrix schenckii. Antivirals: (USMLE Favorite) •• Acyclovir is a highly potent and selective inhibitor of the replication of certain herpesviruses, including herpes simplex virus (HSV) types 1 and 2, varicella-zoster virus (VZV), and Epstein-Barr virus (EBV). •• Valacyclovir –– The L-valyl ester of acyclovir –– It is converted almost entirely to acyclovir after oral administration –– Valacyclovir has pharmacokinetic advantages over orally administered acyclovir –– It exhibits significantly greater oral bioavailability Pharmacology 485 –– Results in higher blood levels and –– Can be given less frequently than acyclovir •• Cidofovir:Cidofovir is a phosphonate nucleotide analogue of cytosine –– Its major use is in CMV infections, particularly retinitis, but it is active against a broad range of herpesviruses, including HSV, human herpesvirus (HHV) type 6, HHV-8 •• Fomivirsen: Fomivirsen is the first antisense oligonucleotide •• Fomivirsen has been approved for intravitreal administration in the treatment of CMV retinitis in AIDS patients who have failed to respond to other treatments or cannot tolerate them •• Ganciclovir: –– An analogue of acyclovir, ganciclovir is active against HSV and VZV and is markedly more active than acyclovir against CMV. •• Famciclovir and Penciclovir •• Foscarnet: Foscarnet (phosphonoformic acid) is a pyrophosphate-containing compound that potently inhibits herpesviruses, including CMV. •• Idoxuridine: Analogue of thymidine –– Idoxuridine inhibits the replication of herpesviruses and poxviruses –– Cannot be given orally •• Trifluridine: Trifluridine is a pyrimidine nucleoside active against HSV-1, HSV-2, and CMV. •• Vidarabine: Vidarabine is a purine nucleoside analogue with activity against HSV-1, HSV-2, VZV, and EBV. USMLE Case Scenario A 29-year-old female diagnosed with AIDS has been suffering from a progressive blurring of vision in her right eye. On funduscopic examination, a small white opaque lesion is noted on the retina of her right eye. This patient is most likely suffering from cytomegalovirus (CMV) retinitis. The best drug treatment for this infection is ganciclovir. Other Antiviral Drugs •• Lamivudine is a pyrimidine nucleoside analogue that is used primarily in combination therapy against HIV infection. It is also active against HBV through inhibition of the viral DNA polymerase and has been approved for the treatment of chronic HBV infection. •• Lobucavir is a synthetic cyclobutane nucleoside analogue with activity against a broad range of herpesviruses, HIV, and HBV. •• Pleconaril is an investigational drug active in vitro against picornavirus replication, including over 90% of the most commonly isolated enterovirus types and 80% of rhinovirus serotypes. •• Interferons are cytokines that exhibit a broad spectrum of antiviral activities as well as immunomodulating and antiproliferative properties. Nucleoside Reverse Transcriptase Analogues •• Zidovudine •• Didanosine •• Zalcitabine •• Stavudine •• Lamivudine •• Abacavir Nonnucleoside Reverse Transcriptase Inhibitors •• Nevirapine •• Delavirdine and •• Efavirenz 486 USMLE Step 1 Platinum Notes Nucleotide Reverse Transcriptase Inhibitors •• Tenofovir Protease Inhibitors •• Saquinavir •• Nelfinavir •• Indinavir •• Atazanavir •• Ritonavir •• Tipranavir Fusion Inhibitor Enfuvertide Sites of action of anti HIV drugs Side Effects Commonly Asked •• •• •• •• •• •• Stavudine, didanosine, zalcitibine Indinavir Efavirenz Zidovudine Didanosine Abacavir •• •• •• •• •• •• Peripheral neuropathy Nephrolithiasis Rash, liver enzymes ↑, CNS effects Myelosuppression, Megaloblastic anemia Pancreatitis Severe hypersensitivity Elvitegravir: HIV integrase inhibitor Interferes with HIV replication by blocking activity of virus to integrate into genetic material. Emtricitabine: NRTI Pharmacology 487 Lobucavir is a synthetic cyclobutane nucleoside analogue with activity against a broad range of herpesviruses, HIV and HBV. It is currently under investigation in clinical trials. Its mechanism of action is through ‘inhibition of viral DNA synthesis’. Lobucavir is initially phosphorylated by virus-induced kinases, and lobucavir triphosphate is a potent inhibitor of HSV, CMV, and HBV DNA polymerases. Raltegravir: (USMLE Favorite) •• It is an antiretroviral drug, the first of a new class of HIV drugs, the integrase inhibitors, to receive such approval •• Integration occurs following production of the double-stranded viral DNA by the viral RNA/DNA-dependent DNA polymerase, reverse transcriptase •• The main function of Integrase is to insert the viral DNA into the host chromosomal DNA, a step that is essential for HIV replication •• Integration is a point of no return for the cell, which becomes a permanent carrier of the viral genome (provirus) •• Integration is in part responsible for the persistence of retroviral infections. After integration, the viral gene expression and particle production may take place immediately or at some point in the future. Bevirimat: (USMLE Favorite) •• It is an anti-HIV drug believed to inhibit HIV by a novel mechanism, so-called maturation inhibition •• Like protease inhibitors, bevirimat and other maturation inhibitors interfere with protease processing of newly translated HIV polyprotein precursor, called gag •• This molecule contains a number of HIV proteins in a single polypeptide which is then cleaved by the enzyme protease to produce functional structural proteins •• However, unlike the protease inhibitors, bevirimat binds the gag protein, not protease •• Once bound to gag, bevirimat prevents a critical cleavage at a site called the capsid-SP1 junction •• The resulting virus particles lack functional capsid protein and have structural defects, rendering them incapable of infecting other cells. Pleconaril is an investigational drug active in vitro against picornavirus replication including over 90% of the most commonly isolated enterovirus types and 80% of rhinovirus serotypes. Neuraminidase Inhibitors: (USMLE Favorite) Neuraminidase inhibitors zanamivir and oseltamivir for both influenza A and influenza B. Oseltamivir is indicated for the treatment of uncomplicated acute infection caused by influenza A virus in patients older than 1 year of age Oseltamivir is indicated for the treatment of uncomplicated acute infection caused by influenza B virus in patients older than 1 year of age Specific antiviral therapy is available for influenza: Amantadine and Rimantadine for influenza A Antituberculous Drugs First-line agents for the treatment of tuberculosis: –– Isoniazid –– Rifampicin –– Pyrazinamide –– Ethambutol and streptomycin Second-line drugs are used only for the treatment of patients with tuberculosis resistant to first-line drugs. Included in this group are the injectable drugs –– Kanamycin, amikacin, capreomycin and the oral agents –– Ethionamide, cycloserine, and PAS, ofloxacin, levofloxacin and sparfloxacin –– Other second-line drugs include clofazimine, amithiozone (thiacetazone) 488 USMLE Step 1 Platinum Notes The treatment regimen of choice for virtually all forms of tuberculosis in both adults and children consists of a 2-month initial phase of isoniazid, rifampicin, and pyrazinamide followed by a 4-month continuation phase of isoniazid and rifampicin Except for patients who seem unlikely on epidemiologic grounds to be initially infected with a drug-resistant strain, ethambutol (or streptomycin) should be included in the regimen for the first 2 months or until the results of drug susceptibility testing become available. •• Tuberculocidal* drugs Isoniazid, Rifampicin, Pyrazinamide, Streptomycin •• Tuberculostatic* drugs Ethambutol, Thiacetazone, PAS, Ethionamide, Cycloserine Mechanism of Action •• ISONIAZID •• Inhibits mycolic acid synthesis •• RIFAMPICIN •• Inhibits RNA polymerase •• ETHAMBUTOL •• Inhibits mycolic acid incorporation into cell wall •• STREPTOMYCIN •• Inhibits protein synthesis SIDE EFFECTS: INH – Remember as –– I - Irritation (epigastric distress) –– N- Neuritis (peripheral neuritis – common in slow acetylator) –– H- Hepatotoxicity (Rare in children, common in elderly & alcoholics) Rifampicin – Remember as Syndromes –– Respiratory syndrome –– Cutaneous syndrome –– Flu like syndrome –– Abdominal syndrome Pyrazinamide – Remember as 3 H’ s –– Hepatotoxicity –– Hyperuricemia –– Hyperglycemia Ethambutol – Most important side effect optic neuritis, blue vision Streptomycin –– Vestibulotoxic Cochleotoxic –– Nephrotoxic •• •• •• •• Antitubercular drug which acts intracellularly– pyrazinamide Antitubercular drug which acts at low pH- pyrazinamide Antitubercular drug which penetrates meninges – pyrazinamide, INH, Rifampicin Antitubercular drug which is contraindicated in renal failure- Ethambutol FIRST-LINE ESSENTIAL DRUGS Rifampicin •• A semisynthetic derivative of Streptomyces mediterranei •• Rifampicin distributes well throughout most body tissues, including inflamed meninges. The fact that rifampicin turns body fluids (urine, saliva, sputum, tears) to a red-orange color •• Has both intracellular and extracellular bactericidal activity •• It blocks RNA synthesis by specifically binding and inhibiting DNA-dependent RNA polymerase •• Other adverse effects of rifampicin include rash, hemolytic anemia, thrombocytopenia and immunosuppression of unknown clinical importance. Rifampin is a potent inducer of the hepatic microsomal enzymes •• Resistance to rifampicin results from spontaneous point mutations that alter the RNA polymerase (rpoB) gene. Pharmacology 489 Isoniazid •• Its mechanism of action involves inhibition of mycolic acid cell-wall synthesis via oxygen-dependent pathways such as the catalase-peroxidase reaction •• Isoniazid is bacteriostatic against resting bacilli and bactericidal against rapidly multiplying organisms, both extracellularly and intracellularly •• The two most important adverse effects of isoniazid therapy are hepatotoxicity and peripheral neuropathy •• Other adverse reactions are either rare or less significant and include rash (2%), fever (1.2%), anemia, acne, arthritic symptoms, a systemic lupus erythematosus-like syndrome, optic atrophy, seizures, and psychiatric symptoms –– Isoniazid-associated hepatitis is idiosyncratic and increases in incidence with age –– The risk of isoniazid-associated hepatitis is increased by daily alcohol consumption, concomitant rifampicin administration, and slow isoniazid acetylation –– Serum concentrations of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) be determined at baseline in patients over 35 years of age who are receiving isoniazid for chemoprophylaxis, with monthly determinations thereafter –– Discontinuation of isoniazid be strongly considered whenever an asymptomatic AST or ALT level exceeds 150 to 200 IU (three to five times the upper limit of normal) in high-risk patients whose baseline values were normal –– Peripheral neuritis associated with isoniazid relates to interference with pyridoxine (vitamin B6) metabolism. This can be reduced with the prophylactic administration of 10 to 50 mg of pyridoxine daily –– Almost all isoniazid-resistant strains have amino acid changes in the catalase-peroxidase gene (katG) or a two-gene locus known as INHA. Pyrazinamide •• •• •• •• •• Bactericidal drug used in short-course therapy for tuberculosis Levels in CSF are high Intracellular action Mechanism of Action Pyrazinamide is similar to isoniazid Adverse hepatotoxicity, Hyperuricemia USMLE Case Scenario A 33-year-old male in US from India on isoniazid (INH) for last five months began to experience muscle fasciculations and convulsions. Administration of which of the following vitamins might have prevented these symptoms: Pyridoxine First-Line Supplemental Drugs •• Ethambutol: Adverse effects retrobulbar optic neuritis is the most serious adverse effect; axial or central neuritis, hyperuricemia •• Streptomycin: An aminoglycoside isolated from streptomyces griseus, streptomycin is available for intramuscular and intravenous administration only. Second-Line Drugs •• Capreomycin: A complex cyclic polypeptide antibiotic derived from Streptomyces capreolus after streptomycin, capreomycin is the injectable drug of choice for tuberculosis. •• Amikacin and Kanamycin these well known aminoglycosides are bactericidal to extracellular organisms. •• Para-Aminosalicylic Acid PAS, drug has a short half-life (1 h), and 80% of the dose is excreted in the urine. •• Thiacetazone •• Viomycin •• Ethionamide •• Cycloserine 490 USMLE Step 1 Platinum Notes Newer Antituberculous Drugs •• This group includes rifabutin, rifapentine •• The newer fluorinated quinolones •• Amoxicillin/clavulanic acid, clofazimine, clarithromycin and rifamycins KRM -1648 (Benzoxazinorifamycin). Resistance is Due to •• Isoniazid, Kat G or Inh A gene •• Rifampicin, rpo B gene •• Pyrazinamide, pnc A gene •• Ethambutol, emb B gene •• Streptomycin 16 s r RNA gene or ribosomal protein S 12 gene Antileprotics •• Multibacillary leprosy: Rifampicin, Dapsone, Clofazamine •• Paucibacillary leprosy: Rifampicin, Dapsone Rifampicin is the drug most rapidly acting and most potent against Leprosy bacilius. (R-R) Dapsone is the ‘drug of choice’ •• Leprostatic •• Acedapsone is repository form used as IM. Side Effects of Dapsone •• Peripheral motor weakness may occur more frequently. •• Fatalities have occurred due to agranulocytosis, aplastic anemia, and other blood dyscrasias. •• Serious cutaneous reactions, such as exfoliative dermatitis, toxic erythema, erythema multiforme, toxic epidermal necrolysis, morbilliform and scarlatiniform reactions, and erythema nodosum may occur. •• A dose-related hemolysis is seen in all patients, (Most common side effect) (with a slight decrease in hemoglobin and an increase in reticulocyte count. Patients with G6PD-deficiency or a decrease in activity in glutathione reductase are more susceptible to hemolysis. •• A low level of methemoglobinemia also occurs in all patients at recommended doses •• Hepatitis •• Infectious mononucleosis like illness •• Fixed drug eruptions Side Effects of Clofazamine •• Reddish black discoloration of skin •• Acneform eruptions •• Enteritis Antiparasitic Drugs: (USMLE Favorite) Parasites Drug of Choice 1. Ascariasis •• Albendazole 2. Capillariasis •• Mebendazole Pharmacology 3. Giardiasis •• Metronidazole 4. Trichuris trichura •• Albendazole 5. Cysticercosis (T solium) •• Praziquental 6. Sheep Liver Fluke (due to Fasciola hepatica) •• a. Triclabendazole-a veterinary fasciolicide is a drug of choice b. Bithionol is alternative drug of choice c. Pranziquantel-generally ineffective. 7. Chinese Liver Fluke (Clonorchis sinensis) •• Pranziquantel 8. Intestinal Fluke (Fasciolopsiasis) •• Pranziquantel 9. Lung Fluke (Paragonimus westermani) •• Pranziquantel 491 10. Tape worms, dwarf tapeworm •• Pranziquantel 11. Schistosomiasis •• Pranziquantel 12. Trichomonius vaginalis •• Metronidazole 13. Dracunculiasis •• Metronidazole 14. Enterobiasis •• Mebendazole 15. Strongyloidiasis •• Ivermectin 16. Pnuemocystis carinii •• Trimethoprim Sulfamethoxazole 17. a. Angiostrongyliasis b. Cutaneous larva migrans •• Thiabendazole 18. Amebic meningoencephalitis Amphotericin B 19. Babesiosis Quinine plus Clindamycin 20. Balantidiasis Tetracycline 21. Filariasis Diethyl carbamazine 22. Leishmaniasis Stibogluconate sodium diazine 23. Toxoplasmosis Pyrimethamine plus either trisulfamethoxazole or, sulfadiazine (Sulfonamides). 24. Trypanosomiasis a. T cruzi (Chagas’ Disease) b. T brucei (Sleeping Sickness) 1. Hemolymphatic stage 2. Late stage (CNS involvement) Suramin Melarsoprol 25. Onchocerciasis (River blindness) Ivermectin 26. Hookworms a. Ancylostoma duodenale b. Necator americanus Mebendazole 27. Uncomplicated Gonorrhea Ceftriaxone 28. Nocardiasis Trimethoprim-Sulfamethoxazole 29. Actinomycosis Penicillin-G ANTIHYPERTENSIVES Beta Blockers •• Half life of esmolol is 10 minutes (shortest) •• Half life of nadolol is 24 hours (longest) •• Esmolol is a class II antiarrhythmic. 492 USMLE Step 1 Platinum Notes •• Cardioselective (beta 1antagonists) are safer to use in asthma, diabetics and peripheral vascular diseases •• Celiprolol has membrane stabilizing properties •• Cardioselective Beta Blockers are (B2EA2M) Betaxolol Bisoprolol Esmolol Atenolol Acebutolol Metoprolol. Beta Blockers with both Alpha and Beta Blocking Properties Are Labetalol Dilevalol Cardivelol USED IN Cardiovascular •• •• •• •• •• •• Angina Hypertension Myocardial Infarction Cardiac Tachyarrhythmias Hepatic portal hypertension Esophageal variceal bleeding Endocrine •• Hyperthyroidism •• Pheochromocytoma CNS •• Anxiety •• Migrane Prophylaxis •• Essential tremor Eye •• Glaucoma (Timolol) ACE Inhibitors •• •• •• •• •• •• •• •• •• •• •• •• Benazepril Captopril Cilazapril Enalapril Enalaprilat Fosinopril Lisinopril Moexipril Perindopril Quinapril Ramipril Trandolapril •• Are used for [treatment of malignant, refractory, or accelerated hypertension, and for treatment of renovascular hypertension (Except in patients with bilateral renal artery stenoses or renal artery stenosis in a solitary kidney) •• Are also indicated, in combination with diuretics and digitalis therapy, for treatment of congestive heart failure not responding to other measures. Pharmacology 493 •• Postmyocardial infarction •• Left ventricular dysfunction •• Indicated for the treatment of hemodynamically stable patients within 24 hours of an acute myocardial infarction to improve survival •• Nephropathy in patients with Type 1 insulin-dependent diabetes mellitus (IDDM) •• Hypertension or renal crisis in scleroderma •• Cause cough because of bradykinin •• Ommission of prior diuretic dose decreases risk of postural hypotension. •• ACE inhibitors are used for reducing proteinuria in both diabetic as well as nondiabetics •• They are however the drugs of choice for reducing proteinuria in Diabetic Renal failure •• ACE Inhibitors delay ESRD in Diabetic Nephropathy. Albuminuria remains stable after ACE INH Therapy •• However it should be remembered that ACE Inhibitors are contraindicated in: •• Patients with Single kidney •• B/L Renal artery stenosis ↓GFR •• Hyperkalemia •• Pregnancy •• NOT used in pheochromocytoma (Angiotensin Receptor Blockers) (USMLE Favorite) Action of angiotensin and aldosterone •• Losartan •• Eprostan •• Irbesartan •• Candersartan •• Olmesartan •• Telmisartan These drugs have effects similar to those of ACE inhibitors However, instead of blocking the production of angiotensin II, they competitively inhibit its binding to the angiotensin II AT1 receptor subtype Their utility and tolerability are similar to those of the ACE inhibitors, but they do not cause cough or angioedema. 494 USMLE Step 1 Platinum Notes Difference in action Malignant Hypertension Nitroprusside is given by continuous intravenous infusion It is the agent of choice in this condition, since it dilates both arterioles and veins It has the advantage over the ganglionic blockers of not being associated with the development of tachyphylaxis and can be used for days with few side effects. The dosage must be controlled with an infusion pump •• ↑Gaunylate cyclase •• No central effects •• ↑NO levels along with hydralazine, nitrates •• Nitroglycerin –– Affects veins more than arterioles –– It is particularly useful in the treatment of hypertension following coronary bypass surgery, myocardial infarction, left ventricular failure, or unstable angina pectoris. •• Diazoxide is the easiest agent to administer, for no individual titration of dosage is required. However, it is probably less effective than the other agents. It primarily affects arteriolar and not venous tone –– Inhibits labor •• Intravenous labetalol maybe particularly useful in patients with a myocardial infarct or angina because it prevents an increase in heart rate. However, it maybe ineffective in patients previously treated with beta blockers and is contraindicated in patients with heart failure, asthma, bradycardia, or heart block Indicated in Pregnancy •• Intravenous hydralazine Causes drug induced lupus Hydralazine should be used with caution in patients with significant coronary artery disease and should be avoided in patients manifesting myocardial ischemia or aortic dissection. It is effective in preeclampsia. •• Esmolol, a beta blocker with an onset of action of 1 to 2 min, is particularly useful in aortic dissection and for perioperative hypertensive crisis. •• Enalaprilat, an intravenous form of the ACE inhibitor enalapril, has also proven effective, particularly in individuals with left heart failure. •• Indapamide: diuretic with vasodilator properties •• Clonidine, methyl dopa, gaunabenz, gaunafacine, moxonidine, rilmenidine: central sympatholytics •• Clonidine: α 2 agonist •• Minoxidil: potassium channel opener Pharmacology 495 USMLE Case Scenario A 67-year-old woman from Chicago is brought to the emergency department with complaints of persistent fever, malaise, and the recent appearance of a malar ‘butterfly’ rash on the face, as well as numerous oral ulcers. The patient states that she is taking one medication for treatment of arrhythmias. If the antinuclear antibody test is positive and the patient is mildly anemic, which of the following medications is she most likely taking? 1. Propafenone 2. Lidocaine 3. Amidarone 4. Mexiletine 5. Procainamide Ans. 5. Procainamide The patient is presenting with signs and symptoms of drug-induced lupus. This complication is associated with procainamide and other agents, including •• Hydralazine •• Chlorpromazine •• Isoniazid •• Methyldopa and •• Quinidine Procainamide is a class IA agent, similar in action to quinidine, and is indicated for the treatment of ventricular arrhythmias. Venodilators •• Nitrates •• Nitroprusside •• ACE inhibitors Arteriolar Dilators •• •• •• •• •• •• •• Calcium channel blockers Minoxidil Hydralazine ACE inhibitors Nitroprusside Alpha blockers Fenoldapam Phenoxybenzamine During perioperative period, patients require medications that block the excessive amounts of noradrenaline and adrenaline that is secreted by the tumor. A medication called ‘Phenoxybenzamine’ is used to block noradrenaline activity. This medication usually controls the hypertension and also allows an expansion of the blood volume. In patients with pheochromocytoma the blood volume is diminished because of the effects of the catecholamines. After some periods of treatment with phenoxybenzamine, a betablocker is added to control the effects of the excessive production of adrenaline from the tumor (p-p) Hypertension in Pregnancy Drugs considered safe in pregnancy are: •• Hydralazine and Methyldopa •• The drug of choice for ‘Hypertension’ in pregnancy is Methyldopa •• The drug of choice for ‘Hypertensive crisis’ in Pregnancy is Hydralazine 496 USMLE Step 1 Platinum Notes •• The drug of choice to control ‘seizures’ in pregnancy is Magnesium sulfate •• ACE inhibitors are absolutely contraindicated in pregnancy. PROLONGED QT SYNDROME (TORSADES DE POINTS) Causes •• Quinidine •• Procanamide •• Disopyramide •• Terfenadine, Astemizole •• Cisapride •• Gatifloxacin •• Sparfloxacin •• Halofantrine •• Mefloquine •• TCA Treatment is by: Beta blockers, Magnesium Sulfate. USMLE Case Scenario Torsades de pointes maybe caused by which one of the following drugs: 1. Quinidine 2. Digoxin 3. Phenytoin 4. Chlorthiazide Ans. 1. Quinidine Antiarrhythmics Class Example Mechanism of action Ia Disopyramide, quinidine, procainamide Block sodium channels Ib Lidocaine, phenytoin, mexilitene Block sodium channels Ic Flecainide, encanide, propafenone Block sodium channels II Propranolol, esmolol, sotalol Beta-adrenoceptor antagonists III Amiodarone, bretylium, ibutilide Block potassium channels IV Verapamil, dilatazem Calcium channel blockers Lignocaine is one of the most useful drugs for Ventricular arrhythmia Lignocaine belongs to Class IB Antiarrhythmic Lignocaine blocks fast Na+ channels Lignocaine decreases APD (action potential duration) Used in Arrhythmias due to: –– Post MI –– Open Heart Surgery –– Digoxin Toxicity Side Effects: –– Hypotension –– Convulsions –– Myocardial depression •• •• •• •• •• Pharmacology 497 Potassium channel blockers used in the treatment of cardiac arrhythmia are classified as class III antiarrhythmic agents. Pottasium channel blockers are: •• •• •• •• •• •• •• •• •• Dofetilide Sotalol Ibutilide Azimilide Bretylium Clofilium Nifekalant Tedisamil Sematilide •• •• •• •• •• •• •• •• •• DOC for ventricular arrhythmias DOC for AF without Heart failure DOC for Atrial flutter without heart failure DOC for AF with Heart failure DOC for Atrial flutter with heart failure DOC for PSVT DOC for WPWS DOC for ventricular ectopics DOC for sinus bradycardia •• •• •• •• •• •• •• •• •• Lidocaine Beta blockers Beta blockers Digoxin Digoxin Adenosine Procainamide Beta blockers Atropine USMLE Case Scenario An elderly 90-year-old man who has been for the past 6 years on some type of antiarrhythmic drug presents with complaints of ringing in his ears, blurred vision. He is taking multiple medications. He has had three episodes of confused, delirious behavior over the last few weeks. Drug responsible is: Quinidine The symptoms described above, tinnitus, blurred vision, and delirium, are known as cinchonism, a side effect of quinidine toxicity. EKG changes such as prolongation of the QT and QRS intervals may also occur. Quinidine is an antiarrhythmic used for the treatment of ventricular arrhythmias and atrial fibrillation. USMLE Case Scenario Drug of choice for Supraventricular tachycardia is: 1. Verapamil 2. Diltiazem 3. Digoxin 4. Phenytoin Ans. 1. Verapamil Amiodarone: USMLE High Yield Drug •• Class III antiarrhythmic •• Has class I, II, III, IV properties •• Potassium channel blocker •• Prevention of atrial and ventricular arrhythmia Causes: •• Pulmonary fibrosis •• Hepatitis 498 •• •• •• •• •• USMLE Step 1 Platinum Notes Photodermatitis Grey blue discoloration of skin Corneal microdeposits Bradycardia, heart block Hypothyroidism/hyperthyroidism Heart Failure (HF) The treatment of HF maybe divided into four components: 1. Removal of the precipitating cause 2. Correction of the underlying cause 3. Prevention of deterioration of cardiac function and 4. Control of the congestive HF state AIMS of CHF treatment Angiotensin-Converting Enzyme Inhibitors: The administration of ACE inhibitors has been shown to prevent or retard the development of HF in patients with left ventricular dysfunction without HF, to reduce symptoms, enhance exercise performance, and to reduce long-term mortality when they are begun in such patients shortly after acute myocardial infarction. These beneficial effects are related only in part to the salutary hemodynamic effects, i.e. the reduction of preload and afterload. Their major effect appears to be on inhibition of local (tissue) renin-angiotensin systems. Lisinopril or enalapril have been shown to be useful in the management of heart failure. Angiotensin Receptor Blockers: In patients who cannot tolerate ACE inhibitors (because of cough, angioneurotic edema, leukopenia), an angiotensin II receptor blocker (type AT1) antagonist (e.g. losartan 50 mg qid) maybe used instead. Aldosterone spironolactone, 25 mg/d reduces total mortality, as well as sudden death and death from pump failure. Since spironolactone is also a useful diuretic its widespread use in systolic heart failure should be considered. B-Adrenoceptor Blockers: Administration of gradually escalating doses of metoprolol, carvedilol, and bisoprolol have been reported to improve the symptoms of HF and to reduce all-cause death, cardiovascular death, sudden death and pump failure death. In patients with moderately severe HF (classes II and III), their administration of has been shown to be beneficial. Angioedema Due to Angiotensin Converting Enzyme Inhibitors USMLE Case Scenario A 41-year-old female came to the emergency room (ER) with an upper lip swelling which she noted when she woke up in the morning. She denied shortness of breath, change in her voice or wheezing. She was taking (lisinopril). The episode did not involve any airway compromise and was treated as an out patient. THIAZIDE DIURETICS Thiazide diuretics are effective and useful in the treatment of HF as long as the glomerular filtration rate exceeds approximately 50% of normal. FUROSEMIDE DOC in acute failure Bumetanide, ethacrynic acid, piretanide, and torsemide Pharmacology 499 These powerful diuretics are useful in all forms of HF, particularly in patients with otherwise refractory HF and pulmonary edema. ALDOSTERONE ANTAGONISTS Spironolactone maybe administered TRIAMTERENE AND AMILORIDE exert renal effects similar to those of the spironolactones Vasodilators Direct vasodilators maybe useful in patients with severe, acute HF who demonstrate systemic vasoconstriction despite ACE inhibitor therapy. The combination of hydralazine (up to 300 mg qd orally) and isosorbide maybe useful for chronic oral administration. Enhancement of Myocardial Contractility Digitalis: The improvement of myocardial contractility by means of cardiac glycosides is useful in the control of HF. Phosphodiesterase, inhibitors: Amrinone and milrinone, are noncatecholamine, nonglycoside agents that exert both positive inotropic and vasodilator actions by inhibiting a specific phosphodiesterase. Other Measures Anticoagulants Patients with severe HF are at increased risk of pulmonary emboli secondary to venous thrombosis and of systemic emboli secondary to intracardiac thrombi and should be treated with warfarin. Patients with HF and atrial fibrillation, previous venous thrombosis, and pulmonary or systemic emboli are at especially high-risk and should receive heparin followed by warfarin Assisted Circulation/Cardiac Transplantation: When patients with HF become unresponsive to a combination of all the aforementioned therapeutic measures, are in New York Heart Association class IV, and are deemed unlikely to survive 1 year, they should be considered for temporary assisted circulation and/or cardiac transplantation. Nesiritide (USMLE Favorite) •• Recombinant brain natriuretic peptider BNP •• It acts by reducing preload •• Has short half-life. Conivaptan: •• V1a and V2 (Vasopressin) receptor Treat (Acute heart failure and Hyponatremia) Digoxin •• Therapeutic level: 05 – 1.5 ng/ml •• Toxic level > 2.4 ng/ml •• Increases ventricular contractile force •• Excreted by kidneys •• Half-life is 40 hours •• Inhibits Na/K ATPase •• Contraindicated in HOCM Digoxin Toxicity Features: Generally unwell, lethargy, N/V, confusion, yellow-green vision, arrhythmias (e.g. AV block, bradycardia) Precipitating factors •• Renal Disease •• Classically: Hypokalemia •• Myocardial Ischemia •• Hypomagnesemia •• Hypoalbuminemia •• Hypothermia •• Hypothyroidism 500 USMLE Step 1 Platinum Notes •• Hypercalcemia, hypernatremia •• Acidosis •• Drugs: amiodarone, quinidine, verapamil, spironolactone (compete for secretion in distal convoluted tubule therefore reduce excretion) Management •• Digibind •• Correct arrhythmia •• Phenytoin •• Monitor K+ Treatment of Acute Pulmonary Edema It is life-threatening and must be considered a medical emergency 1. Morphine is administered intravenously repetitively, as needed, in doses from 2 to 5 mg. This drug reduces anxiety, reduces adrenergic vasoconstrictor stimuli to the arteriolar and venous beds, and thereby helps to break a vicious cycle 2. Naloxone should be available in case respiratory depression occurs 3. Because the alveolar edema interferes with O2 diffusion resulting in arterial hypoxemia, 100% O2 should be administered, preferably under positive pressure. The latter increases intraalveolar pressure, reduces transudation of fluid from the alveolar capillaries, and impedes venous return to the thorax, reducing pulmonary capillary pressure 4. The patient should be maintained in the sitting position, with the legs dangling along the side of the bed, if possible, which tends to reduce venous return 5. Intravenous loop diuretics, such as furosemide (DOC) or ethacrynic acid or bumetanide, will, by rapidly establishing a diuresis, reduce circulating blood volume and thereby hasten the relief of pulmonary edema. In addition, when given intravenously, furosemide also exerts a venodilator action, reduces venous return, and thereby improves pulmonary edema even before the diuresis commences 6. Afterload reduction is achieved with intravenous sodium nitroprusside at 20 to 30 mg/min in patients whose systolic arterial pressures exceed 100 mm Hg 7. Inotropic support should be provided by dopamine or dobutamine 8. Aminophylline (theophylline ethylenediamine), is effective in diminishing bronchoconstriction, increasing renal blood flow and sodium excretion, and augmenting myocardial contractility If the above-mentioned measures are not sufficient, rotating tourniquets

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