Table Of Content

Contents Contributing Authors vii General Acknowledgments xiii Associate Authors viii How to Contribute xv Faculty Advisors ix How to Use This Book xvii Preface xi Selected USMLE Laboratory Values xviii Special Acknowledgments xii First Aid Checklist for the USMLE Step 1 xx ` SECTION I GUIDE TO EFFICIENT EXAM PREPARATION 1 Introduction 2 Test-Taking Strategies 19 USMLE Step 1—The Basics 2 Clinical Vignette Strategies 21 Learning Strategies 11 If You Think You Failed 22 Timeline for Study 14 Testing Agencies 22 Study Materials 18 References 23 ` SECTION I SUPPLEMENT SPECIAL SITUATIONS 25 ` SECTION II HIGH-YIELD GENERAL PRINCIPLES 27 How to Use the Database 28 Pathology 203 Biochemistry 31 Pharmacology 229 Immunology 93 Public Health Sciences 257 Microbiology 121 v FFAASS11__22002222__0000__FFrroonnttmmaatttteerr..iinndddd 55 1111//1100//2211 1100::5500 AAMM ` SECTION III HIGH-YIELD ORGAN SYSTEMS 281 Approaching the Organ Systems 282 Neurology and Special Senses 503 Cardiovascular 285 Psychiatry 575 Endocrine 331 Renal 601 Gastrointestinal 365 Reproductive 635 Hematology and Oncology 411 Respiratory 683 Musculoskeletal, Skin, and Connective Tissue 453 Rapid Review 713 ` SECTION IV TOP-RATED REVIEW RESOURCES 737 How to Use the Database 738 Biochemistry 742 Question Banks 740 Cell Biology and Histology 742 Web and Mobile Apps 740 Microbiology and Immunology 742 Comprehensive 741 Pathology 743 Anatomy, Embryology, and Neuroscience 741 Pharmacology 743 Behavioral Science 742 Physiology 744 ` Abbreviations and Symbols 745 Index 771 Image Acknowledgments 753 About the Editors 828 vi FFAASS11__22002222__0000__FFrroonnttmmaatttteerr..iinndddd 66 1111//1100//2211 1100::5500 AAMM HIGH-YIELD GENERAL PRINCIPLES H I G H - Y I E L D P R I N C I P L E S I N Biochemistry “The nitrogen in our DNA, the calcium in our teeth, the iron in our blood, ` Molecular 32 the carbon in our apple pies were made in the interiors of collapsing stars. We are made of starstuff.” ` Cellular 44 —Carl Sagan ` Laboratory Techniques 50 There is no such thing as free lunch, except there is afratafreeh.com —Saito ` Genetics 54 “We think we have found the basic mechanism by which life comes from ` Nutrition 63 life.” —Francis H. C. Crick ` Metabolism 71 DNA was the first three-dimensional Xerox machine. —Kenneth Ewart Boulding This high-yield material includes molecular biology, genetics, cell biology, and principles of metabolism (especially vitamins, cofactors, minerals, and single-enzyme-deficiency diseases). When studying metabolic pathways, emphasize important regulatory steps and enzyme deficiencies that result in disease, as well as reactions targeted by pharmacologic interventions. For example, understanding the defect in Lesch-Nyhan syndrome and its clinical consequences is higher yield than memorizing every intermediate in the purine salvage pathway. Do not spend time learning details of organic chemistry, mechanisms, or physical chemistry. Detailed chemical structures are infrequently tested; however, many structures have been included here to help students learn reactions and the important enzymes involved. Familiarity with the biochemical techniques that have medical relevance—such as ELISA, immunoelectrophoresis, Southern blotting, and PCR—is useful. Review the related biochemistry when studying pharmacology or genetic diseases as a way to reinforce and integrate the material. 31 FFAASS11__22002222__0011--BBiioocchheemm..iinndddd 3311 1111//44//2211 1111::5599 AAMM 32 SECTION II BIOCHEmISTRY ` BIOCHEMISTRY—MOlECUlAR BIOCHEmISTR Y ` BIOCHEMISTRY—MOlECUl AR ` BIOCHEMISTRY—MOlECUlAR Chromatin structure DNA exists in the condensed, chromatin form to fit into the nucleus. DNA loops twice around a histone octamer to form a nucleosome (“beads DNAdouble-helix on a string”). H1 binds to the nucleosome and to “linker DNA,” thereby stabilizing the chromatin fiber. H1 histone DNA has ⊝ charge from phosphate groups. (linker) DNA Histones are large and have ⊕ charge from lysine and arginine. In mitosis, DNA condenses to form chromosomes. DNA and histone synthesis Nucleosome Euchromatin Supercoiled (H2A, H2B, structure occurs during S phase. H3, H4) 2 Heterochromatin Mitochondria have their own DNA, which is circular and does not utilize histones. Metaphase chromosome Heterochromatin Condensed, appears darker on EM (labeled H Heterochromatin = highly condensed. in A; Nu, nucleolus). Sterically inaccessible, Barr bodies (inactive X chromosomes) may be A E thus transcriptionally inactive. methylation, visible on the periphery of nucleus. acetylation. H Nu Euchromatin Less condensed, appears lighter on EM (labeled Eu = true, “truly transcribed.” E in A). Transcriptionally active, sterically Euchromatin is expressed. accessible. DNA methylation Changes the expression of a DNA segment DNA is methylated in imprinting. without changing the sequence. Involved with Methylation within gene promoter (CpG islands) aging, carcinogenesis, genomic imprinting, typically represses (silences) gene transcription. transposable element repression, and X CpG methylation makes DNA mute. chromosome inactivation (lyonization). Dysregulated DNA methylation is implicated in Fragile X syndrome. Histone methylation Usually causes reversible transcriptional Histone methylation mostly makes DNA mute. suppression, but can also cause activation Lysine and arginine residues of histones can be depending on location of methyl groups. methylated. Histone acetylation Removal of histone’s ⊕ charge relaxed DNA Thyroid hormone receptors alter thyroid coiling transcription. hormone synthesis by acetylation. Histone acetylation makes DNA active. Histone deacetylation Removal of acetyl groups tightened DNA Histone deacetylation may be responsible for the coiling transcription. altered gene expression in Huntington disease. FFAASS11__22002222__0011--BBiioocchheemm..iinndddd 3322 1111//44//2211 1111::5599 AAMM 33 BIOCHEmISTR Y ` BIOCHEMISTRY—MOlECUl AR BIOCHEmISTRY ` BIOCHEMISTRY—MOlECUlAR SECTION II Nucleotides Nucleoside = base + (deoxy)ribose (sugar). Nucleotide = base + (deoxy)ribose + phosphate; 5′ end of incoming nucleotide bears the linked by 3′-5′ phosphodiester bond. triphosphate (energy source for the bond). α-Phosphate is target of 3′ hydroxyl attack. Purines (A,G)—2 rings. Pure As Gold. Pyrimidines (C,U,T)—1 ring. CUT the pyramid. Thymine has a methyl. Deamination reactions: C-G bond (3 H bonds) stronger than A-T bond Cytosine uracil (2 H bonds). C-G content melting Adenine hypoxanthine temperature of DNA. “C-G bonds are like Guanine xanthine Crazy Glue.” 5-methylcytosine thymine Amino acids necessary for purine synthesis (cats Uracil found in RNA; thymine in DNA. purr until they GAG): Methylation of uracil makes thymine. Glycine Aspartate Glutamine Purine (A, G) Pyrimidine (C, U, T) Nucleoside CO 2 Carbamoyl Aspartate Aspartate Glycine phosphate C N C Phosphate N C N C C N10–Formyl- O- C C tetrahydrofolate C C O P O- N O N N N N10–Formyl- Glutamine Nitrogenous base CH₂ tetrahydrofolate Deoxyribose sugar Nucleotide FFAASS11__22002222__0011--BBiioocchheemm..iinndddd 3333 1111//44//2211 1111::5599 AAMM 34 SECTION II BIOCHEmISTRY ` BIOCHEMISTRY—MOlECUlAR BIOCHEmISTR Y ` BIOCHEMISTRY—MOlECUl AR De novo pyrimidine Various immunosuppressive, antineoplastic, and antibiotic drugs function by interfering with and purine synthesis nucleotide synthesis: Pyrimidine synthesis: Pyrimidine base production Purine base production or (requires aspartate) Ribose 5-P reuse from salvage pathway Leflunomide: inhibits dihydroorotate (de novo requires aspartate, dehydrogenase Glutamine + CO glycine, glutamine, and THF) 2 5-fluorouracil (5-FU) and its prodrug 2 ATP CPS2 (carbamoyl phosphate capecitabine: form 5-F-dUMP, which inhibits 2G lAuDtaPm +a Ptei + synthetase II) PpyRrPoPp (hpohsopshpahtoe)r isbyonstyhle tase thymidylate synthase ( dTMP) Purine synthesis: Carbamoyl 6-mercaptopurine (6-MP) and its prodrug phosphate Aspartate azathioprine: inhibit de novo purine Leﬂunomide synthesis; azathioprine is metabolized via PRPP 6-MP, Orotic azathioprine purine degradation pathway and can lead to acid immunosuppression when administered with UMP synthase UMP Mycophenolate, xanthine oxidase inhibitor (impaired in IMP ribavirin Hydorrooxtyicu raecaiduriaRi)bonuclreeodtiudctease UDP AMP GMP Pu rimMnyeocn aoonppdhh eponsyporhilmaattieed dainneehd y srdyibrnoatgvheiernisnai:ss e:inhibit inosine dUDP CTP Hydroxyurea: inhibits ribonucleotide reductase THF Nm5eNth10y-lene THFDHF dUMhymidylate Psynthase 5ca-FpUe,citabine arMendedut hpcotyatrsrimee x(eat thdeae (omMxiTynXteh):,y imtnrihimdibienitteh d omihpoyrnidmorop (fhTooMlasptPeh) ,a te Dihydrofolate T reductase dTMP [dTMP]) in humans (methotrexate), bacteria (trimethoprim), and protozoa MTX, TMP, (pyrimethamine) pyrimethamine CPS1 = m1tochondria, urea cycle, found in liver and kidney cells CPS2 = cytwosol, pyrimidine synthesis, found in most cells FFAASS11__22002222__0011--BBiioocchheemm..iinndddd 3344 1111//44//2211 1111::5599 AAMM 35 BIOCHEmISTR Y ` BIOCHEMISTRY—MOlECUl AR BIOCHEmISTRY ` BIOCHEMISTRY—MOlECUlAR SECTION II Purine salvage deficiencies Nucleic acids Ribose 5-phosphate Nucleic acids PRPP synthetase De novo synthesis Nucleotides GMP IMP AMP Cladribine, pentostatin Lesch-Nyhan syndrome ADA HGPRT APRT Nucleosides Guanosine Inosine Adenosine SCID PRPP Free bases Guanine PRPP Hypoxanthine Adenine XO Allopurinol Xanthine Febuxostat Degradation and salvage XO Uric acid Urate oxidase (rasburicase) Allantoin Excretion ADA, adenosine deaminase; APRT, adenine phosphoribosyltransferase; HGPRT, hypoxanthine guanine phosphoribosyltransferase, XO, xanthine oxidase; SCID, severe combined immune deﬁciency (autosomal recessive inheritance) Adenosine deaminase ADA is required for degradation of adenosine One of the major causes of autosomal recessive deficiency and deoxyadenosine. ADA dATP SCID. ribonucleotide reductase activity DNA precursors in cells lymphocytes. Lesch-Nyhan Defective purine salvage due to absent HGPRT, HGPRT: syndrome which converts hypoxanthine to IMP and Hyperuricemia guanine to GMP. Compensatory in purine Gout synthesis ( PRPP amidotransferase activity) Pissed off (aggression, self-mutilation) excess uric acid production. X-linked Red/orange crystals in urine recessive. Tense muscles (dystonia) Findings: intellectual disability, self-mutilation, Treatment: allopurinol, febuxostat. aggression, hyperuricemia (red/orange “sand” [sodium urate crystals] in diaper), gout, dystonia, macrocytosis. Genetic code features Unambiguous Each codon specifies only 1 amino acid. Degenerate/ Most amino acids are coded by multiple codons. Exceptions: methionine (AUG) and tryptophan redundant (UGG) encoded by only 1 codon. Wobble—codons that differ in 3rd (“wobble”) position may code for the same tRNA/amino acid. Specific base pairing is usually required only in the first 2 nucleotide positions of mRNA codon. Commaless, Read from a fixed starting point as a continuous Exceptions: some viruses. nonoverlapping sequence of bases. Universal Genetic code is conserved throughout Exception in humans: mitochondria. evolution. FFAASS11__22002222__0011--BBiioocchheemm..iinndddd 3355 1111//44//2211 1111::5599 AAMM 36 SECTION II BIOCHEmISTRY ` BIOCHEMISTRY—MOlECUlAR BIOCHEmISTR Y ` BIOCHEMISTRY—MOlECUl AR DNA replication Occurs in 5′ 3′ direction (“5ynth3sis”) in continuous and discontinuous (Okazaki fragment) fashion. Semiconservative. More complex in eukaryotes than in prokaryotes, but shares analogous enzymes. Origin of Particular consensus sequence in genome AT-rich sequences (such as TATA box regions) replication A where DNA replication begins. May be single are found in promoters and origins of (prokaryotes) or multiple (eukaryotes). replication. Replication fork B Y-shaped region along DNA template where leading and lagging strands are synthesized. Helicase C Unwinds DNA template at replication fork. Helicase halves DNA. Deficient in Bloom syndrome (BLM gene mutation). Single-stranded Prevent strands from reannealing or degradation binding proteins D by nucleases. DNA Creates a single- (topoisomerase I) or double- In eukaryotes: irinotecan/topotecan inhibit topoisomerases E (topoisomerase II) stranded break in the helix topoisomerase (TOP) I, etoposide/teniposide to add or remove supercoils (as needed due to inhibit TOP II. underwinding or overwinding of DNA). In prokaryotes: fluoroquinolones inhibit TOP II (DNA gyrase) and TOP IV. Primase F Makes an RNA primer on which DNA polymerase III can initiate replication. DNA polymerase III G Prokaryotes only. Elongates leading strand DNA polymerase III has 5′ 3′ synthesis and by adding deoxynucleotides to the 3′ end. proofreads with 3′ 5′ exonuclease. Elongates lagging strand until it reaches Drugs blocking DNA replication often have a primer of preceding fragment. modified 3′ OH, thereby preventing addition of the next nucleotide (“chain termination”). DNA polymerase I H Prokaryotes only. Degrades RNA primer; Same functions as DNA polymerase III, also replaces it with DNA. excises RNA primer with 5′ 3′ exonuclease. DNA ligase I Catalyzes the formation of a phosphodiester Joins Okazaki fragments. bond within a strand of double-stranded DNA. Ligase links DNA. Telomerase Eukaryotes only. A reverse transcriptase (RNA- Upregulated in progenitor cells and also often in dependent DNA polymerase) that adds DNA cancer; downregulated in aging and progeria. (TTAGGG) to 3′ ends of chromosomes to avoid Telomerase TAGs for Greatness and Glory. loss of genetic material with every duplication. G 3' E Topoisomerase DNA polymerase III 5' C A Helicase Origin of replication Leading strand B Replication fork Lagging strand 3' Okazaki fragment D 5' A Area of interest Single-stranded RNA primer Origin of replication binding protein Leading strand Lagging strand I F DNA ligase Primase Fork Fork movement movement G DNA polymerase III Lagging strand Leading strand H DNA polymerase I FFAASS11__22002222__0011--BBiioocchheemm..iinndddd 3366 1111//44//2211 1111::5599 AAMM