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Step 1 | 1 General Principles

1.1       Biochemistry and molecular biology

1.1.1    gene expression: DNA structure, replication, and exchange     DNA structure: single- and double-stranded DNA, stabilizing forces, supercoiling     analysis of DNA: sequencing, restriction analysis, PCR amplification, hybridization     DNA replication, mutation, repair, degradation, and inactivation     gene structure and organization; chromosomes; centromere, telomere     recombination, insertion sequences, transposons     mechanisms of genetic exchange, including transformation, transduction, conjugation, crossover, recombination, linkage     plasmids and bacteriophages

1.1.2    gene expression:  transcription, including defects     transcription of DNA into RNA, enzymatic reactions, RNA, RNA degradation     regulation:  cis-regulatory elements, transcription factors, enhancers, promoters, silencers, repressants, splicing

1.1.3    gene expression:  translation, including defects     the genetic code     structure and function of tRNA     structure and function of ribosomes     protein synthesis     regulation of translation     post-translational modifications, including phosphorylation, addition of CHO units     protein degradation

1.1.4    structure and function of proteins     principles of protein structure and folding     enzymes: kinetics, reaction mechanisms     structural and regulatory proteins: ligand binding, self-assembly     regulatory properties

1.1.5    energy metabolism, including metabolic sequences and regulation     generation of energy from carbohydrates, fatty acids, and essential amino acids; glycolysis, pentose phosphate pathway, tricarboxylic acid cycle, ketogenesis, electron transport and oxidative phosphorylation, glycogenolysis     storage of energy: gluconeogenesis, glycogenesis, fatty acid and triglyceride synthesis     thermodynamics: free energy, chemical equilibria and group transfer potential, energetics of ATP and other high-energy compounds

1.1.6    metabolic pathways of small molecules and associated diseases     biosynthesis and degradation of amino acids (eg, homocystinuria; maple syrup urine disease)     biosynthesis and degradation of purine and pyrimidine nucleotides     biosynthesis and degradation of lipids (eg, dyslipidemias, carnitine deficiency)     biosynthesis and degradation of porphyrins     galactosemia and other small sugar disorders     biosynthesis and degradation of alcohols and other small molecules

1.1.7    biosynthesis and degradation of other macromolecules and associated abnormalities, complex carbohydrates (eg, lysosomal storage disease), glycoproteins, and proteoglycans (eg, type II glycogen storage disease)

1.2       Biology of cells

1.2.1    structure and function of cell components     endoplasmic reticulum     Golgi complex     mitochondria     lysosome, peroxisome, endosome     centriole, microtubule     ribosome, polysome     plasma membrane (eg, glycolipids, glycoproteins, glycosaminoglycans, membrane fluidity)     cytosol     cilia   nucleus, including chromatin, nucleolus, the nuclear envelope, and nuclear matrix   cytoskeleton (eg, actin filaments, intermediate filaments, microtubules)

1.2.2    signal transduction     basic principles: autocrine, paracrine, endocrine     receptors and channels     protein kinase receptors     non-protein kinase receptors     nuclear receptors     G protein-linked receptors     voltage-gated channels     ligand-gated channels     second messengers (eg, IP3, DAG, PKA, PKC)     signal transduction pathways (eg, MAPK, JNK, TGF-β)

1.2.3    cell-cell and cell-matrix adhesion

1.2.4    cell motility

1.2.5    intracellular sorting (eg, trafficking, endocytosis)

1.2.6    cellular homeostasis (eg, turnover, pH maintenance, proteasome, ions, soluble proteins)

1.2.7    cell cycle     mitosis     meiosis     structure of spindle apparatus     cell cycle regulation (eg, cyclins, cdks, cdk inhibitors)

1.2.8    structure and function of basic tissue components     epithelial cells     connective tissue cells (eg, fibroblasts)     muscle cells     nerve cells     extracellular matrix (eg, basement membranes)

1.2.9    adaptive cell response to injury

1.2.10  intracellular accumulations (eg, pigments, fats, proteins, carbohydrates, minerals, inclusions, vacuoles)

1.2.11  mechanisms of injury and necrosis

1.2.12  apoptosis

1.3       Human development and genetics

1.3.1    embryogenesis: programmed gene expression, tissue differentiation and morphogenesis, homeotic genes; developmental regulation of gene expression

1.3.2    congenital abnormalities: principles, patterns of anomalies, dysmorphogenesis

1.3.3    principles of pedigree analysis     inheritance patterns     occurrence and recurrence risk determination

1.3.4    population genetics: Hardy-Weinberg law, founder effects, mutation-selection equilibrium

1.3.5    genetic mechanisms     chromosomal abnormalities: translocations; deletions; duplications, including nucleotide repeats and inversions, mosaicism     mendelian inheritance     homozygosity, heterozygosity      phenotypic variation: pleiotropy, variable expression, delayed onset     imprinting     polymorphisms     multifactorial diseases

1.3.6    clinical genetics     genetic testing     prenatal diagnosis     newborn screening     genetic counseling: ethics     gene therapy

1.4       Biology of tissue response to disease

1.4.1    inflammation, including cells and mediators     acute inflammation and mediator systems     vascular response to injury, including mediators     inflammatory cell recruitment, including adherence and cell migration, and phagocytosis     bactericidal mechanisms and tissue injury     clinical manifestations (eg, pain, fever, leukocytosis, leukemoid reaction, chills)     chronic inflammation

1.4.2    reparative processes     wound healing, hemostasis, and repair: thrombosis, granulation tissue, angiogenesis, fibrosis, scar/keloid formation     regenerative processes

1.4.3    neoplasia     classification of neoplasms; histologic diagnosis of malignancy     grading and staging of neoplasms     cell biology, biochemistry, and molecular biology of neoplastic cells: transformation, oncogenes, altered cell differentiation and proliferation     hereditary neoplastic disorders     invasion and metastasis     tumor immunology     paraneoplastic manifestations of cancer     cancer epidemiology and prevention

1.5       Gender, ethnic, and behavioral considerations affecting disease treatment and prevention, including psychosocial, cultural, occupational, and environmental

1.5.1    progression through the life cycle, including birth through senescence     cognitive, language, motor skills, and social and interpersonal development     sexual development (eg, puberty, menopause)     influence of developmental stage on physician-patient interview

1.5.2    psychologic and social factors influencing patient behavior     personality traits or coping style, including coping mechanisms     psychodynamic and behavioral factors, related past experience     family and cultural factors, including socioeconomic status, ethnicity, and gender     adaptive behavioral responses to stress and illness     maladaptive behavioral responses to stress and illness (eg, drug- seeking behavior, sleep deprivation)     interactions between the patient and the physician or the health care system (eg, transference)     patient adherence     general     adolescent

1.5.3    patient interviewing, consultation, and interactions with the family     establishing and maintaining rapport     data gathering     approaches to patient education     enticing patients to make lifestyle changes     communicating bad news     “difficult” interviews (eg, anxious or angry patients)     multicultural ethnic characteristics

1.5.4    medical ethics, jurisprudence, and professional behavior     consent and informed consent to treatment     physician-patient relationships (eg, ethical conduct, confidentiality)     death and dying     birth-related issues     issues related to patient participation in research     interactions with other health professionals (eg, referral)     sexuality and the profession; other “boundary” issues     ethics of managed care     organization and cost of health care delivery

1.6       Multisystem processes

1.6.1    nutrition     generation, expenditure, and storage of energy at the whole-body level     assessment of nutritional status across the life span, including calories, protein, essential nutrients, hypoalimentation     functions of nutrients, including essential, trans-fatty acids, cholesterol     protein-calorie malnutrition     vitamin deficiencies and/or toxicities     vitamin A     vitamin B complex     vitamin C     vitamin D     vitamin E     vitamin K     mineral deficiencies and toxicities     eating disorders     obesity     anorexia and bulimia     alternative diets, nutritional supplements, and food fads     treatment of eating disorders

1.6.2    temperature regulation

1.6.3    adaptation to environmental extremes, including occupational exposures     physical and associated disorders     temperature     radiation     burns, including electrocution, lightning     decreased atmospheric pressure, high-altitude sickness     increased water pressure (eg, “bends”)     chemical     gases, vapors, smoke inhalation (eg, poison gases)     agricultural hazards (eg, insecticides)     volatile organic solvents (eg, chloroform)     heavy metals (eg, lead)     principles of poisoning and therapy

1.6.4    fluid, electrolyte, and acid-base balance and disorders (eg, dehydration, acidosis, alkalosis)

1.7       Pharmacodynamic and pharmacokinetic processes

1.7.1    general principles     pharmacokinetics: absorption, distribution, metabolism, excretion, dosage intervals     mechanisms of drug action, structure-activity relationships     concentration- and dose-effect relationships (eg, efficacy, potency), types of agonists (eg, full, partial, inverse) and antagonists and their actions     individual factors altering pharmacokinetics and pharmacodynamics (eg, age, gender, disease, tolerance, compliance, body weight, metabolic proficiency, pharmacogenetics)     drug side effects, overdosage, toxicology     drug interactions     regulatory issues (eg, drug development, approval, scheduling)

1.7.2    general properties of autacoids     peptides and analogs     biogenic amines     prostanoids and their inhibitors     smooth muscle/endothelial autacoids (eg, nitric oxide)

1.7.3    general principles of autonomic pharmacology

1.7.4    general properties of antimicrobials, including mechanisms of action and resistance     antibacterials

1.7.4A        aminoglycosides
1.7.4B        cephalosporins and penicillins
1.7.4C        quinolones and tetracyclines
1.7.4D        antituberculous
1.7.4E         other antibacterials     antivirals

1.7.4F         antiretrovirals
1.7.4G        other antivirals     antifungals

1.7.4H        antifungals     antiparasitics

1.7.4E         antiparasitics

1.7.5    general properties of antineoplastic agents and immunosuppressants, including drug effects on rapidly dividing mammalian cells

1.8       Microbial biology and infection

1.8.1    microbial classification and its basis

1.8.2    bacteria and bacterial diseases     structure and composition     metabolism, physiology, and regulation     genetics     nature and mechanisms of action of virulence factors     pathophysiology of infection     epidemiology and ecology     principles of cultivation, assay, and laboratory diagnosis

1.8.3    viruses and viral diseases     physical and chemical properties     replication     genetics     principles of cultivation, assay, and laboratory diagnosis     molecular basis of pathogenesis     pathophysiology of infection     latent and persistent infections     epidemiology     oncogenic viruses

1.8.4    fungi and fungal infections     structure, physiology, cultivation, and laboratory diagnosis     pathogenesis and epidemiology

1.8.5    parasites and parasitic diseases     structure, physiology, and laboratory diagnosis     pathogenesis and epidemiology

1.8.6    principles of sterilization and pure culture technique

1.9       Immune responses

1.9.1    production and function of granulocytes, natural killer cells, and macrophages

1.9.2    production and function of T lymphocytes, T-lymphocyte receptors

1.9.3    production and function of B lymphocytes and plasma cells; immunoglobulin and antibodies: structure and biologic properties

1.9.4    antigenicity and immunogenicity; antigen presentation; cell activation and regulation; tolerance and clonal deletion

1.9.5    immunologic mediators: chemistry, function, molecular biology, classic and alternative complement pathways, cytokines, chemokines

1.9.6    immunogenetics; MHC structure and function, class I, II molecules; erythrocyte antigens

1.9.7    immunizations: vaccines, protective immunity

1.9.8    alterations in immunologic function     T- or B-lymphocyte deficiencies (DiGeorge syndrome)     deficiencies of phagocytic cells     combined immunodeficiency disease     HIV infection/AIDS and other acquired disorders of immune responsiveness     drug-induced alterations in immune responses, immunopharmacology

1.9.9    immunologically mediated disorders     type I, type II, type III hypersensitivity     type IV hypersensitivity     transplant and transplant rejection     autoimmune disorders     risks of transplantation, transfusion (eg, graft-versus-host disease)     isoimmunization, hemolytic disease of the newborn     immunopathogenesis

1.9.10  immunologic principles underlying diagnostic laboratory tests (eg, ELISA, complement fixation, RIA, agglutination)

1.9.11  innate immunity

1.10     Quantitative methods

1.10.1  fundamental concepts of measurement   scales of measurement   distribution, central tendency, variability, probability   disease prevalence and incidence   disease outcomes (eg, fatality rates)   associations (eg, correlation and covariance)   health impact (eg, risk differences and ratios)   sensitivity, specificity, predictive values

1.10.2  fundamental concepts of study design   types of experimental studies (eg, clinical trials, community intervention trials)   types of observational studies (eg, cohort, case-control, cross- sectional, case series, community surveys)   sampling and sample size   subject selection and exposure allocation (eg, randomization, stratification, self-selection, systematic assignment)   outcome assessment   internal and external validity

1.10.3  fundamental concepts of hypothesis testing and statistical inference   confidence intervals   statistical significance and Type I error   statistical power and Type II error