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General Principles
Third Edition
SENIOR EDITORS EDITORS

TAO LE, MD, MHS LUKE R.G. PIKE, MD, DPhil
Associate Clinical Professor Resident, Harvard Radiation Oncology Program
Chief, Section of Allergy and Immunology Massachusetts General Hospital
Department of Medicine Brigham & Women’s Hospital
University of Louisville
M. SCOTT MOORE, DO
WILLIAM L. HWANG, MD, PhD Clinical Research Fellow
Resident, Harvard Radiation Oncology Program Affiliated Laboratories, Scottsdale
Massachusetts General Hospital
Brigham & Women’s Hospital
New York / Chicago / San Francisco / Athens / London / Madrid / Mexico City
Milan / New Delhi / Singapore / Sydney / Toronto
0 GP_3e_FM_i-xiv.indd 1 10/28/16 3:14 PM

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DEDICATION
To the contributors to this and future editions, who took time to share their knowledge,
insight, and humor for the benefit of students and physicians everywhere.
and
To our families, friends, and loved ones, who supported us

in the task of assembling this guide.

This page intentionally left blank

v
Contents
Contributing Authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi CHAPTER 4. Microbiology . . . . . . . . . . . . . . . . . . . 229
Faculty Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Bacteriology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix Mycology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286
How to Use This Book . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x Parasitology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi Virology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
How to Contribute . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii Microbiology: Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
Antimicrobials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
CHAPTER 1. Anatomy and Histology . . . . . . . . . . . 1
Cellular Anatomy and Histology . . . . . . . . . . . . . . . . . . . . . . 2 CHAPTER 5. Pathology . . . . . . . . . . . . . . . . . . . . . . 395
Gross Anatomy and Histology . . . . . . . . . . . . . . . . . . . . . . . 15
CHAPTER 6. General Pharmacology . . . . . . . . . .417
CHAPTER 2. Biochemistry . . . . . . . . . . . . . . . . . . . . 33
Pharmacokinetics and Pharmacodynamics . . . . . . . . . 418
Molecular Biology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
Nucleotide Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Mutations and DNA Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 CHAPTER 7. Public Health Sciences . . . . . . . . . . 435
Enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
The Cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445
Connective Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 Public Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
Homeostasis and Metabolism . . . . . . . . . . . . . . . . . . . . . . . . 83 Patient Safety and Quality Improvement . . . . . . . . . . . 453
Amino Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 Ethics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 Life Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
Fed Versus Unfed State . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Psychology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Laboratory Tests and Techniques . . . . . . . . . . . . . . . . . . 169
Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 Image Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . 469
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
CHAPTER 3. Immunology . . . . . . . . . . . . . . . . . . . 187
About the Editors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512
Principles of Immunology . . . . . . . . . . . . . . . . . . . . . . . . . 188
Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

vi
CONTRIBUTING AUTHORS
Ezra Baraban, MD Margaret MacGibeny, MS
Yale School of Medicine Rutgers Robert Wood Johnson Medical School and
Class of 2016 Princeton University MD/PhD program
Nashid H. Chaudhury Class of 2020
Medical Scientist Training Program
Benjamin B. Massenburg
Yale School of Medicine
Icahn School of Medicine at Mount Sinai
Class of 2020
Class of 2017
Richard Giovane, MD
Resident, Department of Family Medicine Jake Prigoff, M
University of Alabama Resident, Department of Surgery
Jessica F. Johnston, MSc New York Presbyterian Hospital
Medical Scientist Training Program
Ritchell van Dams, MD, MHS
Intern, Department of Medicine
Class of 2020
Norwalk Hospital
Young H. Lim
Medical Scientist Training Program Zachary Schwam, MD
Yale School of Medicine Yale School of Medicine
Class of 2020 Class of 2016

vii
FACULTY REVIEWERS
Susan Baserga, MD, PhD Gerald Lee, MD
Professor, Molecular Biophysics & Biochemistry Genetics and Assistant Professor, Department of Pediatrics
Therapeutic Radiology University of Louisville School of Medicine
Alexandros D. Polydorides, MD, PhD
Sheldon Campbell, MD, PhD Associate Professor of Pathology and Medicine (Gastroenterology)
Associate Professor of Laboratory Medicine Icahn School of Medicine at Mount Sinai
Co-director, Attacks and Defenses Master Course
Sylvia Wassertheil-Smoller, PhD
Director, Laboratories at VA CT Healthcare System
Distinguished University Professor and
Director, Microbiology Fellowship
Molly Rosen and Maneoloff Chair in Social Medicine, Emerita
Department of Epidemiology and Population Health
Conrad Fischer, MD Albert Einstein College of Medicine
Residency Program Director, Brookdale University Hospital
Brooklyn, New York Howard M. Steinman, PhD
Associate Professor, Medicine, Physiology, and Pharmacology Professor, Department of Biochemistry
Touro College of Medicine Assistant Dean for Biomedical Science Education
Albert Einstein College of Medicine
Matthew Grant, MD
Assistant Professor of Medicine (Infectious Disease) Peter Takizawa, PhD
Director, Yale Health Travel Medicine Assistant Professor, Department of Cell Biology
Yale School of Medicine Director, Medical Studies
Marcel Green, MD
Resident Physician, Department of Psychiatry George J. Trachte, PhD
Mount Sinai Health System, St. Luke’s–Roosevelt Hospital Professor, Department of Biomedical Sciences
University of Minnesota
Peter Heeger, MD
Irene and Arthur Fishberg Professor of Medicine Prashant Vaishnava, MD
Translational Transplant Research Center Assistant Professor, Department of Medicine
Department of Medicine Mount Sinai Hospital and Icahn School of Medicine at Mount
Icahn School of Medicine at Mount Sinai Sinai
Jeffrey W. Hofmann, MD, Ph Ana A. Weil, MD
Resident, Department of Pathology Instructor in Medicine
University of California, San Francisco Massachusetts General Hospital


ix
Preface
With this third edition of First Aid for the Basic Sciences: General Principles, we con-
tinue our commitment to providing students with the most useful and up-to-date
preparation guides for the USMLE Step 1. For the past year, a team of authors and
editors have worked to update and further improve this third edition. This edition
represents a major revision in many ways.
■ Brand new Public Health and Patient Safety sections have been added.
■ Every page has been carefully reviewed and updated to reflect the most high-yield
material for the Step 1 exam.
■ New high-yield figures, tables, and mnemonics have been incorporated.
■ Margin elements, including flash cards, have been added to assist in optimizing the
studying process.
■ Hundreds of user comments and suggestions have been incorporated
■ Emphasis on integration and linkage of concepts was increased.
This book would not have been possible without the help of the hundreds of students
and faculty members who contributed their feedback and suggestions. We invite stu-
dents and faculty to please share their thoughts and ideas to help us improve First Aid
for the Basic Sciences: General Principles. (See How to Contribute, p. xiii.)
Louisville Tao Le
Boston William Hwang

x
How to Use This Book

Both this text and its companion, First Aid for the Basic Sciences: Organ Systems, are
designed to fill the need for a high-quality, in-depth, conceptually driven study guide
for the USMLE Step 1. They can be used alone or in conjunction with the original
First Aid for the USMLE Step 1. In this way, students can tailor their own studying
experience, calling on either series, according to their mastery of each subject.
Medical students who have used the previous editions of this guide have given us
feedback on how best to make use of the book.
■ It is recommended that you begin using this book as early as possible when learn-
ing the basic medical sciences. We advise that you use this book as a companion to
your preclinical medical school courses to provide a guide for the concepts that are
most important for the USMLE Step 1.
■ As you study each discipline, use the corresponding section in First Aid for the
Basic Sciences: General Principles to consolidate the material, deepen your under-
standing, or clarify concepts.
■ As you approach the test, use both First Aid for the Basic Sciences: General Principles
and First Aid for the Basic Sciences: Organ Systems to review challenging concepts.
■ Use the margin elements (ie, Flash Forward, Flash Back, Key Fact, Clinical Cor-
relation, Mnemonic, Flash Cards) to test yourself throughout your studies.
To broaden your learning strategy, you can integrate your First Aid for the Basic Sci-
ences: General Principles study with First Aid for the USMLE Step 1, First Aid Cases
for the USMLE Step 1, and First Aid Q&A for the USMLE Step 1 on a chapter-by-
chapter basis.

xi
Acknowledgments
This has been a collaborative project from the start. We gratefully acknowledge the
thoughtful comments and advice of the residents, international medical graduates,
medical students, and faculty who have supported the editors and authors in the de-
velopment of First Aid for the Basic Sciences: General Principles.
For support and encouragement throughout the process, we are grateful to Thao
Pham and Louise Petersen.
Furthermore, we wish to give credit to our amazing editors and authors, who worked
tirelessly on the manuscript. We never cease to be amazed by their dedication,
thoughtfulness, and creativity.
Thanks to our publisher, McGraw-Hill Education, for their assistance and guidance.
For outstanding editorial work, we thank Allison Battista, Christine Diedrich, Ruth
Kaufman, Isabel Nogueira, Emma Underdown, Catherine Johnson, and Hannah
Warnshuis. A special thanks to Rainbow Graphics, especially David Hommel, for
remarkable production work.
We are also very grateful to the faculty at Uniformed Services University of the
Health Sciences (USUHS) for use of their images and Dr. Richard Usatine for his
outstanding dermatologic and clinical image contributions.
For contributions and corrections, we thank Abraham Abdul-Hak, Mohamed Abdulla,
Zachary Aberman, Andranik Agazaryan, Zain Ahmed, Anas Alabkaa, Allen Avedian,
Syed Ayaz, Andrew Beck, Michael Bellew, Konstantinos Belogiannis, Candace
Benoit, Brandon Bodie, Aaron Bush, Robert Case, Jr., Anup Chalise, Rajdeep
Chana, Sheng-chieh Chang, Yu Chiu, Renee Cholyway, Alice Chuang, Diana
Dean, Douglas Dembinski, Kathryn Demitruk, Regina DePietro, Nolan Derr,
Vikram Eddy, Alejandra Ellison-Barnes, Leonel Estofan, Tim Evans, Matt Fishman,
Emerson Franke, Margaret Funk, Alejandro Garcia, William Gentry, Richard
Godby, Shawn Gogia, Marisol Gonzalez, William Graves, Jessie Hanna, Clare
Herickhoff, Joyce Ho, Jeff Hodges, David Huang, Andrew Iskandar, Anicia Ivey,
Jeffrey James, Angela Jiang, Bradford Jones, Caroline Jones, Charissa Kahue, Sophie
Kerszberg, Michael Kertzner, Mani Khorsand Askari, Peeraphol La-orkanchanakun,
Juhye Lee, Jessica Liu, Jinyu Lu, James McClurg, Gregory McWhir, Rahul Mehta,
Kristen Mengwasser, Aleksandra Miucin, Morgan Moon, Jan Neander, Michael
Nguyen, Jay Patel, Nehal Patel, Iqra Patoli, Matthew Peters, Yelyzaveta Plechysta,
Qiong Qui, Peter Francis Raguindin, Kenny Rivera, Luis Rivera, Benjamin Robbins,
Jorge Roman, Julietta Rubin, Kaivan Salehpour, Abdullah Sarkar, Hoda Shabpiray,
Neal Shah, Chris Shoff, Rachael Snow, Gregory Steinberg, Ryan Town, Michael
Turgeon, Hunter Upton, Zack Vanderlaan, Christopher Vetter, Liliana Villamil
Nunez, Sukanthi Viruthagiri, David Marcus Wang, and Andy Zureick.
Louisville Tao Le
Boston William Hwang


xiii
How to Contribute
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CHAPTER 1
Anatomy and Histology
CELLULAR ANATOMY AND HISTOLOGY 2 Splenic Anatomy 20

The Cell 2 The Lymphatic System 20
Hematopoiesis 8 Peripheral Nervous System 23
The Integumentary System 25
GROSS ANATOMY AND HISTOLOGY 15 The Respiratory System 29
Abdominal Wall Anatomy 15 The Adrenal Glands 31
The Gastrointestinal System 17
1 GP_3e_CH_01_Anat-Histol_1-32.indd 1 10/26/16 2:58 PM

2 CHAPTER 1 ANATOMY AND HISTOLOGY
Cellular Anatomy and Histology
THE CELL
The cell is the most basic structural and functional unit of life. Living organisms are com-
posed of cells, which may exist as independent units or form more complex organisms.
Each cell is a collection of integral, diverse components, required for the biochemical
processes that sustain the life of the organism. The most important eukaryotic cellular
components will be covered in the following sections.
Plasma Membrane
Every eukaryotic cell is enveloped by an asymmetric lipid bilayer membrane. This
membrane consists primarily of two sheets of phospholipids, each one-molecule thick
(Figure 1-1B). Phospholipids are amphipathic molecules, containing both a water-
soluble hydrophilic region and a fat-soluble hydrophobic region (Figure 1-1).
Aqueous phase (extracellular)
Polar or
hydrophilic groups
“Oil” or nonpolar phase
Nonpolar or
hydrophobic groups
Aqueous phase (cytoplasm)

A
A. Phospholipid B
B. Lipid bilayer/
cell membrane
Aqueous phase
Aqueous phase
Nonpolar
phase
polar phase
Non
Aqueous
phase
Lipid
bilayer
C
C. Micelle D
D. Liposome (unilamellar)
Aqueous Lipid
compartments bilayers
EE. Liposome (multilamellar)
F I G U R E 1 - 1 . Amphipathic lipids. A Phospholipid, with a phosphate head group and a lipid

tail; B lipid bilayer with both aqueous and nonpolar phases; C micelle in aqueous solution
surrounding a nonpolar core; D unilamellar; and E multilamellar liposomes.

ANATOMY AND HISTOLOGY CHAPTER 1 3
■ The hydrophilic portions (ie, phosphate groups) of each phospholipid layer face
both the aqueous extracellular environment as well as the aqueous cytoplasm.
■ The hydrophobic portions of each phospholipid layer (ie, fatty acid chains) make
up the fat-soluble center of the phospholipid membrane.
This bilayer membrane also contains steroid molecules (derived from cholesterol), KEY FACT
glycolipids (fatty acids with sugar moieties), sphingolipids, proteins, and glycoproteins
Biologically important proteins include
(proteins with sugar moieties). The cholesterol and glycolipid molecules alter the physi- transmembrane transporters, ligand-
cal properties of the membrane (eg, increase the melting point) in relative proportion receptor complexes, and ion channels.
to their quantity. The proteins serve important and specific roles in the transport and Protein dysfunction underlies many
trafficking of nutrients across the membrane, signal transduction, and interactions diseases.
between the cell and its environment.
The cell membrane performs the following functions:

■ Enhances cellular structural stability.
■ Protects internal organelles from the external environment.
■ Regulates the internal environment (chemical and electrical potential).
■ Enables interactions with the external environment (eg, signal transduction and
cellular adhesion).
FLASH
Nucleus and Nucleolus FORWARD
The nucleus is the control center of the cell. The nucleus contains genetically encoded Genetic mutations may cause
information in the form of DNA, which directs the life processes of the cell. It is sur- dysfunction of regulatory proteins,
often leading to debilitating diseases.
rounded by the nuclear membrane, which is composed of two lipid bilayers: The inner
For example, xeroderma pigmentosum
membrane defines the boundaries of the nucleus, and the outer membrane is continuous is an autosomal recessive disorder of
with the rough endoplasmic reticulum (RER) (Figure 1-2). In addition to DNA, the nucleotide excision repair that leads
nucleus houses a number of important proteins that enable the maintenance (protec- to increased sensitivity to UV light and
tion, repair, and replication), expression (transcription), and transportation of genetic increased rates of skin cancer.
material (capping, transport).
Most of the cell’s ribosomal RNA (rRNA) is produced within the nucleus by the nucleo-
lus. The rRNA then passes through the nuclear pores (transmembrane protein com-
plexes that regulate trafficking across the nuclear membrane) to the cytosol, where it
associates with the RER.
Rough Endoplasmic Reticulum and Ribosomes

As previously described, the RER is home to the majority of the cell’s ribosomes. The
rough in rough endoplasmic reticulum comes from the many ribosomes that stud the
KEY FACT
membrane of the RER. Ribosomes associate with transfer RNA (tRNA) to translate mes-
senger RNA (mRNA) into amino acid sequences and, eventually, into proteins (Figure The RER in neurons is referred to as
1-3). The RER functions primarily as the location for membrane and secretory protein Nissl body when viewed under a
production as well as protein modification (Figure 1-2). The RER is highly developed in microscope.
cell types that produce secretory proteins (eg, pancreatic acinar cells or plasma cells).
Smooth Endoplasmic Reticulum

FLASH
The smooth endoplasmic reticulum (SER) is the site of fatty acid and phospholipid FORWARD
production and therefore is highly developed in cells of the adrenal cortex and steroid-
The cytochrome P-450 system is a
secreting cells of the ovaries and testes. Hepatocytes also have a highly developed SER,
family of enzymes located in the SER or
as they are constantly detoxifying hydrophobic compounds through conjugation and mitochondria that metabolize millions
excretion. of endogenous and exogenous
compounds.
Golgi Apparatus
Shortly after being synthesized, proteins from the RER are packaged into transport
vesicles and secreted from the RER. These vesicles travel to and fuse with the Golgi
apparatus. Within the lumen of the Golgi apparatus, secretory and membrane-bound

Key:
brane
mem
Clathrin sma
Pla
Secretory
vesicle
COPI Late Early
endosome endosome
CLINICAL COPII
Lysosome
CORRELATION
Retrograde trans
Inclusion-cell (I-cell) disease, also
known as mucolipidosis type II, results Anterograde
from a defect in N-acetylglucosaminyl- Golgi
1-phosphotransferase, leading to apparatus
a failure of the Golgi apparatus to
phosphorylate mannose residues (ie,
mannose-6-phosphate) on N-linked cis
glycoproteins. Thus, hydrolytic
enzymes are secreted extracellularly,
rather than delivered to lysosomes, Endoplasmic
hindering the digestion of intracellular reticulum
waste. Coarse facial features and
restricted joint movements result (refer Nuclear envelope
to Biochemistry chapter for discussion
of lysosomal storage disorders).
F I G U R E 1 - 2 . Representation of the rough endoplasmic reticular branch of protein
sorting. Newly synthesized proteins are inserted into the endoplasmic reticulum membrane, or
CLINICAL enter the lumen from membrane-bound polyribosomes, depicted as light blue spheres studding
CORRELATION the endoplasmic reticulum. Those proteins are then transported out of the endoplasmic
reticulum to the Golgi apparatus. Transport to the Golgi apparatus (anterograde transport)
A number of lysosomal storage
is mediated by COPII membrane proteins. Transport from the Golgi apparatus back to the
diseases, such as Tay-Sachs disease,
endoplasmic reticulum (retrograde transport) is mediated by COPI membrane proteins.
result from lysosomal dysfunction
The proteins can be modified in the various subcompartments of the Golgi apparatus and
and the accumulation of protein are then segregated and sorted in the trans-Golgi network. Secretory proteins accumulate in
metabolites targeted for destruction or secretory storage granules, from which they may be expelled. Proteins destined for the plasma
further modification. membrane, or those that are secreted in a constitutive manner, are carried out to the cell
surface in transport vesicles. This transport is mediated by clathrin membrane proteins. Some
proteins enter prelysosomes (late endosomes) and fuse with endosomes to form lysosomes.
60S
Ribosome
proteins undergo modification. Depending on their final destination, these proteins may
be modified in one of the three major regions of Golgi networks: cis (CGN), medial
E P A (MGN), or trans (TGN). These proteins are then packaged in a second set of transport
5' 3' vesicles, which bud from the trans side and are delivered to their target locations (eg,
organelle membranes, plasma membrane, and lysosomes; Figure 1-2).
40S
Functions of the Golgi Apparatus

F I G U R E 1 - 3 . Schematic
representation of translation. Here, ■ Distributes proteins and lipids from the endoplasmic reticulum to the plasma mem-
the 40S and 60S subunits of rRNA brane, lysosomes, and secretory vesicles.
are shown, translating a portion of ■ Modifies N-oligosaccharides on asparagines.
mRNA in the 5′ to 3′ direction. Many ■ Adds O-oligosaccharides to serine and threonine residues.
of these ribosomes are located within ■ Assembles proteoglycans from core proteins.
the membrane of the RER so that
their initial protein product ends up
■ Adds sulfate to sugars in proteoglycans and tyrosine residues on proteins.
within the lumen of the RER, where ■ Adds mannose-6-phosphate to specific proteins (targets the proteins to the lysosome).
it undergoes further modification.
E site, holds Empty tRNA as it Lysosomes
Exits; P site, accommodates growing
Peptide; A site, Arriving Aminoacyl The lysosome is the trash collector of the cell. Bound by a single lipid bilayer, the lyso-
tRNA. some is responsible for hydrolytic degradation of obsolete cellular components. Extra-

cellular materials, ingested via endocytosis or phagocytosis, are enveloped in an endo- CLINICAL
some (temporary vesicle), which fuses with the lysosome, leading to enzymatic CORRELATION
degradation of endosomal contents. Lysosomal enzymes (nucleases, proteases, and
Chédiak-Higashi disease, resulting
phosphatases) are activated at a pH below 4.8. To maintain this pH, the membrane of from abnormal microtubular assembly,
the lysosome contains a hydrogen ion pump, which uses adenosine triphosphate (ATP) leads to impaired polymorphonuclear
to pump protons into the lysosome, against the concentration gradient. leukocytes (PMNs) phagocytosis and
frequent infections.
Mitochondria
The mitochondria are the primary site of ATP production in aerobic respiration. The
CLINICAL
proteins of the outer membrane enable the transport of large molecules (molecular CORRELATION
weight ~10,000 daltons) for oxidative respiration. The inner membrane is separated
Various inherited disorders can
from the outer by the intermembranous space and is more selectively permeable (Figure
be maternally transmitted via
1-4). The inner membrane has a large surface area due to its numerous folds, known as
mitochondrial chromosomes. These
cristae, and it maintains its selectivity with transmembrane proteins. These transmem- can show a variable expression in
brane proteins constitute the electron transport chain, and maintain a proton gradient a population due to heteroplasmy,
between the intermembranous space and the lumen of the inner membrane. The role or the presence of heterogenous
of the electron transport chain is to generate energy for storage in the bonds of ATP. mitochondrial DNA in an individual.
These diseases primarily affect the
Microtubules and Cilia muscles, cerebrum, or the nerves,
where energy is needed the most.
Microtubules are aggregate intracellular protein structures important for cellular sup- For example, myoclonic epilepsy with
port, rigidity, and locomotion. They consist of α- and β-tubulin dimers, each bound ragged-red fibers is a mitochondrial
to two guanosine triphosphate (GTP) molecules, giving them a positive and negative disorder characterized by progressive
polarity. They combine to form cylindrical polymers of of 24 nm in diameter and vari- myoclonic epilepsy, short stature,
able lengths (Figure 1-5A). Polymerization occurs slowly at the positive end of the hearing loss, and “ragged-red fibers” on
microtubule, but depolymerization occurs rapidly unless a GTP cap is in place. biopsy.
Microtubules are incorporated into both flagella and cilia. Within cilia, the microtu-
bules occur in pairs, known as doublets. A single cilium contains nine doublets around KEY FACT
its circumference, each linked by an ATPase, dynein (Figure 1-5B). Dynein, anchored
to one doublet, moves toward the negative end of the microtubule along the length of Drugs that act on microtubules:
a neighboring doublet in a coordinated fashion, resulting in ciliary motion. Kinesin is Drug Disease
another intracellular transport ATPase that moves toward the positive end of a micro- Mebendazole/ Parasitic
tubule, opposite of dynein. albendazole infections
Taxanes Cancers
Griseofulvin Fungal infections
Vincristine/ Cancers
Matrix:
citric acid enzymes, vinblastine
β-oxidation, pyruvate Colchicine Gout
dehydrogenase Cristae of mitochondria
CLINICAL
CORRELATION
A number of diseases arise from
ineffective or insufficient ciliary
motion.
Kartagener syndrome: A dynein arm
defect that impairs ciliary motion
and mucus clearance that results in
recurrent lung infections, hearing
loss, infertility, and dextrocardia situs
Intermembrane: Inner membrane: Outer membrane:
phosphotransferase electron carriers, ATP synthase Acyl CoA synthetase, inversus.
enzymes particles, membrane transporters glycerophosphate acyl Dextrocardia/situs inversus: Proper
transferase
directional development does
not occur during embryogenesis,
F I G U R E 1 - 4 . Structure of the mitochondrial membranes. The inner membrane contains causing all internal organs to be
many folds, or cristae, and the enzymes for the electron transport chain, used in aerobic located on the opposite side of the
cellular respiration, are located here. body.

A 24 nm α−tubulin β−tubulin
(+) end
5 nm
Cross section Longitudinal section Tubulin

dimer
B Enlarged microtubule doublet
Shared
A heterodimers
B
Microtubule B Dynein
Microtubule A
Nexin link
Radial
spokes Microtubule
doublet
Plasma
membrane
Inner
dynein arm
Outer
dynein arm
F I G U R E 1 - 5 . Microtubules. A Structure. The cylindrical structure of a microtubule is

depicted as a circumferential array of 13 dimers of α- and β-tubulin. The tubulin dimers are
being added to the positive end of the microtubule. B Ciliary structure. Nine microtubule
doublets, circumferentially arranged, create motion via coordinated dynein ATP cleavage.
Epithelial Cell Junctions

Transmembrane proteins mediate intercellular interaction by providing cellular adhe-
sion and cell signaling. Cellular adhesion and communication are vitally important to
both the integrity and the function of an organ.
Organs and tissues exposed to the external environment are the most resilient. These
tissues are referred to as epithelial, primarily due to their embryologic origin. The
epithelial cells of these external tissues contain an array of cell junctions that medi-
CLINICAL
CORRELATION ate cellular adhesion and communication processes. There are five principal types of
cell junctions: zonula occludens (tight junctions), zonula adherens (intermediate
Malignant epithelial cells contained junctions), macula adherens (desmosomes), hemidesmosomes, and gap junctions
by the basal membrane are termed (communicating junctions) (Figure 1-6).
carcinoma in situ. Loss of cell
junctions allows penetration through
the basement membrane as invasive Zonula Occludens
carcinoma. When cells enter the Tight junctions, also referred to as occluding junctions, have the following two primary
bloodstream or lymphatics and functions:
establish new tumors at distant sites,
they are considered metastatic. ■ Determine epithelial cell polarity, separating the apical pole from the basolateral
pole.
■ Regulate passage of substances across the epithelial barrier (paracellular transport).
MNEMONIC
In a typical epithelial tissue, the membranes of adjacent cells meet at regular intervals
CADHErins are Calcium-dependent to seal the paracellular space, preventing the paracellular movement of solutes. These
ADHEsion proteins. connections occur during the interaction of the junctional protein complex with neigh-
boring cells, composed of claudins and occludins.

Apical
Tight junction (zonula occludens)—prevents paracellular
E-cadherin movement of solutes; composed of claudins and occludins.
Actin Adherens junction (belt desmosome, zonula adherens)—below

filaments tight junction, forms “belt” connecting actin cytoskeletons of
adjacent cells with CADherins (Ca2+-dependent adhesion
proteins). Loss of E-cadherin may allow metastasis.
Cytokeratin
Desmosome (spot desmosome, macula adherens)—structural
Desmoplakin support via intermediate filament interactions. Autoantibodies
pemphigus vulgaris.
Connexon Gap junction—channel proteins called connexons permit

with central electrical and chemical communication between cells.
channel
Cell membrane
Basolateral Basement membrane
Integrins—membrane proteins that maintain Hemidesmosome—connects keratin in basal cells to
integrity of basolateral membrane by binding underlying basement membrane. Autoantibodies bullous
to collagen and laminin in basement membrane. pemphigoid. (Hemidesmosomes are down “bullow.”)
F I G U R E 1 - 6 . Epithelial cell junctions. Five types of epithelial cell junctions are depicted along with their supporting and component
proteins.
Zonula Adherens CLINICAL

Intermediate junctions are located just below tight junctions, near the apical surface CORRELATION
of an epithelial layer. Like the zonula occludens, the zonula adherens are located in a Pemphigus vulgaris: An
beltlike distribution. Inside the cell, these transmembrane protein complexes are associ- autoimmune disease of the skin
ated with actin microfilaments. Outside the cell, cadherins from adjacent cells use a due to anti-desmosome antibodies.
calcium-dependent mechanism to span wider intercellular spaces than can the zona This disrupts the cohesion between
occludens. Loss of E-cadherin may allow cancer cells to metastasize. keratinocytes, leading to fragile blisters.
The antibodies are distributed in a
reticular or “net-like” pattern. Nikolsky
Macula Adherens sign is positive.
As opposed to the beltlike distribution of the zonula occludens and adherens, desmo-
somes resemble spot welds—single rivets erratically spaced below the apical surface of
the epithelium. Intracellularly, they are associated with keratin intermediate filaments, CLINICAL
providing strength and rigidity to the epithelial surface. Like the zonula adherens, mac- CORRELATION
ula adherens are also mediated by calcium-dependent cadherin interactions. Bullous pemphigoid: An
autoimmune disease of the skin due
Hemidesmosomes to anti-hemidesmosome antibodies.
These disrupt the dermal-epidermal
These asymmetrical anchors provide epithelial adhesion to the underlying connective junction resulting in separation of the
tissue layer, the basement membrane. The hemidesmosomes contain integrin (instead layers in the form of tense bullae. The
of cadherins), an anchoring protein filament that binds the cell to the basement mem- antibodies are distributed linearly along
brane. Although the intracellular portion structurally resembles that of the desmosome, the basement membrane. Nikolsky sign
none of the protein components are conserved, except for the cytoplasmic association is negative.
with intermediate filaments.
Gap Junctions FLASH

FORWARD
These intercellular junctions allow for rapid transmission of electrical or chemical
Gap junctions allow for “coupling” of
information from one cell to the next. A connexon is formed from a complex of six
cardiac myocytes, enabling the rapid
connexin proteins. Each single connexon exists as a hollow cylindrical structure span- transmission of electrical depolarization
ning the plasma membrane. When a connexon of one cell is bound to a connexon of and coordinating contraction during
an adjacent cell, a gap junction is formed, creating an open channel for fluid and the cardiac cycle.
electrolyte transport across cell membranes.

HEMATOPOIESIS
Hematopoietic cells are stem cells residing in the bone marrow that can give rise to all
mature components of circulating blood cells and immune systems.
Blood
Blood is composed of cells suspended in a liquid phase. This liquid phase, which
consists of water, proteins, and electrolytes is known as plasma. O2-carrying red blood
cells, known as erythrocytes, make up about 45% of blood by volume. This percentage
is known as the hematocrit. Erythrocytes can be separated from white blood cells, or
leukocytes, and platelets by centrifugation. Erythrocytes form the lowest layer, and
leukocytes form the next layer, also known as the buffy coat. Plasma from which the
platelets and clotting factors have been extracted is called blood serum.
The Pluripotent Stem Cell

The hematopoietic stem cell is the grandfather of all major blood cells. These cells reside
within the bone marrow, where hematopoiesis (blood cell production) occurs. They are
capable of asymmetrical reproduction: simultaneous self-renewal and differentiation.
■ Self-renewal, integral to the maintenance of future hematopoietic potential, pre-
serves the pool of stem cells.
■ Differentiation leads to the production of specialized mature cells, necessary for
carrying out the major functions of blood.
CLINICAL Two differentiated cell lines derive from the pluripotent stem cell: myeloid and lym-
CORRELATION phoid (Figure 1-7). These cells are considered committed, meaning that they have
begun the process of differentiation and have lost some of their potential to become
RBC cytoskeletal abnormalities (eg,
hereditary spherocytosis, elliptocytosis)
cells in an alternate lineage. The myeloid lineage produces six different types of colony-
and hemoglobinopathies (eg, forming units (CFUs), each ending in a distinct mature cell: erythroid (producing
thalassemias, sickle cell anemia) cause erythrocytes), megakaryocyte (producing platelets), basophil, eosinophil, neutrophil,
significant morbidity and mortality. and monocyte (differentiates into macrophage). The lymphoid lineage produces two
cell lines: T cells and B cells.
Erythrocytes
Erythrocytes are nonnucleated, biconcave disks designed for gas exchange. These cells
measure approximately 8 μm in diameter, and their biconcave shape increases their
surface area for gas exchange, and allows them to squeeze through narrow capillaries.
CLINICAL These cells lack organelles, which are extruded shortly after they enter the bloodstream.
CORRELATION Instead, they contain only a plasma membrane, a cytoskeleton, hemoglobin, and gly-
The reticulocyte count increases when
colytic enzymes that help them survive via anaerobic respiration (90%) and the hexose
the bone marrow increases production monophosphate shunt (10%). This limits the red blood cell life span to approximately
to replenish red cell levels in the blood 120 days, after which they are mainly removed via macrophages in the spleen, and to
in response to anemia. a lesser extent, via the liver. Mature erythrocytes are replaced by immature reticulocytes
produced in the bone marrow. Reticulocytes are distinguished from mature erythrocytes
by their slightly larger diameter and reticular (mesh-like) network of ribosomal RNA.
Erythropoietin is the hormone that stimulates erythroid progenitor cells to mature by
binding to JAK2, a nonreceptor tyrosine kinase.
RBCs are highly dependent on glucose as their energy source, and glucose is transported
across the RBC membrane via the glucose transporter (GLUT-1). They are susceptible
to free radical damage, but can synthesize glutathione, an important antioxidant. Hemo-
globin’s ability to transport oxygen is closely associated with the production of 2,3-bisphos-
phoglycerate (2,3-BPG); 2,3-BPG decreases the affinity of hemoglobin for oxygen, thus
improving oxygen delivery to tissues. The iron in hemoglobin is maintained in the
ferrous state; ferric iron (Fe3+) is reduced to the ferrous (Fe2+) state via an NADH-
dependent methemoglobin reductase system. Finally, RBCs contain certain enzymes

Pluripotent stem cell
Myeloid stem cell Lymphoid stem cell
Erythropoiesis Thrombopoiesis Granulocytopoiesis Lymphopoiesis
Erythroid Thrombocyte Granulocyte/monocyte B– T–

progenitor cell progenitor cell progenitor cell lymphoblast lymphoblast
B– T–
Myeloblast Monoblast lymphocyte lymphocyte
Proerythroblast Megakaryoblast
Eosinophilic Basophilic Neutrophilic

promyelocyte promyelocyte promyelocyte Plasma cell
Basophilic Promegakaryocyte
erythroblast Promonocyte
T-helper T-cytotoxic
Eosinophilic Basophilic Neutrophilic
myelocyte myelocyte myelocyte
Polychromatic
erythroblast
Neutrophilic
Orthochromatic metamyelocyte Monocyte
erythroblast Megakaryocyte Eosinophilic Basophilic
metamyelocyte metamyelocyte
Band
Reticulocyte
Erythrocyte Platelets Eosinophil Basophil Neutrophil Macrophage
F I G U R E 1 - 7 . Blood cell differentiation. A chart of the pluripotent hematopoietic stem cell’s differentiation potential.

CLINICAL of nucleotide metabolism, and a deficiency in these enzymes (eg, adenosine deaminase,
CORRELATION pyrimidine nucleotidase, and adenylate kinase) is involved in some of the hemolytic
anemias.
Activating mutations in JAK2 can
cause myeloproliferative disorders
like polycythemia vera, essential Leukocytes
thrombocythemia, and myelofibrosis. Leukopoiesis is the process of white blood cell production from hematopoietic stem
The most common mutation for
cells. Neutrophils, basophils, mast cells, and eosinophils develop through a common
polycythemia vera is V617F (Figure 1-8).
promyelocyte lineage. Monocytes develop from a monoblast. Lymphocytes, although
separate from myeloid cells, are also considered leukocytes and arise from the lymphoid
stem cell.
EPO
All leukocytes are involved in some aspect of the immune response:

brane
Cell mem ■ Neutrophils affect nonspecific innate immunity in the acute inflammatory
JAK2
P
JAK2
P
response.
P-Y343 ■ Basophils and mast cells mediate allergic responses.
SHP-1
■ Eosinophils help fight parasitic infections.
Inhibitor
recruitment ■ Lymphocytes are integral to both cellular and humoral immunity.
F I G U R E 1 - 8 . Erythropoietin Neutrophils
(EPO) receptor. These products of the myeloid lineage act as acute-phase granulocytes. They begin in
the bone marrow as myeloid stem cells (Figure 1-7) and mature over a period of 10–14
KEY FACT days, producing both primary and secondary granules (promyelocyte stage; Figures 1-9
and 1-10). Once mature, these leukocytes are vital to the success of the innate immune
Leukos = Greek for white. system and are especially prominent in the acute inflammatory response.
Cytos = Greek for cell.
Histologically, these cells are distinguished by their large spherical size, multilobed
nuclei, and azurophilic primary granules (lysosomes). These cells have earned the
CLINICAL alternative name polymorphonucleocytes (PMNs) due to their multilobed nucleus.
CORRELATION
The key to their immune function lies in the ability of PMNs to phagocytose microbes
Chronic granulomatous disease: and destroy them via reactive oxygen species (superoxide, hydrogen peroxide, peroxyl
Congenital deficiency of NADPH radicals, and hydroxyl radicals). Neutrophils contain several enzymes, most notably
oxidase impedes the oxidative burst NADPH oxidase, which produces O2− radicals, directing the oxidative burst, as well as
in neutrophils, causing a difficulty the myeloperoxidase (MPO) system, which uses hydrogen peroxide and chloride to
in forming the reactive oxygen
generate hypochlorous acid (HOCl), a potent bactericidal oxidant.
compounds used to kill pathogens.
This results in recurrent bouts of
bacterial infection, most commonly
pneumonia and skin abscesses.
KEY FACT
Important neutrophil chemotactic

agents: C5a, IL-8, leukotriene B4 (LTB4),
kallikrein, platelet-activating factor.
F I G U R E 1 - 9 . Peripheral blood smear with neutrophilia. This peripheral blood smear

displays an extreme leukemoid reaction (neutrophilia). Most cells are band and segmented
neutrophils.

A B
F I G U R E 1 - 1 0 . Electron microscopy of neutrophils. A Highly activated neutrophils (N) with apoptotic neutrophils (black arrow) and
cell debris (black arrowhead). B Neutrophil.
Eosinophils
MNEMONIC
Eosinophils follow the same pattern of maturation as neutrophils, beginning in the bone
marrow as eosinophilic CFUs. Eosinophils also contain granules with eosinophil per- Causes of eosinophilia—
oxidase. However, they differ in that they are slightly larger than neutrophils with cat- NAACP
ionic proteins, such as major basic protein (antiparasitic) and eosinophilic cationic Neoplasia
protein (antiparasitic) within acidophilic (ie, eosinophilic) granules. Once fully mature, Asthma
eosinophils possess a large, bilobed nucleus (not multi-segmented like neutrophils) and Allergic processes
sparse endoplasmic reticulum and Golgi vesicles (Figure 1-11). Chronic adrenal insufficiency
Parasites (invasive)
Basophils and Mast Cells
Distinguished by large, coarse, darkly staining granules, basophils produce peroxidase,
heparin, and histamine (Figure 1-12). Basophils also release kallikrein, which acts as
an eosinophil chemoattractant during hypersensitivity reactions, such as contact aller-
gies and skin allograft rejection. Because they share a great deal of structural similarities,
basophils can be considered the blood-borne counterpart of the mast cell, which resides
within tissues, near blood vessels. Both mast cells and basophils produce histamine and
A B
F I G U R E 1 - 1 1 . Eosinophil microscopy. A Mature eosinophil with bright red granules.

B Electron microscopy of eosinophils with bilobed nuclei and specific granules in the shape of
a football with a crystalline core made from major basic protein.

F I G U R E 1 - 1 2 . Basophil microscopy. A Electron micrograph of a normal intact mast cell

CLINICAL with homogenous electron-dense granules. B Basophil.
CORRELATION
Mast cells release histamine, which
leads to type I allergic reactions,
heparin, but mast cells also contain serotonin (5-HT), which basophils lack. Mast cells
resulting in unpleasant allergy degranulate during the acute phase of inflammation, acting, via their released granule
symptoms and anaphylaxis. contents, on the nearby vasculature. This leads to vasodilation, fluid transudation, and
swelling of interstitial tissues.
Monocyte Lineage
Monocytes
KEY FACT Monocytes are the myeloid precursor to the mononuclear phagocyte, the tissue mac-
rophage. Morphologically, they appear as spherical cells with scattered small granules,
In tissue = macrophage akin to lysosomes. The blood monocyte is a large (10–18 μm), motile cell that margin-
In blood = monocyte ates along the vessel wall in response to the expression of specific cell adhesion proteins.
During an inflammatory response, these cell adhesion proteins (namely, platelet endo-
thelial cell adhesion molecule, or PECAM-1) facilitate monocyte diapedesis (transmi-
gration) across vessel walls into surrounding tissues. Once in close proximity to the
inflammatory foci, the monocyte differentiates into a macrophage with increased phago-
cytic and lysosomal activity (Figure 1-13).
Macrophages
During differentiation, monocyte cell volume and lysosome numbers increase. These
lysosomes fuse with phagosomes to degrade ingested cellular and noncellular material.
A B
F I G U R E 1 - 1 3 . Macrophage microscopy. A Active macrophage and B multinucleated giant

cell.

Macrophages (20–80 μm) also contain a large number of cell surface receptors. These CLINICAL
differ, depending on the tissue in which the macrophage matures, contributing to the CORRELATION
diversity of macrophage functions (Table 1-1).
Lipid A from bacterial
lipopolysaccharide (LPS) binds CD14
As described in Table 1-1, monocyte-derived cells are distributed among several organs on macrophages to induce cytokine
and tissues (including connective tissue and bone) where they reside (termed tissue- release. Toxic shock syndrome is caused
resident macrophages). Alternatively, monocytes can migrate into tissues during an acute by preformed Staphylococcus aureus
inflammatory response and, there, transform into reactive macrophages to aid the innate toxic shock syndrome toxin (TSST-1),
immune system. Once out of the circulation, monocytes have a half-life of up to 70 which acts as a superantigen and
hours. Their numbers within inflamed tissues begin to overcome those of neutrophils causes massive cytokine release.
after approximately 12 hours.
Multinucleated Giant Cells KEY FACT

At sites of chronic inflammation, such as tuberculous lung tissue, macrophages some-
Macrophages are activated by IFN-γ.
times fuse to produce multinucleated phagocytes (Figure 1-13). These microbicidal cells They can function as antigen-
can be produced in vitro via interferon-γ (IFN- γ) or interleukin-3 (IL-3) stimulation. presenting cells via MHC II.
Antigen-Presenting Cells
Antigen-presenting cells (APCs) are essential to the adaptive immune system. These
monocyte-derived phagocytic cells take up antigens (primarily protein particles), process FLASH
them, display them bound to the major histocompatibility complex (MHC) II cell FORWARD
surface marker, and travel to lymph nodes, where they recruit other cells of the immune
Dendritic cells are the most important
system into action. Dendritic cells are especially important in the initial exposure to a APCs in the body and they are
new antigen. Successful differentiation from monocytes depends on an endothelial cell responsible for initiation of adaptive
signal that is secondary to foreign antigen exposure. In the absence of this second signal, immunity.
these sensitized monocytes transform into macrophages.
Lymphocytes
Lymphocytes are easily distinguished from other leukocytes by their shared morphology
(Figures 1-14 and 1-15). After differentiating from lymphoblasts within the marrow, they
migrate to the blood as spherical cells, 6–15 μm in diameter. Typically, the nucleus
contains tightly packed chromatin, which stains a deep blue or purple and occupies
approximately 90% of the cell cytoplasm.
As the primary actors in the adaptive immune response, lymphocytes undergo bio-
chemical transformation into active immune cells via coordinated stimulatory signals.
These activated lymphocytes then enter the cell cycle, producing a number of identical
daughter cells. They eventually settle into G0 as a memory cell while they await the
T A B L E 1 - 1 . Distribution of Mononuclear Phagocytes
Marrow Monoblasts, promonocytes, monocytes, macrophages
Blood Monocytes
Body cavities Pleural macrophages, peritoneal macrophages
Inflamm tory Epithelioid cells, exudate macrophages, multinucleated giant cells

tissues
Tissues Liver (Kupffer cells), lung (alveolar macrophages), connective tissue (histiocytes), F I G U R E 1 - 1 4 . Light microscopy
spleen (red pulp macrophages), lymph nodes, thymus, bone (osteoclasts), of a lymphocyte from a blood smear.
synovium (type A cells), mucosa-associated lymphoid tissue, gastrointestinal Medium-sized agranular lymphocyte
tract, genitourinary tract, endocrine organs, central nervous system (microglia), (stained purple) with a high nuclear
skin (dendritic cells) to cytoplasmic ratio and a condensed
chromatin pattern.

CD20 CD21 CD8 CD4
CD19 CD3 CD3
B cell Tc Th
A B
F I G U R E 1 - 1 5 . Lymphocytes. A B cell and B T cell.
next stimulation event. Alternatively, following replication, daughter cells can become
terminally differentiated lymphocytes, primed for effector and secretory roles in immu-
nologic defense of the host organism.
B Cells and Plasma Cells

B cells are the “long-range artillery” in the adaptive immune response. After the lympho-
blast stage, the lymphocyte lineage diverges into B cells and T cells, each performing
separate roles in the adaptive, or humoral, immune response. Once committed, B
cells develop in the Bone marrow and then migrate to other lymphoid organs. As they
develop, B cells express immunoglobulins (IgM and IgD) on their surface, in associa-
tion with costimulatory proteins. These B-cell antigen receptor complexes allow for
the recognition of foreign antigens and subsequent activation of the B cell. Downstream
cell signaling leads to the expression of necessary genes for terminal differentiation to
plasma cells that produce and secrete antibodies to aid the specific immune response.
B cells that recognize self-antigens are triggered to undergo programmed cell death, or
apoptosis, to reduce the chance of autoimmunity.
T Cells
MNEMONIC
T cells are the “infantry” of the adaptive immune response. During maturation in the
MHC × CD = 8 (eg, MHC II × CD4 = 8, Thymus, early T cells begin expressing several surface receptors simultaneously, includ-
and MHC I × CD8 = 8). ing the T-cell receptor (TCR), CD4, and CD8. If one of these CD receptors recognizes
receptors of thymic APCs, either MHC II or I, respectively, then this T cell is positively
selected, proliferates, and matures. If a T cell recognizes self-antigen, then it is nega-
KEY FACT tively selected, and undergoes apoptosis. All T cells express CD3, and either CD4
(helper T cells), or CD8 (cytotoxic T cells).
Helper T cells “help” by mediating the
specificity of the adaptive immune Helper T Cells
response. They act as a messenger
between APCs and B cells, triggering Two subtypes of T helper cells are derived from the CD4+ progenitor: Th1 and Th2.
humoral immunity. Th1 responses occur in the presence of intracellular pathogens. Helminthic or parasitic
infections, on the other hand, drive Th2-mediated immune responses.
Helper T cells spring into action when they recognize foreign antigens bound to MHC
II. Once activated, they secrete cytokines, chemical messengers that recruit and activate
other immune effector cells. These cytokines, also called interleukins, specifically attract
B cells, which, in turn, divide and differentiate into plasma cells. After the immune
response is complete, some helper T cells become memory cells—quiescent immune
cells that retain their specificity in case of a rechallenge with the same antigen in the
future. The presence of memory cells increases the speed and efficiency of future
immune responses.
Cytotoxic T Cells
CD8+ T cells also proliferate in response to cytokines; however, they only recognize
antigens in association with class I MHC. These cells are actively involved in immune
surveillance of intracellular pathogens.

Every human cell contains MHC I, but only APCs contain MHC II. FLASH
FORWARD
■ A cell infected by an intracellular pathogen (ie, a virus) processes viral proteins and
presents them on the surface via MHC I. Cytotoxic T cells also destroy
■ A roving CD8+ T cell recognizes this signal and attaches to the infected cell via target cells via the Fas-Fas ligand
cell adhesion molecules. interaction. The interaction of Fas
■ The activated cytotoxic T cell releases perforins, which are proteins that form holes ligand of CD8+ T cells with the Fas
receptor of the infected cell leads to
in the plasma membrane of targeted cells.
apoptosis of the target cell.
Gross Anatomy and Histology KEY FACT
Th1 cells are associated with innate

ABDOMINAL WALL ANATOMY
immunity and cytolytic responses.
Th2 cells are associated with humoral
Layers of the Abdominal Wall immunity and asthma.
The order of the layers of the anterior abdominal wall differs depending on location.
They are depicted in Figure 1-16.
CLINICAL
The abdominal muscle aponeuroses comprising the rectus sheath differ above and below CORRELATION
the arcuate line. The arcuate line is a horizontal line at the level where the inferior
epigastric vessels perforate the rectus abdominis (Figure 1-16). Above the umbilicus, An indirect inguinal hernia enters the
deep inguinal ring lateral to the inferior
the rectus abdominis muscle is enveloped in the aponeurosis of the internal oblique
epigastric vessels. A direct inguinal
muscle, with the aponeurosis of the external oblique anterior to the rectus sheath. Below hernia enters the superficial inguinal
the arcuate line, the anterior rectus sheath is composed of all three abdominal muscle ring via a weakness in the abdominal
aponeuroses (external oblique, internal oblique, and transversus abdominis). Deep to muscles medial to the inferior
the muscle layer is the extraperitoneal tissue and transversalis fascia. The parietal peri- epigastric vessels.
toneum is deep to that fascia.
Inguinal Canal
The inguinal canal is an oblique, inferomedially directed channel through which the
testes and its vessels and nerves traverse the abdominal wall to reach the scrotum (Figure
1-17). As the testis descends, it carries a sheath of peritoneal sac (tunica vaginalis) into
which it invaginates acquiring a partial covering. The inguinal canal lies superior and
parallel to the inguinal ligament, allows the passage of the round ligament of the uterus
in women and the spermatic cord (ductus deferens and testicular vessels) in men. The
canal has two openings: the internal (or deep) and external (or superficial) inguinal CLINICAL
rings. The transversalis fascia evaginates through the abdominal wall and continues CORRELATION
as a covering of structures passing through the abdominal wall. The superficial ring is Internal hemorrhoids are painless
actually an opening through the external oblique aponeurosis. If the protrusion occurs because they occur above the
at the site of the deep inguinal ring, the hernia is indirect (Figure 1-18). If the weak- pectinate line where the innervation
ness occurs medial to the inferior epigastric vessels, the hernia is direct (Figure 1-18). is visceral. External hemorrhoids occur
below the pectinate line and are
Retroperitoneum painful because they receive somatic
innervation. The pectinate line is also a
The posterior abdominal cavity contains several important structures situated between site for portal systemic anastomosis—
the parietal peritoneum and the posterior abdominal wall. This region, the retroperito- rectal bleeding is therefore possible in
neum, contains portions of the gastrointestinal, genitourinary, endocrine, and vascular patients with portal hypertension.
systems (Figure 1-19).
The Pectinate Line

The pectinate (dentate) line is the mucocutaneous junction where the endoderm meets
the ectoderm in the anal canal. In the developing embryo, the endodermally derived
hindgut fuses with the ectodermally derived external anal sphincter (Figure 1-20). Tis-
sues on each side of this boundary are fed by separate neurovascular sources (Table 1-2).

Above arcuate line

Aponeurosis of external Anterior layer of External abdominal
abdominal oblique rectus sheath oblique
Aponeurosis of internal Rectus abdominis Internal abdominal
abdominal oblique oblique
Linea alba
Aponeurosis of Transversus abdominis
transversus abdominis
Posterior layer Transversalis

of rectus sheath fascia
Below arcuate line

Aponeurosis of external Anterior layer of External abdominal
abdominal oblique rectus sheath oblique
Aponeurosis of internal Rectus abdominis Internal abdominal
abdominal oblique oblique
Aponeurosis of Transversus abdominis
transversus abdominis
Urachus Medial umbilical

Transversalis (in median ligament and fold
fascia umbilical fold)
Umbilical
A prevesical fascia
Rectus abdominis Linea alba

Rectus sheath
Peritoneum
Extraperitoneal tissue
Skin
Superficial fascia
External oblique
Internal oblique
Transversus abdominis IVC Aorta

Sympathetic trunk
Transversalis fascia
Psoas
Quadratus lumborum
Latissimus dorsi
B Erector spinae
F I G U R E 1 - 1 6 . Layers of the abdomen and rectus sheath. A The major layers of the abdominal wall are shown, as well as the relation
of several retroperitoneal structures. IVC, inferior vena cava. B Superior to the arcuate line, the rectus abdominis muscle is wrapped by
the aponeurosis of the internal oblique muscle. Inferior to the arcuate line, the rectus abdominis muscle lies posterior to the aponeuroses
of both the internal oblique and transversus abdominis muscles; the posterior wall of the rectus sheath is only formed by the transversalis
fascia.

Abdominal wall
Deep (internal)
Inferior epigastric site of protrusion of
inguinal ring
vessels direct hernia
site of protrusion of
Parietal peritoneum indirect hernia Medial umbilical ligament
Extraperitoneal tissue Median umbilical ligament
Transversalis fascia Rectus abdominis muscle

Pyramidalis muscle
Transversus abdominis muscle
Conjoined tendon
Linea alba
Internal oblique muscle
Spermatic cord (ICE tie)
Aponeurosis of external
oblique muscle
Superficial (external)
Inguinal ligament inguinal ring
Internal spermatic fascia Cremasteric muscle and fascia External spermatic fascia
(transversalis fascia) (internal oblique) (external oblique)
F I G U R E 1 - 1 7 . Inguinal canal. The location and contents of the male inguinal canal, as well as the abdominal wall layers it traverses,
are shown. Other important anatomic relations are also highlighted, including umbilical ligaments and inferior epigastric vessels. The
locations of direct and indirect hernias are also labeled.
THE GASTROINTESTINAL SYSTEM

MNEMONIC
Small Intestinal Layers Retroperitoneal structures—

The small intestine, the major organ of nutrient absorption from the gut, is composed of SAD PUCKER
several layers, each contributing to the coordination of digestion and transport (Figure Suprarenal (adrenal) glands [not shown]
1-21). Aorta and IVC
Duodenum (2nd through 4th parts)
■ Mucosa: Absorption. Pancreas (except tail)
■ Submucosa: Vascular and lymphatic supply. Ureters [not shown]
■ Muscularis externa: Mechanical mixing, dissociation, and propulsion. Colon (descending and ascending)
■ Serosa: Protection. Kidneys
Esophagus (thoracic portion) [not
shown]
Mucosa
Rectum (upper segment) [not shown]
The intestinal mucosa, the absorption barrier of the alimentary canal, is composed of
polarized epithelial cells specialized in transport and uses several molecular and struc-
tural adaptations that allow it to efficiently extract nutrients from food. CLINICAL
CORRELATION
Inguinal Rectus abdominis muscle Ulcers can extend into the submucosa,
(Poupart) inner, or outer muscular layer. Erosions
Inferior
ligament
epigastric vessels
are in the mucosa only.
x Direct inguinal hernia

Indirect
inguinal hernia x Inguinal (Hesselbach) triangle FLASH BACK
x
Femoral artery Femoral hernia Molecularly, the intestinal epithelium
Femoral vein employs cell adhesion molecules to
determine polarity and maintain the
F I G U R E 1 - 1 8 . Inguinal area. Locations where indirect and direct inguinal hernias, and physical barrier between the body
femoral hernias, may occur. and the intestinal lumen (external
environment).

Right Duodenum Left

FLASH
FORWARD Peritoneum
Pancreas
Defects in lactase activity lead to
Ascending
lactose intolerance. Loss of other Descending
colon
intramembranous enzymes (eg, colon
enterocyte toxicity following Perirenal
chemotherapy) leads to osmotic space
Kidney
diarrhea.
Transversalis fascia IVC Aorta
Internal
hemorrhoids F I G U R E 1 - 1 9 . Retroperitoneal structures. The anatomic relations of important
retroperitoneal structures are shown.
Structurally, the mucosa has four adaptations that increase the absorptive surface area:
■ Plicae circulares (circular folds, or valves of Kerckring): Permanent folding of the
mucosa and submucosa into the lumen of the small intestine. They begin in the
duodenum, peak in distribution in the duodenojejunal junction, and end in the
mid ileum.
■ Intestinal villi: Finger-like projections of the mucosa into the lumen that extend
deep into the mucosa to the muscularis mucosa. At the bottom of intestinal villi are
intestinal glands.
■ Intestinal glands (or crypts of Lieberkühn): Nonsecretory glands that enhance
External
hemorrhoid
Pectinate absorption.
line
■ Microvilli (brush border): On the apical border of each enterocyte, or intestinal
F I G U R E 1 - 2 0 . Pectinate line. A epithelial cell, the surface area is approximately 30-fold. Contains a core of paral-
comparison of internal hemorrhoids lel, cross-linked actin filaments bound to cytoskeletal proteins. The brush border is
(internal rectal vessels) and external coated in a glycocalyx, a surface coat of glycoproteins excreted by columnar secretory
hemorrhoids (external rectal goblet cells.
vessels) is shown, highlighting their
separation by the pectinate line. The The luminal membrane of intestinal epithelial cells contains several intramembranous
endodermal and ectodermal origins
of these structures underlie the
enzymes (eg, maltase, lactase, enterokinase) integral to digestion and small-molecule
anatomic distinction between them. absorption. Intracytoplasmic enzymes break down absorbed di- and tripeptides.
CLINICAL Submucosa
CORRELATION
The submucosa is the site of vascular and lymphatic supply to the intestine. This layer,
Only when adenocarcinomas invade composed of loose connective tissue, contains a vascular plexus that extends capillaries
into the submucosa are they able to into the surrounding layers. The lymphatic drainage of the submucosa begins as blind-
metastasize taking advantage of the
ended channels, known as lacteals, within the core of the intestinal villi. These lacteals
rich lymphatic and vascular plexus
empty into a submucosal lymphatic plexus that shuttles antigens to nearby lymphatic
located there.
nodules and emulsified fat-soluble nutrients to the liver.
T A B L E 1 - 2 . Pectinate Line
CHARACTERISTICS ABOVE BELOW

Cell types Glandular epithelium Squamous epithelium
Cancer type Adenocarcinoma Squamous cell carcinoma
Innervation Visceral Somatic
Hemorrhoids Internal (painless) External (painful)
Arterial supply Superior rectal artery (branch of inferior mesenteric artery) Inferior rectal artery (branch of internal pudendal artery)
Venous drainage Superior rectal vein → inferior mesenteric vein → portal Inferior rectal vein → internal pudendal vein → internal iliac
system vein → common iliac vein → IVC

Tunica muscularis
externa Mucosa
Epithelium
Tunica submucosa Lamina propria
Muscularis mucosa
Mesentery
Intestinal villi
Submucosa
Vein Submucosal gland
Artery
Submucosal Lymph vessel
gland
Epithelium Lumen
Submucosal nerve
plexus (Meissner)
Muscularis mucosa
Muscularis
Myenteric nerve plexus Inner circular layer
(Auerbach) Myenteric nerve plexus
(Auerbach)
Tunica serosa Outer longitudinal layer
Enlarged view (peritoneum) Serosa
cross-section
F I G U R E 1 - 2 1 . Anatomy of the small intestines, depicting the various tissue layers and nerve plexuses.
Within the duodenum, the submucosa contains Brunner glands, tubuloacinar mucous CLINICAL
glands that produce an alkaline (pH ~ 9) secretion to neutralize acidified chyme from CORRELATION
the stomach. Within the ileum reside the lymphatic nodules that provide immunologic
MALT lymphoma: A form of lymphoma
surveillance to the intestines. These nodules, also known as Peyer patches (Figure 1-22),
involving the mucosa-associated
or mucosa-associated lymphoid tissue (MALT), contain a germinal center of B cells lymphoid tissue (MALT), frequently
surrounded by specialized APCs: M cells and dendritic cells. Antigens enter the Peyer of the stomach, and caused by
patch through antigen presentation via M cells and dendritic cells. The B cells of the Helicobacter pylori infection.
MALT germinal center are specialized; they produce a specific immunoglobulin, IgA,
which can be secreted into the intestinal lumen to neutralize pathogens before they
invade the epithelium.
The submucosa also houses one of the two neural plexuses located within the small
intestine. The other (myenteric) plexus is located between the two layers of the muscu-
laris externa. Considered part of the autonomic system, these neural networks receive
a great deal of intrinsic input from the intestinal parenchyma. This allows the gut to
operate nearly independently from the central nervous system, although its action can
be modulated via extensive extrinsic neural input. Two networks control the activity of
the small intestine: the submucosal plexus of Meissner and the myenteric plexus of
Auerbach. They are extensively interconnected and probably equally modulate mucosal F I G U R E 1 - 2 2 . Histology of Peyer
and muscular activity, coordinating action to maximize digestion. patches in small intestine.
Muscularis Externa (Propria) FLASH

FORWARD
Intestinal motility is controlled by two layers of smooth muscle. One circular layer is
Dysfunction of the enteric plexuses,
surrounded by a second longitudinal layer (Auerbach’s plexus resides between these
due to either congenital absence
two layers). Coordinated muscular contraction produces two types of mechanical results:
(Hirschsprung disease) or neurologic
propulsion and segmentation. injury (diabetic neuropathy), leads to
■ Propulsion occurs when proximal contraction is coordinated with distal relaxation. decreased intestinal motility.
This leads to increased upstream pressure, which slowly propels food through the
digestive system. Contraction of proximal sphincters ensures that the food bolus
only moves distally. CLINICAL
CORRELATION
■ Segmentation occurs when a bolus of food is mechanically compressed and split
into portions as the lumen constricts near the bolus center, not merely proximal to Pain experienced when an
it. If this contraction is not coordinated with distal relaxation, the bolus cannot be encapsulated organ enlarges is due to
propelled forward. Instead, its contents are mixed by the muscular contractions. the stimulation of the autonomic nerve
endings in the capsule, rather than
caused by the increasing size of the
organ itself.

Serosa
KEY FACT
The serosa is the visceral peritoneum covering the small intestine. It is lined by a single
Gastrosplenic ligament: Connects layer of mesothelium-derived cells.
greater curvature of the stomach to
the spleen. Contains short gastric
and left gastroepiploic vessels and SPLENIC ANATOMY
separates the greater and lesser sacs
on the left. The largest secondary lymphatic organ, the spleen, is located in the upper left quadrant
Splenorenal ligament: Connects the of the abdominal cavity. It is completely surrounded by peritoneum, except at its hilum,
spleen to the posterior abdominal where the vasculature enters and exits. It is bordered laterally and posteriorly by ribs
wall. Contains splenic artery and vein 9–11, superiorly by the diaphragm, anteriorly by the stomach, inferiorly by the left colic
as well as the tail of the pancreas. flexure (splenic flexure), and medially by the left kidney. It is attached to the greater
curvature of the stomach by the gastrosplenic ligament and to the posterior abdominal
wall by the splenorenal ligament. The parenchyma of the spleen is composed of red
pulp and white pulp.
KEY FACT
Red Pulp
Splenic dysfunction: ↓ IgM leads to ↓
complement activation, which leads to The splenic sinusoids of the red pulp make up an interconnected network of vascu-
↓ C3b opsonization and susceptibility lar channels that aid the hematopoietic system by removing senescent and damaged
to encapsulated organisms. erythrocytes from the circulation. These are lined by elongated endothelial cells and a
discontinuous basement membrane made of reticular fibers (Figure 1-23). The walls
separating the sinusoids are called splenic cords (cords of Billroth). The splenic cords
contain plasma cells, macrophages, and blood cells supported by a connective tissue
CLINICAL matrix. Macrophages adjacent to the sinusoids recognize opsonized bacteria, adherent
CORRELATION
antibodies, foreign antigens, and senescent red cells as they filter through the spleen.
Lab findings post splenectomy are as
follows: White Pulp
■ Howell-Jolly bodies (nuclear
remnants) The white pulp is a site of immunologic reinforcements and is composed of nodules
■ Target cells (Malpighian corpuscles) that contain B cells arranged in follicles and T cells arranged
■ Thrombocytosis (loss of in sheaths. Arranged around a central arteriole, the white pulp contains immune cells
sequestration and removal) in a specific orientation that facilitates hematogenous activation of the humoral immune
■ Lymphocytosis (loss of system. As an antigen enters the central arteriole, the vasculature branches into radial
sequestration) arterioles (emanating from the central arteriole like spokes of a wheel), and the antigen
passes through a surrounding sheath of T cells. This region, known as the periarterial
lymphatic sheath (PALS), allows for sampling of the arteriolar contents.
CLINICAL The radial arterioles then empty their contents into the marginal zone, between the red
CORRELATION
and white pulp. This area contains specialized B cells and APCs that capture the blood-
Disordered red cell removal borne antigens for recognition by lymphocytes (Figure 1-23).
occurs in sickle cell anemia,
leading to autosplenectomy
Activated T cells then travel to the adjacent lymphatic nodule for B-cell activation. This
and immunodeficiency (against
process produces active germinal centers within the white pulp where B cells mature.
encapsulated bacteria).
Mature B cells, or plasma cells, defend the host via soluble immunoglobulins secreted
into the circulation.
CLINICAL THE LYMPHATIC SYSTEM

CORRELATION
Asplenic patients should receive The Lymph Node
additional vaccines against
encapsulated organisms: Haemophilus Like little spleens dispersed along the lymphatic system, these small secondary lym-
influenzae type b, pneumococcus, and phatic organs aid regional adaptive immune responses by housing APCs, T cells, and
meningococcus. B cells (Table 1-3). Each node possesses multiple afferent lymphatic channels that enter
through the capsule of the lymph node near the cortex. The efferent lymphatics exit at
the hilum, along with an artery and vein (Figure 1-24). From the afferent lymphatics,
antigens and APCs in the lymph enter the medullary sinus. There, free antigens meet
macrophages for phagocytosis and presentation in association with MHC II for T-cell

A Capsule
Germinal center Trabecula
Red pulp (RBCs)
Mantle zone Sinusoid
Marginal zone
Reticular fibrous
White pulp (WBCs) framework
Follicle (B cells)
Periarteriolar
lymphoid sheath
(T cells)
Open
circulation
Closed
circulation
Pulp vein
Artery
Vein
F I G U R E 1 - 2 3 . Diagram of the functional units of the spleen and histologic section of

splenic sinusoid. A The important functional units of the spleen are delineated here, where a
central arteriole enters and supplies blood first to the periarteriolar lymphoid sheath (PALS)
T-cells, which is surrounded by the follicle of B cells. The marginal zone between the white pulp
and red pulp contains antigen-presenting cells (APCs) and macrophages to capture blood-borne
antigens for recognition by lymphocytes. B Histologic section of the splenic sinusoid showing
vascular channels through the red pulp (red arrow), and T cells in the PALS (white arrow).
FLASH
activation. Activated APCs bypass the adjacent medullary cords to reach the paracortex, FORWARD
where T cells await stimulation. Activated T cells move to the adjacent cortical follicle,
Acute lymphadenitis occurs when brisk
where B cells await costimulatory signals. Once activated, mature B cells travel back to germinal center expansion in response
the medullary cords, where they develop into plasma cells and secrete immunoglobulins to a local bacterial infection (eg, teeth
into the adjacent vascular supply. or tonsils) leads to painfully swollen
lymph nodes.
T A B L E 1 - 3 . Lymph Node Organization
REGION DIVISIONS CONTENTS AND FUNCTION

Cortex Follicle (outer ■ Site of B-cell localization and proliferation
cortex) ■ 1° follicles are dense and contain dormant B cells
■ 2° follicles have pale central active germinal centers
Paracortex ■ Helper T cells reside between follicles and the splenic medulla
QUESTION
■ High endothelial venules allow lymphocytes to enter circulation
What specific organisms classically
Medulla Sinus ■ Reticular cells and macrophages communicate with efferent cause infections in asplenic patients?
lymphatics
Cords ■ Closely packed lymphocytes and plasma cells

lymphatic
Follicles (B cells) 1º follicle

Paracortex 2º follicle
(T cells)
Germinal center
Mantle zone
Medullary cords
(lymphocytes,
Postcapillary
plasma cells)
venule
Vein
Capillary Artery
supply
lymphatic
Trabecula Medullary sinus

(reticular cells,
Capsule macrophages)
F I G U R E 1 - 2 4 . Lymph node. Schematic representation of the lymph node structure shows

the major divisions of the node. The medulla consists of cords of plasma cells and sinuses of
macrophages. The cortex consists of dormant and activated B-cell follicles, as well as a T-cell
paracortex.
Lymphatics
As part of the cardiovascular system, the lymphatic vessels drain interstitial fluid from
surrounding tissues (Tables 1-4 and 1-5, and Figure 1-25). They are also integral to
the process of transporting fats and fat-soluble nutrients and facilitating the humoral
immune response. Their role in immunity involves carrying foreign antigens and APCs
to lymph nodes for T- and B-cell activation.
The lymph vessels are analogous to veins in their structure and organization. The walls
of the lymphatic capillary are made up of a layer of loosely bound endothelial cells, lack-
ing tight junctions and bound to an incomplete basal lamina. This allows fluid to enter
the lumen via hydrostatic pressure. As distal lymphatic capillaries merge, they produce
KEY FACT larger vessels containing valves, just like veins, that maintain the direction of flow. In
addition to interstitial hydrostatic pressure, muscular contractions aid the flow of lymph.
The thoracic duct drains into the left
subclavian vein.
The right lymphatic duct drains into During its course back to the systemic circulation, lymphatic fluid is filtered through
either the right subclavian vein or lymph nodes for immune surveillance. The remaining lymph reaches the bloodstream
the right internal jugular vein. via one of two major routes: the larger thoracic duct or the smaller right lymphatic
duct.
T A B L E 1 - 4 . Primary Lymph Drainage Routes
ANSWER DRAINAGE ROUTE ANATOMIC REGIONS DRAINED

Right lymphatic duct Right arm, right half of head and right thorax
Streptococcus pneumoniae, Hae-
mophilus influenzae type b, Neisseria Thoracic duct All other regions
meningitidis, Escherichia coli, Salmo-
nella spp, Klebsiella pneumoniae, group
B Streptococci (SHiNE SKiS)

T A B L E 1 - 5 . Drainage Routes for the Major Lymph Nodes
LYMPH NODE CLUSTER AREA OF BODY DRAINED Drainage Drainage

of right of thoratic
Cervical Head and neck lymphatic duct
duct
Hilar Lungs
Mediastinal Trachea and esophagus
Axillary Upper limb, breast, skin above umbilicus
Celiac Liver, stomach, spleen, pancreas, upper duodenum
Superior mesenteric Lower duodenum, jejunum, ileum, colon to splenic fl xure
Inferior mesenteric Colon from splenic fl xure to upper rectum
Internal iliac Lower rectum to anal canal (above pectinate line), bladder, vagina
(middle third), prostate F I G U R E 1 - 2 5 . Areas of lymphatic
drainage of the thoracic and right
Para-aortic Testes, ovaries, kidneys, uterus lymphatic ducts. Note that the
thoracic duct drains the lymphatic
Superficial inguina Anal canal (below pectinate line), skin below umbilicus (except
fluid from the entire body, except for
popliteal territory), scrotum the right half of the body superior to
the diaphragm.
Popliteal Dorsolateral foot, posterior calf
PERIPHERAL NERVOUS SYSTEM
Nerve Cells
During embryonic development, neural crest cells migrate into the peripheral tissues,
where they differentiate into neurons of the following tissues:
■ Sensory neurons of the dorsal root ganglia.
■ Neurons of the cranial nerve ganglia.
■ Neurons of the autonomic system (eg, vagus nerve or sympathetic ganglia).
■ Neurons of the myenteric (Auerbach) and submucosal (Meissner) plexus.
Neuronal cells contain three major parts: the cell body (soma), dendrites, and axons.
■ The soma houses the organelles (including the prominent nucleus and the well-
developed RER, referred to as the Nissl body).
■ Dendrites are afferent cytoplasmic processes arising from the soma that provide
increased surface area for axonal synaptic connections, thus facilitating the reception
F I G U R E 1 - 2 6 . Histology of the
and integration of information. Each neuron has many dendrites (Figure 1-26). Purkinje cell of the cerebellum,
■ An axon is the efferent cytoplasmic process sprouting from the soma at the axon hillock demonstrating characteristic
and ending in many synaptic terminals, or boutons. Each neuron has one axon. extensive dendritic branching.
Because neurons are specialized cells for signal transduction, they can secrete several
different neurotransmitters (Table 1-6). These peptide molecules are produced in the QUESTION
RER, stored in secretory vesicles, transported through the axon along microtubules via
An 18-year-old man presents to his
molecular motors, and eventually released from the axon into the synaptic cleft. The
doctor complaining of fatigue and
synaptic cleft is the junction between the synaptic terminal and an adjacent cell. This
sore throat. On exam he has a fever,
vesicular secretion, which is triggered by a transmitted action potential, is the primary hepatosplenomegaly, and symmetrical
method of neural control. lymphadenopathy of the posterior
cervical chain of lymph nodes. He
Schwann Cells also has petechiae on his palate with
enlarged tonsils. What is the most
The Schwann cells (Figure 1-27) are descendents of neural crest cells and envelops
likely diagnosis?
only one peripheral nervous system (PNS) axon with myelin. This is in contrast to the

T A B L E 1 - 6 . Neurotransmitters
LOCATION OF ALZHEIMER HUNTINGTON PARKINSON

NEUROTRANSMITTER SYNTHESIS ANXIETY DEPRESSION SCHIZOPHRENIA DISEASE DISEASE DISEASE
Acetylcholine Basal nucleus of ↓ ↓ ↑
Meynert
Dopamine Ventral ↓ ↑ ↑ ↓
tegmentum,
SNpc
GABA Nucleus ↓ ↓
accumbens
Norepinephrine Locus ceruleus ↑ ↓
Serotonin Raphe nucleus ↓ ↓ ↓
SNpc, substantia nigra pars compacta

Reproduced with permission from Le T, et al. First Aid for the USMLE Step 1 2016. New York, NY: McGraw-Hill Education; 2016: 455.
CLINICAL oligodendroglia of the central nervous system (CNS), which can myelinate multiple
CORRELATION axons (Figure 1-27). Myelin increases conduction velocity due to saltatory conduction.
The endoneurium is the target of the Between myelinated segments are the nodes of Ranvier (Figure 1-28), and the myelin-
autoimmune inflammatory infiltrate in ated segments are referred to as internodes.
Guillain-Barré syndrome.
Peripheral Nerve
The peripheral nerve consists of a bundle of neuronal axons, Schwann cells, and protective
connective tissues. It carries impulses from the CNS to the entire body. Although indi-
vidual neurons are surrounded by Schwann cells, a nerve fiber is more complex (Figure
1-29). Each individual neuron, along with its associated Schwann cells, is encapsulated in
endoneurium. Bundles of these nerves are called a nerve fascicle, which is encapsulated in
perineurium. The perineurium acts as a permeability barrier that regulates nutrient trans-
port from capillaries to the nerve fibers beneath. Nerve fascicles, and their vascular supply,
are covered by epineurium (dense connective tissue), forming the peripheral nerve trunk.
ANSWER
Infectious mononucleosis caused by

Epstein-Barr virus. The diagnosis is
confirmed by the presence of atypical
lymphocytes and heterophile antibod-
ies (Monospot).
F I G U R E 1 - 2 7 . Electron micrograph of myelinated axons in the optic nerve. MVB,

multivesicular bodies.

Brachial Plexus Nucleus Schwann cell

The motor portions of spinal nerves are organized differently from the sensory neurons.
Instead of clear divisions organized by spinal level that serve successively distal regions
of the body, a great deal of mixing of neurons from each spinal level produces a single
nerve supplying a specific muscle group. The upper extremity’s brachial plexus is a Myelin sheath Node of Ranvier
prime example. As motor neurons exit the spinal column between C5 and T1, the
ventral rami begin to exchange individual fibers. These rami are considered the roots F I G U R E 1 - 2 8 . Schwann cells.
of the brachial plexus (Figure 1-30). As the five roots reach the inferior portion of the
neck, C5 and C6 unite to form the superior trunk, as C8 and T1 unite to form the
inferior trunk, leaving C7 as the middle trunk. These three trunks pass beneath the Nerve trunk
clavicle, where they each split into anterior and posterior divisions. The anterior divi- Epineurium
sions of the superior and middle trunks merge to form the lateral cord of the brachial Perineurium
plexus, and the anterior division of the inferior trunk becomes the medial cord. Both Endoneurium
of these cords eventually supply the muscles of the anterior compartments of the upper
Nerve fiber
limb. All three posterior divisions merge to form the posterior cord, which supplies the
posterior compartments of the upper limb. From cords, the plexus divides further into
its terminal infraclavicular branches. Common injuries associated with the brachial F I G U R E 1 - 2 9 . Peripheral nerve
plexus are listed in Table 1-7, and shown in Figure 1-31. layers.
Dermatomes
KEY FACT
Usually, successive spinal levels innervate successive caudal regions. The dermatomal
organization of the body is displayed in Figure 1-32A and dermatomes of the hand are Following trauma, the perineurium
displayed in Figure 1-32B, as projected onto the skin. must be repaired via microsurgery to
ensure proper nerve regeneration and
functional restoration.
THE INTEGUMENTARY SYSTEM
Skin
MNEMONIC
The skin has several functions:
Organization of the brachial
■ Mechanical protection plexus—
■ Moisture retention
Randy Travis Drinks Cold Beer:
■ Body temperature regulation
Roots
■ Nonspecific immune defense
Trunks
■ Salt excretion Divisions
■ Vitamin D synthesis Cords
■ Tactile sensation Branches
Superior
C5
Erb palsy (“waiter’s tip”) Trunk Lateral MNEMONIC
Full claw hand (Klumpke palsy) Musculocutaneous
Axillary and radial nerve palsy C6
Axillary Dermatomes—
Winged scapula
Middle Posterior T10 at the belly but-10
Deltoid paralysis C7 (Extensors) Median (flexors)
“Saturday night palsy” (wrist drop)
L1 at IL (Inguinal Ligament)
Difficulty flexing elbow, variable Inferior Radial L4, down on L-4’s “all fours” (at the
C8 Trunk Medial knees)
sensory loss
Decreased thumb function, Ulnar
“Pope’s blessing” T1
Trunks Divisions Cords Branches
Intrinsic muscles of hand,
partial claw hand
Long thoracic
Roots
F I G U R E 1 - 3 0 . Brachial plexus. Schematic representation of the brachial plexus on the

right. To the left are clinical correlations to some common brachial plexus injuries and the
location of nerve lesions that create them.

T A B L E 1 - 7 . Common Brachial Plexus Injuries
LESION LOCATION SYNDROME DEFICITS

Superior trunk C5/C6 Erb-Duchenne palsy (“waiter’s tip”) ■ Abduction (deltoid)
■ Lateral rotation (infraspinatus, teres minor)
■ Supination (biceps) and supinator muscle
Inferior trunk C8/T1 Interphalangeal joint fl xion and metacarpophalangeal Intrinsic muscles of hand, forearm fl xors of hand
joint extension paralysis (full “claw hand”)
Posterior cord C5/C6/C7/C8 Axillary and radial nerve paralyses Same as for axillary and radial nerves
Long thoracic nerve T1 Winged scapula Serratus anterior paralysis
Axillary nerve Deltoid paralysis Abduction
Radial nerve “Saturday night palsy” Wrist drop (supinator, brachioradialis, triceps,
extensors of wrist/fingers
Musculocutaneous nerve Biceps paralysis Elbow fl xion, sensation on radial/lateral side of

the forearm
Median nerve “Pope’s blessing” on making a fis Thumb abduction, thumb opposition, fourth/fi th
digit extension
Ulnar nerve Fourth/fi th digit paralysis (partial “claw hand”) Grip strength, fourth/fi th digit fl xion, intrinsic
muscles of the hand
The skin is composed of three layers: the epidermis (ectodermally derived), the deep
MNEMONIC dermis, and the hypodermis, or subcutaneous tissues (the latter two of which are mes-
enchymally derived).
Layers of the epidermis—
Californians Like Girls in String
Bikinis: Epidermis
Stratum Corneum The epidermis is predominantly made of keratinocytes, or epithelial cells named for
Stratum Lucidum the intermediate filament protein keratin. The epidermis is organized into five layers
Stratum Granulosum (Figure 1-33).
Stratum Spinosum
Stratum Basalis The stratum basale is composed of columnar keratinocytes bound to a basement mem-
brane via hemidesmosomes. Cellular proliferation occurring at this level maintains the
population of epidermal stem cells, replenishes sloughed skin cells, and contributes to
KEY FACT epidermal wound healing. These columnar keratinocytes undergo a process of differ-
entiation, as they move upwards toward the surface. At the level of the stratum spino-
The stratum lucidum is found only in sum, keratinocytes have a flattened polygonal shape and an ovoid nucleus. By the time
areas of thick skin (eg, palms and soles).
they reach the stratum corneum, they are completely flattened and lack nuclei.
CLINICAL Erb-Duchenne palsy

CORRELATION (”waiter’s tip”)
Albinism: Normal melanocyte number
with reduced melanin production
due to a decrease in tyrosinase
activity or defective tyrosine transport.
Can also be caused by failure of
neural crest cell migration during
development. Increased risk of skin
cancer.
A B C
F I G U R E 1 - 3 1 . A Erb palsy, B claw hand, and C winged scapula.

V1 C2
V2 C3
V3 C4
Important Dermatomes
C5 Median nerve
C6 T1 Forehead V1
Thumb C6 Ulnar nerve
T4 C6
T6 Nipples T4 Radial nerve
T8 C7 Umbilicus T10 Palm of hand
T10
C8 Knee L3/4
T12
S2 L1 C8 Great toe L5 Median nerve
S3 Anus S5
Ulnar nerve
Radial nerve
L4
A L5 B Dorsum of hand
F I G U R E 1 - 3 2 . Landmark dermatomes A , and dermatomes of the hand B .
The epidermis also contains other cell types: melanocytes, Langerhans cells, and
Merkel cells. C
L
■ Melanocytes, derived from the neural crest, produce melanin, a tyrosine derivative
G
responsible for skin pigmentation (Figure 1-34). S
■ Langerhans cells are bone marrow–derived dendritic cells residing in the skin. Once B
activated, they migrate to secondary lymph organs to present antigens to T cells.
■ Merkel cells, found in the stratum basale, contribute to the function of the numer- Dermis
ous mechanoreceptors present in the epidermis. A myelinated sensory axon actually
ends in an unmyelinated portion, called the nerve plate, which synapses on the F I G U R E 1 - 3 3 . Epidermis layers.
Merkel cell. This synapse allows the Merkel cell to signal tactile sensation. C = stratum corneum; L = stratum
lucidum; G = stratum granulosum;
S = stratum spinosum; B = stratum
In addition to Merkel cells, two other specialized sensory structures exist within the basale.
body: Meissner corpuscles in the dermis and Pacinian corpuscles in the deep tissues
(Figure 1-36).
CLINICAL
CORRELATION
Dermis
Vitiligo: Irregular areas of
The epidermis is anchored to its basement membrane by hemidesmosomes. Two indis- complete depigmentation. Caused
tinct layers of the dermis, the papillary layer and the reticular layer, reside just below. by autoimmune destruction of
The uppermost papillary layer (primarily loose connective tissue) consists of fibroblasts, melanocytes (Figure 1-35).
collagen, and fine elastic fibers; the lower reticular layer contains mostly irregularly and
densely packed collagen and elastic fibers.
Phenylalanine
Tyrosine Tyroxine
Tyrosinase
Dopa Tyroxine Norepinephrine Epinephrine
Tyrosinase
Melanin F I G U R E 1 - 3 5 . Clinical findings
on a patient with vitiligo.
F I G U R E 1 - 3 4 . Albinism results from a complete deficien y of the tyrosinase. Thus, the
pigments eumelanin and phaeomelanin are not produced in the albinism tyrosine metabolic
pathway.

Meissner - Small, encapsulated nerve endings found in the

dermis of palms, soles, and digits of skin. Involved
in light discriminatory touch of glabrous (hairless)
skin.
Pacinian - Large, encapsulated nerve endings found in deeper

layers of skin at ligaments, joint capsules, serous
membranes, and mesenteries. Involved in pressure,
coarse touch, vibration, and tension.
Merkel - Cup-shaped nerve endings (tactile disks) in the stratum

basale of the epidermis of fingertips, hair follicles, hard
palate. Involved in light, and crude touch.
F I G U R E 1 - 3 6 . Sensory corpuscles.
MNEMONIC
Skin Appendages
Relation of the pulmonary Skin appendages (hair follicles, sweat glands, and sebaceous glands) are present in
artery to the bronchus at each the dermis, as is the blood supply to the skin (Figure 1-37). Hair shafts are made of
lung hilum— hardened keratin, and the follicular bulb where the hair originates contains stem cells
RALS capable of repopulating the follicular shaft, or even the epidermis following injury.
Right Anterior Sebaceous glands are oil-producing glands that actually empty their contents into the
Left Superior hair follicle, the tubular invagination that the hair shaft follows as it grows to the surface.
Sweat glands occur in two forms: (1) The eccrine sweat gland is a ubiquitous coiled
gland innervated by sympathetic cholinergic nerves and used in temperature regulation.
MNEMONIC (2) The apocrine glands, regulated by adrenergic stimuli, only become active following
puberty. These coiled glands are found in the axilla, mons pubis, and perianal regions.
Eccrine glands: Everywhere
Dermal
Erector pili muscle Sebaceous vascular
gland plexus
Epidermis
Papillary
dermis
Reticular
dermis
Subcutaneous
tissues
Hair Eccrine
follicle gland
Adnexal structures
F I G U R E 1 - 3 7 . Skin appendages. The histologic schematic representation of skin demonstrates

a complex organization of cells, connective tissue, blood vessels, and adnexal structures.

THE RESPIRATORY SYSTEM

Pulmonary artery Alveolar duct
Alveolar sacs
Respiratory Histology
Pulmonary vein
Once air has traveled through the conducting zone (nasal cavities, nasopharynx, oro-
pharynx, larynx, trachea, bronchi, and bronchioles), it enters the respiratory zone (respi-
ratory bronchioles, alveolar ducts, alveolar sacs, and alveoli [Figure 1-38]). Air exchange
occurs in the respiratory zone.
Alveolar capillary beds
Bronchi and Bronchioles Alveoli
Except for their smallest divisions, these airways are involved in conducting inhaled air
F I G U R E 1 - 3 8 . Lung alveolus.
to the lung, rather than gas exchange. Primarily, the walls of the conducting airways The respiratory unit of the lung is the
contain a pseudostratified ciliated columnar epithelium, composed of three cell types: alveolus.
■ Ciliated epithelial cells: Coordinated ciliary motion clears mucus (with trapped
pathogens and debris) from the lungs. These cells extend distally to the begin- KEY FACT
ning of the terminal bronchioles before transitioning to the cuboidal cells.
■ Goblet cells: Produce mucus and protect the airway and lung tissue from inspired Type I pneumocytes are squamous
particles. Goblet cells extend to the end of the bronchi. and thin for optimal gas diffusion. They
■ Basal cells: Provide structural support to the airway and can differentiate into other make up 97% of alveolar surfaces.
epithelial cell types after injury.
Alveolus KEY FACT

The alveolus is the basic functional unit of the lung. The lungs contain about 300 mil- Type II pneumocytes are cuboidal
lion alveoli, which increase the surface area for gas exchange to approximately 75 m2. and clustered cells that secrete
Each alveolar wall consists of two cell types, type I and type II alveolar cells (pneumo- pulmonary surfactant to decrease
cytes), serving separate physiologic functions (Figure 1-39). alveolar surface tension and prevent
alveolar collapse (atelectasis). Also
The primary function of the type I pneumocytes is to form the first layer of the air-blood serve as precursors to type I cells
barrier. They are continuous with the low cuboidal epithelium of the adjacent respira- and other type II cells. Type II cells
tory bronchiole, and cover 97% of the alveolar surface, allowing deoxygenated blood to proliferate during lung damage.
come into close proximity with inhaled environmental O2. Below the type I cells is a
fused (double) layer of basement membranes (from type I cells and endothelial cells)
completing a semipermeable barrier that allows O2 and CO2 diffusion. FLASH
FORWARD
Pulmonary surfactant reduces the
Surfactant surface tension at the air-fluid interface,
(constitutive secretion)
thus decreasing the tendency for
Macrophage
alveolar collapse.
Type II Alveolar
epithelial cell space
Lamellar bodies CO2
Type I
epithelial cell
O2
Blood-air Tight junction
barrier (continuous endothelium) Capillary
lumen
F I G U R E 1 - 3 9 . Gas exchange barrier. The thickness of the gas exchange barrier is

highlighted, as well as the anatomic relations of important cell types: type I and type II
epithelial cells, endothelial cells, macrophages, and red blood cells.

FLASH The type II alveolar cell’s primary function is the production of pulmonary surfactant.
FORWARD Type II alveolar cells also retain the ability to differentiate into type I alveolar cells if
there is an injury to the lung. Clara cells, also known as C cells, also help produce
Amniotic fluid surfactant levels can
be used as a surrogate measure of surfactant in the lungs. C cells act as stem cells, which means they can differentiate
fetal lung maturity. Steroids are given and replace other damaged lung cells. Finally, C cells contain enzymes that can detoxify
to premature infants to increase noxious substances in the lungs.
pneumocyte surfactant production.
Lung Anatomy
The lungs are enveloped in a serosal membrane, known as pleura, which has two layers.
Apposed directly to the lung is the visceral pleura. The parietal pleura is adherent to
KEY FACT the chest wall. Small amounts of fluid within the potential space between the visceral
and parietal pleura, the pleural space or cavity, allows respiratory tissues to slide effort-
Aspirated foreign bodies end up in the
lessly as the lung expands.
right main bronchus more often than
in the left, because the right is wider
and its course is more vertical than that Each lung is divided into lobes, which are further divided into bronchopulmonary
of the left. segments. Each bronchopulmonary segment corresponds to a branch of the bronchial
tree that delivers O2 to the lung. The right lung is composed of three lobes, and the left
lung, two (Figure 1-40). However, the superior lobe of the left lung contains a region,
the lingula, which is analogous to the right lung’s middle lobe. The cardiac notch, into
which the apex of the heart protrudes, replaces the middle lobe on the left side. The
KEY FACT
bronchial tree begins at the trachea, which branches into right and left main-stem
Divisions of the bronchial tree: bronchi. The left bronchus is slightly longer, and the right bronchus makes a shallower
Trachea angle (runs more vertically), with the trachea at its bifurcation. The intersection of the
Right and left main bronchi two mainstem bronchi with the trachea is called the carina.
Lobar bronchi
Segmental bronchi The major vascular supply to each lung begins as a single branch of the pulmonary
Bronchioles artery (carrying deoxygenated blood) and ends as two pulmonary veins (carrying oxy-
Terminal bronchioles genated blood to the left atrium). Between these large vessels, the vasculature branches
Respiratory bronchioles into intrasegmental pulmonary arteries, which travel with branching airways. The pul-
Alveolar ducts
monary veins are along the boundaries of the bronchopulmonary segment. Both end
Alveoli
in a capillary network, within the alveolar septae, which facilitates gas exchange. The
bronchial circulation delivers oxygenated blood from the thoracic aorta to supply the
lung tissue.
MNEMONIC
Anatomic Relations
RALS The lungs reside within the rib cage, under the protection of the bony skeleton. The
Right Anterior apices are at the level of the first rib, and the bases rest in the left and right costodia-
Left Superior phragmatic recesses. Posteriorly, the lungs extend more distally, deep into the costodia-
phragmatic recess, at the 11th or 12th rib. Within the chest, each of the three lung
Trachea Upper lobe
Horizontal
fissure Oblique fissure
Middle lobe Lingula

Lower Lower
lobe lobe
Inferior lobe
Right Left R L L R
A bronchus bronchus B Anterior view Posterior view
F I G U R E 1 - 4 0 . Lungs and bronchi. A Right bronchus is more vertical and wider in diameter than the left bronchus. B Right lung has
three lobes: superior lobe, middle lobe, and inferior lobe. In the left lung, there are two lobes and the lingula. The lingula is a small
projection of the left lung homologous to the middle lobe.

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CHAPTER VII.
HANNIBAL’S FIRST TRIUMPH.
“Now, Maharbal,” quoth the chief, “I would talk to thee no longer as

one general to another, but simply as man to man. What about my
daughter Elissa? Hast thou forgotten her? Hath not perchance all
this terrible fighting for the last six months knocked all the love
nonsense with which thou wast imbued out of thy warlike head, or is
there still left paramount therein the memory of that girl of mine?
Now, wilt thou answer plainly, for I have something to propose to
thee which may be of importance?”
Maharbal made no answer, but Hannibal rose, unlocked a small
casket and drew out a scroll, which he perused while waiting for a
reply.
“Well,” he remarked, seeing that no reply came, “I would know thy
mind on this matter, my friend.”
“Hannibal,” said Maharbal, rising in turn, and confronting his Chief,
“Hannibal,”—then he paused and threw down his sword with a
somewhat angry and impatient movement—“by what right dost thou
talk to me of Elissa? What is it to thee if I should think of her still or
no? As a warrior and my Chief I may listen to thee, ay, both must
and would listen to thee; but what have women to do with me now? I
am here to fight for Carthage and mine honour, ay, and for thine own
honour, too, Hannibal, but nothing more.”
“Honour is honour, but friendship is friendship. War is also war,
and we are all for our country; but private interests, nevertheless,
rule us all at times. Thou knowest this as well as I, therefore, as
friend to friend, tell me now the truth, Maharbal.”
“Well, the truth is this, Hannibal. When I meet a foe and he
confronts me,”—Maharbal excitedly arose and seized his sword and
shook it savagely—“I say to myself, ‘This for Elissa.’ Then I strike
home. When my foe is struck down and bleeding at my feet, and the
point of my weapon is at his throat, again I sometimes say to myself,
‘I spare thee for the sake of Elissa,’ and thus it ofttimes haps that a
human life is saved. When again I charge into the battle, the one
sweet name Elissa is ever on my lips. When I was day after day in
those terrible passes of the Alps, and the rocks and boulders falling
all around me slew so many of my friends and fellow-warriors, but
one thought arose to my brain, and it was this, I care not for death
itself, but will Elissa regret me? And now, Hannibal, my friend and
my Chief, thou hast thine answer; I need say no more.”
“Nay,” said Hannibal, “thou hast said enough; I understand thee—
thou art constant. But will she be equally constant? It may be years
ere thou see her again. But young is she, and springing from a very
passionate stock; her mother was an Iberian woman. What wouldst
thou do supposing that she proved inconstant unto thee and loved
another?”
“Do?—why, fight for Carthage still. What else could I do? Ay, and
scorn her, too, if inconstant; nought else could be done than that.”
“Well, listen, I have something to propose. Thou seest this scroll.
’Tis a letter to my daughter Elissa. To-morrow we may have a fight,
not with these Gauls alone, who have already learned to fear me, but
with Scipio himself, with Roman legions at his back.
“It may be that, owing to the somewhat demoralised condition of
our army, Scipio should prove victorious; it may be otherwise; yet my
belief in the gods is so great, that I think I shall overthrow him.
Whatever may chance, I must send my messengers with tidings
back into Iberia to say that we are now safely across the Alps; to
inform first my daughter Elissa at New Carthage, and then to bear
intelligence unto my brother Hasdrubal, in those northern parts
beyond the Ebro, where, I have learned, that Cnœus Scipio hath
proceeded to attack him. Now, Maharbal, I need a trusty messenger;
wilt thou be the bearer of the message? I have in the camp a
chieftain of the Insubrian Gauls, who hath promised me a small fleet
of ships at Genua, by which thou couldst proceed to New Carthage,
where Elissa will doubtless warmly welcome thee to her loving arms.
Wilt thou go? that is if thou shouldst survive to-morrow’s fight. Think,
my lad, after all this hardship, how sweet will be the delights of love.
Moreover, now that thou hast, by thine incessant toil and valour,
brought the cavalry, or rather a great part of it, over the mountains in
safety, know this, I will no longer withstand thy wish. Thy nuptials
with my daughter shall be recognised, and thou and Elissa shall be
man and wife.”
Maharbal’s face flushed as he leaned forward on his seat and
gazed at Hannibal with undisguised astonishment.
“My lord Hannibal, hast thou then forgotten the toast we drank to
one another at Saguntum? ’Tis true I love Elissa more than all the
world as a woman; but I love thee, mine own honour, and my country
Carthage, more than any woman living, be she even thine own
daughter and mine own beloved bride. Therefore must I decline to
leave thy side, oh Hannibal, to seek repose in thy dearest and most
beloved daughter’s arms. My duty is here, and here, with all
deference unto thee, I stay. Through life and death I am thine, but to
do thy bidding in our country’s cause. My personal longings and
lovings are now things unknown. I fight for Hannibal and for
Carthage; all else is forgotten, or, if not forgotten, must and shall be
crushed from out my breast. And yet, the gods are my witness, I love
Elissa far more than all.”
Maharbal rose, and sought to leave the tent; but as he rose,
Hannibal detained him by placing a hand on his shoulder.
“I admire thee, Maharbal, far more than if thou hadst acceded to
my request. In truth thou hast enacted a right noble part. But should
we both live, I shall not forget it, and thou thyself wilt not regret it.
Should we die, I feel convinced that all the gods who, in my vision,
promised me a future reward, will recognise thy virtue, and bestow a
far higher reward upon thee. Ay, Melcareth shall smile and shower
his blessings upon thee. Tanais shall make thee happy with such a
thrilling and heavenly love as never yet mortal hath known; while the
great Moloch, god of war, shall surely exalt thee to high rank in his
celestial armies. Thou hast, indeed, chosen the higher and the better
path. I pray the great god Melcareth, that, in my prolonged absence
from her side, he inspire Elissa’s heart also with devotion to her
country, with constancy and virtue. But ’twill be merit great, indeed,
to be worthy of a virtue so great as thine. And now, let us go forth,
since I must seek some other messenger to bear her my scroll, and
thou thyself canst, if thou wilt, despatch a letter by the same hand.
But nothing can be done before we have first once met the Romans
here on Italian soil.”
The rest of the day was spent in that camp by the Ticinus in
preparations for the great cavalry reconnaissance, which Hannibal
intended to conduct in person, on the morrow. Armour was furbished
up, swords and darts were sharpened, bits and bridles were seen to.
All the cavalrymen, even although the infantry suffered somewhat in
consequence, were thoroughly well fed, and also supplied with a
liberal allowance of wine. Olive oil was dealt out to them all,
wherewith to anoint themselves and make their limbs supple, and a
day’s rations, to be carried on the morrow, was served out to each
man. Scouts from a reserve body of horse, that was not to be
employed in any fighting on the morrow, were sent out to watch the
enemy’s movements, with instructions to leave a series of detached
posts at intervals, by whom, owing to there being thus relays of fresh
horsemen ready, news could be swiftly conveyed to the Carthaginian
Chief of Scipio’s slightest movements. All these details Hannibal, not
content with trusting to subordinates, saw to personally, for as he
was, saving only Maharbal, the strongest man in the army, so was
he also the most indefatigable. Throughout the whole of that day,
therefore, he scarcely rested, but visited every part of the camp and
every troop in turn, seeing that his instructions were carried out
absolutely to the letter, and speaking grand and noble words of
encouragement wherever he passed.
When, therefore, after a substantial breakfast, the whole of the
cavalry paraded on the following morn, it was no longer a starveling,
dispirited body of men that fell beneath his gaze, but a gallant band
of warriors bearing confidence in their glance, self-reliant, proud, and
anxious for the fray. Well satisfied with the noble bearing of his
followers, after having first ridden round the ranks and complimented
his men upon their brave and soldierly appearance, Hannibal bade
his trumpeter sound the advance, and himself led the way. As he put
his horse in motion, the whole army burst spontaneously into a cheer
—“Hannibal! Long live Hannibal.”
Clad in gorgeous but serviceable armour, with dancing plumes
waving from the crest of his helmet, the gallant Carthaginian General
was indeed, as he marched forth that morn to meet the Romans for
the first time in his career, such a leader as the world had never
seen.
As the cavalry, by troops and squadrons, filed off in succession
after him, silence fell among their ranks. But the infantry soldiers and
also the Gauls remaining behind in camp continued the shouts of
enthusiasm. “Hannibal! Long live Hannibal!” For it was for him, the
General alone, and his personal influence, more than for a Carthage
which was to most of them but a name, that these troops, drawn
from many mixed tribes and nations, were willing and ready to lay
down their lives. And it was ever so; it was Hannibal’s army, not a
Carthaginian army that so often defeated Rome.
Thus gallantly encouraged by the shouts of their comrades did the
whole of the Carthaginian horse march off down the banks of the
river Ticinus. For a considerable distance the ground was broken
and rocky, and considerably wooded, and not at all suitable for the
manœuvring of mounted troops. But, at length, after a march of
some three hours’ duration, just at the very spot which suited his
purpose, Hannibal was met by the first of his scouts coming in and
informing him that Scipio had started with his forces, and was now
crossing the river. They gave the further information that there was
no occasion for hurry, as each relay of messengers had galloped
back hard, and that the remainder of the vedettes, now retiring
leisurely before the advancing foe, would give timely warning of their
nearer approach.
The ground whereon the front of the column was standing when
this news arrived was at the edge of an extensive copse of detached
oak trees, beyond which was a large open plain of what had earlier
in the year been cultivated ground. Drawing up all his forces just
inside the edge, and in the shelter of the trees, in the order of battle
which he intended to employ later on, the Chief now gave the order
for the men to dismount to rest the animals, and to eat a portion of
the rations that they had brought with them. He had a short time
previously made each troop halt in turn at a convenient shallow
place in the river Ticinus to give their horses a mouthful of water—
therefore no possible precaution had been neglected to bring his
forces fresh into battle. While halting in the shelter of the oak trees,
several more groups of messengers came in from the front. From
these Hannibal learned without a doubt that Scipio was advancing
only with his cavalry and light-armed footmen, and that from all
accounts the numbers of the former were, if anything, somewhat
inferior to his own.
He was in high glee as he stood talking to a group of his officers,
and rubbed his hands cheerfully.
“Melcareth hath surely delivered them unto us,” he said, “for this
foolish Scipio hath, by leaving his heavy-armed infantry behind,
played beautifully into my hands. And thou, my bloodthirsty
Monomachus, shalt soon have thy fill of slaying.”
“I care nought so that I slay but Scipio himself! So that ere I perish
myself, I dip my hand into the life-blood of the Roman Consul, I shall
die happy.”
Hannibal laughed, then gave the order to mount, but for the troops
still to remain within the fringe of the covert underneath the
spreading oaks.
While waiting thus, there suddenly arose a fleeting squall of driving
wind and rain, which tore the leaves with fury from the oaks, sending
them whirling in all directions, while the acorns, which abounded, fell
pattering and clattering in shoals upon the armour of the warriors.
The men, who were superstitious, knew not how to interpret the
augury; but their Chief was equal to the occasion.
“A glorious omen!” he proclaimed aloud, with a laugh. “Even as the
falling of these acorns, so shall fall the hordes of the advancing
enemy beneath the storm of our attack. See how the elephants are
calmly picking them up, and devouring them! so shall we also devour
the foe.”
The word was taken up and passed round, and now the men,
reassured and in high good humour, caught the falling acorns and
tossed them gleefully at one another. Meanwhile, as Hannibal had
said, the huge elephants calmly waiting and swinging their fore-legs,
picked up one by one with their trunks all the fallen acorns within
reach and ate them with apparent relish. The sight of these huge
painted and horrible beasts, thus picking up and eating the little
acorns, was in itself so ludicrous that all those who could see the
sight now roared with laughter like very children. For, as all know
who have been present at a battle, during the time, be it short or
long, that men are waiting anxiously for the signal that shall engage
them in mortal conflict, the nerves are on edge. ’Tis then often the
slightest and most trivial circumstance that will sway a whole host to
tears or laughter, to reckless courage, or to shameful retreat. On this
occasion the whole force was overcome with exuberance of spirits,
and thus hearty and boyish laughter rippled along the ranks.
It was, in sooth, a strange sight to see these gigantic animals so
peacefully enjoying themselves at such a moment with such trivial
food. For to look at them they seemed more like monsters ready to
devour men.
There were that day twenty-four of them present, twelve being
placed at intervals on each flank. Every elephant had its head and
trunk painted crimson with vermilion; the body was painted black,
with white stripes on the ribs, and the legs white to the knee and red
below. To each tusk, and all were tuskers, were fastened huge two-
edged swords; round the upper part of each of the fore-legs was
clasped a band set with terrible and glistening spikes; and, to crown
all, each elephant had round its trunk, near the lower extremity,
several heavy iron rings. With these they were trained to strike. An
ordinary elephant is to those with weak nerves a sufficiently
appalling sight. Judge, then, what would be the effect upon those,
who had never seen the beasts before, of the appearance of these
awful monsters. The elephants were that day in light marching order,
and therefore they carried no castles. Instead, on the back of each
was a light pad, on which sat, secured with ropes, and having also
rope foot-rests, eight archers, four on each side, plentifully supplied
with heavy arrows. Seated upon the neck of every beast was an
Indian driver, completely covered with light armour of chain mail, and
carrying, in addition to the goad with which he urged his beast, a
quiver full of short and heavy darts to hurl at the foe at close
quarters.
The order of battle was fully formed. The heavy Spanish cavalry
were in the centre; then on each side were twelve elephants; beyond
them again on each flank large bodies of the Numidian horse,
Maharbal commanding the right wing, and Chœras the left of the
Numidians.
Presently the last of the scouts came in, saying that the Romans
were now close at hand, and almost instantly their light-armed
javeline men and archers appeared, swarming on the plain. In rear of
them, at a short distance, could be seen the allied Gallic and Roman
cavalry advancing at a slow pace in a splendid line, with small
intervals between the separate troops. Hannibal allowed the light-
armed men to advance well out into the plain before he stirred from
the shelter of the oak trees. Thus he was well able to take stock of
the Roman numbers before engaging, while they could not possibly
form any idea of the numbers that he had at his own command.
Speedily sending an aide-de-camp to both Maharbal and Mago with
orders to remain for a short time longer concealed in the forest, he
now caused the “advance” and “the trot” to be sounded by his
trumpeter. In a steady line, with himself and Monomachus at the
head of the centre, the Iberian cavalry instantly emerged from their
shelter, the huge elephants lumbering along with ungainly tread at an
equal pace on each flank, and by command of their drivers, raising
their trunks on high and loudly trumpeting as they advanced. The
sudden appearance of this hitherto unseen army of cavalry, coupled
with the awesome sight of these terrible and frightful creatures, at
once struck terror into the heart of the light-armed Roman troops.
Seeing that certain death awaited them if they remained, they
instantly broke and fled, retreating through the intervals between the
troops of cavalry, and re-forming into companies in rear. But Scipio
himself, whose presence was denoted by a standard surmounted
with the Roman eagle, was with the main body. He had previously
exhorted them: saying that the Carthaginians were but curs with their
tails between their legs, who had fled before his cavalry on the banks
of the Rhone, and they believed him. Hence there was no flinching in
the ranks.
Hannibal now ordered his trumpeter to sound “the gallop,” and in a
second, with thundering footfall, the whole of his heavy cavalry,
armed with both spears and swords, the latter being attached to the
saddle, advanced with the speed of lightning.
Scipio also sounded “the charge,” but the retreat of his light-armed
footmen had somewhat delayed him. Therefore, when the two forces
met in shock of battle, the greater impetus being with the
Carthaginians, the Romans were at first borne backwards, hundreds
of men and horses being cast to the ground at the very first dreadful
onslaught. It was a terrible and an awful sight, that fearful rush and
the meeting between the two cavalry forces. And now it was every
man for himself, and both sides were equally determined. The
Romans, at first borne back, soon rallied; spears on both sides were
cast away as the horses fell in hundreds, and, foot to foot and hand
to hand, the whole plain was soon one seething and struggling mass
of murdering humanity. Now, however, the elephants came in upon
each flank of the Romans. Charging down, striking with their trunks,
destroying with their horrible scythe-like swords, frequently kneeling
upon and crushing their opponents, they carried all before them on
the flanks. All the time, the archers on their backs discharged from
close quarters the heavy-headed arrows from their bows. The effect
of this charge on the flanks, however, was but to consolidate the
Roman centre. Gallantly the Romans fought, never yielding a foot,
and many were the Iberians who fell before their dreadful valour
never to rise again. In the midst of all, mounted on a splendid bay
charger, was Publius Scipio. Separated from him at but a short
distance was Hannibal, above whom, borne by his ensign, waved
the flag of Carthage, the white horse upon a purple ground. The two
Generals could, for a while, plainly see each other, and, each
grinding his teeth and shaking his fist with rage at the other, they
tried to come to mortal combat. But it was in vain: the struggling,
thrusting, killing throng of men, swaying first this way and then that,
swept them apart, and in a short time the rush of battle had severed
them completely. Each had now to defend himself, and they saw one
another no more. At length the tide of battle seemed going to the
Romans. The Carthaginians slowly but gradually began to give
ground. A few of those in rear of the centre began to retire. The
wounded were pouring back in streams; riderless horses, many of
them with their entrails hanging out, were, while shrieking with agony
as only a horse can, wildly careering about the plain.
And now came the opportunity for which the young warrior
Maharbal had been waiting, and he took it. For fully an hour he had,
from his shelter in the oak wood, been watching the ebb and flow of
the battle, and terrible had been his anxiety and great his
impatience. But he had in himself the makings of a great general,
and he wisely refrained from interfering too soon. He sent a
messenger to summon Chœras to him, and imparted certain
instructions before sending him back to his own wing.
“Now, Chœras,” he said, “notice this and no jesting! Keep thou all
thy men carefully concealed until thou shalt see me issue alone from
the wood with this scarf waving on my sword. Then if I raise it slowly
and wave it once downwards, gallop with thy party and attack the
enemy’s right flank. If I raise it again slowly and wave it downwards
twice, do thou, avoiding the enemy’s flank, sweep completely round
and attack the rear. Never mind what mine own movements may be,
thou hast but to obey mine orders. Of one thing be careful, that is, if I
wave twice to slay all those footmen who retreated through the
enemy’s ranks before thou makest any attack upon the cavalry from
the rear. For they are Romans—the cavalry are chiefly Gauls, and I
will dispose of them myself. But do thou be careful to despatch the
footmen first; dost thou understand?”
“Ay, ay, Maharbal, I understand full well; but may I not start now?
The clash and conflict of the battle are getting too much for me; I
cannot, I fear, control either my feelings or my men much longer; I
long to be at them. I can only express my feelings in verse.
“A poet I, yet thirst for blood,

For Roman blood I call!
And I would storm as mountain flood,
E’en though as flood I fall.
“There, would that not do for Sosilus? He would be delighted to

parse, dissect, and destroy that little verse of mine, if he were only
here. But, by Melcareth, Maharbal! versifying apart, do let me get at
them soon; I can hardly keep my seat upon my horse for
impatience.”
“Well spoken, my gallant poet,” replied Maharbal, smiling; “thou
shalt, I wager, soon have plenty of mountaineering work to do in
climbing over the bodies of the slain, so be not impatient. But one
word. In attacking, look thou well to thy guard—you poets are so
incautious. After striking, ever raise thy wrist and cover thyself again
before another blow. Now farewell, and the gods be with thee; return
to thy troops.”
Very shortly after these orders had been given, Maharbal issued
from the wood and waved his sword with the attached handkerchief
twice. Like arrows Chœras and his men started from their cover, and
sweeping over the plain, avoiding the flanks, fell upon the rear of the
Romans. Dreadful then was the slaughter of the footmen who had
retired behind the Roman cavalry. At the same instant Maharbal
swept round the other flank, and, leaving the footmen alone, fell with
his men upon the rear of the Roman cavalry. The whole aspect of
the battle was changed in a moment. The whole Roman force, with
the exception of a band that rallied around Scipio, broke and fled,
and the greater part of the Carthaginian horse pursued them.
Maharbal, however, charged the serried foes around the Roman
leader, and with his terrible blows had soon cut a lane right through
their ranks up to the Commander himself, slaying the standard-
bearer and seizing the standard. Vainly did Scipio raise his already
tired arm to ward off the fearful blow that Maharbal now dealt. He
struck at the Consul with all his force, but his sword, glancing off the
Consul’s helmet, clove his shoulder. It cut clean through his armour
and half-severed his right arm. The shock threw Scipio from the
saddle, and his attendants now fled to a man. Maharbal was about to
dismount, and secure the person of the Consul as his prisoner, when
suddenly Monomachus burst upon the scene, wounded and
dismounted, brandishing a bared dagger which he stooped to strike
into the prostrate Roman’s throat. But first he plunged his hand in the
Roman’s blood.
“Hold! hold, Monomachus!” cried Maharbal. “Slay him not, he is
the General and a noble foe, and he is moreover my prisoner. Thou
shalt not slay him!”
“Curse thee!” cried the slaughterer furiously, “I tell thee I will slay
him, ay, and thee too if thou interfere,” and he knelt over the body of
Scipio to despatch him.
At that moment there came a shock. A young Roman officer with
five or six followers charged in upon the scene. With one spear-
thrust the leader transfixed the neck of the bloody Monomachus, and
then he instantly turned upon Maharbal.
“Ha! we meet again,” he cried, and rushed upon him. It was young
Scipio! But he was no match for Maharbal, who easily avoided the
spear-thrust, and then with a scornful laugh charged him in turn.
Striking him merely with his fist, he knocked him off his saddle.
“Ay, once again we meet and once again I spare thee, Roman!” he
cried, “and again I spare thee simply for thy valour’s sake.”
Then seeing himself surrounded by Romans, he struck down a
couple of them, and pressing his horse out of the throng, escaped,
bearing the Roman eagle with him.
CHAPTER VIII.
EUGENIA.
What a glorious career of successes it was that was inaugurated

with this cavalry victory near the Ticinus! Had not the blood-thirsty
monster Monomachus been slain by young Scipio at the very end of
the action, he might not only have been able to gratify his wish of
plunging his arm into the blood—although it proved not indeed the
life-blood—of the Roman General, but he might have bathed
repeatedly during the next twelve months in rivers of blood. Success
followed on success. Like rats that leave a sinking ship, the Gauls in
the Roman army deserted in their thousands and joined Hannibal;
the Boii and other Cis-Alpine tribes first sent him ambassadors and
hostages, and then themselves came over with all their fighting men,
and, after the battle of the Trebia, the whole of Cis-Alpine Gaul was
in the hands of the invading Carthaginians.
Now the battle of the Trebia was in this wise. After the cavalry
action just described, the wounded consul Publius Scipio fled with
his army first across the Po, and then, after considerable losses at
the crossings of all the rivers, to some high ground near the River
Trebia, where the now-dreaded Numidian Cavalry were unable to get
at him. Here he was joined in his camp by the other consul, Tiberius
Sempronius, who brought his army from Ariminum, the combined
Roman forces amounting to over forty thousand men. The two
consuls were utterly unable to decide upon a concerted plan of
action; the wounded General wishing for time to get well, and to
accustom his newly-raised legions to campaigning for a while before
risking a general action. Tiberius, however, was anxious to gain
some military glory for himself, apart from his brother consul; he was,
moreover, jealous of the possible successes of the succeeding
consuls, the time for whose election was near at hand. He was
therefore only too anxious to risk a combat, and was constantly
urging Scipio to allow him to take the combined consular forces
against Hannibal.
But now mention must be made of the youthful Eugenia and her
amours with Mago.
Mago, the younger brother of Hannibal, was immediately, on the
death of Hannibal Monomachus, appointed to the supreme
command of all the Carthaginian cavalry. After the affair of the
Ticinus, he was ordered on to the pursuit, and he ceased not to
harass Scipio, even when he had encamped under the walls of the
city of Placentia. Here, one day in a bold foray, he destroyed a
portion of the camp outside the town, and in the tent of one of the
generals of the Roman allies, which he looted, he captured an Italian
maiden named Eugenia, a girl about twenty years of age, and of
surpassing beauty. She was by birth an Etruscan, and by some is
reported to have been the daughter, by others the niece, of the
general in whose tent she had been found.
Terrified at first, she was soon fascinated by the charm of Mago,
who was a young man of most handsome appearance, and who
loaded her with gifts and gold, which were liberally supplied by
Hannibal for a purpose. After a very few days, as Mago was well
acquainted with the Latin tongue, he had so completely won her to
him that she would have readily allowed herself to be burned with
fire for his sake, or, at least, to have given her life for his. Not being a
Roman, but an Etruscan, she had no particular love for Rome; but
youthful and ardent, and anxious to prove to Mago her great love for
him, she readily fell in with his wishes. Accordingly, after Scipio had
encamped upon the heights on a spur of the Apennines, she one
day, being aided by Mago, pretended to escape to the Roman camp,
where she arrived with torn raiment, dishevelled hair, and an
appearance of the greatest misery. Her curses and invectives
against the Carthaginians, and the story which she related of her
imaginary wrongs, utterly and at once disarmed all suspicion. The
fair maid Eugenia was therefore received with open arms and made
a most welcome guest in the Roman camp, where everyone pitied
her for the terrible misfortunes she had endured. Thus, there was
nothing that transpired there that she did not know, and when she
had found out all that was going on, she one night took an
opportunity of escaping, and rejoined her lover Mago. To him she
revealed everything, and Hannibal was at once put in possession of
all the information he required. Having thus gained knowledge of all
the cabals that were going on in the Roman headquarters, Hannibal
knew how to act, and determined to precipitate a conflict before the
Roman infantry were really sufficiently seasoned.
This he easily managed.
To Mago, through whose pretty lover he had gained so much
useful information, he assigned the most arduous post—that of
hiding by night in ambush in a wet water-course, with a party of two
thousand chosen horse and foot, to appear at a seasonable
moment.
Then early in the morning, after his own men had breakfasted by
the camp fires, a party of light-armed troops were sent out to draw
out the Romans from their camp, which was easily accomplished,
the Romans, under Sempronius himself, thronging out, all unfed as
they were, and pursuing the apparently flying foe across the swollen
River Trebia. What followed is but history. After a bloody and
prolonged fight, Mago and his hidden troops suddenly appeared
from the water-course in rear of the Romans, and a frightful
slaughter ensued, the Numidians under Maharbal and Chœras
charging, as usual, in small groups, and advancing and retiring,
utterly disconcerting the enemy. The result of this terrible battle,
which was fought in a fearful snow-storm, was that out of forty
thousand troops engaged, only ten thousand survived and escaped
to Placentia. But the savage elephants, despite the snow, pursued
and slaughtered for hours and hours, until they could slay no more.
And this was the last fight in which the elephants were of any avail,
for the bitter cold weather which now set in soon killed them all but
one, and killed also thousands of the allied Carthaginians. As,
however, during the battle, the greatest losses among the
Carthaginians had taken place among the Celts or Gauls, Hannibal
still retained a large number of his original army of Libyans and
Iberians with whom to continue the campaign.
After this battle in the early spring, there were some terrible times,
during which, over and over again, it must be confessed, Maharbal
longed, but longed in vain, that he had taken the opportunity offered
him by the Chief of returning to New Carthage with the letter to his
beloved Elissa.
But there was no going back now, and, as he had cast in his lot
with his wonderful Chief, so was he compelled to go on. Therefore,
in the early spring, he crossed the Apennines, and for four
consecutive days and nights marched through the horrible swamps
and morasses between Lucca and Fæsulæ, where the only dry
places to be found at nights was upon the bodies of the dead
baggage animals. Here daily and nightly he strove to minister to
Hannibal, who, sorely afflicted with a terrible attack of ophthalmia,
which cost him an eye, nevertheless concealed his own agony, and
daily and hourly, riding upon the sole elephant that survived,
encouraged by his presence and example the troops under his
command.
Then came a short period of rest at Fæsulæ, during which the
Carthaginian troops contrived to regain a little of their lost vigour; but,
as many of the horses had lost their hoofs in the awful march
through the swamps, it fell to Maharbal and Mago, during this period,
to continually make sudden excursions where least expected, and
seize upon all the horses they could find.
It was now that Eugenia, the mistress of Mago, became most
useful. Carefully nurtured by Mago, and being accorded by Hannibal
all the comforts possible during this terrible march, she had not only
survived all its terrors, but was as strong and well, and, moreover, as
beautiful at its termination as she had been at its commencement.
She had, for concealment and convenience, been disguised as a
boy, and did not look while attired in male raiment more than about
fourteen years of age. She was strong and hardy, and being herself
an Etruscan, was well able to give every kind of information about
that country of Etruria wherein they now were. She was, however, no
longer entirely devoted to Mago, and this for a variety of reasons.
Perhaps the strongest of all was that she was a woman, and
consequently unable to continue ever in one mind. Therefore,
although she had deliberately given herself to Mago, under no
compulsion, but merely for love’s sake, she now had, so she
discovered, some religious scruples about her conduct. She talked to
Mago of the possible anger of the gods; at times, also, she became
cold to him, and reproached him with the sacrifices she had made for
his sake in leaving the Romans to wander about with him.
Mago for a time put up with these whims and vagaries, for he had
truly learned to love Eugenia; but there was one reason, at present
unexpressed, which daily made her more dissatisfied and
discontented.
Mago at length resented this treatment, as he wearied of her ill-
merited complaints. He now became, or at any rate pretended to be,
neglectful and cold in turn, and appeared to be entirely devoted to a
recently-captured slave girl.
Eugenia had, in reality, recently set her affections upon Maharbal,
and, as the days advanced, she fell madly in love with him.
Accordingly, during the rides through the districts of Etruria in search
of horses, Eugenia, now that Mago neglected her, attached herself
daily to the party led by Maharbal, and trying, indeed, did the young
warrior find these rides. For, faithful himself to Elissa, and quite as
faithful to his friend Mago, he was, nevertheless, violently moved by
the passion inspired by the beautiful Eugenia; and at length, so
overcome was he by her charms, her sweetness, and her very
evident admiration and love for himself, that he felt he must fall, and
yet he would not fall.
A crisis came. One day, when far away upon one of these raiding
expeditions, they had encamped for the mid-day meal in a wood,
and Eugenia, on some pretext, persuaded Maharbal to wander with
her through the most shady parts of the grove. Then suddenly losing
all reserve, she fell with tears upon his neck, and declared that she
loved him. Maharbal was, for a moment, overcome by the passion
with which he thrilled at the contact with her, and, for a fleeting
second, pressed her violently to his heart. But then, with a virtue
almost unknown in those times, he remembered his faith to his lover
—his almost wife—Elissa, and his faith to his friend—almost brother
—Mago, and a feeling of fury rose within him. He loosed the girl’s
arms from his neck with an angry movement.
“May the gods forgive me!” he cried, “but I know not what to do. I
desire thee intensely, thou beautiful Eugenia, and, indeed, I almost
love thee. But thou art not yet mine, and shalt never be mine, for I
will not be false as thou art thyself. And I should be doubly false
should I yield. Therefore, for thine own honour and mine own, thou
must die!”
Swiftly he drew his dagger, and, in spite of her one appealing cry,
slew her there on the spot, striking his dagger into her warm young
breast. Then covering his eyes with his hands, he hurried from the
dreadful place, horrified at what he had done, and yet feeling that the
omnipotent gods alone had guided the hand that struck the fatal
blow. And this, then, was the tragic end of poor Eugenia, who knew
not, when she had won a man’s love and given unto him all the most
precious gift of woman, how to remain faithful.
Maharbal was not the man to conceal an occurrence of this sort.
Upon his return to camp, he straightway repaired to Hannibal’s tent,
and begged for Mago to be summoned. After relating exactly what
had occurred, he bared his breast, and, presenting the hilt of his own
sword to Mago, said:
“Strike, Mago! for I have taken a life that should be dear to thee.
Strike! for I feel myself indeed worthy of death for having sent that
fresh young soul to Hades. But the gods are my judges, and if thou
wilt but strike, I shall soon appear before them to answer for my
conduct. Therefore, I say strike, and strike home!”
Mago did not strike. He burst into tears, and threw himself into
Maharbal’s arms.
“It is mine own fault,” he cried, “oh Maharbal, and deeply do I
grieve for the poor girl Eugenia. But far more deeply, friend, do I
grieve for thee, upon whom the gods have laid such a cruel burden,
as to compel thee, for thine honour’s sake and mine, to slay a
woman. For thou hadst no other alternative, save to become a base
villain.”
And again he wept, and Hannibal, who had in a fatherly way
himself loved the young maiden, being moved beyond words, silently
joined his brother and Maharbal in their tears.
There was much sadness that night in the camp of the generals,
and if virtue be, as the proverb saith, its own reward, then, for the
unhappy Maharbal, that reward was nought but misery.
After this, Maharbal became gloomy and morose. He quite lost the
youthful gaiety which had so often borne him up, and with which he
had in evil days encouraged others. For this affair preyed upon his
mind. In his dreams he would see the dead girl, by turns stretching
out her arms to him in imploring love, and then in imploring despair
as he was about to strike the fatal blow. He refused his food; indeed,
he was quite unable to eat. It was soon evident to all who knew him
that his mind was preying on his body, for daily he looked more wan
and ill, but he could not be comforted despite the efforts of his
friends to cheer him. It was in vain that the worthy and kind-hearted
Sosilus related for his benefit various real or imaginary histories, all
given with due chapter and verse, of some of the god-like heroes of
old, who, in similar cases, had behaved exactly like unto Maharbal
himself; these well-meant histories afforded him no comfort
whatever. He listened in silence. In vain also did Chœras force
himself to the most sprightly jests, or write the most comic and witty
verses, and read them to him aloud.
From sheer politeness’ sake Maharbal would force a smile, and
compliment his friend, but immediately afterwards would relapse into
moody silence as before.
Hannibal and Mago soon became quite alarmed, fearing that his
mind was becoming unhinged by his grief. But although they were as
brothers to him, and showered on him their brotherly love, nought
that they could do was of any avail. For Maharbal was haunted day
and night by the spirit of Eugenia. Throughout all his career, although
many women, in fact nearly all the women whom he met, as Melania
once wrote to Hannibal, fell in love with him, this secret and powerful
attraction which he had experienced for the lovely Eugenia was the
only passion for any other, save Elissa, that ever came to torture
Maharbal. But he kept his thoughts to himself and suffered in
silence, although ever haunted by the phantom of the slaughtered
girl.
Had it not been that the battle of Lake Thrasymene occurred just
about this time to divert the current of his thoughts, there is not the
slightest doubt but that Maharbal would shortly have died a raving
maniac. But Melcareth was merciful, and, by means of the distraction
of active warfare, withdrew the heavy hand which he had laid upon
the young man to try him; so that after the battle of Lake
Thrasymene Maharbal gradually, to the delight of his comrades,
recovered his health and spirits once more.
CHAPTER IX.
THRASYMENE.
The two new Consuls that year were Cnœus Servilius and
Flaminius, and they had between them some sixty thousand troops.
By so unexpectedly crossing the Apennines, and marching through
the awful marshes of the overflowed Arno, Hannibal had entirely
evaded Cnœus Servilius, who was left at Ariminum on the Adriatic,
but he now found Flaminius in Etruria, blocking the way to Rome
with a large force at a place called Arretium. Accordingly, Hannibal,
while still collecting horses and resting his troops, held one day a
council of war to consider the situation.
There were present, Mago, General Hanno, Maharbal, Hasdrubal
the pioneer, who had succeeded Monomachus as head of the
engineering department, Silenus the scribe, with writing materials
handy, and last, but by no means least upon this occasion, Sosilus,
who had, by this time, entirely undertaken the duties of head of the
intelligence department of the army, which were duties in which he
excelled. He had recently organised an excellent system of spies on
a large scale, and the scheme was working admirably. Nothing took
place in the Roman camp, or, for that matter, in Rome itself, without
his being informed; and of all occurrences of interest, Sosilus made
voluminous notes under alphabetical headings, with a view both to
present utility and to incorporation in his future history of the war.
Chœras returned from a horse-raiding expedition just as the
proceedings were commencing. He was not entitled by his rank in
the army to be present at a council of war, but Hannibal, who was
very partial to him on account of his ready humour, called him in as
he saw him marching, with a band of captured horses, past the open
door of the council tent. Hannibal was still suffering agonies from the
attack of ophthalmia, which had already cost him one eye.
Nevertheless, with his usual indomitable courage, as he sat at the
head of the council table, with a silk bandage over the diseased eye,
he looked as unconcerned and jovial as possible. No one could, for a

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Anatomy and Histology

CELLULAR ANATOMY AND HISTOLOGY 2 Splenic Anatomy 20

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Cellular Anatomy and Histology

Aqueous phase (extracellular)

“Oil” or nonpolar phase

Aqueous phase (cytoplasm)

F I G U R E 1 - 1 . Amphipathic lipids. A Phospholipid, with a phosphate head group and a lipid

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The cell membrane performs the following functions:

Rough Endoplasmic Reticulum and Ribosomes

Smooth Endoplasmic Reticulum

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Functions of the Golgi Apparatus

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Cross section Longitudinal section Tubulin

B Enlarged microtubule doublet

F I G U R E 1 - 5 . Microtubules. A Structure. The cylindrical structure of a microtubule is

Epithelial Cell Junctions

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Actin Adherens junction (belt desmosome, zonula adherens)—below

Connexon Gap junction—channel proteins called connexons permit

Zonula Adherens CLINICAL

Gap Junctions FLASH

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The Pluripotent Stem Cell

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Pluripotent stem cell

Myeloid stem cell Lymphoid stem cell

Erythropoiesis Thrombopoiesis Granulocytopoiesis Lymphopoiesis

Erythroid Thrombocyte Granulocyte/monocyte B– T–

Eosinophilic Basophilic Neutrophilic

Erythrocyte Platelets Eosinophil Basophil Neutrophil Macrophage

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All leukocytes are involved in some aspect of the immune response:

Important neutrophil chemotactic

F I G U R E 1 - 9 . Peripheral blood smear with neutrophilia. This peripheral blood smear

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F I G U R E 1 - 1 1 . Eosinophil microscopy. A Mature eosinophil with bright red granules.

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F I G U R E 1 - 1 2 . Basophil microscopy. A Electron micrograph of a normal intact mast cell

F I G U R E 1 - 1 3 . Macrophage microscopy. A Active macrophage and B multinucleated giant

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