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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.

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previously sent secret messengers to report on the respective
appearance and bearing of Ferdinand and the French Duke, and the
comparison was hardly favourable to the latter, who was a weakling
with thin ungainly limbs and watery eyes. She could thus estimate
the worth of the Cardinal’s statements and replied firmly that “she
could not dispose of her hand in marriage save by the advice of the
leading nobles and knights of the kingdoms, and that having
consulted them she would do what God ordained.”
This was equivalent to a refusal; and the Cardinal, having exerted
his eloquence once more in vain, returned to France, nursing his
resentment and wrath. He left the Princess in a critical position; for
her brother could draw but one conclusion from her refusal of such
an advantageous match; and he and the Master of Santiago now
strained every effort to stop her marriage with the King of Sicily.
Unable to leave Andalusia themselves, they warned the citizens of
Madrigal that any favour shown to the Princess would be regarded as
an act of treachery to the Crown, while she was so surrounded by
spies and enemies that even her faithful lady-in-waiting, Beatriz de
Bobadilla, grew frightened and besought her to break off the
Aragonese alliance. Isabel knew that, once intimidated into doing
this, she would remain absolutely at her brother’s mercy, and she
therefore implored the Archbishop of Toledo to come to her
assistance before it was too late. A lover of bold and decisive actions,
that warlike prelate was soon at the gates of Madrigal at the head of
an armed force; and Isabel, refusing to listen to the threats of the
Bishop of Burgos, at once joined him, going with him to Valladolid,
the headquarters of the Admiral, Don Fadrique.
She had burned her boats, and it only remained for the man on
whom she had pinned her faith to play his part in the drama
adequately. Both Ferdinand and his father realized the seriousness of
the situation. If the treaty of Fuenterrabia had spelled trouble and
disaster for Castile, it had been the source of even greater evils in
Aragon; for the Catalans, far from returning to their old allegiance,
as they were advised, had continued to maintain their desperate
resistance in Barcelona. They had elected as their Count first one
prince of royal extraction and then another; each new puppet
doomed to ultimate failure, but leaving behind him a defiance
increasing in ferocity as it lost power in other ways.
Nor was chronic rebellion John II.’s only serious trouble. The
important counties of Roussillon and Cerdagne, pledged to Louis XI.
in return for troops, had been seized by that monarch, as soon as he
saw his neighbour too involved in difficulties to show practical
resentment; and the web of French diplomacy was now being spun
over Navarre, through the medium of the King of Aragon’s son-in-
law, the Count of Foix. Personal sorrows added their quota: the loss
of sight at a time when political clouds looked blackest, followed by
the death of Queen Joanna, whose courage and brains had made her
a fitting helpmate for her ambitious husband, whether in the council-
chamber or on the battlefield. John was indeed repaid with added
measure for the turbulence and treachery of his early days; but like
many men of his type he showed better in adversity than in success.
Doggedly he laid fresh plans, and Providence that seldom hates the
brave rewarded him by the recovery of his eyesight.
The realization of his son’s marriage with Isabel of Castile, always
favoured by him, was now his dearest ambition; for he believed that
the final union of the two kingdoms would mean the death-blow to
Louis XI.’s hopes of dominating the Pyrenees, as well as the building
up of the power of the Crown at home against unruly subjects. Such
designs were, however, of the future, while the immediate steps to
achieve them were fraught with danger.
Isabel, the bride-elect was at Valladolid, temporarily protected by
the Archbishop of Toledo and the Admiral; but to the north lay the
hostile Bishopric of Burgos, to the south-east a line of fortified
strongholds, all in the hands of the Mendozas, the chief supporters of
Joanna La Beltraneja and therefore enemies of the Aragonese match.
It only needed the return of Henry IV. from Andalusia to make her
position untenable.
Isabel and the Archbishop of Toledo therefore dispatched
messengers to Aragon in haste to insist that the King of Sicily should
come to Valladolid. They found him in Saragossa, and suggested
that, as every moment of delay increased the danger, he should
disguise himself and go to Castile with only a few adherents, thus
hoodwinking the Mendozas, who would never expect him to take this
risk, and who also believed the negotiations for the marriage to be at
a much earlier stage.
Notwithstanding his later reputation for a hard head and a cool
heart, Ferdinand in his youth possessed a certain vein of
adventurous chivalry. It was with difficulty that he had been
prevented from leading an entirely rash expedition to Isabel’s rescue
at Madrigal, and he now readily agreed to a scheme, whose chief
merit lay in its apparent impossibility.
Sending one of the Castilian messengers on before to announce his
coming, he and a few of the most trusted members of his household
boldly crossed the frontier. The rest were disguised as merchants,
Ferdinand himself as a servant; and at the inns where they were
forced to halt he played his part, waiting at table and tending the
mules. They did not stop often, riding in spite of the intense cold by
day and night; with the result that they arrived before they were
expected at the friendly town of Burgo de Osma. Ferdinand, whom
excitement had rendered less tired and sleepy than the others,
spurred forward as they came in sight of the gates, narrowly escaping
death at the hands of an over-zealous sentry. Soon, however, their
identity was explained, and amid the blowing of trumpets and joyful
shouts the young King was welcomed by his allies.
At Valladolid the news of his arrival into safe territory was the
signal for feasting and jousts, and preparations for the marriage were
pushed on apace. Ferdinand came by night to Valladolid, and, being
met at a postern gate by the Archbishop of Toledo was led to the
house where the Princess lodged.
Four days later, on October 18, 1469, the formal betrothal took
place. Isabel and Ferdinand as second cousins stood within the
prohibited degrees of consanguinity; but the Archbishop of Toledo
produced a bull, affording the necessary dispensation. This bore the
signature of Pius II., who had died in 1464, and authorized
Ferdinand to marry within the third degree of consanguinity, on the
expiration of four years from the date of the bull. Granted its
authenticity, the marriage was perfectly legal; but it is almost certain
the document was an elaborate forgery, constructed by John of
Aragon and the Archbishop to meet their pressing needs.[2] The
dispensation was essential to satisfy, not only Isabel, but any
wavering supporters of orthodox views. On the other hand, apart
from the haste required and known dilatoriness of the Papal Court,
Paul II., who at that time occupied the See of Saint Peter, was the
sworn ally of Henry IV.; and those who were negotiating the
Aragonese alliance recognized that there could be no successful
appeal to his authority.
2. See Clemencin, Elogio de Isabella, Illustracion II.
Another matter requiring delicate handling had been the marriage
settlement that, signed by Ferdinand and ratified by his father, was
read aloud at the betrothal ceremony by the Archbishop of Toledo. In
it Ferdinand declared his devotion to the Mother Church and
Apostolic See, and his undying allegiance to Henry IV. The document
then went on to say that the signatures of both husband and wife
must be affixed to all ordinances and public deeds; while the
remainder of the clauses were directed to allaying the suspicions of
those who feared that the King of Sicily might use his new position
for the good of Aragon rather than Castile. In them he promised not
to leave the kingdom himself without consent of the Princess, nor to
remove any children that they might have, whether sons or
daughters. He would not on his own account make peace nor war nor
any alliance. He would not appoint to offices any save natives of
Castile; while he pledged himself to take no new steps with regard to
the lands that had once belonged to his father but had since been
alienated.
After the ceremony was over, Ferdinand retired with the
Archbishop to his lodging in Valladolid; and the next day, October
19th, he and Isabel were married; and for six days the town kept
festival in honour of the event.
Henry learned of his sister’s marriage from the Master of Santiago,
and naturally nothing of the insolence of such proceedings towards
himself was lost in the telling. The news found him in broken health,
the result of his life-long self-indulgence, and with his vanity badly
wounded by the scorn and defiance he had encountered in
Andalusia. He was therefore in no mood for conciliation, and
received Isabel’s letters, explaining the necessity under which she
had acted and her assurances of loyalty, in gloomy silence, lending a
willing ear to the Master of Santiago’s suggestion that he might
retract the oath he had taken at the Toros de Guisandos.
Circumstances favoured such a course; for Louis XI., who looked
on the Castilian-Aragonese alliance with alarm as inimical to French
expansion, offered Isabel’s rejected suitor, Charles, now Duke of
Guienne, to the Infanta Joanna, the underlying condition being of
course that Henry should disinherit Isabel in her favour.
Negotiations were at once begun; and in 1470, the Cardinal of Arras
appeared at the Spanish Court charged with the final conclusion of
the terms. He had never forgiven the Infanta’s indifference to his
oratory; and, as diligent enquiry had made him cognizant of the fact
that Pius II.’s bull must be a forgery, he proceeded to denounce her
in words, according to Enriquez de Castillo, “so outrageous that they
are more worthy to be passed over in silence than recorded.”
Henry far from being shocked was obviously pleased; and, having
completed the agreement with the Cardinal, in October, 1470, he
publicly withdrew his oath, taken at the Toros de Guisandos, and
acknowledged the Infanta Joanna, then nine years old, as his
daughter and heir. Her formal betrothal to the Duke of Guienne
followed, and then the little Princess was handed over to the care of
the Master of Santiago, much to the indignation of the Marquis of
Santillana and the Mendozas, in whose keeping she had hitherto
been.
Henry now published a manifesto, in which he declared that his
sister had broken her oath in marrying without his consent, and had
aggravated her offence by her choice of an enemy of Castile, and by
not waiting to obtain a dispensation from the Pope. He had therefore
judged her unfit to succeed to the throne and had restored Doña
Joanna to her rights.
This document did not meet with general approval. Indeed the
principal towns of Andalusia, already disaffected, openly expressed
their refusal to consent to its terms. Yet to Isabel in Dueñas, where
her first child, a daughter named after herself, had been born in the
October of this year, the prospect seemed bleak enough. Her
difficulties in Castile were intensified by the ill-fortunes of John of
Aragon in his war against Louis XI. for the recovery of Roussillon
and Cerdagne; so that in spite of the critical position of affairs at
home, she was forced to let Ferdinand go to his father’s assistance.
Hiding her fears, she replied to Henry’s manifesto by a counter-
protest, in which she recalled her own moderation in refusing the
crown on her brother Alfonso’s death, and vindicated her marriage
as performed on the advice of the wiser and larger section of the
leading nobility. Henry, she declared had broken his oath, not only in
acknowledging Joanna, who was known to be illegitimate, as his
daughter and heiress; but long before, when he had failed to divorce
and send away the Queen as he had promised, and when he had tried
to force his sister to marry the King of Portugal against her will.
In the meanwhile, in spite of the flourish of trumpets with which
the betrothal had taken place, the French marriage hung fire. Gossip
maintained that the Duke of Guienne’s interest in Joanna had been
merely the result of pique at Isabel’s refusal; while Louis XI. had
used it as a temporary expedient against his enemy, the King of
Aragon. At any rate the French Prince was openly courting the
heiress, Mary of Burgundy, when death cut short his hopes in May,
1472.
Various bridegrooms were now suggested for the Infanta Joanna;
amongst them her own uncle the King of Portugal.
Henry IV. was at this time at Segovia, whose Alcayde, Andres de
Cabrera, husband of Isabel’s lady-in-waiting, Beatriz de Bobadilla,
had always been one of his faithful adherents. In the Alcazar was
stored a considerable sum of money; and the Master of Santiago now
advised the King to demand its surrender and also that of the
fortress, hoping to get them into his own hands, as he had done with
the Alcazar at Madrid. Cabrera, suspecting rightly a plot for his own
ruin, stoutly refused; and his enemy, after stirring up in the town a
rebellion which the Alcayde promptly quelled, left the city in disgust.
Henry, who loved Segovia, remained behind, unable to make up his
mind to any decisive action.
The favourite’s departure was the opportunity for which those
inclined to Isabel’s interests had long been waiting; and Beatriz de
Bobadilla urged her husband to effect a reconciliation between the
King and his sister. This plan met with the approval of no less
important a person than Pedro Gonsalez de Mendoza, Bishop of
Siguenza, whose material position had been lately increased, not
only by the Archbishopric of Seville, but also by receiving a long-
coveted Cardinal’s hat. At the time of the Aragonese marriage the
Mendozas had been amongst Isabel’s most formidable opponents,
but their enforced surrender of the Infanta Joanna to the Master of
Santiago after the French betrothal, had quite altered their views;
and the Cardinal of Spain, as Pedro Gonsalez was usually called, now
worked to secure Isabel’s accession, as the best means of ruining his
rival.
Another person, who had set himself to negotiate an agreement,
was the Papal Legate, Cardinal Rodrigo Borgia, by birth a Valencian.
John of Aragon’s old enemy, Paul II. had died in 1471; and Sixtus IV.,
his successor, when dispatching Cardinal Borgia to Castile, in 1473,
to demand a clerical subsidy, gave him at the same time a bull of
dispensation, which legalized Ferdinand and Isabel’s marriage, and
also affirmed the legitimacy of their daughter and her rights of
inheritance.
Isabel’s prospects had considerably brightened, and a bold action
on her part was to put them to the test. One day, Beatriz de
Bobadilla, who had secretly kept her informed of the current state of
affairs, disguised herself as a countrywoman and, mounted on an ass,
rode out to the city of Aranda, where her mistress was living. She
begged her to come to Segovia immediately; and, on a day arranged,
Isabel and the Archbishop of Toledo appeared in the city before
dawn and were received into the Alcazar. Henry was then in his
hunting-box in the woods outside, but that evening he returned to
the palace and saw his sister. With his usual impressionability he
echoed the joy of all around him, and embracing her informed her of
his goodwill and the pleasure her coming had given him. The next
day they rode through the city together, his hand on her bridle-rein;
and some little time afterwards Ferdinand, who had been hastily
summoned, was reconciled to his brother-in-law.
Andres de Cabrera, delighted at the success of his hazardous
scheme, arranged an elaborate dinner on the Feast of the Epiphany
of that year, 1474, in order to celebrate the occasion; but
unfortunately Henry, who was in delicate health, fell ill. Secret
supporters of the Master of Santiago cleverly suggested that he had
been poisoned, and that this had been the main object of the
reconciliation. Henry, thoroughly alarmed, in spite of all his sister’s
efforts to allay his fears, left Segovia, as soon as he was well enough
to bear the journey, joining the Master of Santiago and the Infanta
Joanna at Madrid.
All the old trouble and discord seemed destined to begin once
more, but in reality the labours of both schemer and dupe were
nearly at an end. Early in the autumn the Master of Santiago
hastened to Estremadura to gain possession of a certain fortress, and
there, on the eve of achieving his purpose, he fell ill and died.
Henry, though almost inconsolable at the news, transferred his
affections to his favourite’s son, the Marquis of Villena, confirming
him in all his father’s offices and titles and creating him Master of
Santiago. It was to be almost the last of the many honours and gifts
that he bestowed in the course of his long reign, for on December 11,
1474, a few weeks before his fiftieth birthday, he also died.
The same atmosphere of vacillation, in which he had moved in his
life, enveloped his death-bed. When questioned as to the succession,
the chronicler, Alonso de Palencia, declares that he equivocated,
saying that his secretary knew what he wished; other writers that he
confessed to a friar that the Princess Joanna was indeed his
daughter, and that he left a will to this effect. Enriquez del Castillo,
his chaplain and chronicler, makes no mention of Joanna’s name.
Henry’s personal beliefs and wishes had availed little in his own day,
and he may have guessed that they would carry no weight after his
death. One at any rate was fulfilled, and he was buried, as he had
asked, in the Church of Sancta Maria de Guadalupe, at the foot of his
mother’s tomb.
CHAPTER IV
ACCESSION OF ISABEL: THE PORTUGUESE
WAR
1475–1479
The news of Henry IV.’s death was the signal for Isabel’s
proclamation as Queen in Segovia. Riding through the crowded
streets, her palfrey led by two of the “regidores” of the city, she came
amid the shouts of the people to the principal square. Before her
walked four kings-at-arms, and after them Gutierre de Cardenas,
bearing a naked sword, emblem of the justice that should emanate
from kingship. In the square stood a high scaffold, hung with rich
embroidered stuffs, and on it a throne, raised by three steps from the
surrounding platform. Isabel ascended these and took her place; and
then, a king-at-arms having called for silence, a herald cried in a loud
voice: “Castile! Castile for the King Don Fernando and the Queen
Doña Isabel, his wife.” Those watching below took up the shout, and
amid cheers the royal standard was raised.
Ferdinand was in Aragon; but news had at once been sent him of
the King’s death, and in the meanwhile Isabel received the homage of
the great nobles and knights who were ready to pledge themselves to
her cause. Chief amongst them were the Admiral of Castile, the
Cardinal of Spain, his brother, the Marquis of Santillana, and the rest
of the Mendozas; while they brought with them Beltran de La Cueva,
Duke of Alburquerque, whose fortunes scandal would naturally have
linked with the cause of the Infanta Joanna.
Significant was the tardy appearance of the Archbishop of Toledo,
once so hot in Isabel’s cause. Now he came in the train of all the rest,
with little enthusiasm in his homage or in the oath he took in the hall
of the palace, his hand resting on a copy of the Gospels. On the 2d of
January he and the Cardinal of Spain rode out to meet the King of
Sicily, returning with him, one on either side, amid such crowds that
it was past sunset before they reached the palace.
He was a young man of twenty and two years ... [says Colmenares, the historian
of Segovia, commenting on Ferdinand’s appearance], of medium height, finely
built, his face grave but handsome and of a fair complexion, his hair chestnut in
shade but somewhat spare on the temples, his nose and mouth small, his eyes
bright with a certain joyful dignity, a healthy colour in his cheeks and lips, his head
well set on his shoulders, his voice clear and restful. He carried himself boldly both
on horse and foot.
His character, his new subjects could not fully gauge; but the
contrast with Henry’s vacillating puerility was obvious. Here at any
rate was a man, who would not fail in what he undertook through
indecision or lack of courage.
The Cardinal of Spain and Archbishop of Toledo proceeded to
draw up “Provisions” for the future government of the kingdom,
adjusting the exact relations of the sovereigns on the basis of the
marriage settlement. Royal letters and proclamations were to be
signed by both, the seals affixed to be stamped with the joint arms of
Castile and Aragon, the coinage engraved with the double likeness.
Justice was to be awarded by the two sovereigns, when together; by
each, when separated. Castile safeguarded her independence by
placing the control of the Treasury in the hand of the Queen, and by
insisting that the governors of cities and fortresses should do homage
to her alone. She alone, also, might appoint “corregidores” and
provide incumbents for ecclesiastical benefices, though the
nominations were to bear Ferdinand’s signature as well as her own.
FERDINAND OF ARAGON
FROM “ICONOGRAFIA ESPAÑOLA” BY

VALENTIN CARDERERA Y SOLANO
It can be imagined that such a settlement would depend for its

success largely on the goodwill and tact of those called on to fulfil it;
and Ferdinand though he consented to sign his name to the
document did so with considerable reluctance. Many of the nobles in
Segovia, though mainly those of Aragonese birth, had professed their
annoyance that Ferdinand’s position should be in any way
subordinated to that of his wife. They declared that the Salic law,
excluding women from the royal succession, should hold good in
Castile as well as in France; and that, the Castilian House of
Trastamara having died out in the male line with Henry IV., the
crown should pass directly to the Aragonese branch, in the person of
King John and his son, the King of Sicily.
Loud was the indignation of Isabel’s Castilian supporters at this
suggestion. The Salic law, they maintained, had never been
acknowledged in Castile; on the contrary, cases could be cited in
which women had succeeded to the throne to the detriment of the
obvious male heir.
Thus, between arguments on the one side and the other, feelings
ran high, for Ferdinand himself inclined to a theory that flattered his
love of power and independence. Isabel, who had no intention of
ceding her rights, at length exerted her influence to win him to her
point of view.
“Señor,” she said, after a stormy council-meeting that had in the
end upheld her right of succession, “this matter need never have
been discussed, because, owing to the union that, by the Grace of
God, there is betwixt us, there can be no real disagreement.”
She then alluded to her duty of obedience as his wife; but perhaps
to Ferdinand her most convincing argument was the pertinent
suggestion that if the Salic law were acknowledged and they should
have no male heirs, their daughter Isabel could not lawfully succeed
them. It would ill have pleased Ferdinand to leave his possessions to
any of his Aragonese cousins. “The King,” we are told, “having heard
the Queen’s reasons was highly pleased, because he knew them to be
true; and both he and she gave orders that there should be no more
talk on this matter.”
The chronicler then goes on to remark on the complete concord
that ever afterwards existed between the sovereigns.
And when it was necessary that the King should go to look after affairs in one
part of the kingdom and the Queen in another, it never happened that he or she
issued a command that conflicted with those that the other gave. Circumstances
might separate them, but love held their wills joined.
Ferdinand and Isabel had shown their wisdom in refusing to let

the rift between them widen into an open quarrel. In a crisis the least
straw may turn the balance; and the condition of affairs required
their combined energies in the one scale. It is true that the majority
of nobles and knights had either in person, or by deputy, expressed
their allegiance; but there still remained a small though powerful
group, headed by the young Marquis of Villena, who maintained that
the Infanta Joanna was the rightful Queen.
That their objective was rather self-interest than any deep loyalty
to the little Princess was obvious from Villena’s letter, mentioning
the terms on which he and his followers would consent to submit.
For himself he demanded, first his acknowledgment as Master of
Santiago, next the confirmation of all lands, castles, and revenues
that had belonged to his father, including the Alcazar at Madrid, and
thirdly a yearly income of over two million maravedis to be paid by
the Crown. The Count of Plasencia, his ally, whom Henry IV. had
created Duke of Arévalo with the gift of that town (taken from the
widowed Queen Isabel for the purpose), sought also the confirmation
of his honours.
With regard to Joanna, whom Villena and his followers styled
“Princess of Castile,” they insisted that she should be suitably
married; and on this demand all negotiations ultimately broke down.
Ferdinand and Isabel were willing to grant the Marquis the
Mastership, in spite of the clamours of seven other candidates; they
agreed to the idea of Joanna’s marriage; but their stipulation that,
while this subject was under consideration, she should be handed
over to some trustworthy person, virtually put an end to all hopes of
reconciliation. Joanna was the Marquis’s trump card, and he had no
intention of playing her until he was certain of his trick, far less of
passing her into the hands of anyone, whom her rivals would
consider trustworthy.
Dazzled by the schemes he had planned, he believed it would be an
easy matter to secure Isabel’s ruin, and in this view he was
strengthened by the secret correspondence he had been carrying on
with his great-uncle, the Archbishop of Toledo. The latter’s conduct
is on the surface inexplicable; for, having maintained Isabel’s cause
with unswerving loyalty throughout the negotiations for her
marriage, when she was in danger of imprisonment and he of
incurring, on her account, not only papal censure but the loss of his
archbishopric, he had yet at the end of Henry IV.’s reign reconciled
himself to that monarch and his favourite the young Marquis of
Villena, to the weakening of his old allegiance. His tardy appearance
at Segovia, and the sulky manner he had adopted towards Ferdinand
and the Queen, were alike in keeping with a change of policy that in a
man of his ambitions seemed as shortsighted as it was
unaccountable. The explanation lies in Carrillo’s lack of self-control
that made his ambition the plaything of his besetting vice.
Like Juan Pacheco, he loved wealth, the more that he was in secret
an alchemist and squandered the revenues of his see in a vain
endeavour to make gold; but even the glitter of precious metals lost
its charm beside his lust for power and influence. He must be first.
This was the motive that had driven him to desert Henry IV., to
break with his nephew in the revolt of the League, and now, finally,
when the cause for which he had laboured was on the eve of success,
to renounce his allegiance to Isabel, because of his jealousy of her
new adviser the Cardinal of Spain.
In vain the Queen, who knew his character, tried to dissipate his
suspicions. Carrillo’s temperament set his imagination afire at the
least glimmer of insult or neglect; his manner grew morose and
overbearing, his desire for gifts and rewards every day more
rapacious. At length, when Ferdinand ventured to oppose his
demands, the Archbishop openly expressed his anger and, leaving
the Court, withdrew to his town of Alcalá de Henares, where he
began to plot secretly with Joanna’s supporters.
Between them he and the Marquis hatched a scheme, whose
success would, they hoped, make them the arbiters of Castile. This
was nothing less than a Portuguese alliance by which Alfonso V.,
married to his niece, would in her name cross the border, and aided
by his Castilian allies drive out Ferdinand and his Queen. With this
intention, the Marquis dispatched a letter to Alfonso full of showy
promises. The most important Castilian nobles, he declared,
including himself and all his relations, the Duke of Arévalo, and the
Archbishop of Toledo, were pledged to Joanna’s cause; while
numbers were only waiting to follow their example as soon as they
were reassured by the first victory. Furthermore, he guaranteed the
goodwill of fourteen of the principal towns in the kingdom; while,
alluding to the factions that convulsed the rest, he prophesied that
one side would be certain to adopt the Portuguese cause and with a
little help secure the upper hand. Victory was the more certain by
reason of the penniless state in which Henry IV. had left the treasury.
It was impossible that Ferdinand and Isabel could compete without
financial assistance against the wealth and well-known military
strength of Portugal.
Such arguments had a surface plausibility; though a statesman
might have asked himself if they did not take Fortune’s smiles too
much for granted. Was it safe to ignore the deep-rooted dislike that
Castile bore Portugal, or to assume the friendliness of the larger
towns, on whose possession the ultimate victory must depend?
Alfonso V. was not the type of man to ask uncomfortable questions.
He saw the object of his desire in a glamour that obscured the pitfalls
along the road on which he must travel; and where courage and
enthusiasm were the pilgrim’s main requisites he was rewarded by
success. Three times he had defeated the Moors beyond the sea; and,
dowered with the proud title “El Africano,” he now aspired to be the
victor of a second Aljubarrota. The rôle pleased his romantic and
highly strung nature for, while posing as the defender of injured
womanhood in the person of his niece, he could also hope to avenge
on Queen Isabel the slight his vanity had suffered from her persistent
refusal of his suit.
Practical-minded councillors shook their heads over his sanguine
expectations and pointed out the untrustworthy reputations of the
Marquis of Villena and the Archbishop of Toledo. That these same
men had sworn to Joanna’s illegitimacy and made it a cause of
rebellion against King Henry looked as if love of self rather than love
of justice were now their inspiration.
Isabel and the Cardinal of Spain wrote letters of remonstrance to
the same effect, begging Alfonso to submit the matter to arbitration;
but that credulous monarch chose to believe that their advice arose
merely from a desire to gain time, and therefore hurried on his
preparations for war.
In May, 1475, having collected an army of 5600 horse and 14,000
foot, he crossed the border and advanced to Plasencia. His plan of
campaign was to march from there northwards in the direction of
Toro and Zamora, as secret correspondence had aroused his hope of
winning both these strongholds. At Plasencia he halted, until the
Marquis of Villena and the Duke of Arévalo appeared with his niece,
and then he and Joanna were married on a lofty platform in the
centre of the city, the marriage awaiting fulfilment pending the
necessary dispensation from Rome. A herald, however, using the old
formula at once proclaimed the union: “Castile! Castile for the King
Don Alfonso of Portugal and the Queen Doña Joanna his wife, the
rightful owner of these kingdoms.”
From Plasencia the Portuguese at length marched to Arévalo,
where another delay, this time of two months, took place, Alfonso
determining to await the troops that had been promised him by his
Castilian allies. He had with him the chivalry of his own Court, young
hot-bloods, who had pledged their estates in the prospect of speedy
glory and pillage. In their self-confidence the easy theories of Villena
found an echo; and they loudly boasted that Ferdinand and his wife
would never dare to meet them, but were in all probability on the
road to Aragon. “Before gaining the victory they divided the spoil,”
comments Pulgar sarcastically.
The Castilian sovereigns were far from meditating flight. The war
had not been of their choosing, but, since it had been forced upon
them, they were ready to prosecute it to the end. For the moment
affairs looked threatening. Not only was their treasury practically
empty, and a hostile army on the march across their western border,
but news came from France that Louis XI., who had at first
expressed his pleasure at their accession, was now in league with
their enemies and intended to invade the provinces of Biscay and
Guipuzcoa; Villena and his companions were in arms; the
Archbishop of Toledo sulking in Alcalá de Henares.
To him the Queen determined to go and address a last appeal in
person, leaving her husband to watch the movements of the
Portuguese from Valladolid. Some of those at Court, who knew the
pitch of resentment and fury to which the old Primate had brought
his broodings, assured her that her mission would be in vain, saying
that it was beneath her dignity to thus humble herself to a subject.
Isabel replied that she counted as little on his service as she feared
his disloyalty, and that if he had been anyone else, she would most
certainly have weighed the matter more carefully, but she added, “I
would not accuse myself later with the thought that if I had gone to
him in person, he would have withdrawn from the false road he now
seeks to follow.”
She then set out southwards, accompanied by the Marquis of
Santillana newly-created Duke of Infantado, and the Constable of
Castile, the Count of Haro, sending the latter on in advance as they
drew near to Alcalá to announce her coming. Carrillo listened to the
Constable’s skilful reasoning in uneasy silence; but he was not to be
cajoled either by his conscience or by appeals to his vanity, and at
length burst into a storm of passion, declaring that it was his
intention to serve the King of Portugal, and none should turn him
from it. If Isabel entered Alcalá by one gate, he himself would leave
by another.
This was plain speaking; and the Queen, who had planned the
interview less from policy than out of regard for the old man, whose
restless jealousy she knew so well, continued on her way to Toledo,
where she intended to make preparations for the defence of
Estremadura and Andalusia.
Ferdinand, in the meanwhile, mustered his forces in Valladolid. So
great was the hatred of the Portuguese that many of the towns of Old
Castile sent citizens equipped at their own expense; while nobles in
mail, and ginetes, or lightly-armed horsemen, flocked to the royal
standard along with Biscayan archers and hardy mountaineers from
the north. Joined with the levies of Segovia and Avila, that Isabel had
collected on her journey to Toledo, the whole army mustered about
12,000 horse and 80,000 foot, as it advanced to the relief of the
citadel of Toro, both that town and Zamora having surrendered to
the Portuguese through the treachery of their respective governors.
The enthusiasm was general, and Ferdinand himself burned with the
desire to achieve some great deed.
Unfortunately Toro, flanked by fortresses in the power of the
Portuguese, and protected on the rear by the Douro, whence
provisions could be passed into the town, proved altogether too
strong for the besiegers. A stormy council-of-war was held in the
Castilian camp, it being decided that the only wise course would be
to retreat. This rumour spread, gradually taking the shape that the
nobles were forcing the King for their own ends to give up the siege;
and in a fury the ordinary soldiery rushed to the royal tent, swearing
to stand by Ferdinand in whatever act of daring he sought to do, and
above all to protect him from traitors. In bitterness of spirit they
learned that he also counselled retreat, and in disorderly fashion they
shook the dust of Toro from their feet and returned to Valladolid.
Their departure resulted in the surrender of the citadel to the
Portuguese, with whom the Archbishop of Toledo now openly allied
himself, rancorously declaring that he had called Isabel from her
spinning-wheel and would send her back to it again.
From Valladolid Ferdinand was summoned to Burgos. The city
was almost entirely in his favour, but the fortress and the church of
Santa Maria La Blanca were held by the men of the Duke of Arévalo,
whose catapults caused so much destruction that the inhabitants
declared unless help was given they must surrender. In one of the
principal streets alone, over three hundred houses had been burned,
while the firing never ceased by night or day.
Ferdinand and his illegitimate brother, Alfonso, Duke of
Villahermosa, were soon on the scenes, for Burgos was too important
a place to be lost; and earthworks and fortifications were hastily
constructed over against the citadel to prevent help reaching it from
the King of Portugal. All this, however, cost time, and, still more
disastrous, money; for the contents of the treasury in Segovia,
handed over by Andres de Cabrera, were exhausted, and the land,
impoverished by Henry IV.’s misgovernment, could obviously yield
few taxes.
The sovereigns, in deep gloom, called a meeting of the Cortes in
Medina del Campo, and laid their monetary difficulties before it.
How was the army to be paid? The problem was the harder for the
reckless generosity of the Portuguese, who gave fine promises of
lands and revenues to all who joined them, the fulfilment depending
on the success of the war. One solution was to permit the Castilian
troops to provide for themselves by pillage and robbery. This the
sovereigns at once rejected, nor would they consent to alienate the
few royal estates still remaining to them. A third suggestion was to
exact a loan from the Church, and it speaks well for the reputation
that Ferdinand and Isabel had already established, that the clergy at
once consented to this arrangement. In the end it was settled that the
Church should surrender half her silver plate to specified royal
officials, and that this should be redeemed at the end of three years
by the payment of thirty millions of maravedis.
The war now continued with unabated vigour, not only in the
north-west corner, occupied by Alfonso V., but throughout Castile
and even across the Portuguese border. On hearing of the
proclamation at Plasencia, Ferdinand and Isabel, by way of
retaliation, had added to their titles that of King and Queen of
Portugal. This encouraged their partisans in Galicia and
Estremadura to cross the frontier and seize certain of the enemy’s
strongholds, from which they raided the country round, carrying off
cattle and burning villages. In the neighbourhood of Toledo, those
who were discontented with the over-lordship of Archbishop Carrillo
and his nephew the Marquis of Villena took the opportunity to
proclaim their allegiance to Isabel, and in the latter’s name threw off
the yoke they hated. The Count of Paredes, an old warrior who had
fought against the Moors, and who was one of the candidates for the
Mastership of Santiago, joyfully went to their assistance with a large
body of troops, collecting his rival’s revenues at the point of the
sword, until the turmoil forced Villena to leave the King of Portugal
and hurry to the protection of his own estates.
He did not attempt to conceal his indignation with his ally,
insisting that Alfonso should go immediately to Madrid, that from
there he might aid those who had put their trust in him. To this the
King replied with equal bitterness that he saw no reason to risk the
loss of Toro and Zamora by leaving the north; nor was his conscience
burdened with the ill-luck of his allies, seeing that their help had
fallen far short of their promises. This was very true. But a small
portion of the nobles committed to Joanna’s cause had appeared
when expected at Arévalo, the majority of the defaulters not having
dared to leave their own territory, where Ferdinand and Isabel’s
partisans kept them occupied in the defence of their houses and
lands.
Isabel herself from Valladolid placed careful guard over the road to
Burgos, that the King of Portugal might not send relief to that citadel.
Ever since the beginning of the war, she had spared herself no pains
or trouble, in her effort to aid Ferdinand in his campaign. At one
time she had journeyed to Toledo to raise the levies of New Castile, at
another hastened northwards to rescue Leon from a governor
suspected of treachery; then again collected and dispatched troops to
the help of Guipuzcoa, where Louis XI. was endeavouring to win a
stretch of coveted seaboard. One evil result of the strain entailed by
such exertions had been her miscarriage in the summer of 1475. Her
daughter Isabel was now doubly precious; and her parents for her
better safety had sent her to Segovia, where she remained in the
charge of Andres de Cabrera, lately created for his services Marquis
of Moya.
While the siege of Burgos still delayed, Ferdinand succeeded in
gaining possession of the town of Zamora, after secret
correspondence with the captain who had guard of the main
entrance, a strongly fortified bridge. The Portuguese King was forced
to retreat to Toro, and the Castilians, entering at once, placed siege
to the citadel; Isabel supplied troops and artillery from Valladolid,
while each day fresh loyalists appeared from Galicia.
TOLEDO, LA PUERTA DEL SOL
FROM A PHOTOGRAPH BY
ANDERSON, ROME
Alfonso now found himself cut off from Portugal, and, aware that
his fortunes had not matched his hopes, began to try and negotiate
favourable terms of peace. These were still in keeping with his lofty
pretensions; for, in addition to a large sum of money and the

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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