Preface

Abstract:
Human Anatomy and Physiology is designed for the two-semester anatomy and physiology course taken by life science and allied health students. The textbook follows the scope and sequence of most Human Anatomy and Physiology courses, and its coverage and organization were informed by hundreds of instructors who teach the course. Instructors can customize the book, adapting it to the approach that works best in their classroom.
The artwork for this textbook is aimed focusing student learning through a powerful blend of traditional depictions and instructional innovations. Color is used sparingly, to emphasize the most important aspects of any given illustration. Significant use of micrographs from the University of Michigan complement the illustrations, and provide the students with a meaningful alternate depiction of each concept. Finally, enrichment elements provide relevance and deeper context for students, particularly in the areas of health, disease, and information relevant to their intended careers.

About OpenStax

OpenStax is part of Rice University, which is a 501(c)(3) nonprofit charitable corporation. As an educational initiative, it's our mission to transform learning so that education works for every student. Through our partnerships with philanthropic foundations and our alliance with other educational resource companies, we're breaking down the most common barriers to learning. Because we believe that everyone should and can have access to knowledge.

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About *Anatomy and Physiology 2e*

Additional Resources

About the Authors

Special Thanks

OpenStax wishes to thank the Regents of University of Michigan Medical School for the use of their extensive micrograph collection. Many of the UM micrographs that appear in *Anatomy and Physiology 2e* are interactive WebScopes, which students can explore by zooming in and out.

Levels of Organization

An Introduction to the Human Body

Introduction

Overview of Anatomy and Physiology

Abstract:
By the end of this section, you will be able to:

* Compare and contrast anatomy and physiology, including their specializations and methods of study
* Discuss the fundamental relationship between anatomy and physiology

Structural Organization of the Human Body

Abstract:
By the end of this section, you will be able to:

* Describe the structure of the human body in terms of six levels of organization
* List the eleven organ systems of the human body and identify at least one organ and one major function of each

The Levels of Organization

To study the chemical level of organization, scientists consider the simplest building blocks of matter: subatomic particles, atoms and molecules. All matter in the universe is composed of one or more unique pure substances called elements, familiar examples of which are hydrogen, oxygen, carbon, nitrogen, calcium, and iron. The smallest unit of any of these pure substances (elements) is an atom. Atoms are made up of subatomic particles such as the proton, electron and neutron. Two or more atoms combine to form a molecule, such as the water molecules, proteins, and sugars found in living things. Molecules are the chemical building blocks of all body structures.

Functions of Human Life

Abstract:
By the end of this section, you will be able to:

* Explain the importance of organization to the function of the human organism
* Distinguish between metabolism, anabolism, and catabolism
* Provide at least two examples of human responsiveness and human movement
* Compare and contrast growth, differentiation, and reproduction

Organization

A human body consists of trillions of cells organized in a way that maintains distinct internal compartments. These compartments keep body cells separated from external environmental threats and keep the cells moist and nourished. They also separate internal body fluids from the countless microorganisms that grow on body surfaces, including the lining of certain passageways that connect to the outer surface of the body. The intestinal tract, for example, is home to more bacterial cells than the total of all human cells in the body, yet these bacteria are outside the body and cannot be allowed to circulate freely inside the body.

Metabolism

The first law of thermodynamics holds that energy can neither be created nor destroyed—it can only change form. Your basic function as an organism is to consume (ingest) energy and molecules in the foods you eat, convert some of it into fuel for movement, sustain your body functions, and build and maintain your body structures. There are two types of reactions that accomplish this: anabolism and catabolism.

Responsiveness

Responsiveness is the ability of an organism to adjust to changes in its internal and external environments. An example of responsiveness to external stimuli could include moving toward sources of food and water and away from perceived dangers. Changes in an organism’s internal environment, such as increased body temperature, can cause the responses of sweating and the dilation of blood vessels in the skin in order to decrease body temperature, as shown by the runners in [link].

Movement

Human movement includes not only actions at the joints of the body, but also the motion of individual organs and even individual cells. As you read these words, red and white blood cells are moving throughout your body, muscle cells are contracting and relaxing to maintain your posture and to focus your vision, and glands are secreting chemicals to regulate body functions. Your body is coordinating the action of entire muscle groups to enable you to move air into and out of your lungs, to push blood throughout your body, and to propel the food you have eaten through your digestive tract. Consciously, of course, you contract your skeletal muscles to move the bones of your skeleton to get from one place to another (as the runners are doing in [link]), and to carry out all of the activities of your daily life.

Development, growth and reproduction

Development is all of the changes the body goes through in life. Development includes the process of differentiation, in which unspecialized cells become specialized in structure and function to perform certain tasks in the body. Development also includes the processes of growth and repair, both of which involve cell differentiation.

Requirements for Human Life

Abstract:
By the end of this section, you will be able to:

* Discuss the role of oxygen and nutrients in maintaining human survival
* Explain why extreme heat and extreme cold threaten human survival
* Explain how the pressure exerted by gases and fluids influences human survival

Oxygen

Atmospheric air is only about 20 percent oxygen, but that oxygen is a key component of the chemical reactions that keep the body alive, including the reactions that produce ATP. Brain cells are especially sensitive to lack of oxygen because of their requirement for a high-and-steady production of ATP. Brain damage is likely within five minutes without oxygen, and death is likely within ten minutes.

Nutrients

A nutrient is a substance in foods and beverages that is essential to human survival. The three basic classes of nutrients are water, the energy-yielding and body-building nutrients, and the micronutrients (vitamins and minerals).

Narrow Range of Temperature

You have probably seen news stories about athletes who died of heat stroke, or hikers who died of exposure to cold. Such deaths occur because the chemical reactions upon which the body depends can only take place within a narrow range of body temperature, from just below to just above 37°C (98.6°F). When body temperature rises well above or drops well below normal, certain proteins (enzymes) that facilitate chemical reactions lose their normal structure and their ability to function and the chemical reactions of metabolism cannot proceed.

Narrow Range of Atmospheric Pressure

Pressure is a force exerted by a substance that is in contact with another substance. Atmospheric pressure is pressure exerted by the mixture of gases (primarily nitrogen and oxygen) in the Earth’s atmosphere. Although you may not perceive it, atmospheric pressure is constantly pressing down on your body. This pressure keeps gases within your body, such as the gaseous nitrogen in body fluids, dissolved. If you were suddenly ejected from a space ship above Earth’s atmosphere, you would go from a situation of normal pressure to one of very low pressure. The pressure of the nitrogen gas in your blood would be much higher than the pressure of nitrogen in the space surrounding your body. As a result, the nitrogen gas in your blood would expand, forming bubbles that could block blood vessels and even cause cells to break apart.

Homeostasis

Abstract:
By the end of this section, you will be able to:

* Discuss the role of homeostasis in healthy functioning
* Contrast negative and positive feedback, giving one physiologic example of each mechanism

Negative Feedback

A negative feedback system has three basic components ([link]**a**). A sensor, also referred to a receptor, is a component of a feedback system that monitors a physiological value. This value is reported to the control center. The control center is the component in a feedback system that compares the value to the normal range. If the value deviates too much from the set point, then the control center activates an effector. An effector is the component in a feedback system that causes a change to reverse the situation and return the value to the normal range.

Positive Feedback

Positive feedback intensifies a change in the body’s physiological condition rather than reversing it. A deviation from the normal range results in more change, and the system moves farther away from the normal range. Positive feedback in the body is normal only when there is a definite end point. Childbirth and the body’s response to blood loss are two examples of positive feedback loops that are normal but are activated only when needed.

Anatomical Terminology

Abstract:
By the end of this section, you will be able to:

* Demonstrate the anatomical position
* Describe the human body using directional and regional terms
* Identify three planes most commonly used in the study of anatomy
* Distinguish between the posterior (dorsal) and the anterior (ventral) body cavities, identifying their subdivisions and representative organs found in each
* Describe serous membrane and explain its function

Anatomical Position

To further increase precision, anatomists standardize the way in which they view the body. Just as maps are normally oriented with north at the top, the standard body “map,” or anatomical position, is that of the body standing upright, with the feet at shoulder width and parallel, toes forward. The upper limbs are held out to each side, and the palms of the hands face forward as illustrated in [link]. Using this standard position reduces confusion. It does not matter how the body being described is oriented, the terms are used as if it is in anatomical position. For example, a scar in the “anterior (front) carpal (wrist) region” would be present on the palm side of the wrist. The term “anterior” would be used even if the hand were palm down on a table.

Regional Terms

The human body’s numerous regions have specific terms to help increase precision (see [link]). Notice that the term “brachium” or “arm” is reserved for the “upper arm” and “antebrachium” or “forearm” is used rather than “lower arm.” Similarly, “femur” or “thigh” is correct, and “leg” or “crus” is reserved for the portion of the lower limb between the knee and the ankle. You will be able to describe the body’s regions using the terms from the figure.

Directional Terms

Certain directional anatomical terms appear throughout this and any other anatomy textbook ([link]). These terms are essential for describing the relative locations of different body structures. For instance, an anatomist might describe one band of tissue as “inferior to” another or a physician might describe a tumor as “superficial to” a deeper body structure. Commit these terms to memory to avoid confusion when you are studying or describing the locations of particular body parts.

Body Planes

A section is a two-dimensional surface of a three-dimensional structure that has been cut. Modern medical imaging devices enable clinicians to obtain “virtual sections” of living bodies. We call these scans. Body sections and scans can be correctly interpreted, however, only if the viewer understands the plane along which the section was made. A plane is an imaginary two-dimensional surface that passes through the body. There are three planes commonly referred to in anatomy and medicine, as illustrated in [link].

Body Cavities and Serous Membranes

The body maintains its internal organization by means of membranes, sheaths, and other structures that separate compartments. The dorsal (posterior) cavity and the ventral (anterior) cavity are the largest body compartments ([link]). These cavities contain and protect delicate internal organs, and the ventral cavity allows for significant changes in the size and shape of the organs as they perform their functions. The lungs, heart, stomach, and intestines, for example, can expand and contract without distorting other tissues or disrupting the activity of nearby organs.

Medical Imaging

Abstract:
By the end of this section, you will be able to:

* Discuss the uses and drawbacks of X-ray imaging
* Identify four modern medical imaging techniques and how they are used

X-Rays

German physicist Wilhelm Röntgen (1845–1923) was experimenting with electrical current when he discovered that a mysterious and invisible “ray” would pass through his flesh but leave an outline of his bones on a screen coated with a metal compound. In 1895, Röntgen made the first durable record of the internal parts of a living human: an “X-ray” image (as it came to be called) of his wife’s hand. Scientists around the world quickly began their own experiments with X-rays, and by 1900, X-rays were widely used to detect a variety of injuries and diseases. In 1901, Röntgen was awarded the first Nobel Prize for physics for his work in this field.

Modern Medical Imaging

X-rays can depict a two-dimensional image of a body region, and only from a single angle. In contrast, more recent medical imaging technologies produce data that is integrated and analyzed by computers to produce three-dimensional images or images that reveal aspects of body functioning.

The Chemical Level of Organization

Introduction

Elements and Atoms: The Building Blocks of Matter

Abstract:
By the end of this section, you will be able to:

* Discuss the relationships between matter, mass, elements, compounds, atoms, and subatomic particles
* Distinguish between atomic number and mass number
* Identify the key distinction between isotopes of the same element
* Explain how electrons occupy electron shells and their contribution to an atom’s relative stability

Elements and Compounds

All matter in the natural world is composed of one or more of the 92 fundamental substances called elements. An element is a pure substance that is distinguished from all other matter by the fact that it cannot be created or broken down by ordinary chemical means. While your body can assemble many of the chemical compounds needed for life from their constituent elements, it cannot make elements. They must come from the environment. A familiar example of an element that you must take in is calcium (Ca). Calcium is essential to the human body; it is absorbed and used for a number of processes, including strengthening bones. When you consume dairy products your digestive system breaks down the food into components small enough to cross into the bloodstream. Among these is calcium, which, because it is an element, cannot be broken down further. The elemental calcium in cheese, therefore, is the same as the calcium that forms your bones. Some other elements you might be familiar with are oxygen, sodium, and iron. The elements in the human body are shown in [link], beginning with the most abundant: oxygen (O), carbon (C), hydrogen (H), and nitrogen (N). Each element’s name can be replaced by a one- or two-letter symbol; you will become familiar with some of these during this course. All the elements in your body are derived from the foods you eat and the air you breathe.

Atoms and Subatomic Particles

An atom is the smallest quantity of an element that retains the unique properties of that element. In other words, an atom of hydrogen is a unit of hydrogen—the smallest amount of hydrogen that can exist. As you might guess, atoms are almost unfathomably small. The period at the end of this sentence is millions of atoms wide.

The Behavior of Electrons

In the human body, atoms do not exist as independent entities. Rather, they are constantly reacting with other atoms to form and to break down more complex substances. To fully understand anatomy and physiology you must grasp how atoms participate in such reactions. The key is understanding the behavior of electrons.

Chemical Bonds

Abstract:
By the end of this section, you will be able to:

* Explain the relationship between molecules and compounds
* Distinguish between ions, cations, and anions
* Identify the key difference between ionic and covalent bonds
* Distinguish between nonpolar and polar covalent bonds
* Explain how water molecules link via hydrogen bonds

Ions and Ionic Bonds

Recall that an atom typically has the same number of positively charged protons and negatively charged electrons. As long as this situation remains, the atom is electrically neutral. But when an atom participates in a chemical reaction that results in the donation or acceptance of one or more electrons, the atom will then become positively or negatively charged. This happens frequently for most atoms in order to have a full valence shell, as described previously. This can happen either by gaining electrons to fill a shell that is more than half-full, or by giving away electrons to empty a shell that is less than half-full, thereby leaving the next smaller electron shell as the new, full, valence shell. An atom that has an electrical charge—whether positive or negative—is an ion.

Covalent Bonds

Unlike ionic bonds formed by the attraction between a cation’s positive charge and an anion’s negative charge, molecules formed by a covalent bond share electrons in a mutually stabilizing relationship. Like next-door neighbors whose kids hang out first at one home and then at the other, the atoms do not lose or gain electrons permanently. Instead, the electrons move back and forth between the elements. Because of the close sharing of pairs of electrons (one electron from each of two atoms), covalent bonds are stronger than ionic bonds.

Hydrogen Bonds

A hydrogen bond is formed when a weakly positive hydrogen atom already bonded to one electronegative atom (for example, the oxygen in the water molecule) is attracted to another electronegative atom from another molecule. In other words, hydrogen bonds always include hydrogen that is already part of a polar molecule.

Chemical Reactions

Abstract:
By the end of this section, you will be able to:

* Distinguish between kinetic and potential energy, and between exergonic and endergonic chemical reactions
* Identify four forms of energy important in human functioning
* Describe the three basic types of chemical reactions
* Identify several factors influencing the rate of chemical reactions

The Role of Energy in Chemical Reactions

Chemical reactions require a sufficient amount of energy to cause the matter to collide with enough precision and force that old chemical bonds can be broken and new ones formed. In general, kinetic energy is the form of energy powering any type of matter in motion. Imagine you are building a brick wall. The energy it takes to lift and place one brick atop another is kinetic energy—the energy matter possesses because of its motion. Once the wall is in place, it stores potential energy. Potential energy is the energy of position, or the energy matter possesses because of the positioning or structure of its components. If the brick wall collapses, the stored potential energy is released as kinetic energy as the bricks fall.

Forms of Energy Important in Human Functioning

You have already learned that chemical energy is absorbed, stored, and released by chemical bonds. In addition to chemical energy, mechanical, radiant, and electrical energy are important in human functioning.

Characteristics of Chemical Reactions

All chemical reactions begin with a reactant, the general term for the one or more substances that enter into the reaction. Sodium and chloride ions, for example, are the reactants in the production of table salt. The one or more substances produced by a chemical reaction are called the product.

Factors Influencing the Rate of Chemical Reactions

If you pour vinegar into baking soda, the reaction is instantaneous; the concoction will bubble and fizz. But many chemical reactions take time. A variety of factors influence the rate of chemical reactions. This section, however, will consider only the most important in human functioning.

Inorganic Compounds Essential to Human Functioning

Abstract:
By the end of this section, you will be able to:

* Compare and contrast inorganic and organic compounds
* Identify the properties of water that make it essential to life
* Explain the role of salts in body functioning
* Distinguish between acids and bases, and explain their role in pH
* Discuss the role of buffers in helping the body maintain pH homeostasis

Water

As much as 70 percent of an adult’s body weight is water. This water is contained both within the cells and between the cells that make up tissues and organs. Its several roles make water indispensable to human functioning.

Salts

Recall that salts are formed when ions form ionic bonds. In these reactions, one atom gives up one or more electrons, and thus becomes positively charged, whereas the other accepts one or more electrons and becomes negatively charged. You can now define a salt as a substance that, when dissolved in water, dissociates into ions other than H+ or OH–. This fact is important in distinguishing salts from acids and bases, discussed next.

Acids and Bases

Acids and bases, like salts, dissociate in water into electrolytes. Acids and bases can very much change the properties of the solutions in which they are dissolved.

Organic Compounds Essential to Human Functioning

Abstract:
By the end of this section, you will be able to:

* Identify four types of organic molecules essential to human functioning
* Explain the chemistry behind carbon’s affinity for covalently bonding in organic compounds
* Provide examples of three types of carbohydrates, and identify the primary functions of carbohydrates in the body
* Discuss four types of lipids important in human functioning
* Describe the structure of proteins, and discuss their importance to human functioning
* Identify the building blocks of nucleic acids, and the roles of DNA, RNA, and ATP in human functioning

The Chemistry of Carbon

What makes organic compounds ubiquitous is the chemistry of their carbon core. Recall that carbon atoms have four electrons in their valence shell, and that the octet rule dictates that atoms tend to react in such a way as to complete their valence shell with eight electrons. Carbon atoms do not complete their valence shells by donating or accepting four electrons. Instead, they readily share electrons via covalent bonds.

Carbohydrates

The term carbohydrate means “hydrated carbon.” Recall that the root hydro- indicates water. A carbohydrate is a molecule composed of carbon, hydrogen, and oxygen; in most carbohydrates, hydrogen and oxygen are found in the same two-to-one relative proportions they have in water. In fact, the chemical formula for a “generic” molecule of carbohydrate is (CH2O)*n*.

Lipids

A lipid is one of a highly diverse group of compounds made up mostly of hydrocarbons. The few oxygen atoms they contain are often at the periphery of the molecule. Their nonpolar hydrocarbons make all lipids hydrophobic. In water, lipids do not form a true solution, but they may form an emulsion, which is the term for a mixture of solutions that do not mix well.

Proteins

You might associate proteins with muscle tissue, but in fact, proteins are critical components of all tissues and organs. A protein is an organic molecule composed of amino acids linked by peptide bonds. Proteins include the keratin in the epidermis of skin that protects underlying tissues, the collagen found in the dermis of skin, in bones, and in the meninges that cover the brain and spinal cord. Proteins are also components of many of the body’s functional chemicals, including digestive enzymes in the digestive tract, antibodies, the neurotransmitters that neurons use to communicate with other cells, and the peptide-based hormones that regulate certain body functions (for instance, growth hormone). While carbohydrates and lipids are composed of hydrocarbons and oxygen, all proteins also contain nitrogen (N), and many contain sulfur (S), in addition to carbon, hydrogen, and oxygen.

Nucleotides

The fourth type of organic compound important to human structure and function are the nucleotides ([link]). A nucleotide is one of a class of organic compounds composed of three subunits:

The Cellular Level of Organization

Introduction

The Cell Membrane

Abstract:
By the end of this section, you will be able to:

* Describe the molecular components that make up the cell membrane
* Explain the major features and properties of the cell membrane
* Differentiate between materials that can and cannot diffuse through the lipid bilayer
* Compare and contrast different types of passive transport with active transport, providing examples of each

Structure and Composition of the Cell Membrane

The cell membrane is an extremely pliable structure composed primarily of back-to-back phospholipids (a “bilayer”). Cholesterol is also present, which contributes to the fluidity of the membrane, and there are various proteins embedded within the membrane that have a variety of functions.

Membrane Proteins

The lipid bilayer forms the basis of the cell membrane, but it is peppered throughout with various proteins. Two different types of proteins that are commonly associated with the cell membrane are the integral proteins and peripheral protein ([link]). As its name suggests, an integral protein is a protein that is embedded in the membrane. A channel protein is an example of an integral protein that selectively allows particular materials, such as certain ions, to pass into or out of the cell.

Transport across the Cell Membrane

One of the great wonders of the cell membrane is its ability to regulate the concentration of substances inside the cell. These substances include ions such as Ca++, Na+, K+, and Cl–; nutrients including sugars, fatty acids, and amino acids; and waste products, particularly carbon dioxide (CO2), which must leave the cell.

The Cytoplasm and Cellular Organelles

Abstract:
By the end of this section, you will be able to:

* Describe the structure and function of the cellular organelles associated with the endomembrane system, including the endoplasmic reticulum, Golgi apparatus, and lysosomes
* Describe the structure and function of mitochondria and peroxisomes
* Explain the three components of the cytoskeleton, including their composition and functions

Organelles of the Endomembrane System

A set of three major organelles together form a system within the cell called the endomembrane system. These organelles work together to perform various cellular jobs, including the task of producing, packaging, and exporting certain cellular products. The organelles of the endomembrane system include the endoplasmic reticulum, Golgi apparatus, and vesicles.

Organelles for Energy Production and Detoxification

In addition to the jobs performed by the endomembrane system, the cell has many other important functions. Just as you must consume nutrients to provide yourself with energy, so must each of your cells take in nutrients, some of which convert to chemical energy that can be used to power biochemical reactions. Another important function of the cell is detoxification. Humans take in all sorts of toxins from the environment and also produce harmful chemicals as byproducts of cellular processes. Cells called hepatocytes in the liver detoxify many of these toxins.

The Cytoskeleton

Much like the bony skeleton structurally supports the human body, the cytoskeleton helps the cells to maintain their structural integrity. The cytoskeleton is a group of fibrous proteins that provide structural support for cells, but this is only one of the functions of the cytoskeleton. Cytoskeletal components are also critical for cell motility, cell reproduction, and transportation of substances within the cell.

The Nucleus and DNA Replication

Abstract:
By the end of this section, you will be able to:

* Describe the structure and features of the nuclear membrane
* List the contents of the nucleus
* Explain the organization of the DNA molecule within the nucleus
* Describe the process of DNA replication

Organization of the Nucleus and Its DNA

Like most other cellular organelles, the nucleus is surrounded by a membrane called the nuclear envelope. This membranous covering consists of two adjacent lipid bilayers with a thin fluid space in between them. Spanning these two bilayers are nuclear pores. A nuclear pore is a tiny passageway for the passage of proteins, RNA, and solutes between the nucleus and the cytoplasm. Proteins called pore complexes lining the nuclear pores regulate the passage of materials into and out of the nucleus.

DNA Replication

In order for an organism to grow, develop, and maintain its health, cells must reproduce themselves by dividing to produce two new daughter cells, each with the full complement of DNA as found in the original cell. Billions of new cells are produced in an adult human every day. Only very few cell types in the body do not divide, including nerve cells, skeletal muscle fibers, and cardiac muscle cells. The division time of different cell types varies. Epithelial cells of the skin and gastrointestinal lining, for instance, divide very frequently to replace those that are constantly being rubbed off of the surface by friction.

Protein Synthesis

Abstract:
By the end of this section, you will be able to:

* Explain how the genetic code stored within DNA determines the protein that will form
* Describe the process of transcription
* Describe the process of translation
* Discuss the function of ribosomes

From DNA to RNA: Transcription

DNA is housed within the nucleus, and protein synthesis takes place in the cytoplasm, thus there must be some sort of intermediate messenger that leaves the nucleus and manages protein synthesis. This intermediate messenger is messenger RNA (mRNA), a single-stranded nucleic acid that carries a copy of the genetic code for a single gene out of the nucleus and into the cytoplasm where it is used to produce proteins.

From RNA to Protein: Translation

Like translating a book from one language into another, the codons on a strand of mRNA must be translated into the amino acid alphabet of proteins. Translation is the process of synthesizing a chain of amino acids called a polypeptide. Translation requires two major aids: first, a “translator,” the molecule that will conduct the translation, and second, a substrate on which the mRNA strand is translated into a new protein, like the translator’s “desk.” Both of these requirements are fulfilled by other types of RNA. The substrate on which translation takes place is the ribosome.

Cell Growth and Division

Abstract:
By the end of this section, you will be able to:

* Describe the stages of the cell cycle
* Discuss how the cell cycle is regulated
* Describe the implications of losing control over the cell cycle
* Describe the stages of mitosis and cytokinesis, in order

The Cell Cycle

One “turn” or cycle of the cell cycle consists of two general phases: interphase, followed by mitosis and cytokinesis. Interphase is the period of the cell cycle during which the cell is not dividing. The majority of cells are in interphase most of the time. Mitosis is the division of genetic material, during which the cell nucleus breaks down and two new, fully functional, nuclei are formed. Cytokinesis divides the cytoplasm into two distinctive cells.

Cell Cycle Control

A very elaborate and precise system of regulation controls direct the way cells proceed from one phase to the next in the cell cycle and begin mitosis. The control system involves molecules within the cell as well as external triggers. These internal and external control triggers provide “stop” and “advance” signals for the cell. Precise regulation of the cell cycle is critical for maintaining the health of an organism, and loss of cell cycle control can lead to cancer.

Cellular Differentiation

Abstract:
By the end of this section, you will be able to:

* Discuss how the generalized cells of a developing embryo or the stem cells of an adult organism become differentiated into specialized cells
* Distinguish between the categories of stem cells

Stem Cells

A stem cell is an unspecialized cell that can divide without limit as needed and can, under specific conditions, differentiate into specialized cells. Stem cells are divided into several categories according to their potential to differentiate.

Differentiation

When a cell differentiates (becomes more specialized), it may undertake major changes in its size, shape, metabolic activity, and overall function. Because all cells in the body, beginning with the fertilized egg, contain the same DNA, how do the different cell types come to be so different? The answer is analogous to a movie script. The different actors in a movie all read from the same script, however, they are each only reading their own part of the script. Similarly, all cells contain the same full complement of DNA, but each type of cell only “reads” the portions of DNA that are relevant to its own function. In biology, this is referred to as the unique genetic expression of each cell.

The Tissue Level of Organization

Introduction

Types of Tissues

Abstract:
By the end of this section, you will be able to:

* Identify the four main tissue types
* Discuss the functions of each tissue type
* Relate the structure of each tissue type to their function
* Discuss the embryonic origin of tissue
* Identify the three major germ layers
* Identify the main types of tissue membranes

The Four Types of Tissues

Epithelial tissue, also referred to as epithelium, refers to the sheets of cells that cover exterior surfaces of the body, line internal cavities and passageways, and form certain glands. Connective tissue, as its name implies, binds the cells and organs of the body together and functions in the protection, support, and integration of all parts of the body. Muscle tissue is excitable, responding to stimulation and contracting to provide movement, and occurs as three major types: skeletal (voluntary) muscle, smooth muscle, and cardiac muscle in the heart. Nervous tissue is also excitable, allowing the propagation of electrochemical signals in the form of nerve impulses that communicate between different regions of the body ([link]).

Embryonic Origin of Tissues

The zygote, or fertilized egg, is a single cell formed by the fusion of an egg and sperm. After fertilization the zygote gives rise to rapid mitotic cycles, generating many cells to form the embryo. The first embryonic cells generated have the ability to differentiate into any type of cell in the body and, as such, are called totipotent, meaning each has the capacity to divide, differentiate, and develop into a new organism. As cell proliferation progresses, three major cell lineages are established within the embryo. As explained in a later chapter, each of these lineages of embryonic cells forms the distinct germ layers from which all the tissues and organs of the human body eventually form. Each germ layer is identified by its relative position: ectoderm (ecto- = “outer”), mesoderm (meso- = “middle”), and endoderm (endo- = “inner”). [link] shows the types of tissues and organs associated with the each of the three germ layers. Note that epithelial tissue originates in all three layers, whereas nervous tissue derives primarily from the ectoderm and muscle tissue from mesoderm.

Tissue Membranes

A tissue membrane is a thin layer or sheet of cells that covers the outside of the body (for example, skin), the organs (for example, pericardium), internal passageways that lead to the exterior of the body (for example, mucosa of stomach), and the lining of the moveable joint cavities. There are two basic types of tissue membranes: connective tissue and epithelial membranes ([link]).

Epithelial Tissue

Abstract:
By the end of this section, you will be able to:

* Explain the structure and function of epithelial tissue
* Distinguish between tight junctions, anchoring junctions, and gap junctions
* Distinguish between simple epithelia and stratified epithelia, as well as between squamous, cuboidal, and columnar epithelia
* Describe the structure and function of endocrine and exocrine glands and their respective secretions

Generalized Functions of Epithelial Tissue

Epithelial tissues provide the body’s first line of protection from physical, chemical, and biological wear and tear. The cells of an epithelium act as gatekeepers of the body controlling permeability and allowing selective transfer of materials across a physical barrier. All substances that enter the body must cross an epithelium. Some epithelia often include structural features that allow the selective transport of molecules and ions across their cell membranes.

The Epithelial Cell

Epithelial cells are typically characterized by the polarized distribution of organelles and membrane-bound proteins between their basal and apical surfaces. Particular structures found in some epithelial cells are an adaptation to specific functions. Certain organelles are segregated to the basal sides, whereas other organelles and extensions, such as cilia, when present, are on the apical surface.

Cell to Cell Junctions

Cells of epithelia are closely connected and are not separated by intracellular material. Three basic types of connections allow varying degrees of interaction between the cells: tight junctions, anchoring junctions, and gap junctions ([link]).

Classification of Epithelial Tissues

Epithelial tissues are classified according to the shape of the cells and number of the cell layers formed ([link]). Cell shapes can be squamous (flattened and thin), cuboidal (boxy, as wide as it is tall), or columnar (rectangular, taller than it is wide). Similarly, the number of cell layers in the tissue can be one—where every cell rests on the basal lamina—which is a simple epithelium, or more than one, which is a stratified epithelium and only the basal layer of cells rests on the basal lamina. Pseudostratified (pseudo- = “false”) describes tissue with a single layer of irregularly shaped cells that give the appearance of more than one layer. Transitional describes a form of specialized stratified epithelium in which the shape of the cells can vary.

Glandular Epithelium

A gland is a structure made up of one or more cells modified to synthesize and secrete chemical substances. Most glands consist of groups of epithelial cells. A gland can be classified as an endocrine gland, a ductless gland that releases secretions directly into surrounding tissues and fluids (endo- = “inside”), or an exocrine gland whose secretions leave through a duct that opens directly, or indirectly, to the external environment (exo- = “outside”).

Connective Tissue Supports and Protects

Abstract:
By the end of this section, you will be able to:

* Identify and distinguish between the types of connective tissue: proper, supportive, and fluid
* Explain the functions of connective tissues

Functions of Connective Tissues

Connective tissues perform many functions in the body, but most importantly, they support and connect other tissues; from the connective tissue sheath that surrounds muscle cells, to the tendons that attach muscles to bones, and to the skeleton that supports the positions of the body. Protection is another major function of connective tissue, in the form of fibrous capsules and bones that protect delicate organs and, of course, the skeletal system. Specialized cells in connective tissue defend the body from microorganisms that enter the body. Transport of fluid, nutrients, waste, and chemical messengers is ensured by specialized fluid connective tissues, such as blood and lymph. Adipose cells store surplus energy in the form of fat and contribute to the thermal insulation of the body.

Embryonic Connective Tissue

All connective tissues derive from the mesodermal layer of the embryo (see [link]). The first connective tissue to develop in the embryo is mesenchyme, the stem cell line from which all connective tissues are later derived. Clusters of mesenchymal cells are scattered throughout adult tissue and supply the cells needed for replacement and repair after a connective tissue injury. A second type of embryonic connective tissue forms in the umbilical cord, called mucous connective tissue or Wharton’s jelly. This tissue is no longer present after birth, leaving only scattered mesenchymal cells throughout the body.

Classification of Connective Tissues

The three broad categories of connective tissue are classified according to the characteristics of their ground substance and the types of fibers found within the matrix ([link]). Connective tissue proper includes loose connective tissue and dense connective tissue. Both tissues have a variety of cell types and protein fibers suspended in a viscous ground substance. Dense connective tissue is reinforced by bundles of fibers that provide tensile strength, elasticity, and protection. In loose connective tissue, the fibers are loosely organized, leaving large spaces in between. Supportive connective tissue—bone and cartilage—provide structure and strength to the body and protect soft tissues. A few distinct cell types and densely packed fibers in a matrix characterize these tissues. In bone, the matrix is rigid and described as calcified because of the deposited calcium salts. In fluid connective tissue, in other words, lymph and blood, various specialized cells circulate in a watery fluid containing salts, nutrients, and dissolved proteins.

Connective Tissue Proper

Fibroblasts are present in all connective tissue proper ([link]). Fibrocytes, adipocytes, and mesenchymal cells are fixed cells, which means they remain within the connective tissue. Other cells move in and out of the connective tissue in response to chemical signals. Macrophages, mast cells, lymphocytes, plasma cells, and phagocytic cells are found in connective tissue proper but are actually part of the immune system protecting the body.

Supportive Connective Tissues

Two major forms of supportive connective tissue, cartilage and bone, allow the body to maintain its posture and protect internal organs.

Fluid Connective Tissue

Blood and lymph are fluid connective tissues. Cells circulate in a liquid extracellular matrix. The formed elements circulating in blood are all derived from hematopoietic stem cells located in bone marrow ([link]). Erythrocytes, red blood cells, transport oxygen and some carbon dioxide. Leukocytes, white blood cells, are responsible for defending against potentially harmful microorganisms or molecules. Platelets are cell fragments involved in blood clotting. Some white blood cells have the ability to cross the endothelial layer that lines blood vessels and enter adjacent tissues. Nutrients, salts, and wastes are dissolved in the liquid matrix and transported through the body.

Muscle Tissue and Motion

Abstract:
By the end of this section, you will be able to:

* Identify the three types of muscle tissue
* Compare and contrast the functions of each muscle tissue type
* Explain how muscle tissue can enable motion

Nervous Tissue Mediates Perception and Response

Abstract:
By the end of this section, you will be able to:

* Identify the classes of cells that make up nervous tissue
* Discuss how nervous tissue mediates perception and response

Tissue Injury and Aging

Abstract:
By the end of this section, you will be able to:

* Identify the cardinal signs of inflammation
* List the body’s response to tissue injury
* Explain the process of tissue repair
* Discuss the progressive impact of aging on tissue
* Describe cancerous mutations’ effect on tissue

Tissue Injury and Repair

Inflammation is the standard, initial response of the body to injury. Whether biological, chemical, physical, or radiation burns, all injuries lead to the same sequence of physiological events. Inflammation limits the extent of injury, partially or fully eliminates the cause of injury, and initiates repair and regeneration of damaged tissue. Necrosis, or accidental cell death, causes inflammation. Apoptosis is programmed cell death, a normal step-by-step process that destroys cells no longer needed by the body. By mechanisms still under investigation, apoptosis does not initiate the inflammatory response. Acute inflammation resolves over time by the healing of tissue. If inflammation persists, it becomes chronic and leads to diseased conditions. Arthritis and tuberculosis are examples of chronic inflammation. The suffix “-itis” denotes inflammation of a specific organ or type, for example, peritonitis is the inflammation of the peritoneum, and meningitis refers to the inflammation of the meninges, the tough membranes that surround the central nervous system

Tissue and Aging

According to poet Ralph Waldo Emerson, “The surest poison is time.” In fact, biology confirms that many functions of the body decline with age. All the cells, tissues, and organs are affected by senescence, with noticeable variability between individuals owing to different genetic makeup and lifestyles. The outward signs of aging are easily recognizable. The skin and other tissues become thinner and drier, reducing their elasticity, contributing to wrinkles and high blood pressure. Hair turns gray because follicles produce less melanin, the brown pigment of hair and the iris of the eye. The face looks flabby because elastic and collagen fibers decrease in connective tissue and muscle tone is lost. Glasses and hearing aids may become parts of life as the senses slowly deteriorate, all due to reduced elasticity. Overall height decreases as the bones lose calcium and other minerals. With age, fluid decreases in the fibrous cartilage disks intercalated between the vertebrae in the spine. Joints lose cartilage and stiffen. Many tissues, including those in muscles, lose mass through a process called atrophy. Lumps and rigidity become more widespread. As a consequence, the passageways, blood vessels, and airways become more rigid. The brain and spinal cord lose mass. Nerves do not transmit impulses with the same speed and frequency as in the past. Some loss of thought clarity and memory can accompany aging. More severe problems are not necessarily associated with the aging process and may be symptoms of underlying illness.

Support and Movement

The Integumentary System

Introduction

Layers of the Skin

Abstract:
By the end of this section, you will be able to:

* Identify the components of the integumentary system
* Describe the layers of the skin and the functions of each layer
* Identify and describe the hypodermis and deep fascia
* Describe the role of keratinocytes and their life cycle
* Describe the role of melanocytes in skin pigmentation

The Epidermis

The epidermis is composed of keratinized, stratified squamous epithelium. It is made of four or five layers of epithelial cells, depending on its location in the body. It does not have any blood vessels within it (i.e., it is avascular). Skin that has four layers of cells is referred to as “thin skin.” From deep to superficial, these layers are the stratum basale, stratum spinosum, stratum granulosum, and stratum corneum. Most of the skin can be classified as thin skin. “Thick skin” is found only on the palms of the hands and the soles of the feet. It has a fifth layer, called the stratum lucidum, located between the stratum corneum and the stratum granulosum ([link]).

Dermis

The dermis might be considered the “core” of the integumentary system (derma- = “skin”), as distinct from the epidermis (epi- = “upon” or “over”) and hypodermis (hypo- = “below”). It contains blood and lymph vessels, nerves, and other structures, such as hair follicles and sweat glands. The dermis is made of two layers of connective tissue that compose an interconnected mesh of elastin and collagenous fibers, produced by fibroblasts ([link]).

Hypodermis

The hypodermis (also called the subcutaneous layer or superficial fascia) is a layer directly below the dermis and serves to connect the skin to the underlying fascia (fibrous tissue) of the bones and muscles. It is not strictly a part of the skin, although the border between the hypodermis and dermis can be difficult to distinguish. The hypodermis consists of well-vascularized, loose, areolar connective tissue and adipose tissue, which functions as a mode of fat storage and provides insulation and cushioning for the integument.

Pigmentation

The color of skin is influenced by a number of pigments, including melanin, carotene, and hemoglobin. Recall that melanin is produced by cells called melanocytes, which are found scattered throughout the stratum basale of the epidermis. The melanin is transferred into the keratinocytes via a cellular vesicle called a melanosome ([link]).

Accessory Structures of the Skin

Abstract:
By the end of this section, you will be able to:

* Identify the accessory structures of the skin
* Describe the structure and function of hair and nails
* Describe the structure and function of sweat glands and sebaceous glands

Hair

Hair is a keratinous filament growing out of the epidermis. It is primarily made of dead, keratinized cells. Strands of hair originate in an epidermal penetration of the dermis called the hair follicle. The hair shaft is the part of the hair not anchored to the follicle, and much of this is exposed at the skin’s surface. The rest of the hair, which is anchored in the follicle, lies below the surface of the skin and is referred to as the hair root. The hair root ends deep in the dermis at the hair bulb, and includes a layer of mitotically active basal cells called the hair matrix. The hair bulb surrounds the hair papilla, which is made of connective tissue and contains blood capillaries and nerve endings from the dermis ([link]).

Nails

The nail bed is a specialized structure of the epidermis that is found at the tips of our fingers and toes. The nail body is formed on the nail bed, and protects the tips of our fingers and toes as they are the farthest extremities and the parts of the body that experience the maximum mechanical stress ([link]). In addition, the nail body forms a back-support for picking up small objects with the fingers. The nail body is composed of densely packed dead keratinocytes. The epidermis in this part of the body has evolved a specialized structure upon which nails can form. The nail body forms at the nail root, which has a matrix of proliferating cells from the stratum basale that enables the nail to grow continuously. The lateral nail fold overlaps the nail on the sides, helping to anchor the nail body. The nail fold that meets the proximal end of the nail body forms the nail cuticle, also called the eponychium. The nail bed is rich in blood vessels, making it appear pink, except at the base, where a thick layer of epithelium over the nail matrix forms a crescent-shaped region called the lunula (the “little moon”). The area beneath the free edge of the nail, furthest from the cuticle, is called the hyponychium. It consists of a thickened layer of stratum corneum.

Sweat Glands

When the body becomes warm, sudoriferous glands produce sweat to cool the body. Sweat glands develop from epidermal projections into the dermis and are classified as merocrine glands; that is, the secretions are excreted by exocytosis through a duct without affecting the cells of the gland. There are two types of sweat glands, each secreting slightly different products.

Sebaceous Glands

A sebaceous gland is a type of oil gland that is found all over the body and helps to lubricate and waterproof the skin and hair. Most sebaceous glands are associated with hair follicles. They generate and excrete sebum, a mixture of lipids, onto the skin surface, thereby naturally lubricating the dry and dead layer of keratinized cells of the stratum corneum, keeping it pliable. The fatty acids of sebum also have antibacterial properties, and prevent water loss from the skin in low-humidity environments. The secretion of sebum is stimulated by hormones, many of which do not become active until puberty. Thus, sebaceous glands are relatively inactive during childhood.

Functions of the Integumentary System

Abstract:
By the end of this section, you will be able to:

* Describe the different functions of the skin and the structures that enable them
* Explain how the skin helps maintain body temperature

Protection

The skin protects the rest of the body from the basic elements of nature such as wind, water, and UV sunlight. It acts as a protective barrier against water loss, due to the presence of layers of keratin and glycolipids in the stratum corneum. It also is the first line of defense against abrasive activity due to contact with grit, microbes, or harmful chemicals. Sweat excreted from sweat glands deters microbes from over-colonizing the skin surface by generating dermicidin, which has antibiotic properties.

Sensory Function

The fact that you can feel an ant crawling on your skin, allowing you to flick it off before it bites, is because the skin, and especially the hairs projecting from hair follicles in the skin, can sense changes in the environment. The hair root plexus surrounding the base of the hair follicle senses a disturbance, and then transmits the information to the central nervous system (brain and spinal cord), which can then respond by activating the skeletal muscles of your eyes to see the ant and the skeletal muscles of the body to act against the ant.

Thermoregulation

The integumentary system helps regulate body temperature through its tight association with the sympathetic nervous system, the division of the nervous system involved in our fight-or-flight responses. The sympathetic nervous system is continuously monitoring body temperature and initiating appropriate motor responses. Recall that sweat glands, accessory structures to the skin, secrete water, salt, and other substances to cool the body when it becomes warm. Even when the body does not appear to be noticeably sweating, approximately 500 mL of sweat (insensible perspiration) are secreted a day. If the body becomes excessively warm due to high temperatures, vigorous activity ([link]**ac**), or a combination of the two, sweat glands will be stimulated by the sympathetic nervous system to produce large amounts of sweat, as much as 0.7 to 1.5 L per hour for an active person. When the sweat evaporates from the skin surface, the body is cooled as body heat is dissipated.

Vitamin D Synthesis

The epidermal layer of human skin synthesizes vitamin D when exposed to UV radiation. In the presence of sunlight, a form of vitamin D3 called cholecalciferol is synthesized from a derivative of the steroid cholesterol in the skin. The liver converts cholecalciferol to calcidiol, which is then converted to calcitriol (the active chemical form of the vitamin) in the kidneys. Vitamin D is essential for normal absorption of calcium and phosphorous, which are required for healthy bones. The absence of sun exposure can lead to a lack of vitamin D in the body, leading to a condition called rickets, a painful condition in children where the bones are misshapen due to a lack of calcium, causing bowleggedness. Elderly individuals who suffer from vitamin D deficiency can develop a condition called osteomalacia, a softening of the bones. In present day society, vitamin D is added as a supplement to many foods, including milk and orange juice, compensating for the need for sun exposure.

Diseases, Disorders, and Injuries of the Integumentary System

Abstract:
By the end of this section, you will be able to:

* Describe several different diseases and disorders of the skin
* Describe the effect of injury to the skin and the process of healing

Diseases

One of the most talked about diseases is skin cancer. Cancer is a broad term that describes diseases caused by abnormal cells in the body dividing uncontrollably. Most cancers are identified by the organ or tissue in which the cancer originates. One common form of cancer is skin cancer. The Skin Cancer Foundation reports that one in five Americans will experience some type of skin cancer in their lifetime. The degradation of the ozone layer in the atmosphere and the resulting increase in exposure to UV radiation has contributed to its rise. Overexposure to UV radiation damages DNA, which can lead to the formation of cancerous lesions. Although melanin offers some protection against DNA damage from the sun, often it is not enough. The fact that cancers can also occur on areas of the body that are normally not exposed to UV radiation suggests that there are additional factors that can lead to cancerous lesions.

Skin Disorders

Two common skin disorders are eczema and acne. Eczema is an inflammatory condition and occurs in individuals of all ages. Acne involves the clogging of pores, which can lead to infection and inflammation, and is often seen in adolescents. Other disorders, not discussed here, include seborrheic dermatitis (on the scalp), psoriasis, cold sores, impetigo, scabies, hives, and warts.

Injuries

Because the skin is the part of our bodies that meets the world most directly, it is especially vulnerable to injury. Injuries include burns and wounds, as well as scars and calluses. They can be caused by sharp objects, heat, or excessive pressure or friction to the skin.

Bone Tissue and the Skeletal System

Introduction

The Functions of the Skeletal System

Abstract:
By the end of this section, you will be able to:

* Define bone, cartilage, and the skeletal system
* List and describe the functions of the skeletal system

Support, Movement, and Protection

The most apparent functions of the skeletal system are the gross functions—those visible by observation. Simply by looking at a person, you can see how the bones support, facilitate movement, and protect the human body.

Mineral Storage, Energy Storage, and Hematopoiesis

On a metabolic level, bone tissue performs several critical functions. For one, the bone matrix acts as a reservoir for a number of minerals important to the functioning of the body, especially calcium, and phosphorus. These minerals, incorporated into bone tissue, can be released back into the bloodstream to maintain levels needed to support physiological processes. Calcium ions, for example, are essential for muscle contractions and controlling the flow of other ions involved in the transmission of nerve impulses.

Bone Classification

Abstract:
By the end of this section, you will be able to:

* Classify bones according to their shapes
* Describe the function of each category of bones

Long Bones

A long bone is one that is cylindrical in shape, being longer than it is wide. Keep in mind, however, that the term describes the shape of a bone, not its size. Long bones are found in the arms (humerus, ulna, radius) and legs (femur, tibia, fibula), as well as in the fingers (metacarpals, phalanges) and toes (metatarsals, phalanges). Long bones function as levers; they move when muscles contract.

Short Bones

A short bone is one that is cube-like in shape, being approximately equal in length, width, and thickness. The only short bones in the human skeleton are in the carpals of the wrists and the tarsals of the ankles. Short bones provide stability and support as well as some limited motion.

Flat Bones

The term “flat bone” is somewhat of a misnomer because, although a flat bone is typically thin, it is also often curved. Examples include the cranial (skull) bones, the scapulae (shoulder blades), the sternum (breastbone), and the ribs. Flat bones serve as points of attachment for muscles and often protect internal organs.

Irregular Bones

An irregular bone is one that does not have any easily characterized shape and therefore does not fit any other classification. These bones tend to have more complex shapes, like the vertebrae that support the spinal cord and protect it from compressive forces. Many facial bones, particularly the ones containing sinuses, are classified as irregular bones.

Sesamoid Bones

A sesamoid bone is a small, round bone that, as the name suggests, is shaped like a sesame seed. These bones form in tendons (the sheaths of tissue that connect bones to muscles) where a great deal of pressure is generated in a joint. The sesamoid bones protect tendons by helping them overcome compressive forces. Sesamoid bones vary in number and placement from person to person but are typically found in tendons associated with the feet, hands, and knees. The patellae (singular = patella) are the only sesamoid bones found in common with every person. [link] reviews bone classifications with their associated features, functions, and examples.

Bone Structure

Abstract:
By the end of this section, you will be able to:

* Identify the anatomical features of a bone
* Define and list examples of bone markings
* Describe the histology of bone tissue
* Compare and contrast compact and spongy bone
* Identify the structures that compose compact and spongy bone
* Describe how bones are nourished and innervated

Gross Anatomy of Bone

The structure of a long bone allows for the best visualization of all of the parts of a bone ([link]). A long bone has two parts: the diaphysis and the epiphysis. The diaphysis is the tubular shaft that runs between the proximal and distal ends of the bone. The hollow region in the diaphysis is called the medullary cavity, which is filled with yellow marrow. The walls of the diaphysis are composed of dense and hard compact bone.

Bone Markings

The surface features of bones vary considerably, depending on the function and location in the body. [link] describes the bone markings, which are illustrated in ([link]). There are three general classes of bone markings: (1) articulations, (2) projections, and (3) holes. As the name implies, an articulation is where two bone surfaces come together (articulus = “joint”). These surfaces tend to conform to one another, such as one being rounded and the other cupped, to facilitate the function of the articulation. A projection is an area of a bone that projects above the surface of the bone. These are the attachment points for tendons and ligaments. In general, their size and shape is an indication of the forces exerted through the attachment to the bone. A hole is an opening or groove in the bone that allows blood vessels and nerves to enter the bone. As with the other markings, their size and shape reflect the size of the vessels and nerves that penetrate the bone at these points.

Bone Cells and Tissue

Bone contains a relatively small number of cells entrenched in a matrix of collagen fibers that provide a surface for inorganic salt crystals to adhere. These salt crystals form when calcium phosphate and calcium carbonate combine to create hydroxyapatite, which incorporates other inorganic salts like magnesium hydroxide, fluoride, and sulfate as it crystallizes, or calcifies, on the collagen fibers. The hydroxyapatite crystals give bones their hardness and strength, while the collagen fibers give them flexibility so that they are not brittle.

Compact and Spongy Bone

The differences between compact and spongy bone are best explored via their histology. Most bones contain compact and spongy osseous tissue, but their distribution and concentration vary based on the bone’s overall function. Compact bone is dense so that it can withstand compressive forces, while spongy (cancellous) bone has open spaces and supports shifts in weight distribution.

Blood and Nerve Supply

The spongy bone and medullary cavity receive nourishment from arteries that pass through the compact bone. The arteries enter through the nutrient foramen (plural = foramina), small openings in the diaphysis ([link]). The osteocytes in spongy bone are nourished by blood vessels of the periosteum that penetrate spongy bone and blood that circulates in the marrow cavities. As the blood passes through the marrow cavities, it is collected by veins, which then pass out of the bone through the foramina.

Bone Formation and Development

Abstract:
By the end of this section, you will be able to:

* Explain the function of cartilage
* List the steps of intramembranous ossification
* List the steps of endochondral ossification
* Explain the growth activity at the epiphyseal plate
* Compare and contrast the processes of modeling and remodeling

Cartilage Templates

Bone is a replacement tissue; that is, it uses a model tissue on which to lay down its mineral matrix. For skeletal development, the most common template is cartilage. During fetal development, a framework is laid down that determines where bones will form. This framework is a flexible, semi-solid matrix produced by chondroblasts and consists of hyaluronic acid, chondroitin sulfate, collagen fibers, and water. As the matrix surrounds and isolates chondroblasts, they are called chondrocytes. Unlike most connective tissues, cartilage is avascular, meaning that it has no blood vessels supplying nutrients and removing metabolic wastes. All of these functions are carried on by diffusion through the matrix. This is why damaged cartilage does not repair itself as readily as most tissues do.

Intramembranous Ossification

During intramembranous ossification, compact and spongy bone develops directly from sheets of mesenchymal (undifferentiated) connective tissue. The flat bones of the face, most of the cranial bones, and the clavicles (collarbones) are formed via intramembranous ossification.

Endochondral Ossification

In endochondral ossification, bone develops by *replacing* hyaline cartilage. Cartilage does not become bone. Instead, cartilage serves as a template to be completely replaced by new bone. Endochondral ossification takes much longer than intramembranous ossification. Bones at the base of the skull and long bones form via endochondral ossification.

How Bones Grow in Length

The epiphyseal plate is the area of growth in a long bone. It is a layer of hyaline cartilage where ossification occurs in immature bones. On the epiphyseal side of the epiphyseal plate, cartilage is formed. On the diaphyseal side, cartilage is ossified, and the diaphysis grows in length. The epiphyseal plate is composed of four zones of cells and activity ([link]). The reserve zone is the region closest to the epiphyseal end of the plate and contains small chondrocytes within the matrix. These chondrocytes do not participate in bone growth but secure the epiphyseal plate to the osseous tissue of the epiphysis.

How Bones Grow in Diameter

While bones are increasing in length, they are also increasing in diameter; growth in diameter can continue even after longitudinal growth ceases. This is called appositional growth. Osteoclasts resorb old bone that lines the medullary cavity, while osteoblasts, via intramembranous ossification, produce new bone tissue beneath the periosteum. The erosion of old bone along the medullary cavity and the deposition of new bone beneath the periosteum not only increase the diameter of the diaphysis but also increase the diameter of the medullary cavity. This process is called modeling.

Bone Remodeling

The process in which matrix is resorbed on one surface of a bone and deposited on another is known as bone modeling. Modeling primarily takes place during a bone’s growth. However, in adult life, bone undergoes remodeling, in which resorption of old or damaged bone takes place on the same surface where osteoblasts lay new bone to replace that which is resorbed. Injury, exercise, and other activities lead to remodeling. Those influences are discussed later in the chapter, but even without injury or exercise, about 5 to 10 percent of the skeleton is remodeled annually just by destroying old bone and renewing it with fresh bone.

Fractures: Bone Repair

Abstract:
By the end of this section, you will be able to:

* Differentiate among the different types of fractures
* Describe the steps involved in bone repair

Types of Fractures

Fractures are classified by their complexity, location, and other features ([link]). [link] outlines common types of fractures. Some fractures may be described using more than one term because it may have the features of more than one type (e.g., an open transverse fracture).

Bone Repair

When a bone breaks, blood flows from any vessel torn by the fracture. These vessels can be in the periosteum, osteons, and/or medullary cavity. The blood begins to clot, and about six to eight hours after the fracture, the clotting blood forms a fracture hematoma ([link]**a**). The disruption of blood flow to the bone results in the death of bone cells around the fracture.

Exercise, Nutrition, Hormones, and Bone Tissue

Abstract:
By the end of this section, you will be able to:

* Describe the effect exercise has on bone tissue
* List the nutrients that affect bone health
* Discuss the role those nutrients play in bone health
* Describe the effects of hormones on bone tissue

Exercise and Bone Tissue

During long space missions, astronauts can lose approximately 1 to 2 percent of their bone mass per month. This loss of bone mass is thought to be caused by the lack of mechanical stress on astronauts’ bones due to the low gravitational forces in space. Lack of mechanical stress causes bones to lose mineral salts and collagen fibers, and thus strength. Similarly, mechanical stress stimulates the deposition of mineral salts and collagen fibers. The internal and external structure of a bone will change as stress increases or decreases so that the bone is an ideal size and weight for the amount of activity it endures. That is why people who exercise regularly have thicker bones than people who are more sedentary. It is also why a broken bone in a cast atrophies while its contralateral mate maintains its concentration of mineral salts and collagen fibers. The bones undergo remodeling as a result of forces (or lack of forces) placed on them.

Nutrition and Bone Tissue

The vitamins and minerals contained in all of the food we consume are important for all of our organ systems. However, there are certain nutrients that affect bone health.

Hormones and Bone Tissue

The endocrine system produces and secretes hormones, many of which interact with the skeletal system. These hormones are involved in controlling bone growth, maintaining bone once it is formed, and remodeling it.

Calcium Homeostasis: Interactions of the Skeletal System and Other Organ Systems

Abstract:
By the end of this section, you will be able to:

* Describe the effect of too much or too little calcium on the body
* Explain the process of calcium homeostasis

Axial Skeleton

Introduction

Divisions of the Skeletal System

Abstract:
By the end of this section, you will be able to:

* Discuss the functions of the skeletal system
* Distinguish between the axial skeleton and appendicular skeleton
* Define the axial skeleton and its components
* Define the appendicular skeleton and its components

The Axial Skeleton

The skeleton is subdivided into two major divisions—the axial and appendicular. The axial skeleton forms the vertical, central axis of the body and includes all bones of the head, neck, chest, and back ([link]). It serves to protect the brain, spinal cord, heart, and lungs. It also serves as the attachment site for muscles that move the head, neck, and back, and for muscles that act across the shoulder and hip joints to move their corresponding limbs.

The Appendicular Skeleton

The appendicular skeleton includes all bones of the upper and lower limbs, plus the bones that attach each limb to the axial skeleton. There are 126 bones in the appendicular skeleton of an adult. The bones of the appendicular skeleton are covered in a separate chapter.

The Skull

Abstract:
By the end of this section, you will be able to:

* List and identify the bones of the brain case and face
* Locate the major suture lines of the skull and name the bones associated with each
* Locate and define the boundaries of the anterior, middle, and posterior cranial fossae, the temporal fossa, and infratemporal fossa
* Define the paranasal sinuses and identify the location of each
* Name the bones that make up the walls of the orbit and identify the openings associated with the orbit
* Identify the bones and structures that form the nasal septum and nasal conchae, and locate the hyoid bone
* Identify the bony openings of the skull

Anterior View of Skull

The anterior skull consists of the facial bones and provides the bony support for the eyes and structures of the face. This view of the skull is dominated by the openings of the orbits and the nasal cavity. Also seen are the upper and lower jaws, with their respective teeth ([link]).

Lateral View of Skull

A view of the lateral skull is dominated by the large, rounded brain case above and the upper and lower jaws with their teeth below ([link]). Separating these areas is the bridge of bone called the zygomatic arch. The zygomatic arch is the bony arch on the side of skull that spans from the area of the cheek to just above the ear canal. It is formed by the junction of two bony processes: a short anterior component, the temporal process of the zygomatic bone (the cheekbone) and a longer posterior portion, the zygomatic process of the temporal bone, extending forward from the temporal bone. Thus the temporal process (anteriorly) and the zygomatic process (posteriorly) join together, like the two ends of a drawbridge, to form the zygomatic arch. One of the major muscles that pulls the mandible upward during biting and chewing arises from the zygomatic arch.

Bones of the Brain Case

The brain case contains and protects the brain. The interior space that is almost completely occupied by the brain is called the cranial cavity. This cavity is bounded superiorly by the rounded top of the skull, which is called the calvaria (skullcap), and the lateral and posterior sides of the skull. The bones that form the top and sides of the brain case are usually referred to as the “flat” bones of the skull.

Sutures of the Skull

A suture is an immobile joint between adjacent bones of the skull. The narrow gap between the bones is filled with dense, fibrous connective tissue that unites the bones. The long sutures located between the bones of the brain case are not straight, but instead follow irregular, tightly twisting paths. These twisting lines serve to tightly interlock the adjacent bones, thus adding strength to the skull for brain protection.

Facial Bones of the Skull

The facial bones of the skull form the upper and lower jaws, the nose, nasal cavity and nasal septum, and the orbit. The facial bones include 14 bones, with six paired bones and two unpaired bones. The paired bones are the maxilla, palatine, zygomatic, nasal, lacrimal, and inferior nasal conchae bones. The unpaired bones are the vomer and mandible bones. Although classified with the brain-case bones, the ethmoid bone also contributes to the nasal septum and the walls of the nasal cavity and orbit.

The Orbit

The orbit is the bony socket that houses the eyeball and contains the muscles that move the eyeball or open the upper eyelid. Each orbit is cone-shaped, with a narrow posterior region that widens toward the large anterior opening. To help protect the eye, the bony margins of the anterior opening are thickened and somewhat constricted. The medial walls of the two orbits are parallel to each other but each lateral wall diverges away from the midline at a 45° angle. This divergence provides greater lateral peripheral vision.

The Nasal Septum and Nasal Conchae

The nasal septum consists of both bone and cartilage components ([link]; see also [link]). The upper portion of the septum is formed by the perpendicular plate of the ethmoid bone. The lower and posterior parts of the septum are formed by the triangular-shaped vomer bone. In an anterior view of the skull, the perpendicular plate of the ethmoid bone is easily seen inside the nasal opening as the upper nasal septum, but only a small portion of the vomer is seen as the inferior septum. A better view of the vomer bone is seen when looking into the posterior nasal cavity with an inferior view of the skull, where the vomer forms the full height of the nasal septum. The anterior nasal septum is formed by the septal cartilage, a flexible plate that fills in the gap between the perpendicular plate of the ethmoid and vomer bones. This cartilage also extends outward into the nose where it separates the right and left nostrils. The septal cartilage is not found in the dry skull.

Cranial Fossae

Inside the skull, the floor of the cranial cavity is subdivided into three cranial fossae (spaces), which increase in depth from anterior to posterior (see [link], [link]**b**, and [link]). Since the brain occupies these areas, the shape of each conforms to the shape of the brain regions that it contains. Each cranial fossa has anterior and posterior boundaries and is divided at the midline into right and left areas by a significant bony structure or opening.

Paranasal Sinuses

The paranasal sinuses are hollow, air-filled spaces located within certain bones of the skull ([link]). All of the sinuses communicate with the nasal cavity (paranasal = “next to nasal cavity”) and are lined with nasal mucosa. They serve to reduce bone mass and thus lighten the skull, and they also add resonance to the voice. This second feature is most obvious when you have a cold or sinus congestion. These produce swelling of the mucosa and excess mucus production, which can obstruct the narrow passageways between the sinuses and the nasal cavity, causing your voice to sound different to yourself and others. This blockage can also allow the sinuses to fill with fluid, with the resulting pressure producing pain and discomfort.

Hyoid Bone

The hyoid bone is an independent bone that does not contact any other bone and thus is not part of the skull ([link]). It is a small U-shaped bone located in the upper neck near the level of the inferior mandible, with the tips of the “U” pointing posteriorly. The hyoid serves as the base for the tongue above, and is attached to the larynx below and the pharynx posteriorly. The hyoid is held in position by a series of small muscles that attach to it either from above or below. These muscles act to move the hyoid up/down or forward/back. Movements of the hyoid are coordinated with movements of the tongue, larynx, and pharynx during swallowing and speaking.

The Vertebral Column

Abstract:
By the end of this section, you will be able to:

* Describe each region of the vertebral column and the number of bones in each region
* Discuss the curves of the vertebral column and how these change after birth
* Describe a typical vertebra and determine the distinguishing characteristics for vertebrae in each vertebral region and features of the sacrum and the coccyx
* Describe the structure of an intervertebral disc
* Determine the location of the ligaments that provide support for the vertebral column

Regions of the Vertebral Column

The vertebral column originally develops as a series of 33 vertebrae, but this number is eventually reduced to 24 vertebrae, plus the sacrum and coccyx. The vertebral column is subdivided into five regions, with the vertebrae in each area named for that region and numbered in descending order. In the neck, there are seven cervical vertebrae, each designated with the letter “C” followed by its number. Superiorly, the C1 vertebra articulates (forms a joint) with the occipital condyles of the skull. Inferiorly, C1 articulates with the C2 vertebra, and so on. Below these are the 12 thoracic vertebrae, designated T1–T12. The lower back contains the L1–L5 lumbar vertebrae. The single sacrum, which is also part of the pelvis, is formed by the fusion of five sacral vertebrae. Similarly, the coccyx, or tailbone, results from the fusion of four small coccygeal vertebrae. However, the sacral and coccygeal fusions do not start until age 20 and are not completed until middle age.

Curvatures of the Vertebral Column

The adult vertebral column does not form a straight line, but instead has four curvatures along its length (see [link]). These curves increase the vertebral column’s strength, flexibility, and ability to absorb shock. When the load on the spine is increased, by carrying a heavy backpack for example, the curvatures increase in depth (become more curved) to accommodate the extra weight. They then spring back when the weight is removed. The four adult curvatures are classified as either primary or secondary curvatures. Primary curves are retained from the original fetal curvature, while secondary curvatures develop after birth.

General Structure of a Vertebra

Within the different regions of the vertebral column, vertebrae vary in size and shape, but they all follow a similar structural pattern. A typical vertebra will consist of a body, a vertebral arch, and seven processes ([link]).

Regional Modifications of Vertebrae

In addition to the general characteristics of a typical vertebra described above, vertebrae also display characteristic size and structural features that vary between the different vertebral column regions. Thus, cervical vertebrae are smaller than lumbar vertebrae due to differences in the proportion of body weight that each supports. Thoracic vertebrae have sites for rib attachment, and the vertebrae that give rise to the sacrum and coccyx have fused together into single bones.

Intervertebral Discs and Ligaments of the Vertebral Column

The bodies of adjacent vertebrae are strongly anchored to each other by an intervertebral disc. This structure provides padding between the bones during weight bearing, and because it can change shape, also allows for movement between the vertebrae. Although the total amount of movement available between any two adjacent vertebrae is small, when these movements are summed together along the entire length of the vertebral column, large body movements can be produced. Ligaments that extend along the length of the vertebral column also contribute to its overall support and stability.

The Thoracic Cage

Abstract:
By the end of this section, you will be able to:

* Discuss the components that make up the thoracic cage
* Identify the parts of the sternum and define the sternal angle
* Discuss the parts of a rib and rib classifications

Sternum

The sternum is the elongated bony structure that anchors the anterior thoracic cage. It consists of three parts: the manubrium, body, and xiphoid process. The manubrium is the wider, superior portion of the sternum. The top of the manubrium has a shallow, U-shaped border called the jugular (suprasternal) notch. This can be easily felt at the anterior base of the neck, between the medial ends of the clavicles. The clavicular notch is the shallow depression located on either side at the superior-lateral margins of the manubrium. This is the site of the sternoclavicular joint, between the sternum and clavicle. The first ribs also attach to the manubrium.

Ribs

Each rib is a curved, flattened bone that contributes to the wall of the thorax. The ribs articulate posteriorly with the T1–T12 thoracic vertebrae, and most attach anteriorly via their costal cartilages to the sternum. There are 12 pairs of ribs. The ribs are numbered 1–12 in accordance with the thoracic vertebrae.

Embryonic Development of the Axial Skeleton

Abstract:
By the end of this section, you will be able to:

* Discuss the two types of embryonic bone development within the skull
* Describe the development of the vertebral column and thoracic cage

Development of the Skull

During the third week of embryonic development, a rod-like structure called the notochord develops dorsally along the length of the embryo. The tissue overlying the notochord enlarges and forms the neural tube, which will give rise to the brain and spinal cord. By the fourth week, mesoderm tissue located on either side of the notochord thickens and separates into a repeating series of block-like tissue structures, each of which is called a somite. As the somites enlarge, each one will split into several parts. The most medial of these parts is called a sclerotome. The sclerotomes consist of an embryonic tissue called mesenchyme, which will give rise to the fibrous connective tissues, cartilages, and bones of the body.

Development of the Vertebral Column and Thoracic cage

Development of the vertebrae begins with the accumulation of mesenchyme cells from each sclerotome around the notochord. These cells differentiate into a hyaline cartilage model for each vertebra, which then grow and eventually ossify into bone through the process of endochondral ossification. As the developing vertebrae grow, the notochord largely disappears. However, small areas of notochord tissue persist between the adjacent vertebrae and this contributes to the formation of each intervertebral disc.

The Appendicular Skeleton

Introduction

The Pectoral Girdle

Abstract:
By the end of this section, you will be able to:

* Describe the bones that form the pectoral girdle
* List the functions of the pectoral girdle

Clavicle

The clavicle is the only long bone that lies in a horizontal position in the body (see [link]). The clavicle has several important functions. First, anchored by muscles from above, it serves as a strut that extends laterally to support the scapula. This in turn holds the shoulder joint superiorly and laterally from the body trunk, allowing for maximal freedom of motion for the upper limb. The clavicle also transmits forces acting on the upper limb to the sternum and axial skeleton. Finally, it serves to protect the underlying nerves and blood vessels as they pass between the trunk of the body and the upper limb.

Scapula

The scapula is also part of the pectoral girdle and thus plays an important role in anchoring the upper limb to the body. The scapula is located on the posterior side of the shoulder. It is surrounded by muscles on both its anterior (deep) and posterior (superficial) sides, and thus does not articulate with the ribs of the thoracic cage.

Bones of the Upper Limb

Abstract:
By the end of this section, you will be able to:

* Identify the divisions of the upper limb and describe the bones in each region
* List the bones and bony landmarks that articulate at each joint of the upper limb

Humerus

The humerus is the single bone of the upper arm region ([link]). At its proximal end is the head of the humerus. This is the large, round, smooth region that faces medially. The head articulates with the glenoid cavity of the scapula to form the glenohumeral (shoulder) joint. The margin of the smooth area of the head is the anatomical neck of the humerus. Located on the lateral side of the proximal humerus is an expanded bony area called the greater tubercle. The smaller lesser tubercle of the humerus is found on the anterior aspect of the humerus. Both the greater and lesser tubercles serve as attachment sites for muscles that act across the shoulder joint. Passing between the greater and lesser tubercles is the narrow intertubercular groove (sulcus), which is also known as the bicipital groove because it provides passage for a tendon of the biceps brachii muscle. The surgical neck is located at the base of the expanded, proximal end of the humerus, where it joins the narrow shaft of the humerus. The surgical neck is a common site of arm fractures. The deltoid tuberosity is a roughened, V-shaped region located on the lateral side in the middle of the humerus shaft. As its name indicates, it is the site of attachment for the deltoid muscle.

Ulna

The ulna is the medial bone of the forearm. It runs parallel to the radius, which is the lateral bone of the forearm ([link]). The proximal end of the ulna resembles a crescent wrench with its large, C-shaped trochlear notch. This region articulates with the trochlea of the humerus as part of the elbow joint. The inferior margin of the trochlear notch is formed by a prominent lip of bone called the coronoid process of the ulna. Just below this on the anterior ulna is a roughened area called the ulnar tuberosity. To the lateral side and slightly inferior to the trochlear notch is a small, smooth area called the radial notch of the ulna. This area is the site of articulation between the proximal radius and the ulna, forming the proximal radioulnar joint. The posterior and superior portions of the proximal ulna make up the olecranon process, which forms the bony tip of the elbow.

Radius

The radius runs parallel to the ulna, on the lateral (thumb) side of the forearm (see [link]). The head of the radius is a disc-shaped structure that forms the proximal end. The small depression on the surface of the head articulates with the capitulum of the humerus as part of the elbow joint, whereas the smooth, outer margin of the head articulates with the radial notch of the ulna at the proximal radioulnar joint. The neck of the radius is the narrowed region immediately below the expanded head. Inferior to this point on the medial side is the radial tuberosity, an oval-shaped, bony protuberance that serves as a muscle attachment point. The shaft of the radius is slightly curved and has a small ridge along its medial side. This ridge forms the interosseous border of the radius, which, like the similar border of the ulna, is the line of attachment for the interosseous membrane that unites the two forearm bones. The distal end of the radius has a smooth surface for articulation with two carpal bones to form the radiocarpal joint or wrist joint ([link] and [link]). On the medial side of the distal radius is the ulnar notch of the radius. This shallow depression articulates with the head of the ulna, which together form the distal radioulnar joint. The lateral end of the radius has a pointed projection called the styloid process of the radius. This provides attachment for ligaments that support the lateral side of the wrist joint. Compared to the styloid process of the ulna, the styloid process of the radius projects more distally, thereby limiting the range of movement for lateral deviations of the hand at the wrist joint.

Carpal Bones

The wrist and base of the hand are formed by a series of eight small carpal bones (see [link]). The carpal bones are arranged in two rows, forming a proximal row of four carpal bones and a distal row of four carpal bones. The bones in the proximal row, running from the lateral (thumb) side to the medial side, are the scaphoid (“boat-shaped”), lunate (“moon-shaped”), triquetrum (“three-cornered”), and pisiform (“pea-shaped”) bones. The small, rounded pisiform bone articulates with the anterior surface of the triquetrum bone. The pisiform thus projects anteriorly, where it forms the bony bump that can be felt at the medial base of your hand. The distal bones (lateral to medial) are the trapezium (“table”), trapezoid (“resembles a table”), capitate (“head-shaped”), and hamate (“hooked bone”) bones. The hamate bone is characterized by a prominent bony extension on its anterior side called the hook of the hamate bone.

Metacarpal Bones

The palm of the hand contains five elongated metacarpal bones. These bones lie between the carpal bones of the wrist and the bones of the fingers and thumb (see [link]). The proximal end of each metacarpal bone articulates with one of the distal carpal bones. Each of these articulations is a carpometacarpal joint (see [link]). The expanded distal end of each metacarpal bone articulates at the metacarpophalangeal joint with the proximal phalanx bone of the thumb or one of the fingers. The distal end also forms the knuckles of the hand, at the base of the fingers. The metacarpal bones are numbered 1–5, beginning at the thumb.

Phalanx Bones

The fingers and thumb contain 14 bones, each of which is called a phalanx bone (plural = phalanges), named after the ancient Greek phalanx (a rectangular block of soldiers). The thumb (pollex) is digit number 1 and has two phalanges, a proximal phalanx, and a distal phalanx bone (see [link]). Digits 2 (index finger) through 5 (little finger) have three phalanges each, called the proximal, middle, and distal phalanx bones. An interphalangeal joint is one of the articulations between adjacent phalanges of the digits (see [link]).

The Pelvic Girdle and Pelvis

Abstract:
By the end of this section, you will be able to:

* Define the pelvic girdle and describe the bones and ligaments of the pelvis
* Explain the three regions of the hip bone and identify their bony landmarks
* Describe the openings of the pelvis and the boundaries of the greater and lesser pelvis

Hip Bone

The hip bone, or coxal bone, forms the pelvic girdle portion of the pelvis. The paired hip bones are the large, curved bones that form the lateral and anterior aspects of the pelvis. Each adult hip bone is formed by three separate bones that fuse together during the late teenage years. These bony components are the ilium, ischium, and pubis ([link]). These names are retained and used to define the three regions of the adult hip bone.

Pelvis

The pelvis consists of four bones: the right and left hip bones, the sacrum, and the coccyx (see [link]). The pelvis has several important functions. Its primary role is to support the weight of the upper body when sitting and to transfer this weight to the lower limbs when standing. It serves as an attachment point for trunk and lower limb muscles, and also protects the internal pelvic organs. When standing in the anatomical position, the pelvis is tilted anteriorly. In this position, the anterior superior iliac spines and the pubic tubercles lie in the same vertical plane, and the anterior (internal) surface of the sacrum faces forward and downward.

Bones of the Lower Limb

Abstract:
By the end of this section, you will be able to:

* Identify the divisions of the lower limb and describe the bones of each region
* Describe the bones and bony landmarks that articulate at each joint of the lower limb

Femur

The femur, or thigh bone, is the single bone of the thigh region ([link]). It is the longest and strongest bone of the body, and accounts for approximately one-quarter of a person’s total height. The rounded, proximal end is the head of the femur, which articulates with the acetabulum of the hip bone to form the hip joint. The fovea capitis is a minor indentation on the medial side of the femoral head that serves as the site of attachment for the ligament of the head of the femur. This ligament spans the femur and acetabulum, but is weak and provides little support for the hip joint. It does, however, carry an important artery that supplies the head of the femur.

Patella

The patella (kneecap) is the largest sesamoid bone of the body (see [link]). A sesamoid bone is a bone that is incorporated into the tendon of a muscle where that tendon crosses a joint. The sesamoid bone articulates with the underlying bones to prevent damage to the muscle tendon due to rubbing against the bones during movements of the joint. The patella is found in the tendon of the quadriceps femoris muscle, the large muscle of the anterior thigh that passes across the anterior knee to attach to the tibia. The patella articulates with the patellar surface of the femur and thus prevents rubbing of the muscle tendon against the distal femur. The patella also lifts the tendon away from the knee joint, which increases the leverage power of the quadriceps femoris muscle as it acts across the knee. The patella does not articulate with the tibia.

Tibia

The tibia (shin bone) is the medial bone of the leg and is larger than the fibula, with which it is paired ([link]). The tibia is the main weight-bearing bone of the lower leg and the second longest bone of the body, after the femur. The medial side of the tibia is located immediately under the skin, allowing it to be easily palpated down the entire length of the medial leg.

Fibula

The fibula is the slender bone located on the lateral side of the leg (see [link]). The fibula does not bear weight. It serves primarily for muscle attachments and thus is largely surrounded by muscles. Only the proximal and distal ends of the fibula can be palpated.

Tarsal Bones

The posterior half of the foot is formed by seven tarsal bones ([link]). The most superior bone is the talus. This has a relatively square-shaped, upper surface that articulates with the tibia and fibula to form the ankle joint. Three areas of articulation form the ankle joint: The superomedial surface of the talus bone articulates with the medial malleolus of the tibia, the top of the talus articulates with the distal end of the tibia, and the lateral side of the talus articulates with the lateral malleolus of the fibula. Inferiorly, the talus articulates with the calcaneus (heel bone), the largest bone of the foot, which forms the heel. Body weight is transferred from the tibia to the talus to the calcaneus, which rests on the ground. The medial calcaneus has a prominent bony extension called the sustentaculum tali (“support for the talus”) that supports the medial side of the talus bone.

Metatarsal Bones

The anterior half of the foot is formed by the five metatarsal bones, which are located between the tarsal bones of the posterior foot and the phalanges of the toes (see [link]). These elongated bones are numbered 1–5, starting with the medial side of the foot. The first metatarsal bone is shorter and thicker than the others. The second metatarsal is the longest. The base of the metatarsal bone is the proximal end of each metatarsal bone. These articulate with the cuboid or cuneiform bones. The base of the fifth metatarsal has a large, lateral expansion that provides for muscle attachments. This expanded base of the fifth metatarsal can be felt as a bony bump at the midpoint along the lateral border of the foot. The expanded distal end of each metatarsal is the head of the metatarsal bone. Each metatarsal bone articulates with the proximal phalanx of a toe to form a metatarsophalangeal joint. The heads of the metatarsal bones also rest on the ground and form the ball (anterior end) of the foot.

Phalanges

The toes contain a total of 14 phalanx bones (phalanges), arranged in a similar manner as the phalanges of the fingers (see [link]). The toes are numbered 1–5, starting with the big toe (hallux). The big toe has two phalanx bones, the proximal and distal phalanges. The remaining toes all have proximal, middle, and distal phalanges. A joint between adjacent phalanx bones is called an interphalangeal joint.

Arches of the Foot

When the foot comes into contact with the ground during walking, running, or jumping activities, the impact of the body weight puts a tremendous amount of pressure and force on the foot. During running, the force applied to each foot as it contacts the ground can be up to 2.5 times your body weight. The bones, joints, ligaments, and muscles of the foot absorb this force, thus greatly reducing the amount of shock that is passed superiorly into the lower limb and body. The arches of the foot play an important role in this shock-absorbing ability. When weight is applied to the foot, these arches will flatten somewhat, thus absorbing energy. When the weight is removed, the arch rebounds, giving “spring” to the step. The arches also serve to distribute body weight side to side and to either end of the foot.

Development of the Appendicular Skeleton

Abstract:
By the end of this section, you will be able to:

* Describe the growth and development of the embryonic limb buds
* Discuss the appearance of primary and secondary ossification centers

Limb Growth

Each upper and lower limb initially develops as a small bulge called a limb bud, which appears on the lateral side of the early embryo. The upper limb bud appears near the end of the fourth week of development, with the lower limb bud appearing shortly after ([link]).

Ossification of Appendicular Bones

All of the girdle and limb bones, except for the clavicle, develop by the process of endochondral ossification. This process begins as the mesenchyme within the limb bud differentiates into hyaline cartilage to form cartilage models for future bones. By the twelfth week, a primary ossification center will have appeared in the diaphysis (shaft) region of the long bones, initiating the process that converts the cartilage model into bone. A secondary ossification center will appear in each epiphysis (expanded end) of these bones at a later time, usually after birth. The primary and secondary ossification centers are separated by the epiphyseal plate, a layer of growing hyaline cartilage. This plate is located between the diaphysis and each epiphysis. It continues to grow and is responsible for the lengthening of the bone. The epiphyseal plate is retained for many years, until the bone reaches its final, adult size, at which time the epiphyseal plate disappears and the epiphysis fuses to the diaphysis. (Seek additional content on ossification in the chapter on bone tissue.)

Joints

Introduction

Classification of Joints

Abstract:
By the end of this section, you will be able to:

* Distinguish between the functional and structural classifications for joints
* Describe the three functional types of joints and give an example of each
* List the three types of diarthrodial joints

Structural Classification of Joints

The structural classification of joints is based on whether the articulating surfaces of the adjacent bones are directly connected by fibrous connective tissue or cartilage, or whether the articulating surfaces contact each other within a fluid-filled joint cavity. These differences serve to divide the joints of the body into three structural classifications. A fibrous joint is where the adjacent bones are united by fibrous connective tissue. At a cartilaginous joint, the bones are joined by hyaline cartilage or fibrocartilage. At a synovial joint, the articulating surfaces of the bones are not directly connected, but instead come into contact with each other within a joint cavity that is filled with a lubricating fluid. Synovial joints allow for free movement between the bones and are the most common joints of the body.

Functional Classification of Joints

The functional classification of joints is determined by the amount of mobility found between the adjacent bones. Joints are thus functionally classified as a synarthrosis or immobile joint, an amphiarthrosis or slightly moveable joint, or as a diarthrosis, which is a freely moveable joint (arthroun = “to fasten by a joint”). Depending on their location, fibrous joints may be functionally classified as a synarthrosis (immobile joint) or an amphiarthrosis (slightly mobile joint). Cartilaginous joints are also functionally classified as either a synarthrosis or an amphiarthrosis joint. All synovial joints are functionally classified as a diarthrosis joint.

Fibrous Joints

Abstract:
By the end of this section, you will be able to:

* Describe the structural features of fibrous joints
* Distinguish between a suture, syndesmosis, and gomphosis
* Give an example of each type of fibrous joint

Suture

All the bones of the skull, except for the mandible, are joined to each other by a fibrous joint called a suture. The fibrous connective tissue found at a suture (“to bind or sew”) strongly unites the adjacent skull bones and thus helps to protect the brain and form the face. In adults, the skull bones are closely opposed and fibrous connective tissue fills the narrow gap between the bones. The suture is frequently convoluted, forming a tight union that prevents most movement between the bones. (See [link]**a**.) Thus, skull sutures are functionally classified as a synarthrosis, although some sutures may allow for slight movements between the cranial bones.

Syndesmosis

A syndesmosis (“fastened with a band”) is a type of fibrous joint in which two parallel bones are united to each other by fibrous connective tissue. The gap between the bones may be narrow, with the bones joined by ligaments, or the gap may be wide and filled in by a broad sheet of connective tissue called an interosseous membrane.

Gomphosis

A gomphosis (“fastened with bolts”) is the specialized fibrous joint that anchors the root of a tooth into its bony socket within the maxillary bone (upper jaw) or mandible bone (lower jaw) of the skull. A gomphosis is also known as a peg-and-socket joint. Spanning between the bony walls of the socket and the root of the tooth are numerous short bands of dense connective tissue, each of which is called a periodontal ligament (see [link]**c**). Due to the immobility of a gomphosis, this type of joint is functionally classified as a synarthrosis.

Cartilaginous Joints

Abstract:
By the end of this section, you will be able to:

* Describe the structural features of cartilaginous joints
* Distinguish between a synchondrosis and symphysis
* Give an example of each type of cartilaginous joint

Synchondrosis

A synchondrosis (“joined by cartilage”) is a cartilaginous joint where bones are joined together by hyaline cartilage, or where bone is united to hyaline cartilage. A synchondrosis may be temporary or permanent. A temporary synchondrosis is the epiphyseal plate (growth plate) of a growing long bone. The epiphyseal plate is the region of growing hyaline cartilage that unites the diaphysis (shaft) of the bone to the epiphysis (end of the bone). Bone lengthening involves growth of the epiphyseal plate cartilage and its replacement by bone, which adds to the diaphysis. For many years during childhood growth, the rates of cartilage growth and bone formation are equal and thus the epiphyseal plate does not change in overall thickness as the bone lengthens. During the late teens and early 20s, growth of the cartilage slows and eventually stops. The epiphyseal plate is then completely replaced by bone, and the diaphysis and epiphysis portions of the bone fuse together to form a single adult bone. This fusion of the diaphysis and epiphysis is a synostosis. Once this occurs, bone lengthening ceases. For this reason, the epiphyseal plate is considered to be a temporary synchondrosis. Because cartilage is softer than bone tissue, injury to a growing long bone can damage the epiphyseal plate cartilage, thus stopping bone growth and preventing additional bone lengthening.

Symphysis

A cartilaginous joint where the bones are joined by fibrocartilage is called a symphysis (“growing together”). Fibrocartilage is very strong because it contains numerous bundles of thick collagen fibers, thus giving it a much greater ability to resist pulling and bending forces when compared with hyaline cartilage. This gives symphyses the ability to strongly unite the adjacent bones, but can still allow for limited movement to occur. Thus, a symphysis is functionally classified as an amphiarthrosis.

Synovial Joints

Abstract:
By the end of this section, you will be able to:

* Describe the structural features of a synovial joint
* Discuss the function of additional structures associated with synovial joints
* List the six types of synovial joints and give an example of each

Structural Features of Synovial Joints

Synovial joints are characterized by the presence of a joint cavity. The walls of this space are formed by the articular capsule, a fibrous connective tissue structure that is attached to each bone just outside the area of the bone’s articulating surface. The bones of the joint articulate with each other within the joint cavity.

Additional Structures Associated with Synovial Joints

A few synovial joints of the body have a fibrocartilage structure located between the articulating bones. This is called an articular disc, which is generally small and oval-shaped, or a meniscus, which is larger and C-shaped. These structures can serve several functions, depending on the specific joint. In some places, an articular disc may act to strongly unite the bones of the joint to each other. Examples of this include the articular discs found at the sternoclavicular joint or between the distal ends of the radius and ulna bones. At other synovial joints, the disc can provide shock absorption and cushioning between the bones, which is the function of each meniscus within the knee joint. Finally, an articular disc can serve to smooth the movements between the articulating bones, as seen at the temporomandibular joint. Some synovial joints also have a fat pad, which can serve as a cushion between the bones.

Types of Synovial Joints

Synovial joints are subdivided based on the shapes of the articulating surfaces of the bones that form each joint. The six types of synovial joints are pivot, hinge, condyloid, saddle, plane, and ball-and socket-joints ([link]).

Types of Body Movements

Abstract:
By the end of this section, you will be able to:

* Define the different types of body movements
* Identify the joints that allow for these motions

Flexion and Extension

Flexion and extension are typically movements that take place within the sagittal plane and involve anterior or posterior movements of the neck, trunk, or limbs. For the vertebral column, flexion (anterior flexion) is an anterior (forward) bending of the neck or trunk, while extension involves a posterior-directed motion, such as straightening from a flexed position or bending backward. Lateral flexion of the vertebral column occurs in the coronal plane and is defined as the bending of the neck or trunk toward the right or left side. These movements of the vertebral column involve both the symphysis joint formed by each intervertebral disc, as well as the plane type of synovial joint formed between the inferior articular processes of one vertebra and the superior articular processes of the next lower vertebra.

Abduction and Adduction

Abduction and adduction motions occur within the coronal plane and involve medial-lateral motions of the limbs, fingers, toes, or thumb. Abduction moves the limb laterally away from the midline of the body, while adduction is the opposing movement that brings the limb toward the body or across the midline. For example, abduction is raising the arm at the shoulder joint, moving it laterally away from the body, while adduction brings the arm down to the side of the body. Similarly, abduction and adduction at the wrist moves the hand away from or toward the midline of the body. Spreading the fingers or toes apart is also abduction, while bringing the fingers or toes together is adduction. For the thumb, abduction is the anterior movement that brings the thumb to a 90° perpendicular position, pointing straight out from the palm. Adduction moves the thumb back to the anatomical position, next to the index finger. Abduction and adduction movements are seen at condyloid, saddle, and ball-and-socket joints (see [link]**e**).

Circumduction

Circumduction is the movement of a body region in a circular manner, in which one end of the body region being moved stays relatively stationary while the other end describes a circle. It involves the sequential combination of flexion, adduction, extension, and abduction at a joint. This type of motion is found at biaxial condyloid and saddle joints, and at multiaxial ball-and-sockets joints (see [link]**e**).

Rotation

Rotation can occur within the vertebral column, at a pivot joint, or at a ball-and-socket joint. Rotation of the neck or body is the twisting movement produced by the summation of the small rotational movements available between adjacent vertebrae. At a pivot joint, one bone rotates in relation to another bone. This is a uniaxial joint, and thus rotation is the only motion allowed at a pivot joint. For example, at the atlantoaxial joint, the first cervical (C1) vertebra (atlas) rotates around the dens, the upward projection from the second cervical (C2) vertebra (axis). This allows the head to rotate from side to side as when shaking the head “no.” The proximal radioulnar joint is a pivot joint formed by the head of the radius and its articulation with the ulna. This joint allows for the radius to rotate along its length during pronation and supination movements of the forearm.

Supination and Pronation

Supination and pronation are movements of the forearm. In the anatomical position, the upper limb is held next to the body with the palm facing forward. This is the supinated position of the forearm. In this position, the radius and ulna are parallel to each other. When the palm of the hand faces backward, the forearm is in the pronated position, and the radius and ulna form an X-shape.

Dorsiflexion and Plantar Flexion

Dorsiflexion and plantar flexion are movements at the ankle joint, which is a hinge joint. Lifting the front of the foot, so that the top of the foot moves toward the anterior leg is dorsiflexion, while lifting the heel of the foot from the ground or pointing the toes downward is plantar flexion. These are the only movements available at the ankle joint (see [link]**h**).

Inversion and Eversion

Inversion and eversion are complex movements that involve the multiple plane joints among the tarsal bones of the posterior foot (intertarsal joints) and thus are not motions that take place at the ankle joint. Inversion is the turning of the foot to angle the bottom of the foot toward the midline, while eversion turns the bottom of the foot away from the midline. The foot has a greater range of inversion than eversion motion. These are important motions that help to stabilize the foot when walking or running on an uneven surface and aid in the quick side-to-side changes in direction used during active sports such as basketball, racquetball, or soccer (see [link]**i**).

Protraction and Retraction

Protraction and retraction are anterior-posterior movements of the scapula or mandible. Protraction of the scapula occurs when the shoulder is moved forward, as when pushing against something or throwing a ball. Retraction is the opposite motion, with the scapula being pulled posteriorly and medially, toward the vertebral column. For the mandible, protraction occurs when the lower jaw is pushed forward, to stick out the chin, while retraction pulls the lower jaw backward. (See [link]**j**.)

Depression and Elevation

Depression and elevation are downward and upward movements of the scapula or mandible. The upward movement of the scapula and shoulder is elevation, while a downward movement is depression. These movements are used to shrug your shoulders. Similarly, elevation of the mandible is the upward movement of the lower jaw used to close the mouth or bite on something, and depression is the downward movement that produces opening of the mouth (see [link]**k**).

Excursion

Excursion is the side to side movement of the mandible. Lateral excursion moves the mandible away from the midline, toward either the right or left side. Medial excursion returns the mandible to its resting position at the midline.

Superior Rotation and Inferior Rotation

Superior and inferior rotation are movements of the scapula and are defined by the direction of movement of the glenoid cavity. These motions involve rotation of the scapula around a point inferior to the scapular spine and are produced by combinations of muscles acting on the scapula. During superior rotation, the glenoid cavity moves upward as the medial end of the scapular spine moves downward. This is a very important motion that contributes to upper limb abduction. Without superior rotation of the scapula, the greater tubercle of the humerus would hit the acromion of the scapula, thus preventing any abduction of the arm above shoulder height. Superior rotation of the scapula is thus required for full abduction of the upper limb. Superior rotation is also used without arm abduction when carrying a heavy load with your hand or on your shoulder. You can feel this rotation when you pick up a load, such as a heavy book bag and carry it on only one shoulder. To increase its weight-bearing support for the bag, the shoulder lifts as the scapula superiorly rotates. Inferior rotation occurs during limb adduction and involves the downward motion of the glenoid cavity with upward movement of the medial end of the scapular spine.

Opposition and Reposition

Opposition is the thumb movement that brings the tip of the thumb in contact with the tip of a finger. This movement is produced at the first carpometacarpal joint, which is a saddle joint formed between the trapezium carpal bone and the first metacarpal bone. Thumb opposition is produced by a combination of flexion and abduction of the thumb at this joint. Returning the thumb to its anatomical position next to the index finger is called reposition (see [link]**l**).

Anatomy of Selected Synovial Joints

Abstract:
By the end of this section, you will be able to:

* Describe the bones that articulate together to form selected synovial joints
* Discuss the movements available at each joint
* Describe the structures that support and prevent excess movements at each joint

Articulations of the Vertebral Column

In addition to being held together by the intervertebral discs, adjacent vertebrae also articulate with each other at synovial joints formed between the superior and inferior articular processes called zygapophysial joints (facet joints) (see [link]). These are plane joints that provide for only limited motions between the vertebrae. The orientation of the articular processes at these joints varies in different regions of the vertebral column and serves to determine the types of motions available in each vertebral region. The cervical and lumbar regions have the greatest ranges of motions.

Temporomandibular Joint

The temporomandibular joint (TMJ) is the joint that allows for opening (mandibular depression) and closing (mandibular elevation) of the mouth, as well as side-to-side and protraction/retraction motions of the lower jaw. This joint involves the articulation between the mandibular fossa and articular tubercle of the temporal bone, with the condyle (head) of the mandible. Located between these bony structures, filling the gap between the skull and mandible, is a flexible articular disc ([link]). This disc serves to smooth the movements between the temporal bone and mandibular condyle.

Shoulder Joint

The shoulder joint is called the glenohumeral joint. This is a ball-and-socket joint formed by the articulation between the head of the humerus and the glenoid cavity of the scapula ([link]). This joint has the largest range of motion of any joint in the body. However, this freedom of movement is due to the lack of structural support and thus the enhanced mobility is offset by a loss of stability.

Elbow Joint

The elbow joint is a uniaxial hinge joint formed by the humeroulnar joint, the articulation between the trochlea of the humerus and the trochlear notch of the ulna. Also associated with the elbow are the humeroradial joint and the proximal radioulnar joint. All three of these joints are enclosed within a single articular capsule ([link]).

Hip Joint

The hip joint is a multiaxial ball-and-socket joint between the head of the femur and the acetabulum of the hip bone ([link]). The hip carries the weight of the body and thus requires strength and stability during standing and walking. For these reasons, its range of motion is more limited than at the shoulder joint.

Knee Joint

The knee joint is the largest joint of the body ([link]). It actually consists of three articulations. The femoropatellar joint is found between the patella and the distal femur. The medial tibiofemoral joint and lateral tibiofemoral joint are located between the medial and lateral condyles of the femur and the medial and lateral condyles of the tibia. All of these articulations are enclosed within a single articular capsule. The knee functions as a hinge joint, allowing flexion and extension of the leg. This action is generated by both rolling and gliding motions of the femur on the tibia. In addition, some rotation of the leg is available when the knee is flexed, but not when extended. The knee is well constructed for weight bearing in its extended position, but is vulnerable to injuries associated with hyperextension, twisting, or blows to the medial or lateral side of the joint, particularly while weight bearing.

Ankle and Foot Joints

The ankle is formed by the talocrural joint ([link]). It consists of the articulations between the talus bone of the foot and the distal ends of the tibia and fibula of the leg (crural = “leg”). The superior aspect of the talus bone is square-shaped and has three areas of articulation. The top of the talus articulates with the inferior tibia. This is the portion of the ankle joint that carries the body weight between the leg and foot. The sides of the talus are firmly held in position by the articulations with the medial malleolus of the tibia and the lateral malleolus of the fibula, which prevent any side-to-side motion of the talus. The ankle is thus a uniaxial hinge joint that allows only for dorsiflexion and plantar flexion of the foot.

Development of Joints

Abstract:
By the end of this section, you will be able to:

* Describe the two processes by which mesenchyme can give rise to bone
* Discuss the process by which joints of the limbs are formed

Muscle Tissue

Introduction

Overview of Muscle Tissues

Abstract:
By the end of this section, you will be able to:

* Describe the different types of muscle
* Explain contractibility and extensibility

Skeletal Muscle

Abstract:
By the end of this section, you will be able to:

* Describe the layers of connective tissues packaging skeletal muscle
* Explain how muscles work with tendons to move the body
* Identify areas of the skeletal muscle fibers
* Describe excitation-contraction coupling

Skeletal Muscle Fibers

Because skeletal muscle cells are long and cylindrical, they are commonly referred to as muscle fibers. Skeletal muscle fibers can be quite large for human cells, with diameters up to 100 *μ*m and lengths up to 30 cm (11.8 in) in the Sartorius of the upper leg. During early development, embryonic myoblasts, each with its own nucleus, fuse with up to hundreds of other myoblasts to form the multinucleated skeletal muscle fibers. Multiple nuclei mean multiple copies of genes, permitting the production of the large amounts of proteins and enzymes needed for muscle contraction.

The Sarcomere

The striated appearance of skeletal muscle fibers is due to the arrangement of the myofilaments of actin and myosin in sequential order from one end of the muscle fiber to the other. Each packet of these microfilaments and their regulatory proteins, troponin and tropomyosin (along with other proteins) is called a sarcomere.

The Neuromuscular Junction

Another specialization of the skeletal muscle is the site where a motor neuron’s terminal meets the muscle fiber—called the neuromuscular junction (NMJ). This is where the muscle fiber first responds to signaling by the motor neuron. Every skeletal muscle fiber in every skeletal muscle is innervated by a motor neuron at the NMJ. Excitation signals from the neuron are the only way to functionally activate the fiber to contract.

Excitation-Contraction Coupling

All living cells have membrane potentials, or electrical gradients across their membranes. The inside of the membrane is usually around -60 to -90 mV, relative to the outside. This is referred to as a cell’s membrane potential. Neurons and muscle cells can use their membrane potentials to generate electrical signals. They do this by controlling the movement of charged particles, called ions, across their membranes to create electrical currents. This is achieved by opening and closing specialized proteins in the membrane called ion channels. Although the currents generated by ions moving through these channel proteins are very small, they form the basis of both neural signaling and muscle contraction.

Muscle Fiber Contraction and Relaxation

Abstract:
By the end of this section, you will be able to:

* Describe the components involved in a muscle contraction
* Explain how muscles contract and relax
* Describe the sliding filament model of muscle contraction

The Sliding Filament Model of Contraction

When signaled by a motor neuron, a skeletal muscle fiber contracts as the thin filaments are pulled and then slide past the thick filaments within the fiber’s sarcomeres. This process is known as the sliding filament model of muscle contraction ([link]). The sliding can only occur when myosin-binding sites on the actin filaments are exposed by a series of steps that begins with Ca++ entry into the sarcoplasm.

ATP and Muscle Contraction

For thin filaments to continue to slide past thick filaments during muscle contraction, myosin heads must pull the actin at the binding sites, detach, re-cock, attach to more binding sites, pull, detach, re-cock, etc. This repeated movement is known as the cross-bridge cycle. This motion of the myosin heads is similar to the oars when an individual rows a boat: The paddle of the oars (the myosin heads) pull, are lifted from the water (detach), repositioned (re-cocked) and then immersed again to pull ([link]). Each cycle requires energy, and the action of the myosin heads in the sarcomeres repetitively pulling on the thin filaments also requires energy, which is provided by ATP.

Sources of ATP

ATP supplies the energy for muscle contraction to take place. In addition to its direct role in the cross-bridge cycle, ATP also provides the energy for the active-transport Ca++ pumps in the SR. Muscle contraction does not occur without sufficient amounts of ATP. The amount of ATP stored in muscle is very low, only sufficient to power a few seconds worth of contractions. As it is broken down, ATP must therefore be regenerated and replaced quickly to allow for sustained contraction. There are three mechanisms by which ATP can be regenerated in muscle cells: creatine phosphate metabolism, anaerobic glycolysis, and aerobic respiration.

Relaxation of a Skeletal Muscle

Relaxing skeletal muscle fibers, and ultimately, the skeletal muscle, begins with the motor neuron, which stops releasing its chemical signal, ACh, into the synapse at the NMJ. The muscle fiber will repolarize, which closes the gates in the SR where Ca++ was being released. ATP-driven pumps will move Ca++ out of the sarcoplasm back into the SR. This results in the “reshielding” of the actin-binding sites on the thin filaments. Without the ability to form cross-bridges between the thin and thick filaments, the muscle fiber loses its tension and relaxes.

Muscle Strength

The number of skeletal muscle fibers in a given muscle is genetically determined and does not change. Muscle strength is directly related to the amount of myofibrils and sarcomeres within each fiber. Factors, such as hormones and stress (and artificial anabolic steroids), acting on the muscle can increase the production of sarcomeres and myofibrils within the muscle fibers, a change called hypertrophy, which results in the increased mass and bulk in a skeletal muscle. Likewise, decreased use of a skeletal muscle results in atrophy, where the number of sarcomeres and myofibrils disappear (but not the number of muscle fibers). It is common for a limb in a cast to show atrophied muscles when the cast is removed, and certain diseases, such as polio, show atrophied muscles.

Nervous System Control of Muscle Tension

Abstract:
By the end of this section, you will be able to:

* Explain concentric, isotonic, and eccentric contractions
* Describe the length-tension relationship
* Describe the three phases of a muscle twitch
* Define wave summation, tetanus, and treppe

Motor Units

As you have learned, every skeletal muscle fiber must be innervated by the axon terminal of a motor neuron in order to contract. Each muscle fiber is innervated by only one motor neuron. The actual group of muscle fibers in a muscle innervated by a single motor neuron is called a motor unit. The size of a motor unit is variable depending on the nature of the muscle.

The Length-Tension Range of a Sarcomere

When a skeletal muscle fiber contracts, myosin heads attach to actin to form cross-bridges followed by the thin filaments sliding over the thick filaments as the heads pull the actin, and this results in sarcomere shortening, creating the tension of the muscle contraction. The cross-bridges can only form where thin and thick filaments already overlap, so that the length of the sarcomere has a direct influence on the force generated when the sarcomere shortens. This is called the length-tension relationship.

The Frequency of Motor Neuron Stimulation

A single action potential from a motor neuron will produce a single contraction in the muscle fibers of its motor unit. This isolated contraction is called a twitch. A twitch can last for a few milliseconds or 100 milliseconds, depending on the muscle type. The tension produced by a single twitch can be measured by a myogram, an instrument that measures the amount of tension produced over time ([link]). Each twitch undergoes three phases. The first phase is the latent period, during which the action potential is being propagated along the sarcolemma and Ca++ ions are released from the SR. This is the phase during which excitation and contraction are being coupled but contraction has yet to occur. The contraction phase occurs next. The Ca++ ions in the sarcoplasm have bound to troponin, tropomyosin has shifted away from myosin-binding sites on actin, cross-bridges have formed, and sarcomeres are actively shortening to the point of peak tension. The last phase is the relaxation phase, when tension decreases as contraction stops. Ca++ ions are pumped out of the sarcoplasm into the SR, and cross-bridge cycling stops, returning the muscle fibers to their resting state.

Treppe

When a skeletal muscle has been dormant for an extended period and then activated to contract, with all other things being equal, the initial contractions generate about one-half the force of later contractions. The muscle tension increases in a graded manner that to some looks like a set of stairs. This tension increase is called treppe, a condition where muscle contractions become more efficient. It’s also known as the “staircase effect” ([link]).

Muscle Tone

Skeletal muscles are rarely completely relaxed, or flaccid. Even if a muscle is not producing movement, it is contracted a small amount to maintain its contractile proteins and produce muscle tone. The tension produced by muscle tone allows muscles to continually stabilize joints and maintain posture.

Types of Muscle Fibers

Abstract:
By the end of this section, you will be able to:

* Describe the types of skeletal muscle fibers
* Explain fast and slow muscle fibers

Exercise and Muscle Performance

Abstract:
By the end of this section, you will be able to:

* Describe hypertrophy and atrophy
* Explain how resistance exercise builds muscle
* Explain how performance-enhancing substances affect muscle

Endurance Exercise

Slow fibers are predominantly used in endurance exercises that require little force but involve numerous repetitions. The aerobic metabolism used by slow-twitch fibers allows them to maintain contractions over long periods. Endurance training modifies these slow fibers to make them even more efficient by producing more mitochondria to enable more aerobic metabolism and more ATP production. Endurance exercise can also increase the amount of myoglobin in a cell, as increased aerobic respiration increases the need for oxygen. Myoglobin is found in the sarcoplasm and acts as an oxygen storage supply for the mitochondria.

Resistance Exercise

Resistance exercises, as opposed to endurance exercise, require large amounts of FG fibers to produce short, powerful movements that are not repeated over long periods. The high rates of ATP hydrolysis and cross-bridge formation in FG fibers result in powerful muscle contractions. Muscles used for power have a higher ratio of FG to SO/FO fibers, and trained athletes possess even higher levels of FG fibers in their muscles. Resistance exercise affects muscles by increasing the formation of myofibrils, thereby increasing the thickness of muscle fibers. This added structure causes hypertrophy, or the enlargement of muscles, exemplified by the large skeletal muscles seen in body builders and other athletes ([link]). Because this muscular enlargement is achieved by the addition of structural proteins, athletes trying to build muscle mass often ingest large amounts of protein.

Performance-Enhancing Substances

Some athletes attempt to boost their performance by using various agents that may enhance muscle performance. Anabolic steroids are one of the more widely known agents used to boost muscle mass and increase power output. Anabolic steroids are a form of testosterone, a male sex hormone that stimulates muscle formation, leading to increased muscle mass.

Cardiac Muscle Tissue

Abstract:
By the end of this section, you will be able to:

* Describe intercalated discs and gap junctions
* Describe a desmosome

Smooth Muscle

Abstract:
By the end of this section, you will be able to:

* Describe a dense body
* Explain how smooth muscle works with internal organs and passageways through the body
* Explain how smooth muscles differ from skeletal and cardiac muscles
* Explain the difference between single-unit and multi-unit smooth muscle

Hyperplasia in Smooth Muscle

Similar to skeletal and cardiac muscle cells, smooth muscle can undergo hypertrophy to increase in size. Unlike other muscle, smooth muscle can also divide to produce more cells, a process called hyperplasia. This can most evidently be observed in the uterus at puberty, which responds to increased estrogen levels by producing more uterine smooth muscle fibers, and greatly increases the size of the myometrium.

Development and Regeneration of Muscle Tissue

Abstract:
By the end of this section, you will be able to:

* Describe the function of satellite cells
* Define fibrosis
* Explain which muscle has the greatest regeneration ability

The Muscular System

Introduction

Interactions of Skeletal Muscles, Their Fascicle Arrangement, and Their Lever Systems

Abstract:
By the end of this section, you will be able to:

* Compare and contrast agonist and antagonist muscles
* Describe how fascicles are arranged within a skeletal muscle
* Explain the major events of a skeletal muscle contraction within a muscle in generating force

Interactions of Skeletal Muscles in the Body

To pull on a bone, that is, to change the angle at its synovial joint, which essentially moves the skeleton, a skeletal muscle must also be attached to a fixed part of the skeleton. The moveable end of the muscle that attaches to the bone being pulled is called the muscle’s insertion, and the end of the muscle attached to a fixed (stabilized) bone is called the origin. During forearm flexion—bending the elbow—the brachioradialis assists the brachialis.

Patterns of Fascicle Organization

Skeletal muscle is enclosed in connective tissue scaffolding at three levels. Each muscle fiber (cell) is covered by endomysium and the entire muscle is covered by epimysium. When a group of muscle fibers is “bundled” as a unit within the whole muscle by an additional covering of a connective tissue called perimysium, that bundled group of muscle fibers is called a fascicle. Fascicle arrangement by perimysia is correlated to the force generated by a muscle; it also affects the range of motion of the muscle. Based on the patterns of fascicle arrangement, skeletal muscles can be classified in several ways. What follows are the most common fascicle arrangements.

The Lever System of Muscle and Bone Interactions

Skeletal muscles do not work by themselves. Muscles are arranged in pairs based on their functions. For muscles attached to the bones of the skeleton, the connection determines the force, speed, and range of movement. These characteristics depend on each other and can explain the general organization of the muscular and skeletal systems.

Naming Skeletal Muscles

Abstract:
By the end of this section, you will be able to:

* Describe the criteria used to name skeletal muscles
* Explain how understanding the muscle names helps describe shapes, location, and actions of various muscles

Axial Muscles of the Head, Neck, and Back

Abstract:
By the end of this section, you will be able to:

* Identify the axial muscles of the face, head, and neck
* Identify the movement and function of the face, head, and neck muscles

Muscles That Create Facial Expression

The origins of the muscles of facial expression are on the surface of the skull (remember, the origin of a muscle does not move). The insertions of these muscles have fibers intertwined with connective tissue and the dermis of the skin. Because the muscles insert in the skin rather than on bone, when they contract, the skin moves to create facial expression ([link]).

Muscles That Move the Eyes

The movement of the eyeball is under the control of the extrinsic eye muscles, which originate outside the eye and insert onto the outer surface of the white of the eye. These muscles are located inside the eye socket and cannot be seen on any part of the visible eyeball ([link] and [link]). If you have ever been to a doctor who held up a finger and asked you to follow it up, down, and to both sides, the doctor is checking to make sure your eye muscles are acting in a coordinated pattern.

Muscles That Move the Lower Jaw

In anatomical terminology, chewing is called mastication. Muscles involved in chewing must be able to exert enough pressure to bite through and then chew food before it is swallowed ([link] and [link]). The masseter muscle is the main muscle used for chewing because it elevates the mandible (lower jaw) to close the mouth, and it is assisted by the temporalis muscle, which retracts the mandible. You can feel the temporalis move by putting your fingers to your temple as you chew.

Muscles That Move the Tongue

Although the tongue is obviously important for tasting food, it is also necessary for mastication, deglutition (swallowing), and speech ([link] and [link]). Because it is so moveable, the tongue facilitates complex speech patterns and sounds.

Muscles of the Anterior Neck

The muscles of the anterior neck assist in deglutition (swallowing) and speech by controlling the positions of the larynx (voice box), and the hyoid bone, a horseshoe-shaped bone that functions as a solid foundation on which the tongue can move. The muscles of the neck are categorized according to their position relative to the hyoid bone ([link]). Suprahyoid muscles are superior to it, and the infrahyoid muscles are located inferiorly.

Muscles That Move the Head

The head, attached to the top of the vertebral column, is balanced, moved, and rotated by the neck muscles ([link]). When these muscles act unilaterally, the head rotates. When they contract bilaterally, the head flexes or extends. The major muscle that laterally flexes and rotates the head is the sternocleidomastoid. In addition, both muscles working together are the flexors of the head. Place your fingers on both sides of the neck and turn your head to the left and to the right. You will feel the movement originate there. This muscle divides the neck into anterior and posterior triangles when viewed from the side ([link]).

Muscles of the Posterior Neck and the Back

The posterior muscles of the neck are primarily concerned with head movements, like extension. The back muscles stabilize and move the vertebral column, and are grouped according to the lengths and direction of the fascicles.

Axial Muscles of the Abdominal Wall, and Thorax

Abstract:
By the end of this section, you will be able to:

* Identify the intrinsic skeletal muscles of the back and neck, and the skeletal muscles of the abdominal wall and thorax
* Identify the movement and function of the intrinsic skeletal muscles of the back and neck, and the skeletal muscles of the abdominal wall and thorax

Muscles of the Abdomen

There are four pairs of abdominal muscles that cover the anterior and lateral abdominal region and meet at the anterior midline. These muscles of the anterolateral abdominal wall can be divided into four groups: the external obliques, the internal obliques, the transversus abdominis, and the rectus abdominis ([link] and [link]).

Muscles of the Thorax

The muscles of the chest serve to facilitate breathing by changing the size of the thoracic cavity ([link]). When you inhale, your chest rises because the cavity expands. Alternately, when you exhale, your chest falls because the thoracic cavity decreases in size.

Muscles of the Pelvic Floor and Perineum

The pelvic floor is a muscular sheet that defines the inferior portion of the pelvic cavity. The pelvic diaphragm, spanning anteriorly to posteriorly from the pubis to the coccyx, comprises the levator ani and the ischiococcygeus. Its openings include the anal canal and urethra, and the vagina in females.

Muscles of the Pectoral Girdle and Upper Limbs

Abstract:
By the end of this section, you will be able to:

* Identify the muscles of the pectoral girdle and upper limbs
* Identify the movement and function of the pectoral girdle and upper limbs

Muscles That Position the Pectoral Girdle

Muscles that position the pectoral girdle are located either on the anterior thorax or on the posterior thorax ([link] and [link]). The anterior muscles include the subclavius, pectoralis minor, and serratus anterior. The posterior muscles include the trapezius, rhomboid major, and rhomboid minor. When the rhomboids are contracted, your scapula moves medially, which can pull the shoulder and upper limb posteriorly.

Muscles That Move the Humerus

Similar to the muscles that position the pectoral girdle, muscles that cross the shoulder joint and move the humerus bone of the arm include both axial and scapular muscles ([link] and [link]). The two axial muscles are the pectoralis major and the latissimus dorsi. The pectoralis major is thick and fan-shaped, covering much of the superior portion of the anterior thorax. The broad, triangular latissimus dorsi is located on the inferior part of the back, where it inserts into a thick connective tissue sheath called an aponeurosis.

Muscles That Move the Forearm

The forearm, made of the radius and ulna bones, has four main types of action at the hinge of the elbow joint: flexion, extension, pronation, and supination. The forearm flexors include the biceps brachii, brachialis, and brachioradialis. The extensors are the triceps brachii and anconeus. The pronators are the pronator teres and the pronator quadratus, and the supinator is the only one that turns the forearm anteriorly. When the forearm faces anteriorly, it is supinated. When the forearm faces posteriorly, it is pronated.

Muscles That Move the Wrist, Hand, and Fingers

Wrist, hand, and finger movements are facilitated by two groups of muscles. The forearm is the origin of the extrinsic muscles of the hand. The palm is the origin of the intrinsic muscles of the hand.

Appendicular Muscles of the Pelvic Girdle and Lower Limbs

Abstract:
By the end of this section, you will be able to:

* Identify the appendicular muscles of the pelvic girdle and lower limb
* Identify the movement and function of the pelvic girdle and lower limb

Muscles of the Thigh

What would happen if the pelvic girdle, which attaches the lower limbs to the torso, were capable of the same range of motion as the pectoral girdle? For one thing, walking would expend more energy if the heads of the femurs were not secured in the acetabula of the pelvis. The body’s center of gravity is in the area of the pelvis. If the center of gravity were not to remain fixed, standing up would be difficult as well. Therefore, what the leg muscles lack in range of motion and versatility, they make up for in size and power, facilitating the body’s stabilization, posture, and movement.

Muscles That Move the Feet and Toes

Similar to the thigh muscles, the muscles of the leg are divided by deep fascia into compartments, although the leg has three: anterior, lateral, and posterior ([link] and [link]).

Regulation, Integration, and Control

The Nervous System and Nervous Tissue

Introduction

Basic Structure and Function of the Nervous System

Abstract:
By the end of this section, you will be able to:

* Identify the anatomical and functional divisions of the nervous system
* Relate the functional and structural differences between gray matter and white matter structures of the nervous system to the structure of neurons
* List the basic functions of the nervous system

The Central and Peripheral Nervous Systems

The nervous system can be divided into two major regions: the central and peripheral nervous systems. The central nervous system (CNS) is the brain and spinal cord, and the peripheral nervous system (PNS) is everything else ([link]). The brain is contained within the cranial cavity of the skull, and the spinal cord is contained within the vertebral cavity of the vertebral column. It is a bit of an oversimplification to say that the CNS is what is inside these two cavities and the peripheral nervous system is outside of them, but that is one way to start to think about it. In actuality, there are some elements of the peripheral nervous system that are within the cranial or vertebral cavities. The peripheral nervous system is so named because it is on the periphery—meaning beyond the brain and spinal cord. Depending on different aspects of the nervous system, the dividing line between central and peripheral is not necessarily universal.

Functional Divisions of the Nervous System

The nervous system can also be divided on the basis of its functions, but anatomical divisions and functional divisions are different. The CNS and the PNS both contribute to the same functions, but those functions can be attributed to different regions of the brain (such as the cerebral cortex or the hypothalamus) or to different ganglia in the periphery. The problem with trying to fit functional differences into anatomical divisions is that sometimes the same structure can be part of several functions. For example, the optic nerve carries signals from the retina that are either used for the conscious perception of visual stimuli, which takes place in the cerebral cortex, or for the reflexive responses of smooth muscle tissue that are processed through the hypothalamus.

Nervous Tissue

Abstract:
By the end of this section, you will be able to:

* Describe the basic structure of a neuron
* Identify the different types of neurons on the basis of polarity
* List the glial cells of the CNS and describe their function
* List the glial cells of the PNS and describe their function

Neurons

Neurons are the cells considered to be the basis of nervous tissue. They are responsible for the electrical signals that communicate information about sensations, and that produce movements in response to those stimuli, along with inducing thought processes within the brain. An important part of the function of neurons is in their structure, or shape. The three-dimensional shape of these cells makes the immense numbers of connections within the nervous system possible.

Glial Cells

Glial cells, or neuroglia or simply glia, are the other type of cell found in nervous tissue. They are considered to be supporting cells, and many functions are directed at helping neurons complete their function for communication. The name glia comes from the Greek word that means “glue,” and was coined by the German pathologist Rudolph Virchow, who wrote in 1856: “This connective substance, which is in the brain, the spinal cord, and the special sense nerves, is a kind of glue (neuroglia) in which the nervous elements are planted.” Today, research into nervous tissue has shown that there are many deeper roles that these cells play. And research may find much more about them in the future.

The Function of Nervous Tissue

Abstract:
By the end of this section, you will be able to:

* Distinguish the major functions of the nervous system: sensation, integration, and response
* List the sequence of events in a simple sensory receptor–motor response pathway

The Action Potential

Abstract:
By the end of this section, you will be able to:

* Describe the components of the membrane that establish the resting membrane potential
* Describe the changes that occur to the membrane that result in the action potential

Electrically Active Cell Membranes

Most cells in the body make use of charged particles, ions, to build up a charge across the cell membrane. Previously, this was shown to be a part of how muscle cells work. For skeletal muscles to contract, based on excitation–contraction coupling, requires input from a neuron. Both of the cells make use of the cell membrane to regulate ion movement between the extracellular fluid and cytosol.

The Membrane Potential

The electrical state of the cell membrane can have several variations. These are all variations in the membrane potential. A potential is a distribution of charge across the cell membrane, measured in millivolts (mV). The standard is to compare the inside of the cell relative to the outside, so the membrane potential is a value representing the charge on the intracellular side of the membrane based on the outside being zero, relatively speaking ([link]).

Communication Between Neurons

Abstract:
By the end of this section, you will be able to:

* Explain the differences between the types of graded potentials
* Categorize the major neurotransmitters by chemical type and effect

Graded Potentials

Local changes in the membrane potential are called graded potentials and are usually associated with the dendrites of a neuron. The amount of change in the membrane potential is determined by the size of the stimulus that causes it. In the example of testing the temperature of the shower, slightly warm water would only initiate a small change in a thermoreceptor, whereas hot water would cause a large amount of change in the membrane potential.

Synapses

There are two types of connections between electrically active cells, chemical synapses and electrical synapses. In a chemical synapse, a chemical signal—namely, a neurotransmitter—is released from one cell and it affects the other cell. In an electrical synapse, there is a direct connection between the two cells so that ions can pass directly from one cell to the next. If one cell is depolarized in an electrical synapse, the joined cell also depolarizes because the ions pass between the cells. Chemical synapses involve the transmission of chemical information from one cell to the next. This section will concentrate on the chemical type of synapse.

Anatomy of the Nervous System

Introduction

The Embryologic Perspective

Abstract:
By the end of this section, you will be able to:

* Describe the growth and differentiation of the neural tube
* Relate the different stages of development to the adult structures of the central nervous system
* Explain the expansion of the ventricular system of the adult brain from the central canal of the neural tube
* Describe the connections of the diencephalon and cerebellum on the basis of patterns of embryonic development

The Neural Tube

To begin, a sperm cell and an egg cell fuse to become a fertilized egg. The fertilized egg cell, or zygote, starts dividing to generate the cells that make up an entire organism. Sixteen days after fertilization, the developing embryo’s cells belong to one of three germ layers that give rise to the different tissues in the body. The endoderm, or inner tissue, is responsible for generating the lining tissues of various spaces within the body, such as the mucosae of the digestive and respiratory systems. The mesoderm, or middle tissue, gives rise to most of the muscle and connective tissues. Finally the ectoderm, or outer tissue, develops into the integumentary system (the skin) and the nervous system. It is probably not difficult to see that the outer tissue of the embryo becomes the outer covering of the body. But how is it responsible for the nervous system?

Primary Vesicles

As the anterior end of the neural tube starts to develop into the brain, it undergoes a couple of enlargements; the result is the production of sac-like vesicles. Similar to a child’s balloon animal, the long, straight neural tube begins to take on a new shape. Three vesicles form at the first stage, which are called primary vesicles. These vesicles are given names that are based on Greek words, the main root word being *enkephalon*, which means “brain” (en- = “inside”; kephalon = “head”). The prefix to each generally corresponds to its position along the length of the developing nervous system.

Secondary Vesicles

The brain continues to develop, and the vesicles differentiate further (see [link]**b**). The three primary vesicles become five secondary vesicles. The prosencephalon enlarges into two new vesicles called the telencephalon and the diencephalon. The telecephalon will become the cerebrum. The diencephalon gives rise to several adult structures; two that will be important are the thalamus and the hypothalamus. In the embryonic diencephalon, a structure known as the eye cup develops, which will eventually become the retina, the nervous tissue of the eye called the retina. This is a rare example of nervous tissue developing as part of the CNS structures in the embryo, but becoming a peripheral structure in the fully formed nervous system.

Spinal Cord Development

While the brain is developing from the anterior neural tube, the spinal cord is developing from the posterior neural tube. However, its structure does not differ from the basic layout of the neural tube. It is a long, straight cord with a small, hollow space down the center. The neural tube is defined in terms of its anterior versus posterior portions, but it also has a dorsal–ventral dimension. As the neural tube separates from the rest of the ectoderm, the side closest to the surface is dorsal, and the deeper side is ventral.

Relating Embryonic Development to the Adult Brain

Embryonic development can help in understanding the structure of the adult brain because it establishes a framework on which more complex structures can be built. First, the neural tube establishes the anterior–posterior dimension of the nervous system, which is called the neuraxis. The embryonic nervous system in mammals can be said to have a standard arrangement. Humans (and other primates, to some degree) make this complicated by standing up and walking on two legs. The anterior–posterior dimension of the neuraxis overlays the superior–inferior dimension of the body. However, there is a major curve between the brain stem and forebrain, which is called the cephalic flexure. Because of this, the neuraxis starts in an inferior position—the end of the spinal cord—and ends in an anterior position, the front of the cerebrum. If this is confusing, just imagine a four-legged animal standing up on two legs. Without the flexure in the brain stem, and at the top of the neck, that animal would be looking straight up instead of straight in front ([link]).

The Central Nervous System

Abstract:
By the end of this section, you will be able to:

* Name the major regions of the adult brain
* Describe the connections between the cerebrum and brain stem through the diencephalon, and from those regions into the spinal cord
* Recognize the complex connections within the subcortical structures of the basal nuclei
* Explain the arrangement of gray and white matter in the spinal cord

The Cerebrum

The iconic gray mantle of the human brain, which appears to make up most of the mass of the brain, is the cerebrum ([link]). The wrinkled portion is the cerebral cortex, and the rest of the structure is beneath that outer covering. There is a large separation between the two sides of the cerebrum called the longitudinal fissure. It separates the cerebrum into two distinct halves, a right and left cerebral hemisphere. Deep within the cerebrum, the white matter of the corpus callosum provides the major pathway for communication between the two hemispheres of the cerebral cortex.

The Diencephalon

The diencephalon is the one region of the adult brain that retains its name from embryologic development. The etymology of the word diencephalon translates to “through brain.” It is the connection between the cerebrum and the rest of the nervous system, with one exception. The rest of the brain, the spinal cord, and the PNS all send information to the cerebrum through the diencephalon. Output from the cerebrum passes through the diencephalon. The single exception is the system associated with olfaction, or the sense of smell, which connects directly with the cerebrum. In the earliest vertebrate species, the cerebrum was not much more than olfactory bulbs that received peripheral information about the chemical environment (to call it smell in these organisms is imprecise because they lived in the ocean).

Brain Stem

The midbrain and hindbrain (composed of the pons and the medulla) are collectively referred to as the brain stem ([link]). The structure emerges from the ventral surface of the forebrain as a tapering cone that connects the brain to the spinal cord. Attached to the brain stem, but considered a separate region of the adult brain, is the cerebellum. The midbrain coordinates sensory representations of the visual, auditory, and somatosensory perceptual spaces. The pons is the main connection with the cerebellum. The pons and the medulla regulate several crucial functions, including the cardiovascular and respiratory systems and rates.

The Cerebellum

The cerebellum, as the name suggests, is the “little brain.” It is covered in gyri and sulci like the cerebrum, and looks like a miniature version of that part of the brain ([link]). The cerebellum is largely responsible for comparing information from the cerebrum with sensory feedback from the periphery through the spinal cord. It accounts for approximately 10 percent of the mass of the brain.

The Spinal Cord

The description of the CNS is concentrated on the structures of the brain, but the spinal cord is another major organ of the system. Whereas the brain develops out of expansions of the neural tube into primary and then secondary vesicles, the spinal cord maintains the tube structure and is only specialized into certain regions. As the spinal cord continues to develop in the newborn, anatomical features mark its surface. The anterior midline is marked by the anterior median fissure, and the posterior midline is marked by the posterior median sulcus. Axons enter the posterior side through the dorsal (posterior) nerve root, which marks the posterolateral sulcus on either side. The axons emerging from the anterior side do so through the ventral (anterior) nerve root. Note that it is common to see the terms dorsal (dorsal = “back”) and ventral (ventral = “belly”) used interchangeably with posterior and anterior, particularly in reference to nerves and the structures of the spinal cord. You should learn to be comfortable with both.

Circulation and the Central Nervous System

Abstract:
By the end of this section, you will be able to:

* Describe the vessels that supply the CNS with blood
* Name the components of the ventricular system and the regions of the brain in which each is located
* Explain the production of cerebrospinal fluid and its flow through the ventricles
* Explain how a disruption in circulation would result in a stroke

Blood Supply to the Brain

A lack of oxygen to the CNS can be devastating, and the cardiovascular system has specific regulatory reflexes to ensure that the blood supply is not interrupted. There are multiple routes for blood to get into the CNS, with specializations to protect that blood supply and to maximize the ability of the brain to get an uninterrupted perfusion.

Protective Coverings of the Brain and Spinal Cord

The outer surface of the CNS is covered by a series of membranes composed of connective tissue called the meninges, which protect the brain. The dura mater is a thick fibrous layer and a strong protective sheath over the entire brain and spinal cord. It is anchored to the inner surface of the cranium and vertebral cavity. The arachnoid mater is a membrane of thin fibrous tissue that forms a loose sac around the CNS. Beneath the arachnoid is a thin, filamentous mesh called the arachnoid trabeculae, which looks like a spider web, giving this layer its name. Directly adjacent to the surface of the CNS is the pia mater, a thin fibrous membrane that follows the convolutions of gyri and sulci in the cerebral cortex and fits into other grooves and indentations ([link]).

The Ventricular System

Cerebrospinal fluid (CSF) circulates throughout and around the CNS. In other tissues, water and small molecules are filtered through capillaries as the major contributor to the interstitial fluid. In the brain, CSF is produced in special structures to perfuse through the nervous tissue of the CNS and is continuous with the interstitial fluid. Specifically, CSF circulates to remove metabolic wastes from the interstitial fluids of nervous tissues and return them to the blood stream. The ventricles are the open spaces within the brain where CSF circulates. In some of these spaces, CSF is produced by filtering of the blood that is performed by a specialized membrane known as a choroid plexus. The CSF circulates through all of the ventricles to eventually emerge into the subarachnoid space where it will be reabsorbed into the blood.

The Peripheral Nervous System

Abstract:
By the end of this section, you will be able to:

* Describe the structures found in the PNS
* Distinguish between somatic and autonomic structures, including the special peripheral structures of the enteric nervous system
* Name the twelve cranial nerves and explain the functions associated with each
* Describe the sensory and motor components of spinal nerves and the plexuses that they pass through

Ganglia

A ganglion is a group of neuron cell bodies in the periphery. Ganglia can be categorized, for the most part, as either sensory ganglia or autonomic ganglia, referring to their primary functions. The most common type of sensory ganglion is a dorsal (posterior) root ganglion. These ganglia are the cell bodies of neurons with axons that are sensory endings in the periphery, such as in the skin, and that extend into the CNS through the dorsal nerve root. The ganglion is an enlargement of the nerve root. Under microscopic inspection, it can be seen to include the cell bodies of the neurons, as well as bundles of fibers that are the posterior nerve root ([link]). The cells of the dorsal root ganglion are unipolar cells, classifying them by shape. Also, the small round nuclei of satellite cells can be seen surrounding—as if they were orbiting—the neuron cell bodies.

Nerves

Bundles of axons in the PNS are referred to as nerves. These structures in the periphery are different than the central counterpart, called a tract. Nerves are composed of more than just nervous tissue. They have connective tissues invested in their structure, as well as blood vessels supplying the tissues with nourishment. The outer surface of a nerve is a surrounding layer of fibrous connective tissue called the epineurium. Within the nerve, axons are further bundled into fascicles, which are each surrounded by their own layer of fibrous connective tissue called perineurium. Finally, individual axons are surrounded by loose connective tissue called the endoneurium ([link]). These three layers are similar to the connective tissue sheaths for muscles. Nerves are associated with the region of the CNS to which they are connected, either as cranial nerves connected to the brain or spinal nerves connected to the spinal cord.

The Somatic Nervous System

Introduction

Sensory Perception

Abstract:
By the end of this section, you will be able to:

* Describe different types of sensory receptors
* Describe the structures responsible for the special senses of taste, smell, hearing, balance, and vision
* Distinguish how different tastes are transduced
* Describe the means of mechanoreception for hearing and balance
* List the supporting structures around the eye and describe the structure of the eyeball
* Describe the processes of phototransduction

Sensory Receptors

Stimuli in the environment activate specialized receptor cells in the peripheral nervous system. Different types of stimuli are sensed by different types of receptor cells. Receptor cells can be classified into types on the basis of three different criteria: cell type, position, and function. Receptors can be classified structurally on the basis of cell type and their position in relation to stimuli they sense. They can also be classified functionally on the basis of the transduction of stimuli, or how the mechanical stimulus, light, or chemical changed the cell membrane potential.

Sensory Modalities

Ask anyone what the senses are, and they are likely to list the five major senses—taste, smell, touch, hearing, and sight. However, these are not all of the senses. The most obvious omission from this list is balance. Also, what is referred to simply as touch can be further subdivided into pressure, vibration, stretch, and hair-follicle position, on the basis of the type of mechanoreceptors that perceive these touch sensations. Other overlooked senses include temperature perception by thermoreceptors and pain perception by nociceptors.

Sensory Nerves

Once any sensory cell transduces a stimulus into a nerve impulse, that impulse has to travel along axons to reach the CNS. In many of the special senses, the axons leaving the sensory receptors have a topographical arrangement, meaning that the location of the sensory receptor relates to the location of the axon in the nerve. For example, in the retina, axons from RGCs in the fovea are located at the center of the optic nerve, where they are surrounded by axons from the more peripheral RGCs.

Central Processing

Abstract:
By the end of this section, you will be able to:

* Describe the pathways that sensory systems follow into the central nervous system
* Differentiate between the two major ascending pathways in the spinal cord
* Describe the pathway of somatosensory input from the face and compare it to the ascending pathways in the spinal cord
* Explain topographical representations of sensory information in at least two systems
* Describe two pathways of visual processing and the functions associated with each

Sensory Pathways

Specific regions of the CNS coordinate different somatic processes using sensory inputs and motor outputs of peripheral nerves. A simple case is a reflex caused by a synapse between a dorsal sensory neuron axon and a motor neuron in the ventral horn. More complex arrangements are possible to integrate peripheral sensory information with higher processes. The important regions of the CNS that play a role in somatic processes can be separated into the spinal cord brain stem, diencephalon, cerebral cortex, and subcortical structures.

Cortical Processing

As described earlier, many of the sensory axons are positioned in the same way as their corresponding receptor cells in the body. This allows identification of the position of a stimulus on the basis of which receptor cells are sending information. The cerebral cortex also maintains this sensory topography in the particular areas of the cortex that correspond to the position of the receptor cells. The somatosensory cortex provides an example in which, in essence, the locations of the somatosensory receptors in the body are mapped onto the somatosensory cortex. This mapping is often depicted using a sensory homunculus ([link]).

Motor Responses

Abstract:
By the end of this section, you will be able to:

* List the components of the basic processing stream for the motor system
* Describe the pathway of descending motor commands from the cortex to the skeletal muscles
* Compare different descending pathways, both by structure and function
* Explain the initiation of movement from the neurological connections
* Describe several reflex arcs and their functional roles

Cortical Responses

Let’s start with sensory stimuli that have been registered through receptor cells and the information relayed to the CNS along ascending pathways. In the cerebral cortex, the initial processing of sensory perception progresses to associative processing and then integration in multimodal areas of cortex. These levels of processing can lead to the incorporation of sensory perceptions into memory, but more importantly, they lead to a response. The completion of cortical processing through the primary, associative, and integrative sensory areas initiates a similar progression of motor processing, usually in different cortical areas.

Descending Pathways

The motor output from the cortex descends into the brain stem and to the spinal cord to control the musculature through motor neurons. Neurons located in the primary motor cortex, named Betz cells, are large cortical neurons that synapse with lower motor neurons in the brain stem or in the spinal cord. The two descending pathways travelled by the axons of Betz cells are the corticobulbar tract and the corticospinal tract, respectively. Both tracts are named for their origin in the cortex and their targets—either the brain stem (the term “bulbar” refers to the brain stem as the bulb, or enlargement, at the top of the spinal cord) or the spinal cord.

Extrapyramidal Controls

Other descending connections between the brain and the spinal cord are called the extrapyramidal system. The name comes from the fact that this system is outside the corticospinal pathway, which includes the pyramids in the medulla. A few pathways originating from the brain stem contribute to this system.

Ventral Horn Output

The somatic nervous system provides output strictly to skeletal muscles. The lower motor neurons, which are responsible for the contraction of these muscles, are found in the ventral horn of the spinal cord. These large, multipolar neurons have a corona of dendrites surrounding the cell body and an axon that extends out of the ventral horn. This axon travels through the ventral nerve root to join the emerging spinal nerve. The axon is relatively long because it needs to reach muscles in the periphery of the body. The diameters of cell bodies may be on the order of hundreds of micrometers to support the long axon; some axons are a meter in length, such as the lumbar motor neurons that innervate muscles in the first digits of the feet.

Reflexes

This chapter began by introducing reflexes as an example of the basic elements of the somatic nervous system. Simple somatic reflexes do not include the higher centers discussed for conscious or voluntary aspects of movement. Reflexes can be spinal or cranial, depending on the nerves and central components that are involved. The example described at the beginning of the chapter involved heat and pain sensations from a hot stove causing withdrawal of the arm through a connection in the spinal cord that leads to contraction of the biceps brachii. The description of this withdrawal reflex was simplified, for the sake of the introduction, to emphasize the parts of the somatic nervous system. But to consider reflexes fully, more attention needs to be given to this example.

The Autonomic Nervous System

Introduction

Divisions of the Autonomic Nervous System

Abstract:
By the end of this section, you will be able to:

* Name the components that generate the sympathetic and parasympathetic responses of the autonomic nervous system
* Explain the differences in output connections within the two divisions of the autonomic nervous system
* Describe the signaling molecules and receptor proteins involved in communication within the two divisions of the autonomic nervous system

Sympathetic Division of the Autonomic Nervous System

To respond to a threat—to fight or to run away—the sympathetic system causes divergent effects as many different effector organs are activated together for a common purpose. More oxygen needs to be inhaled and delivered to skeletal muscle. The respiratory, cardiovascular, and musculoskeletal systems are all activated together. Additionally, sweating keeps the excess heat that comes from muscle contraction from causing the body to overheat. The digestive system shuts down so that blood is not absorbing nutrients when it should be delivering oxygen to skeletal muscles. To coordinate all these responses, the connections in the sympathetic system diverge from a limited region of the central nervous system (CNS) to a wide array of ganglia that project to the many effector organs simultaneously. The complex set of structures that compose the output of the sympathetic system make it possible for these disparate effectors to come together in a coordinated, systemic change.

Parasympathetic Division of the Autonomic Nervous System

The parasympathetic system can also be referred to as the craniosacral system (or outflow) because the preganglionic neurons are located in nuclei of the brain stem and the lateral horn of the sacral spinal cord.

Chemical Signaling in the Autonomic Nervous System

Where an autonomic neuron connects with a target, there is a synapse. The electrical signal of the action potential causes the release of a signaling molecule, which will bind to receptor proteins on the target cell. Synapses of the autonomic system are classified as either cholinergic, meaning that acetylcholine (ACh) is released, or adrenergic, meaning that norepinephrine is released. The terms cholinergic and adrenergic refer not only to the signaling molecule that is released but also to the class of receptors that each binds.

Autonomic Reflexes and Homeostasis

Abstract:
By the end of this section, you will be able to:

* Compare the structure of somatic and autonomic reflex arcs
* Explain the differences in sympathetic and parasympathetic reflexes
* Differentiate between short and long reflexes
* Determine the effect of the autonomic nervous system on the regulation of the various organ systems on the basis of the signaling molecules involved
* Describe the effects of drugs that affect autonomic function

The Structure of Reflexes

One difference between a somatic reflex, such as the withdrawal reflex, and a visceral reflex, which is an autonomic reflex, is in the efferent branch. The output of a somatic reflex is the lower motor neuron in the ventral horn of the spinal cord that projects directly to a skeletal muscle to cause its contraction. The output of a visceral reflex is a two-step pathway starting with the preganglionic fiber emerging from a lateral horn neuron in the spinal cord, or a cranial nucleus neuron in the brain stem, to a ganglion—followed by the postganglionic fiber projecting to a target effector. The other part of a reflex, the afferent branch, is often the same between the two systems. Sensory neurons receiving input from the periphery—with cell bodies in the sensory ganglia, either of a cranial nerve or a dorsal root ganglion adjacent to the spinal cord—project into the CNS to initiate the reflex ([link]). The Latin root “effere” means “to carry.” Adding the prefix “ef-” suggests the meaning “to carry away,” whereas adding the prefix “af-” suggests “to carry toward or inward.”

Balance in Competing Autonomic Reflex Arcs

The autonomic nervous system is important for homeostasis because its two divisions compete at the target effector. The balance of homeostasis is attributable to the competing inputs from the sympathetic and parasympathetic divisions (dual innervation). At the level of the target effector, the signal of which system is sending the message is strictly chemical. A signaling molecule binds to a receptor that causes changes in the target cell, which in turn causes the tissue or organ to respond to the changing conditions of the body.

Central Control

Abstract:
By the end of this section, you will be able to:

* Describe the role of higher centers of the brain in autonomic regulation
* Explain the connection of the hypothalamus to homeostasis
* Describe the regions of the CNS that link the autonomic system with emotion
* Describe the pathways important to descending control of the autonomic system

Forebrain Structures

Autonomic control is based on the visceral reflexes, composed of the afferent and efferent branches. These homeostatic mechanisms are based on the balance between the two divisions of the autonomic system, which results in tone for various organs that is based on the predominant input from the sympathetic or parasympathetic systems. Coordinating that balance requires integration that begins with forebrain structures like the hypothalamus and continues into the brain stem and spinal cord.

The Medulla

The medulla contains nuclei referred to as the cardiovascular center, which controls the smooth and cardiac muscle of the cardiovascular system through autonomic connections. When the homeostasis of the cardiovascular system shifts, such as when blood pressure changes, the coordination of the autonomic system can be accomplished within this region. Furthermore, when descending inputs from the hypothalamus stimulate this area, the sympathetic system can increase activity in the cardiovascular system, such as in response to anxiety or stress. The preganglionic sympathetic fibers that are responsible for increasing heart rate are referred to as the cardiac accelerator nerves, whereas the preganglionic sympathetic fibers responsible for constricting blood vessels compose the vasomotor nerves.

Drugs that Affect the Autonomic System

Abstract:
By the end of this section, you will be able to:

* List the classes of pharmaceuticals that interact with the autonomic nervous system
* Differentiate between cholinergic and adrenergic compounds
* Differentiate between sympathomimetic and sympatholytic drugs
* Relate the consequences of nicotine abuse with respect to autonomic control of the cardiovascular system

Broad Autonomic Effects

One important drug that affects the autonomic system broadly is not a pharmaceutical therapeutic agent associated with the system. This drug is nicotine. The effects of nicotine on the autonomic nervous system are important in considering the role smoking can play in health.

Sympathetic Effect

The neurochemistry of the sympathetic system is based on the adrenergic system. Norepinephrine and epinephrine influence target effectors by binding to the α-adrenergic or β-adrenergic receptors. Drugs that affect the sympathetic system affect these chemical systems. The drugs can be classified by whether they enhance the functions of the sympathetic system or interrupt those functions. A drug that enhances adrenergic function is known as a sympathomimetic drug, whereas a drug that interrupts adrenergic function is a sympatholytic drug.

Parasympathetic Effects

Drugs affecting parasympathetic functions can be classified into those that increase or decrease activity at postganglionic terminals. Parasympathetic postganglionic fibers release ACh, and the receptors on the targets are muscarinic receptors. There are several types of muscarinic receptors, M1–M5, but the drugs are not usually specific to the specific types. Parasympathetic drugs can be either muscarinic agonists or antagonists, or have indirect effects on the cholinergic system. Drugs that enhance cholinergic effects are called parasympathomimetic drugs, whereas those that inhibit cholinergic effects are referred to as anticholinergic drugs.

The Neurological Exam

Introduction

Overview of the Neurological Exam

Abstract:
By the end of this section, you will be able to:

* List the major sections of the neurological exam
* Explain the connection between location and function in the nervous system
* Explain the benefit of a rapid assessment for neurological function in a clinical setting
* List the causes of neurological deficits
* Describe the different ischemic events in the nervous system

Neuroanatomy and the Neurological Exam

Localization of function is the concept that circumscribed locations are responsible for specific functions. The neurological exam highlights this relationship. For example, the cognitive functions that are assessed in the mental status exam are based on functions in the cerebrum, mostly in the cerebral cortex. Several of the subtests examine language function. Deficits in neurological function uncovered by these examinations usually point to damage to the left cerebral cortex. In the majority of individuals, language function is localized to the left hemisphere between the superior temporal lobe and the posterior frontal lobe, including the intervening connections through the inferior parietal lobe.

Causes of Neurological Deficits

Damage to the nervous system can be limited to individual structures or can be distributed across broad areas of the brain and spinal cord. Localized, limited injury to the nervous system is most often the result of circulatory problems. Neurons are very sensitive to oxygen deprivation and will start to deteriorate within 1 or 2 minutes, and permanent damage (cell death) could result within a few hours. The loss of blood flow to part of the brain is known as a stroke, or a cerebrovascular accident (CVA).

The Mental Status Exam

Abstract:
By the end of this section, you will be able to:

* Describe the relationship of mental status exam results to cerebral functions
* Explain the categorization of regions of the cortex based on anatomy and physiology
* Differentiate between primary, association, and integration areas of the cerebral cortex
* Provide examples of localization of function related to the cerebral cortex

Functions of the Cerebral Cortex

The cerebrum is the seat of many of the higher mental functions, such as memory and learning, language, and conscious perception, which are the subjects of subtests of the mental status exam. The cerebral cortex is the thin layer of gray matter on the outside of the cerebrum. On average, it is approximately 2.55 mm thick and highly folded to fit within the limited space of the cranial vault. These higher functions are distributed across various regions of the cortex, and specific locations can be said to be responsible for particular functions. There is a limited set of regions, for example, that are involved in language function, and they can be subdivided on the basis of the particular part of language function that each governs.

Cognitive Abilities

Assessment of cerebral functions is directed at cognitive abilities. The abilities assessed through the mental status exam can be separated into four groups: orientation and memory, language and speech, sensorium, and judgment and abstract reasoning.

The Cranial Nerve Exam

Abstract:
By the end of this section, you will be able to:

* Describe the functional grouping of cranial nerves
* Match the regions of the forebrain and brain stem that are connected to each cranial nerve
* Suggest diagnoses that would explain certain losses of function in the cranial nerves
* Relate cranial nerve deficits to damage of adjacent, unrelated structures

Sensory Nerves

The olfactory, optic, and vestibulocochlear nerves (cranial nerves I, II, and VIII) are dedicated to four of the special senses: smell, vision, equilibrium, and hearing, respectively. Taste sensation is relayed to the brain stem through fibers of the facial and glossopharyngeal nerves. The trigeminal nerve is a mixed nerve that carries the general somatic senses from the head, similar to those coming through spinal nerves from the rest of the body.

Gaze Control

The three nerves that control the extraocular muscles are the oculomotor, trochlear, and abducens nerves, which are the third, fourth, and sixth cranial nerves. As the name suggests, the abducens nerve is responsible for abducting the eye, which it controls through contraction of the lateral rectus muscle. The trochlear nerve controls the superior oblique muscle to rotate the eye along its axis in the orbit medially, which is called intorsion, and is a component of focusing the eyes on an object close to the face. The oculomotor nerve controls all the other extraocular muscles, as well as a muscle of the upper eyelid. Movements of the two eyes need to be coordinated to locate and track visual stimuli accurately. When moving the eyes to locate an object in the horizontal plane, or to track movement horizontally in the visual field, the lateral rectus muscle of one eye and medial rectus muscle of the other eye are both active. The lateral rectus is controlled by neurons of the abducens nucleus in the superior medulla, whereas the medial rectus is controlled by neurons in the oculomotor nucleus of the midbrain.

Nerves of the Face and Oral Cavity

An iconic part of a doctor’s visit is the inspection of the oral cavity and pharynx, suggested by the directive to “open your mouth and say ‘ah.’” This is followed by inspection, with the aid of a tongue depressor, of the back of the mouth, or the opening of the oral cavity into the pharynx known as the fauces. Whereas this portion of a medical exam inspects for signs of infection, such as in tonsillitis, it is also the means to test the functions of the cranial nerves that are associated with the oral cavity.

Motor Nerves of the Neck

The accessory nerve, also referred to as the spinal accessory nerve, innervates the sternocleidomastoid and trapezius muscles ([link]). When both the sternocleidomastoids contract, the head flexes forward; individually, they cause rotation to the opposite side. The trapezius can act as an antagonist, causing extension and hyperextension of the neck. These two superficial muscles are important for changing the position of the head. Both muscles also receive input from cervical spinal nerves. Along with the spinal accessory nerve, these nerves contribute to elevating the scapula and clavicle through the trapezius, which is tested by asking the patient to shrug both shoulders, and watching for asymmetry. For the sternocleidomastoid, those spinal nerves are primarily sensory projections, whereas the trapezius also has lateral insertions to the clavicle and scapula, and receives motor input from the spinal cord. Calling the nerve the spinal accessory nerve suggests that it is aiding the spinal nerves. Though that is not precisely how the name originated, it does help make the association between the function of this nerve in controlling these muscles and the role these muscles play in movements of the trunk or shoulders.

The Sensory and Motor Exams

Abstract:
By the end of this section, you will be able to:

* Describe the arrangement of sensory and motor regions in the spinal cord
* Relate damage in the spinal cord to sensory or motor deficits
* Differentiate between upper motor neuron and lower motor neuron diseases
* Describe the clinical indications of common reflexes

Sensory Modalities and Location

The general senses are distributed throughout the body, relying on nervous tissue incorporated into various organs. Somatic senses are incorporated mostly into the skin, muscles, or tendons, whereas the visceral senses come from nervous tissue incorporated into the majority of organs such as the heart or stomach. The somatic senses are those that usually make up the conscious perception of the how the body interacts with the environment. The visceral senses are most often below the limit of conscious perception because they are involved in homeostatic regulation through the autonomic nervous system.

Muscle Strength and Voluntary Movement

The skeletomotor system is largely based on the simple, two-cell projection from the precentral gyrus of the frontal lobe to the skeletal muscles. The corticospinal tract represents the neurons that send output from the primary motor cortex. These fibers travel through the deep white matter of the cerebrum, then through the midbrain and pons, into the medulla where most of them decussate, and finally through the spinal cord white matter in the lateral (crossed fibers) or anterior (uncrossed fibers) columns. These fibers synapse on motor neurons in the ventral horn. The ventral horn motor neurons then project to skeletal muscle and cause contraction. These two cells are termed the upper motor neuron (UMN) and the lower motor neuron (LMN). Voluntary movements require these two cells to be active.

Reflexes

Reflexes combine the spinal sensory and motor components with a sensory input that directly generates a motor response. The reflexes that are tested in the neurological exam are classified into two groups. A deep tendon reflex is commonly known as a stretch reflex (see the chapter on The Somatic Nervous System ), and is elicited by a strong tap to a tendon, such as in the knee-jerk reflex. A superficial reflex is elicited through gentle stimulation of the skin and causes contraction of the associated muscles.

Comparison of Upper and Lower Motor Neuron Damage

Many of the tests of motor function can indicate differences that will address whether damage to the motor system is in the upper or lower motor neurons. Signs that suggest a UMN lesion include muscle weakness, strong deep tendon reflexes, decreased control of movement or slowness, pronator drift, a positive Babinski sign, spasticity, and the clasp-knife response. Spasticity is an excess contraction in resistance to stretch. It can result in hyperflexia, which is when joints are overly flexed. The clasp-knife response occurs when the patient initially resists movement, but then releases, and the joint will quickly flex like a pocket knife closing.

The Coordination and Gait Exams

Abstract:
By the end of this section, you will be able to:

* Explain the relationship between the location of the cerebellum and its function in movement
* Chart the major divisions of the cerebellum
* List the major connections of the cerebellum
* Describe the relationship of the cerebellum to axial and appendicular musculature
* Explain the prevalent causes of cerebellar ataxia

Location and Connections of the Cerebellum

The cerebellum is located in apposition to the dorsal surface of the brain stem, centered on the pons. The name of the pons is derived from its connection to the cerebellum. The word means “bridge” and refers to the thick bundle of myelinated axons that form a bulge on its ventral surface. Those fibers are axons that project from the gray matter of the pons into the contralateral cerebellar cortex. These fibers make up the middle cerebellar peduncle (MCP) and are the major physical connection of the cerebellum to the brain stem ([link]). Two other white matter bundles connect the cerebellum to the other regions of the brain stem. The superior cerebellar peduncle (SCP) is the connection of the cerebellum to the midbrain and forebrain. The inferior cerebellar peduncle (ICP) is the connection to the medulla.

Coordination and Alternating Movement

Testing for cerebellar function is the basis of the coordination exam. The subtests target appendicular musculature, controlling the limbs, and axial musculature for posture and gait. The assessment of cerebellar function will depend on the normal functioning of other systems addressed in previous sections of the neurological exam. Motor control from the cerebrum, as well as sensory input from somatic, visual, and vestibular senses, are important to cerebellar function.

Posture and Gait

Gait can either be considered a separate part of the neurological exam or a subtest of the coordination exam that addresses walking and balance. Testing posture and gait addresses functions of the spinocerebellum and the vestibulocerebellum because both are part of these activities. A subtest called station begins with the patient standing in a normal position to check for the placement of the feet and balance. The patient is asked to hop on one foot to assess the ability to maintain balance and posture during movement. Though the station subtest appears to be similar to the Romberg test, the difference is that the patient’s eyes are open during station. The Romberg test has the patient stand still with the eyes closed. Any changes in posture would be the result of proprioceptive deficits, and the patient is able to recover when they open their eyes.

Ataxia

A movement disorder of the cerebellum is referred to as ataxia. It presents as a loss of coordination in voluntary movements. Ataxia can also refer to sensory deficits that cause balance problems, primarily in proprioception and equilibrium. When the problem is observed in movement, it is ascribed to cerebellar damage. Sensory and vestibular ataxia would likely also present with problems in gait and station.

The Endocrine System

Introduction

An Overview of the Endocrine System

Abstract:
By the end of this section, you will be able to:

* Distinguish the types of intercellular communication, their importance, mechanisms, and effects
* Identify the major organs and tissues of the endocrine system and their location in the body

Neural and Endocrine Signaling

The nervous system uses two types of intercellular communication—electrical and chemical signaling—either by the direct action of an electrical potential, or in the latter case, through the action of chemical neurotransmitters such as serotonin or norepinephrine. Neurotransmitters act locally and rapidly. When an electrical signal in the form of an action potential arrives at the synaptic terminal, they diffuse across the synaptic cleft (the gap between a sending neuron and a receiving neuron or muscle cell). Once the neurotransmitters interact (bind) with receptors on the receiving (post-synaptic) cell, the receptor stimulation is transduced into a response such as continued electrical signaling or modification of cellular response. The target cell responds within milliseconds of receiving the chemical “message”; this response then ceases very quickly once the neural signaling ends. In this way, neural communication enables body functions that involve quick, brief actions, such as movement, sensation, and cognition.In contrast, the endocrine system uses just one method of communication: chemical signaling. These signals are sent by the endocrine organs, which secrete chemicals—the hormone—into the extracellular fluid. Hormones are transported primarily via the bloodstream throughout the body, where they bind to receptors on target cells, inducing a characteristic response. As a result, endocrine signaling requires more time than neural signaling to prompt a response in target cells, though the precise amount of time varies with different hormones. For example, the hormones released when you are confronted with a dangerous or frightening situation, called the fight-or-flight response, occur by the release of adrenal hormones—epinephrine and norepinephrine—within seconds. In contrast, it may take up to 48 hours for target cells to respond to certain reproductive hormones.

Structures of the Endocrine System

The endocrine system consists of cells, tissues, and organs that secrete hormones as a primary or secondary function. The endocrine gland is the major player in this system. The primary function of these ductless glands is to secrete their hormones directly into the surrounding fluid. The interstitial fluid and the blood vessels then transport the hormones throughout the body. The endocrine system includes the pituitary, thyroid, parathyroid, adrenal, and pineal glands ([link]). Some of these glands have both endocrine and non-endocrine functions. For example, the pancreas contains cells that function in digestion as well as cells that secrete the hormones insulin and glucagon, which regulate blood glucose levels. The hypothalamus, thymus, heart, kidneys, stomach, small intestine, liver, skin, ovaries, and testes are other organs that contain cells with endocrine function. Moreover, adipose tissue has long been known to produce hormones, and recent research has revealed that even bone tissue has endocrine functions.

Other Types of Chemical Signaling

In endocrine signaling, hormones secreted into the extracellular fluid diffuse into the blood or lymph, and can then travel great distances throughout the body. In contrast, autocrine signaling takes place within the same cell. An autocrine (auto- = “self”) is a chemical that elicits a response in the same cell that secreted it. Interleukin-1, or IL-1, is a signaling molecule that plays an important role in inflammatory response. The cells that secrete IL-1 have receptors on their cell surface that bind these molecules, resulting in autocrine signaling.

Hormones

Abstract:
By the end of this section, you will be able to:

* Identify the three major classes of hormones on the basis of chemical structure
* Compare and contrast intracellular and cell membrane hormone receptors
* Describe signaling pathways that involve cAMP and IP3
* Identify several factors that influence a target cell’s response
* Discuss the role of feedback loops and humoral, hormonal, and neural stimuli in hormone control

Types of Hormones

The hormones of the human body can be divided into two major groups on the basis of their chemical structure. Hormones derived from amino acids include amines, peptides, and proteins. Those derived from lipids include steroids ([link]). These chemical groups affect a hormone’s distribution, the type of receptors it binds to, and other aspects of its function.

Pathways of Hormone Action

The message a hormone sends is received by a hormone receptor, a protein located either inside the cell or within the cell membrane. The receptor will process the message by initiating other signaling events or cellular mechanisms that result in the target cell’s response. Hormone receptors recognize molecules with specific shapes and side groups, and respond only to those hormones that are recognized. The same type of receptor may be located on cells in different body tissues, and trigger somewhat different responses. Thus, the response triggered by a hormone depends not only on the hormone, but also on the target cell.

Factors Affecting Target Cell Response

You will recall that target cells must have receptors specific to a given hormone if that hormone is to trigger a response. But several other factors influence the target cell response. For example, the presence of a significant level of a hormone circulating in the bloodstream can cause its target cells to decrease their number of receptors for that hormone. This process is called downregulation, and it allows cells to become less reactive to the excessive hormone levels. When the level of a hormone is chronically reduced, target cells engage in upregulation to increase their number of receptors. This process allows cells to be more sensitive to the hormone that is present. Cells can also alter the sensitivity of the receptors themselves to various hormones.

Regulation of Hormone Secretion

To prevent abnormal hormone levels and a potential disease state, hormone levels must be tightly controlled. The body maintains this control by balancing hormone production and degradation. Feedback loops govern the initiation and maintenance of most hormone secretion in response to various stimuli.

The Pituitary Gland and Hypothalamus

Abstract:
By the end of this section, you will be able to:

* Explain the interrelationships of the anatomy and functions of the hypothalamus and the posterior and anterior lobes of the pituitary gland
* Identify the two hormones released from the posterior pituitary, their target cells, and their principal actions
* Identify the six hormones produced by the anterior lobe of the pituitary gland, their target cells, their principal actions, and their regulation by the hypothalamus

Posterior Pituitary

The posterior pituitary is actually an extension of the neurons of the paraventricular and supraoptic nuclei of the hypothalamus. The cell bodies of these regions rest in the hypothalamus, but their axons descend as the hypothalamic–hypophyseal tract within the infundibulum, and end in axon terminals that comprise the posterior pituitary ([link]).

Anterior Pituitary

The anterior pituitary originates from the digestive tract in the embryo and migrates toward the brain during fetal development. There are three regions: the pars distalis is the most anterior, the pars intermedia is adjacent to the posterior pituitary, and the pars tuberalis is a slender “tube” that wraps the infundibulum.

Intermediate Pituitary: Melanocyte-Stimulating Hormone

The cells in the zone between the pituitary lobes secrete a hormone known as melanocyte-stimulating hormone (MSH) that is formed by cleavage of the pro-opiomelanocortin (POMC) precursor protein. Local production of MSH in the skin is responsible for melanin production in response to UV light exposure. The role of MSH made by the pituitary is more complicated. For instance, people with lighter skin generally have the same amount of MSH as people with darker skin. Nevertheless, this hormone is capable of darkening of the skin by inducing melanin production in the skin’s melanocytes. People also show increased MSH production during pregnancy; in combination with estrogens, it can lead to darker skin pigmentation, especially the skin of the areolas and labia minora. [link] is a summary of the pituitary hormones and their principal effects.

The Thyroid Gland

Abstract:
By the end of this section, you will be able to:

* Describe the location and anatomy of the thyroid gland
* Discuss the synthesis of triiodothyronine and thyroxine
* Explain the role of thyroid hormones in the regulation of basal metabolism
* Identify the hormone produced by the parafollicular cells of the thyroid

Synthesis and Release of Thyroid Hormones

Hormones are produced in the colloid when atoms of the mineral iodine attach to a glycoprotein, called thyroglobulin, that is secreted into the colloid by the follicle cells. The following steps outline the hormones’ assembly:

Regulation of TH Synthesis

The release of T3 and T4 from the thyroid gland is regulated by thyroid-stimulating hormone (TSH). As shown in [link], low blood levels of T3 and T4 stimulate the release of thyrotropin-releasing hormone (TRH) from the hypothalamus, which triggers secretion of TSH from the anterior pituitary. In turn, TSH stimulates the thyroid gland to secrete T3 and T4. The levels of TRH, TSH, T3, and T4 are regulated by a negative feedback system in which increasing levels of T3 and T4 decrease the production and secretion of TSH.

Functions of Thyroid Hormones

The thyroid hormones, T3 and T4, are often referred to as metabolic hormones because their levels influence the body’s basal metabolic rate, the amount of energy used by the body at rest. When T3 and T4 bind to intracellular receptors located on the mitochondria, they cause an increase in nutrient breakdown and the use of oxygen to produce ATP. In addition, T3 and T4 initiate the transcription of genes involved in glucose oxidation. Although these mechanisms prompt cells to produce more ATP, the process is inefficient, and an abnormally increased level of heat is released as a byproduct of these reactions. This so-called calorigenic effect (calor- = “heat”) raises body temperature.

Calcitonin

The thyroid gland also secretes a hormone called calcitonin that is produced by the parafollicular cells (also called C cells) that stud the tissue between distinct follicles. Calcitonin is released in response to a rise in blood calcium levels. It appears to have a function in decreasing blood calcium concentrations by:

The Parathyroid Glands

Abstract:
By the end of this section, you will be able to:

* Describe the location and structure of the parathyroid glands
* Describe the hormonal control of blood calcium levels
* Discuss the physiological response of parathyroid dysfunction

The Adrenal Glands

Abstract:
By the end of this section, you will be able to:

* Describe the location and structure of the adrenal glands
* Identify the hormones produced by the adrenal cortex and adrenal medulla, and summarize their target cells and effects

Adrenal Cortex

The adrenal cortex consists of multiple layers of lipid-storing cells that occur in three structurally distinct regions. Each of these regions produces different hormones.

Adrenal Medulla

As noted earlier, the adrenal cortex releases glucocorticoids in response to long-term stress such as severe illness. In contrast, the adrenal medulla releases its hormones in response to acute, short-term stress mediated by the sympathetic nervous system (SNS).

Disorders Involving the Adrenal Glands

Several disorders are caused by the dysregulation of the hormones produced by the adrenal glands. For example, Cushing’s disease is a disorder characterized by high blood glucose levels and the accumulation of lipid deposits on the face and neck. It is caused by hypersecretion of cortisol. The most common source of Cushing’s disease is a pituitary tumor that secretes cortisol or ACTH in abnormally high amounts. Other common signs of Cushing’s disease include the development of a moon-shaped face, a buffalo hump on the back of the neck, rapid weight gain, and hair loss. Chronically elevated glucose levels are also associated with an elevated risk of developing type 2 diabetes. In addition to hyperglycemia, chronically elevated glucocorticoids compromise immunity, resistance to infection, and memory, and can result in rapid weight gain and hair loss.

The Pineal Gland

Abstract:
By the end of this section, you will be able to:

* Describe the location and structure of the pineal gland
* Discuss the function of melatonin

Gonadal and Placental Hormones

Abstract:
By the end of this section, you will be able to:

* Identify the most important hormones produced by the testes and ovaries
* Name the hormones produced by the placenta and state their functions

The Endocrine Pancreas

Abstract:
By the end of this section, you will be able to:

* Describe the location and structure of the pancreas, and the morphology and function of the pancreatic islets
* Compare and contrast the functions of insulin and glucagon

Cells and Secretions of the Pancreatic Islets

The pancreatic islets each contain four varieties of cells:

Regulation of Blood Glucose Levels by Insulin and Glucagon

Glucose is required for cellular respiration and is the preferred fuel for all body cells. The body derives glucose from the breakdown of the carbohydrate-containing foods and drinks we consume. Glucose not immediately taken up by cells for fuel can be stored by the liver and muscles as glycogen, or converted to triglycerides and stored in the adipose tissue. Hormones regulate both the storage and the utilization of glucose as required. Receptors located in the pancreas sense blood glucose levels, and subsequently the pancreatic cells secrete glucagon or insulin to maintain normal levels.

Organs with Secondary Endocrine Functions

Abstract:
By the end of this section, you will be able to:

* Identify the organs with a secondary endocrine function, the hormone they produce, and its effects

Heart

When the body experiences an increase in blood volume or pressure, the cells of the heart’s atrial wall stretch. In response, specialized cells in the wall of the atria produce and secrete the peptide hormone atrial natriuretic peptide (ANP). ANP signals the kidneys to reduce sodium reabsorption, thereby decreasing the amount of water reabsorbed from the urine filtrate and reducing blood volume. Other actions of ANP include the inhibition of renin secretion, thus inhibition of the renin-angiotensin-aldosterone system (RAAS) and vasodilation. Therefore, ANP aids in decreasing blood pressure, blood volume, and blood sodium levels.

Gastrointestinal Tract

The endocrine cells of the GI tract are located in the mucosa of the stomach and small intestine. Some of these hormones are secreted in response to eating a meal and aid in digestion. An example of a hormone secreted by the stomach cells is gastrin, a peptide hormone secreted in response to stomach distention that stimulates the release of hydrochloric acid. Secretin is a peptide hormone secreted by the small intestine as acidic chyme (partially digested food and fluid) moves from the stomach. It stimulates the release of bicarbonate from the pancreas, which buffers the acidic chyme, and inhibits the further secretion of hydrochloric acid by the stomach. Cholecystokinin (CCK) is another peptide hormone released from the small intestine. It promotes the secretion of pancreatic enzymes and the release of bile from the gallbladder, both of which facilitate digestion. Other hormones produced by the intestinal cells aid in glucose metabolism, such as by stimulating the pancreatic beta cells to secrete insulin, reducing glucagon secretion from the alpha cells, or enhancing cellular sensitivity to insulin.

Kidneys

The kidneys participate in several complex endocrine pathways and produce certain hormones. A decline in blood flow to the kidneys stimulates them to release the enzyme renin, triggering the renin-angiotensin-aldosterone (RAAS) system, and stimulating the reabsorption of sodium and water. The reabsorption increases blood flow and blood pressure. The kidneys also play a role in regulating blood calcium levels through the production of calcitriol from vitamin D3, which is released in response to the secretion of parathyroid hormone (PTH). In addition, the kidneys produce the hormone erythropoietin (EPO) in response to low oxygen levels. EPO stimulates the production of red blood cells (erythrocytes) in the bone marrow, thereby increasing oxygen delivery to tissues. You may have heard of EPO as a performance-enhancing drug (in a synthetic form).

Skeleton

Although bone has long been recognized as a target for hormones, only recently have researchers recognized that the skeleton itself produces at least two hormones. Fibroblast growth factor 23 (FGF23) is produced by bone cells in response to increased blood levels of vitamin D3 or phosphate. It triggers the kidneys to inhibit the formation of calcitriol from vitamin D3 and to increase phosphorus excretion. Osteocalcin, produced by osteoblasts, stimulates the pancreatic beta cells to increase insulin production. It also acts on peripheral tissues to increase their sensitivity to insulin and their utilization of glucose.

Adipose Tissue

Adipose tissue produces and secretes several hormones involved in lipid metabolism and storage. One important example is leptin, a protein manufactured by adipose cells that circulates in amounts directly proportional to levels of body fat. Leptin is released in response to food consumption and acts by binding to brain neurons involved in energy intake and expenditure. Binding of leptin produces a feeling of satiety after a meal, thereby reducing appetite. It also appears that the binding of leptin to brain receptors triggers the sympathetic nervous system to regulate bone metabolism, increasing deposition of cortical bone. Adiponectin—another hormone synthesized by adipose cells—appears to reduce cellular insulin resistance and to protect blood vessels from inflammation and atherosclerosis. Its levels are lower in people who are obese, and rise following weight loss.

Skin

The skin functions as an endocrine organ in the production of the inactive form of vitamin D3, cholecalciferol. When cholesterol present in the epidermis is exposed to ultraviolet radiation, it is converted to cholecalciferol, which then enters the blood. In the liver, cholecalciferol is converted to an intermediate that travels to the kidneys and is further converted to calcitriol, the active form of vitamin D3. Vitamin D is important in a variety of physiological processes, including intestinal calcium absorption and immune system function. In some studies, low levels of vitamin D have been associated with increased risks of cancer, severe asthma, and multiple sclerosis. Vitamin D deficiency in children causes rickets, and in adults, osteomalacia—both of which are characterized by bone deterioration.

Thymus

The thymus is an organ of the immune system that is larger and more active during infancy and early childhood, and begins to atrophy as we age. Its endocrine function is the production of a group of hormones called thymosins that contribute to the development and differentiation of T lymphocytes, which are immune cells. Although the role of thymosins is not yet well understood, it is clear that they contribute to the immune response. Thymosins have been found in tissues other than the thymus and have a wide variety of functions, so the thymosins cannot be strictly categorized as thymic hormones.

Liver

The liver is responsible for secreting at least four important hormones or hormone precursors: insulin-like growth factor (somatomedin), angiotensinogen, thrombopoietin, and hepcidin. Insulin-like growth factor-1 is the immediate stimulus for growth in the body, especially of the bones. Angiotensinogen is the precursor to angiotensin, mentioned earlier, which increases blood pressure. Thrombopoietin stimulates the production of the blood’s platelets. Hepcidins block the release of iron from cells in the body, helping to regulate iron homeostasis in our body fluids. The major hormones of these other organs are summarized in [link].

Development and Aging of the Endocrine System

Abstract:
By the end of this section, you will be able to:

* Describe the embryonic origins of the endocrine system
* Discuss the effects of aging on the endocrine system

Fluids and Transport

The Cardiovascular System: Blood

Introduction

An Overview of Blood

Abstract:
By the end of this section, you will be able to:

* Identify the primary functions of blood in transportation, defense, and maintenance of homeostasis
* Name the fluid component of blood and the three major types of formed elements, and identify their relative proportions in a blood sample
* Discuss the unique physical characteristics of blood
* Identify the composition of blood plasma, including its most important solutes and plasma proteins

Functions of Blood

The primary function of blood is to deliver oxygen and nutrients to and remove wastes from body cells, but that is only the beginning of the story. The specific functions of blood also include defense, distribution of heat, and maintenance of homeostasis.

Composition of Blood

You have probably had blood drawn from a superficial vein in your arm, which was then sent to a lab for analysis. Some of the most common blood tests—for instance, those measuring lipid or glucose levels in plasma—determine which substances are present within blood and in what quantities. Other blood tests check for the composition of the blood itself, including the quantities and types of formed elements.

Characteristics of Blood

When you think about blood, the first characteristic that probably comes to mind is its color. Blood that has just taken up oxygen in the lungs is bright red, and blood that has released oxygen in the tissues is a more dusky red. This is because hemoglobin is a pigment that changes color, depending upon the degree of oxygen saturation.

Blood Plasma

Like other fluids in the body, plasma is composed primarily of water: In fact, it is about 92 percent water. Dissolved or suspended within this water is a mixture of substances, most of which are proteins. There are literally hundreds of substances dissolved or suspended in the plasma, although many of them are found only in very small quantities.

Production of the Formed Elements

Abstract:
By the end of this section, you will be able to:

* Trace the generation of the formed elements of blood from bone marrow stem cells
* Discuss the role of hemopoietic growth factors in promoting the production of the formed elements

Sites of Hemopoiesis

Prior to birth, hemopoiesis occurs in a number of tissues, beginning with the yolk sac of the developing embryo, and continuing in the fetal liver, spleen, lymphatic tissue, and eventually the red bone marrow. Following birth, most hemopoiesis occurs in the red marrow, a connective tissue within the spaces of spongy (cancellous) bone tissue. In children, hemopoiesis can occur in the medullary cavity of long bones; in adults, the process is largely restricted to the cranial and pelvic bones, the vertebrae, the sternum, and the proximal epiphyses of the femur and humerus.

Differentiation of Formed Elements from Stem Cells

All formed elements arise from stem cells of the red bone marrow. Recall that stem cells undergo mitosis plus cytokinesis (cellular division) to give rise to new daughter cells: One of these remains a stem cell and the other differentiates into one of any number of diverse cell types. Stem cells may be viewed as occupying a hierarchal system, with some loss of the ability to diversify at each step. The totipotent stem cell is the zygote, or fertilized egg. The totipotent (toti- = “all”) stem cell gives rise to all cells of the human body. The next level is the pluripotent stem cell, which gives rise to multiple types of cells of the body and some of the supporting fetal membranes. Beneath this level, the mesenchymal cell is a stem cell that develops only into types of connective tissue, including fibrous connective tissue, bone, cartilage, and blood, but not epithelium, muscle, and nervous tissue. One step lower on the hierarchy of stem cells is the hematopoietic stem cell, or hemocytoblast. All of the formed elements of blood originate from this specific type of cell.

Hemopoietic Growth Factors

Development from stem cells to precursor cells to mature cells is again initiated by hemopoietic growth factors. These include the following:

Bone Marrow Sampling and Transplants

Sometimes, a healthcare provider will order a bone marrow biopsy, a diagnostic test of a sample of red bone marrow, or a bone marrow transplant, a treatment in which a donor’s healthy bone marrow—and its stem cells—replaces the faulty bone marrow of a patient. These tests and procedures are often used to assist in the diagnosis and treatment of various severe forms of anemia, such as thalassemia major and sickle cell anemia, as well as some types of cancer, specifically leukemia.

Erythrocytes

Abstract:
By the end of this section, you will be able to:

* Describe the anatomy of erythrocytes
* Discuss the various steps in the lifecycle of an erythrocyte
* Explain the composition and function of hemoglobin

Shape and Structure of Erythrocytes

As an erythrocyte matures in the red bone marrow, it extrudes its nucleus and most of its other organelles. During the first day or two that it is in the circulation, an immature erythrocyte, known as a reticulocyte, will still typically contain remnants of organelles. Reticulocytes should comprise approximately 1–2 percent of the erythrocyte count and provide a rough estimate of the rate of RBC production, with abnormally low or high rates indicating deviations in the production of these cells. These remnants, primarily of networks (reticulum) of ribosomes, are quickly shed, however, and mature, circulating erythrocytes have few internal cellular structural components. Lacking mitochondria, for example, they rely on anaerobic respiration. This means that they do not utilize any of the oxygen they are transporting, so they can deliver it all to the tissues. They also lack endoplasmic reticula and do not synthesize proteins. Erythrocytes do, however, contain some structural proteins that help the blood cells maintain their unique structure and enable them to change their shape to squeeze through capillaries. This includes the protein spectrin, a cytoskeletal protein element.

Hemoglobin

Hemoglobin is a large molecule made up of proteins and iron. It consists of four folded chains of a protein called globin, designated alpha 1 and 2, and beta 1 and 2 ([link]**a**). Each of these globin molecules is bound to a red pigment molecule called heme, which contains an ion of iron (Fe2+) ([link]**b**).

Lifecycle of Erythrocytes

Production of erythrocytes in the marrow occurs at the staggering rate of more than 2 million cells per second. For this production to occur, a number of raw materials must be present in adequate amounts. These include the same nutrients that are essential to the production and maintenance of any cell, such as glucose, lipids, and amino acids. However, erythrocyte production also requires several trace elements:

Disorders of Erythrocytes

The size, shape, and number of erythrocytes, and the number of hemoglobin molecules can have a major impact on a person’s health. When the number of RBCs or hemoglobin is deficient, the general condition is called anemia. There are more than 400 types of anemia and more than 3.5 million Americans suffer from this condition. Anemia can be broken down into three major groups: those caused by blood loss, those caused by faulty or decreased RBC production, and those caused by excessive destruction of RBCs. Clinicians often use two groupings in diagnosis: The kinetic approach focuses on evaluating the production, destruction, and removal of RBCs, whereas the morphological approach examines the RBCs themselves, paying particular emphasis to their size. A common test is the mean corpuscle volume (MCV), which measures size. Normal-sized cells are referred to as normocytic, smaller-than-normal cells are referred to as microcytic, and larger-than-normal cells are referred to as macrocytic. Reticulocyte counts are also important and may reveal inadequate production of RBCs. The effects of the various anemias are widespread, because reduced numbers of RBCs or hemoglobin will result in lower levels of oxygen being delivered to body tissues. Since oxygen is required for tissue functioning, anemia produces fatigue, lethargy, and an increased risk for infection. An oxygen deficit in the brain impairs the ability to think clearly, and may prompt headaches and irritability. Lack of oxygen leaves the patient short of breath, even as the heart and lungs work harder in response to the deficit.

Leukocytes and Platelets

Abstract:
By the end of this section, you will be able to:

* Describe the general characteristics of leukocytes
* Classify leukocytes according to their lineage, their main structural features, and their primary functions
* Discuss the most common malignancies involving leukocytes
* Identify the lineage, basic structure, and function of platelets

Characteristics of Leukocytes

Although leukocytes and erythrocytes both originate from hematopoietic stem cells in the bone marrow, they are very different from each other in many significant ways. For instance, leukocytes are far less numerous than erythrocytes: Typically there are only 5000 to 10,000 per *µ*L. They are also larger than erythrocytes and are the only formed elements that are complete cells, possessing a nucleus and organelles. And although there is just one type of erythrocyte, there are many types of leukocytes. Most of these types have a much shorter lifespan than that of erythrocytes, some as short as a few hours or even a few minutes in the case of acute infection.

Classification of Leukocytes

When scientists first began to observe stained blood slides, it quickly became evident that leukocytes could be divided into two groups, according to whether their cytoplasm contained highly visible granules:

Lifecycle of Leukocytes

Most leukocytes have a relatively short lifespan, typically measured in hours or days. Production of all leukocytes begins in the bone marrow under the influence of CSFs and interleukins. Secondary production and maturation of lymphocytes occurs in specific regions of lymphatic tissue known as germinal centers. Lymphocytes are fully capable of mitosis and may produce clones of cells with identical properties. This capacity enables an individual to maintain immunity throughout life to many threats that have been encountered in the past.

Disorders of Leukocytes

Leukopenia is a condition in which too few leukocytes are produced. If this condition is pronounced, the individual may be unable to ward off disease. Excessive leukocyte proliferation is known as leukocytosis. Although leukocyte counts are high, the cells themselves are often nonfunctional, leaving the individual at increased risk for disease.

Platelets

You may occasionally see platelets referred to as thrombocytes, but because this name suggests they are a type of cell, it is not accurate. A platelet is not a cell but rather a fragment of the cytoplasm of a cell called a megakaryocyte that is surrounded by a plasma membrane. Megakaryocytes are descended from myeloid stem cells (see [link]) and are large, typically 50–100 *µ*m in diameter, and contain an enlarged, lobed nucleus. As noted earlier, thrombopoietin, a glycoprotein secreted by the kidneys and liver, stimulates the proliferation of megakaryoblasts, which mature into megakaryocytes. These remain within bone marrow tissue ([link]) and ultimately form platelet-precursor extensions that extend through the walls of bone marrow capillaries to release into the circulation thousands of cytoplasmic fragments, each enclosed by a bit of plasma membrane. These enclosed fragments are platelets. Each megakaryocyte releases 2000–3000 platelets during its lifespan. Following platelet release, megakaryocyte remnants, which are little more than a cell nucleus, are consumed by macrophages.

Disorders of Platelets

Thrombocytosis is a condition in which there are too many platelets. This may trigger formation of unwanted blood clots (thrombosis), a potentially fatal disorder. If there is an insufficient number of platelets, called thrombocytopenia, blood may not clot properly, and excessive bleeding may result.

Hemostasis

Abstract:
By the end of this section, you will be able to:

* Describe the three mechanisms involved in hemostasis
* Explain how the extrinsic and intrinsic coagulation pathways lead to the common pathway, and the coagulation factors involved in each
* Discuss disorders affecting hemostasis

Vascular Spasm

When a vessel is severed or punctured, or when the wall of a vessel is damaged, vascular spasm occurs. In vascular spasm, the smooth muscle in the walls of the vessel contracts dramatically. This smooth muscle has both circular layers; larger vessels also have longitudinal layers. The circular layers tend to constrict the flow of blood, whereas the longitudinal layers, when present, draw the vessel back into the surrounding tissue, often making it more difficult for a surgeon to locate, clamp, and tie off a severed vessel. The vascular spasm response is believed to be triggered by several chemicals called endothelins that are released by vessel-lining cells and by pain receptors in response to vessel injury. This phenomenon typically lasts for up to 30 minutes, although it can last for hours.

Formation of the Platelet Plug

In the second step, platelets, which normally float free in the plasma, encounter the area of vessel rupture with the exposed underlying connective tissue and collagenous fibers. The platelets begin to clump together, become spiked and sticky, and bind to the exposed collagen and endothelial lining. This process is assisted by a glycoprotein in the blood plasma called von Willebrand factor, which helps stabilize the growing platelet plug. As platelets collect, they simultaneously release chemicals from their granules into the plasma that further contribute to hemostasis. Among the substances released by the platelets are:

Coagulation

Those more sophisticated and more durable repairs are collectively called coagulation, the formation of a blood clot. The process is sometimes characterized as a cascade, because one event prompts the next as in a multi-level waterfall. The result is the production of a gelatinous but robust clot made up of a mesh of fibrin—an insoluble filamentous protein derived from fibrinogen, the plasma protein introduced earlier—in which platelets and blood cells are trapped. [link] summarizes the three steps of hemostasis.

Fibrinolysis

The stabilized clot is acted upon by contractile proteins within the platelets. As these proteins contract, they pull on the fibrin threads, bringing the edges of the clot more tightly together, somewhat as we do when tightening loose shoelaces (see [link]**a**). This process also wrings out of the clot a small amount of fluid called serum, which is blood plasma without its clotting factors.

Plasma Anticoagulants

An anticoagulant is any substance that opposes coagulation. Several circulating plasma anticoagulants play a role in limiting the coagulation process to the region of injury and restoring a normal, clot-free condition of blood. For instance, a cluster of proteins collectively referred to as the protein C system inactivates clotting factors involved in the intrinsic pathway. TFPI (tissue factor pathway inhibitor) inhibits the conversion of the inactive factor VII to the active form in the extrinsic pathway. Antithrombin inactivates factor X and opposes the conversion of prothrombin (factor II) to thrombin in the common pathway. And as noted earlier, basophils release heparin, a short-acting anticoagulant that also opposes prothrombin. Heparin is also found on the surfaces of cells lining the blood vessels. A pharmaceutical form of heparin is often administered therapeutically, for example, in surgical patients at risk for blood clots.

Disorders of Clotting

Either an insufficient or an excessive production of platelets can lead to severe disease or death. As discussed earlier, an insufficient number of platelets, called thrombocytopenia, typically results in the inability of blood to form clots. This can lead to excessive bleeding, even from minor wounds.

Blood Typing

Abstract:
By the end of this section, you will be able to:

* Describe the two basic physiological consequences of transfusion of incompatible blood
* Compare and contrast ABO and Rh blood groups
* Identify which blood groups may be safely transfused into patients with different ABO types
* Discuss the pathophysiology of hemolytic disease of the newborn

Antigens, Antibodies, and Transfusion Reactions

Antigens are substances that may trigger a defensive response from leukocytes of the immune system if the body does not recognize the antigen as belonging to "self." (Seek more content for additional information on immunity.) Here, we will focus on the role of immunity in blood transfusion reactions. With RBCs in particular, you may see the antigens referred to as isoantigens or agglutinogens (surface antigens) and the antibodies referred to as isoantibodies or agglutinins. In this chapter, we will use the more common terms antigens and antibodies.

The ABO Blood Group

Although the ABO blood group name consists of three letters, ABO blood typing designates the presence or absence of just two antigens, A and B. Both are glycoproteins. People whose erythrocytes have A antigens on their erythrocyte membrane surfaces are designated blood type A, and those whose erythrocytes have B antigens are blood type B. People can also have both A and B antigens on their erythrocytes, in which case they are blood type AB. People with neither A nor B antigens are designated blood type O. ABO blood types are genetically determined.

Rh Blood Groups

The Rh blood group is classified according to the presence or absence of a second erythrocyte antigen identified as Rh. (It was first discovered in a type of primate known as a rhesus macaque, which is often used in research, because its blood is similar to that of humans.) Although dozens of Rh antigens have been identified, only one, designated D, is clinically important. Those who have the Rh D antigen present on their erythrocytes—about 85 percent of Americans—are described as Rh positive (Rh+) and those who lack it are Rh negative (Rh−). Note that the Rh group is distinct from the ABO group, so any individual, no matter their ABO blood type, may have or lack this Rh antigen. When identifying a patient’s blood type, the Rh group is designated by adding the word positive or negative to the ABO type. For example, A positive (A+) means ABO group A blood with the Rh antigen present, and AB negative (AB−) means ABO group AB blood without the Rh antigen.

Determining ABO Blood Types

Clinicians are able to determine a patient’s blood type quickly and easily using commercially prepared antibodies. An unknown blood sample is allocated into separate wells. Into one well a small amount of anti-A antibody is added, and to another a small amount of anti-B antibody. If the antigen is present, the antibodies will cause visible agglutination of the cells ([link]). The blood should also be tested for Rh antibodies.

ABO Transfusion Protocols

To avoid transfusion reactions, it is best to transfuse only matching blood types; that is, a type B+ recipient should ideally receive blood only from a type B+ donor and so on. That said, in emergency situations, when acute hemorrhage threatens the patient’s life, there may not be time for cross matching to identify blood type. In these cases, blood from a universal donor—an individual with type O− blood—may be transfused. Recall that type O erythrocytes do not display A or B antigens. Thus, anti-A or anti-B antibodies that might be circulating in the patient’s blood plasma will not encounter any erythrocyte surface antigens on the donated blood and therefore will not be provoked into a response. One problem with this designation of universal donor is if the O− individual had prior exposure to Rh antigen, Rh antibodies may be present in the donated blood. Also, introducing type O blood into an individual with type A, B, or AB blood will nevertheless introduce antibodies against both A and B antigens, as these are always circulating in the type O blood plasma. This may cause problems for the recipient, but because the volume of blood transfused is much lower than the volume of the patient’s own blood, the adverse effects of the relatively few infused plasma antibodies are typically limited. Rh factor also plays a role. If Rh− individuals receiving blood have had prior exposure to Rh antigen, antibodies for this antigen may be present in the blood and trigger agglutination to some degree. Although it is always preferable to cross match a patient’s blood before transfusing, in a true life-threatening emergency situation, this is not always possible, and these procedures may be implemented.

The Cardiovascular System: The Heart

Introduction

Heart Anatomy

Abstract:
By the end of this section, you will be able to:

* Describe the location and position of the heart within the body cavity
* Describe the internal and external anatomy of the heart
* Identify the tissue layers of the heart
* Relate the structure of the heart to its function as a pump
* Compare systemic circulation to pulmonary circulation
* Identify the veins and arteries of the coronary circulation system
* Trace the pathway of oxygenated and deoxygenated blood thorough the chambers of the heart

Location of the Heart

The human heart is located within the thoracic cavity, medially between the lungs in the space known as the mediastinum. [link] shows the position of the heart within the thoracic cavity. Within the mediastinum, the heart is separated from the other mediastinal structures by a tough membrane known as the pericardium, or pericardial sac, and sits in its own space called the pericardial cavity. The dorsal surface of the heart lies near the bodies of the vertebrae, and its anterior surface sits deep to the sternum and costal cartilages. The great veins, the superior and inferior venae cavae, and the great arteries, the aorta and pulmonary trunk, are attached to the superior surface of the heart, called the base. The base of the heart is located at the level of the third costal cartilage, as seen in [link]. The inferior tip of the heart, the apex, lies just to the left of the sternum between the junction of the fourth and fifth ribs near their articulation with the costal cartilages. The right side of the heart is deflected anteriorly, and the left side is deflected posteriorly. It is important to remember the position and orientation of the heart when placing a stethoscope on the chest of a patient and listening for heart sounds, and also when looking at images taken from a midsagittal perspective. The slight deviation of the apex to the left is reflected in a depression in the medial surface of the superior lobe of the left lung, called the cardiac notch.

Shape and Size of the Heart

The shape of the heart is similar to a pinecone, rather broad at the superior surface and tapering to the apex (see [link]). A typical heart is approximately the size of your fist: 12 cm (5 in) in length, 8 cm (3.5 in) wide, and 6 cm (2.5 in) in thickness. Given the size difference between most members of the sexes, the weight of a female heart is approximately 250–300 grams (9 to 11 ounces), and the weight of a male heart is approximately 300–350 grams (11 to 12 ounces). The heart of a well-trained athlete, especially one specializing in aerobic sports, can be considerably larger than this. Cardiac muscle responds to exercise in a manner similar to that of skeletal muscle. That is, exercise results in the addition of protein myofilaments that increase the size of the individual cells without increasing their numbers, a concept called hypertrophy. Hearts of athletes can pump blood more effectively at lower rates than those of nonathletes. Enlarged hearts are not always a result of exercise; they can result from pathologies, such as hypertrophic cardiomyopathy. The cause of an abnormally enlarged heart muscle is unknown, but the condition is often undiagnosed and can cause sudden death in apparently otherwise healthy young people.

Chambers and Circulation through the Heart

The human heart consists of four chambers: The left side and the right side each have one atrium and one ventricle. Each of the upper chambers, the right atrium (plural = atria) and the left atrium, acts as a receiving chamber and contracts to push blood into the lower chambers, the right ventricle and the left ventricle. The ventricles serve as the primary pumping chambers of the heart, propelling blood to the lungs or to the rest of the body.

Membranes, Surface Features, and Layers

Our exploration of more in-depth heart structures begins by examining the membrane that surrounds the heart, the prominent surface features of the heart, and the layers that form the wall of the heart. Each of these components plays its own unique role in terms of function.

Internal Structure of the Heart

Recall that the heart’s contraction cycle follows a dual pattern of circulation—the pulmonary and systemic circuits—because of the pairs of chambers that pump blood into the circulation. In order to develop a more precise understanding of cardiac function, it is first necessary to explore the internal anatomical structures in more detail.

Coronary Circulation

You will recall that the heart is a remarkable pump composed largely of cardiac muscle cells that are incredibly active throughout life. Like all other cells, a cardiomyocyte requires a reliable supply of oxygen and nutrients, and a way to remove wastes, so it needs a dedicated, complex, and extensive coronary circulation. And because of the critical and nearly ceaseless activity of the heart throughout life, this need for a blood supply is even greater than for a typical cell. However, coronary circulation is not continuous; rather, it cycles, reaching a peak when the heart muscle is relaxed and nearly ceasing while it is contracting.

Cardiac Muscle and Electrical Activity

Abstract:
By the end of this section, you will be able to:

* Describe the structure of cardiac muscle
* Identify and describe the components of the conducting system that distributes electrical impulses through the heart
* Compare the effect of ion movement on membrane potential of cardiac conductive and contractile cells
* Relate characteristics of an electrocardiogram to events in the cardiac cycle
* Identify blocks that can interrupt the cardiac cycle

Structure of Cardiac Muscle

Compared to the giant cylinders of skeletal muscle, cardiac muscle cells, or cardiomyocytes, are considerably shorter with much smaller diameters. Cardiac muscle also demonstrates striations, the alternating pattern of dark A bands and light I bands attributed to the precise arrangement of the myofilaments and fibrils that are organized in sarcomeres along the length of the cell ([link]**a**). These contractile elements are virtually identical to skeletal muscle. T (transverse) tubules penetrate from the surface plasma membrane, the sarcolemma, to the interior of the cell, allowing the electrical impulse to reach the interior. The T tubules are only found at the Z discs, whereas in skeletal muscle, they are found at the junction of the A and I bands. Therefore, there are one-half as many T tubules in cardiac muscle as in skeletal muscle. In addition, the sarcoplasmic reticulum stores few calcium ions, so most of the calcium ions must come from outside the cells. The result is a slower onset of contraction. Mitochondria are plentiful, providing energy for the contractions of the heart. Typically, cardiomyocytes have a single, central nucleus, but two or more nuclei may be found in some cells.

Conduction System of the Heart

If embryonic heart cells are separated into a Petri dish and kept alive, each is capable of generating its own electrical impulse followed by contraction. When two independently beating embryonic cardiac muscle cells are placed together, the cell with the higher inherent rate sets the pace, and the impulse spreads from the faster to the slower cell to trigger a contraction. As more cells are joined together, the fastest cell continues to assume control of the rate. A fully developed adult heart maintains the capability of generating its own electrical impulse, triggered by the fastest cells, as part of the cardiac conduction system. The components of the cardiac conduction system include the sinoatrial node, the atrioventricular node, the atrioventricular bundle, the atrioventricular bundle branches, and the Purkinje cells ([link]).

Electrocardiogram

By careful placement of surface electrodes on the body, it is possible to record the complex, compound electrical signal of the heart. This tracing of the electrical signal is the electrocardiogram (ECG), also commonly abbreviated EKG (K coming kardiology, from the German term for cardiology). Careful analysis of the ECG reveals a detailed picture of both normal and abnormal heart function, and is an indispensable clinical diagnostic tool. The standard electrocardiograph (the instrument that generates an ECG) uses 3, 5, or 12 leads. The greater the number of leads an electrocardiograph uses, the more information the ECG provides. The term “lead” may be used to refer to the cable from the electrode to the electrical recorder, but it typically describes the voltage difference between two of the electrodes. The 12-lead electrocardiograph uses 10 electrodes placed in standard locations on the patient’s skin ([link]). In continuous ambulatory electrocardiographs, the patient wears a small, portable, battery-operated device known as a Holter monitor, or simply a Holter, that continuously monitors heart electrical activity, typically for a period of 24 hours during the patient’s normal routine.

Cardiac Muscle Metabolism

Normally, cardiac muscle metabolism is entirely aerobic. Oxygen from the lungs is brought to the heart, and every other organ, attached to the hemoglobin molecules within the erythrocytes. Heart cells also store appreciable amounts of oxygen in myoglobin. Normally, these two mechanisms, circulating oxygen and oxygen attached to myoglobin, can supply sufficient oxygen to the heart, even during peak performance.

Cardiac Cycle

Abstract:
By the end of this section, you will be able to:

* Describe the relationship between blood pressure and blood flow
* Summarize the events of the cardiac cycle
* Compare atrial and ventricular systole and diastole
* Relate heart sounds detected by auscultation to action of heart’s valves

Pressures and Flow

Fluids, whether gases or liquids, are materials that flow according to pressure gradients—that is, they move from regions that are higher in pressure to regions that are lower in pressure. Accordingly, when the heart chambers are relaxed (diastole), blood will flow into the atria from the veins, which are higher in pressure. As blood flows into the atria, the pressure will rise, so the blood will initially move passively from the atria into the ventricles. When the action potential triggers the muscles in the atria to contract (atrial systole), the pressure within the atria rises further, pumping blood into the ventricles. During ventricular systole, pressure rises in the ventricles, pumping blood into the pulmonary trunk from the right ventricle and into the aorta from the left ventricle. Again, as you consider this flow and relate it to the conduction pathway, the elegance of the system should become apparent.

Phases of the Cardiac Cycle

At the beginning of the cardiac cycle, both the atria and ventricles are relaxed (diastole). Blood is flowing into the right atrium from the superior and inferior venae cavae and the coronary sinus. Blood flows into the left atrium from the four pulmonary veins. The two atrioventricular valves, the tricuspid and mitral valves, are both open, so blood flows unimpeded from the atria and into the ventricles. Approximately 70–80 percent of ventricular filling occurs by this method. The two semilunar valves, the pulmonary and aortic valves, are closed, preventing backflow of blood into the right and left ventricles from the pulmonary trunk on the right and the aorta on the left.

Heart Sounds

One of the simplest, yet effective, diagnostic techniques applied to assess the state of a patient’s heart is auscultation using a stethoscope.

Cardiac Physiology

Abstract:
By the end of this section, you will be able to:

* Relate heart rate to cardiac output
* Describe the effect of exercise on heart rate
* Identify cardiovascular centers and cardiac reflexes that regulate heart function
* Describe factors affecting heart rate
* Distinguish between positive and negative factors that affect heart contractility
* Summarize factors affecting stroke volume and cardiac output
* Describe the cardiac response to variations in blood flow and pressure

Resting Cardiac Output

Cardiac output (CO) is a measurement of the amount of blood pumped by each ventricle in one minute. To calculate this value, multiply stroke volume (SV), the amount of blood pumped by each ventricle, by heart rate (HR), in contractions per minute (or beats per minute, bpm). It can be represented mathematically by the following equation:

Exercise and Maximum Cardiac Output

In healthy young individuals, HR may increase to 150 bpm during exercise. SV can also increase from 70 to approximately 130 mL due to increased strength of contraction. This would increase CO to approximately 19.5 L/min, 4–5 times the resting rate. Top cardiovascular athletes can achieve even higher levels. At their peak performance, they may increase resting CO by 7–8 times.

Heart Rates

HRs vary considerably, not only with exercise and fitness levels, but also with age. Newborn resting HRs may be 120 bpm. HR gradually decreases until young adulthood and then gradually increases again with age.

Correlation Between Heart Rates and Cardiac Output

Initially, physiological conditions that cause HR to increase also trigger an increase in SV. During exercise, the rate of blood returning to the heart increases. However as the HR rises, there is less time spent in diastole and consequently less time for the ventricles to fill with blood. Even though there is less filling time, SV will initially remain high. However, as HR continues to increase, SV gradually decreases due to decreased filling time. CO will initially stabilize as the increasing HR compensates for the decreasing SV, but at very high rates, CO will eventually decrease as increasing rates are no longer able to compensate for the decreasing SV. Consider this phenomenon in a healthy young individual. Initially, as HR increases from resting to approximately 120 bpm, CO will rise. As HR increases from 120 to 160 bpm, CO remains stable, since the increase in rate is offset by decreasing ventricular filling time and, consequently, SV. As HR continues to rise above 160 bpm, CO actually decreases as SV falls faster than HR increases. So although aerobic exercises are critical to maintain the health of the heart, individuals are cautioned to monitor their HR to ensure they stay within the target heart rate range of between 120 and 160 bpm, so CO is maintained. The target HR is loosely defined as the range in which both the heart and lungs receive the maximum benefit from the aerobic workout and is dependent upon age.

Cardiovascular Centers

Nervous control over HR is centralized within the two paired cardiovascular centers of the medulla oblongata ([link]). The cardioaccelerator regions stimulate activity via sympathetic stimulation of the cardioaccelerator nerves, and the cardioinhibitory centers decrease heart activity via parasympathetic stimulation as one component of the vagus nerve, cranial nerve X. During rest, both centers provide slight stimulation to the heart, contributing to autonomic tone. This is a similar concept to tone in skeletal muscles. Normally, vagal stimulation predominates as, left unregulated, the SA node would initiate a sinus rhythm of approximately 100 bpm.

Input to the Cardiovascular Center

The cardiovascular center receives input from a series of visceral receptors with impulses traveling through visceral sensory fibers within the vagus and sympathetic nerves via the cardiac plexus. Among these receptors are various proprioreceptors, baroreceptors, and chemoreceptors, plus stimuli from the limbic system. Collectively, these inputs normally enable the cardiovascular centers to regulate heart function precisely, a process known as cardiac reflexes. Increased physical activity results in increased rates of firing by various proprioreceptors located in muscles, joint capsules, and tendons. Any such increase in physical activity would logically warrant increased blood flow. The cardiac centers monitor these increased rates of firing, and suppress parasympathetic stimulation and increase sympathetic stimulation as needed in order to increase blood flow.

Other Factors Influencing Heart Rate

Using a combination of autorhythmicity and innervation, the cardiovascular center is able to provide relatively precise control over HR. However, there are a number of other factors that have an impact on HR as well, including epinephrine, NE, and thyroid hormones; levels of various ions including calcium, potassium, and sodium; body temperature; hypoxia; and pH balance ([link] and [link]). After reading this section, the importance of maintaining homeostasis should become even more apparent.

Stroke Volume

Many of the same factors that regulate HR also impact cardiac function by altering SV. While a number of variables are involved, SV is ultimately dependent upon the difference between EDV and ESV. The three primary factors to consider are preload, or the stretch on the ventricles prior to contraction; the contractility, or the force or strength of the contraction itself; and afterload, the force the ventricles must generate to pump blood against the resistance in the vessels. These factors are summarized in [link] and [link].

Development of the Heart

Abstract:
By the end of this section, you will be able to:

* Describe the embryological development of heart structures
* Identify five regions of the fetal heart
* Relate fetal heart structures to adult counterparts

The Cardiovascular System: Blood Vessels and Circulation

Introduction

Structure and Function of Blood Vessels

Abstract:
By the end of this section, you will be able to:

* Compare and contrast the three tunics that make up the walls of most blood vessels
* Distinguish between elastic arteries, muscular arteries, and arterioles on the basis of structure, location, and function
* Describe the basic structure of a capillary bed, from the supplying metarteriole to the venule into which it drains
* Explain the structure and function of venous valves in the large veins of the extremities

Shared Structures

Different types of blood vessels vary slightly in their structures, but they share the same general features. Arteries and arterioles have thicker walls than veins and venules because they are closer to the heart and receive blood that is surging at a far greater pressure ([link]). Each type of vessel has a lumen—a hollow passageway through which blood flows. Arteries have smaller lumens than veins, a characteristic that helps to maintain the pressure of blood moving through the system. Together, their thicker walls and smaller diameters give arterial lumens a more rounded appearance in cross section than the lumens of veins.

Arteries

An artery is a blood vessel that conducts blood away from the heart. All arteries have relatively thick walls that can withstand the high pressure of blood ejected from the heart. However, those close to the heart have the thickest walls, containing a high percentage of elastic fibers in all three of their tunics. This type of artery is known as an elastic artery ([link]). Vessels larger than 10 mm in diameter are typically elastic. Their abundant elastic fibers allow them to expand, as blood pumped from the ventricles passes through them, and then to recoil after the surge has passed. If artery walls were rigid and unable to expand and recoil, their resistance to blood flow would greatly increase and blood pressure would rise to even higher levels, which would in turn require the heart to pump harder to increase the volume of blood expelled by each pump (the stroke volume) and maintain adequate pressure and flow. Artery walls would have to become even thicker in response to this increased pressure. The elastic recoil of the vascular wall helps to maintain the pressure gradient that drives the blood through the arterial system. An elastic artery is also known as a conducting artery, because the large diameter of the lumen enables it to accept a large volume of blood from the heart and conduct it to smaller branches.

Arterioles

An arteriole is a very small artery that leads to a capillary. Arterioles have the same three tunics as the larger vessels, but the thickness of each is greatly diminished. The critical endothelial lining of the tunica intima is intact. The tunica media is restricted to one or two smooth muscle cell layers in thickness. The tunica externa remains but is very thin (see [link]).

Capillaries

A capillary is a microscopic channel that supplies blood to the tissues, a process called perfusion. Exchange of gases and other substances occurs between the blood in capillaries and the surrounding cells and their tissue fluid (interstitial fluid). The diameter of a capillary lumen ranges from 5–10 micrometers; the smallest are just barely wide enough for an erythrocyte to squeeze through. Flow through capillaries is often described as microcirculation.

Metarterioles and Capillary Beds

A metarteriole is a type of vessel that has structural characteristics of both an arteriole and a capillary. Slightly larger than the typical capillary, the smooth muscle of the tunica media of the metarteriole is not continuous but forms rings of smooth muscle (sphincters) prior to the entrance to the capillaries. Each metarteriole arises from a terminal arteriole and branches to supply blood to a capillary bed that may consist of 10–100 capillaries.

Venules

A venule is an extremely small vein, generally 8–100 micrometers in diameter. Postcapillary venules join multiple capillaries exiting from a capillary bed. Multiple venules join to form veins. The walls of venules consist of endothelium, a thin middle layer with a few muscle cells and elastic fibers, plus an outer layer of connective tissue fibers that constitute a very thin tunica externa ([link]). Venules as well as capillaries are the primary sites of emigration or diapedesis, in which the white blood cells adhere to the endothelial lining of the vessels and then squeeze through adjacent cells to enter the tissue fluid.

Veins

A vein is a blood vessel that conducts blood toward the heart. Compared to arteries, veins are thin-walled vessels with large and irregular lumens (see [link]). Because they are low-pressure vessels, larger veins are commonly equipped with valves that promote the unidirectional flow of blood toward the heart and prevent backflow toward the capillaries caused by the inherent low blood pressure in veins as well as the pull of gravity. [link] compares the features of arteries and veins.

Veins as Blood Reservoirs

In addition to their primary function of returning blood to the heart, veins may be considered blood reservoirs, since systemic veins contain approximately 64 percent of the blood volume at any given time ([link]). Their ability to hold this much blood is due to their high capacitance, that is, their capacity to distend (expand) readily to store a high volume of blood, even at a low pressure. The large lumens and relatively thin walls of veins make them far more distensible than arteries; thus, they are said to be capacitance vessels.

Blood Flow, Blood Pressure, and Resistance

Abstract:
By the end of this section, you will be able to:

* Distinguish between systolic pressure, diastolic pressure, pulse pressure, and mean arterial pressure
* Describe the clinical measurement of pulse and blood pressure
* Identify and discuss five variables affecting arterial blood flow and blood pressure
* Discuss several factors affecting blood flow in the venous system

Components of Arterial Blood Pressure

Arterial blood pressure in the larger vessels consists of several distinct components ([link]): systolic and diastolic pressures, pulse pressure, and mean arterial pressure.

Pulse

After blood is ejected from the heart, elastic fibers in the arteries help maintain a high-pressure gradient as they expand to accommodate the blood, then recoil. This expansion and recoiling effect, known as the pulse, can be palpated manually or measured electronically. Although the effect diminishes over distance from the heart, elements of the systolic and diastolic components of the pulse are still evident down to the level of the arterioles.

Measurement of Blood Pressure

Blood pressure is one of the critical parameters measured on virtually every patient in every healthcare setting. The technique used today was developed more than 100 years ago by a pioneering Russian physician, Dr. Nikolai Korotkoff. Turbulent blood flow through the vessels can be heard as a soft ticking while measuring blood pressure; these sounds are known as Korotkoff sounds. The technique of measuring blood pressure requires the use of a sphygmomanometer (a blood pressure cuff attached to a measuring device) and a stethoscope. The technique is as follows:

Variables Affecting Blood Flow and Blood Pressure

Five variables influence blood flow and blood pressure:

Venous System

The pumping action of the heart propels the blood into the arteries, from an area of higher pressure toward an area of lower pressure. If blood is to flow from the veins back into the heart, the pressure in the veins must be greater than the pressure in the atria of the heart. Two factors help maintain this pressure gradient between the veins and the heart. First, the pressure in the atria during diastole is very low, often approaching zero when the atria are relaxed (atrial diastole). Second, two physiologic “pumps” increase pressure in the venous system. The use of the term “pump” implies a physical device that speeds flow. These physiological pumps are less obvious.

Capillary Exchange

Abstract:
By the end of this section, you will be able to:

* Identify the primary mechanisms of capillary exchange
* Distinguish between capillary hydrostatic pressure and blood colloid osmotic pressure, explaining the contribution of each to net filtration pressure
* Compare filtration and reabsorption
* Explain the fate of fluid that is not reabsorbed from the tissues into the vascular capillaries

Bulk Flow

The mass movement of fluids into and out of capillary beds requires a transport mechanism far more efficient than mere diffusion. This movement, often referred to as bulk flow, involves two pressure-driven mechanisms: Volumes of fluid move from an area of higher pressure in a capillary bed to an area of lower pressure in the tissues via filtration. In contrast, the movement of fluid from an area of higher pressure in the tissues into an area of lower pressure in the capillaries is reabsorption. Two types of pressure interact to drive each of these movements: hydrostatic pressure and osmotic pressure.

The Role of Lymphatic Capillaries

Since overall CHP is higher than BCOP, it is inevitable that more net fluid will exit the capillary through filtration at the arterial end than enters through reabsorption at the venous end. Considering all capillaries over the course of a day, this can be quite a substantial amount of fluid: Approximately 24 liters per day are filtered, whereas 20.4 liters are reabsorbed. This excess fluid is picked up by capillaries of the lymphatic system. These extremely thin-walled vessels have copious numbers of valves that ensure unidirectional flow through ever-larger lymphatic vessels that eventually drain into the subclavian veins in the neck. An important function of the lymphatic system is to return the fluid (lymph) to the blood. Lymph may be thought of as recycled blood plasma. (Seek additional content for more detail on the lymphatic system.)

Homeostatic Regulation of the Vascular System

Abstract:
By the end of this section, you will be able to:

* Discuss the mechanisms involved in the neural regulation of vascular homeostasis
* Describe the contribution of a variety of hormones to the renal regulation of blood pressure
* Identify the effects of exercise on vascular homeostasis
* Discuss how hypertension, hemorrhage, and circulatory shock affect vascular health

Neural Regulation

The nervous system plays a critical role in the regulation of vascular homeostasis. The primary regulatory sites include the cardiovascular centers in the brain that control both cardiac and vascular functions. In addition, more generalized neural responses from the limbic system and the autonomic nervous system are factors.

Endocrine Regulation

Endocrine control over the cardiovascular system involves the catecholamines, epinephrine and norepinephrine, as well as several hormones that interact with the kidneys in the regulation of blood volume.

Autoregulation of Perfusion

As the name would suggest, autoregulation mechanisms require neither specialized nervous stimulation nor endocrine control. Rather, these are local, self-regulatory mechanisms that allow each region of tissue to adjust its blood flow—and thus its perfusion. These local mechanisms include chemical signals and myogenic controls.

Effect of Exercise on Vascular Homeostasis

The heart is a muscle and, like any muscle, it responds dramatically to exercise. For a healthy young adult, cardiac output (heart rate × stroke volume) increases in the nonathlete from approximately 5.0 liters (5.25 quarts) per minute to a maximum of about 20 liters (21 quarts) per minute. Accompanying this will be an increase in blood pressure from about 120/80 to 185/75. However, well-trained aerobic athletes can increase these values substantially. For these individuals, cardiac output soars from approximately 5.3 liters (5.57 quarts) per minute resting to more than 30 liters (31.5 quarts) per minute during maximal exercise. Along with this increase in cardiac output, blood pressure increases from 120/80 at rest to 200/90 at maximum values.

Clinical Considerations in Vascular Homeostasis

Any disorder that affects blood volume, vascular tone, or any other aspect of vascular functioning is likely to affect vascular homeostasis as well. That includes hypertension, hemorrhage, and shock.

Circulatory Pathways

Abstract:
By the end of this section, you will be able to:

* Identify the vessels through which blood travels within the pulmonary circuit, beginning from the right ventricle of the heart and ending at the left atrium
* Create a flow chart showing the major systemic arteries through which blood travels from the aorta and its major branches, to the most significant arteries feeding into the right and left upper and lower limbs
* Create a flow chart showing the major systemic veins through which blood travels from the feet to the right atrium of the heart

Pulmonary Circulation

Recall that blood returning from the systemic circuit enters the right atrium ([link]) via the superior and inferior venae cavae and the coronary sinus, which drains the blood supply of the heart muscle. These vessels will be described more fully later in this section. This blood is relatively low in oxygen and relatively high in carbon dioxide, since much of the oxygen has been extracted for use by the tissues and the waste gas carbon dioxide was picked up to be transported to the lungs for elimination. From the right atrium, blood moves into the right ventricle, which pumps it to the lungs for gas exchange. This system of vessels is referred to as the pulmonary circuit.

Overview of Systemic Arteries

Blood relatively high in oxygen concentration is returned from the pulmonary circuit to the left atrium via the four pulmonary veins. From the left atrium, blood moves into the left ventricle, which pumps blood into the aorta. The aorta and its branches—the systemic arteries—send blood to virtually every organ of the body ([link]).

The Aorta

The aorta is the largest artery in the body ([link]). It arises from the left ventricle and eventually descends to the abdominal region, where it bifurcates at the level of the fourth lumbar vertebra into the two common iliac arteries. The aorta consists of the ascending aorta, the aortic arch, and the descending aorta, which passes through the diaphragm and a landmark that divides into the superior thoracic and inferior abdominal components. Arteries originating from the aorta ultimately distribute blood to virtually all tissues of the body. At the base of the aorta is the aortic semilunar valve that prevents backflow of blood into the left ventricle while the heart is relaxing. After exiting the heart, the ascending aorta moves in a superior direction for approximately 5 cm and ends at the sternal angle. Following this ascent, it reverses direction, forming a graceful arc to the left, called the aortic arch. The aortic arch descends toward the inferior portions of the body and ends at the level of the intervertebral disk between the fourth and fifth thoracic vertebrae. Beyond this point, the descending aorta continues close to the bodies of the vertebrae and passes through an opening in the diaphragm known as the aortic hiatus. Superior to the diaphragm, the aorta is called the thoracic aorta, and inferior to the diaphragm, it is called the abdominal aorta. The abdominal aorta terminates when it bifurcates into the two common iliac arteries at the level of the fourth lumbar vertebra. See [link] for an illustration of the ascending aorta, the aortic arch, and the initial segment of the descending aorta plus major branches; [link] summarizes the structures of the aorta.

Arteries Serving the Upper Limbs

As the subclavian artery exits the thorax into the axillary region, it is renamed the axillary artery. Although it does branch and supply blood to the region near the head of the humerus (via the humeral circumflex arteries), the majority of the vessel continues into the upper arm, or brachium, and becomes the brachial artery ([link]). The brachial artery supplies blood to much of the brachial region and divides at the elbow into several smaller branches, including the deep brachial arteries, which provide blood to the posterior surface of the arm, and the ulnar collateral arteries, which supply blood to the region of the elbow. As the brachial artery approaches the coronoid fossa, it bifurcates into the radial and ulnar arteries, which continue into the forearm, or antebrachium. The radial artery and ulnar artery parallel their namesake bones, giving off smaller branches until they reach the wrist, or carpal region. At this level, they fuse to form the superficial and deep palmar arches that supply blood to the hand, as well as the digital arteries that supply blood to the digits. [link] shows the distribution of systemic arteries from the heart into the upper limb. [link] summarizes the arteries serving the upper limbs.

Arteries Serving the Lower Limbs

The external iliac artery exits the body cavity and enters the femoral region of the lower leg ([link]). As it passes through the body wall, it is renamed the femoral artery. It gives off several smaller branches as well as the lateral deep femoral artery that in turn gives rise to a lateral circumflex artery. These arteries supply blood to the deep muscles of the thigh as well as ventral and lateral regions of the integument. The femoral artery also gives rise to the genicular artery, which provides blood to the region of the knee. As the femoral artery passes posterior to the knee near the popliteal fossa, it is called the popliteal artery. The popliteal artery branches into the anterior and posterior tibial arteries.

Overview of Systemic Veins

Systemic veins return blood to the right atrium. Since the blood has already passed through the systemic capillaries, it will be relatively low in oxygen concentration. In many cases, there will be veins draining organs and regions of the body with the same name as the arteries that supplied these regions and the two often parallel one another. This is often described as a “complementary” pattern. However, there is a great deal more variability in the venous circulation than normally occurs in the arteries. For the sake of brevity and clarity, this text will discuss only the most commonly encountered patterns. However, keep this variation in mind when you move from the classroom to clinical practice.

Hepatic Portal System

The liver is a complex biochemical processing plant. It packages nutrients absorbed by the digestive system; produces plasma proteins, clotting factors, and bile; and disposes of worn-out cell components and waste products. Instead of entering the circulation directly, absorbed nutrients and certain wastes (for example, materials produced by the spleen) travel to the liver for processing. They do so via the hepatic portal system ([link]). Portal systems begin and end in capillaries. In this case, the initial capillaries from the stomach, small intestine, large intestine, and spleen lead to the hepatic portal vein and end in specialized capillaries within the liver, the hepatic sinusoids. You saw the only other portal system with the hypothalamic-hypophyseal portal vessel in the endocrine chapter.

Development of Blood Vessels and Fetal Circulation

Abstract:
By the end of this section, you will be able to:

* Describe the development of blood vessels
* Describe the fetal circulation

The Lymphatic and Immune System

Introduction

Anatomy of the Lymphatic and Immune Systems

Abstract:
By the end of this section, you will be able to:

* Describe the structure and function of the lymphatic tissue (lymph fluid, vessels, ducts, and organs)
* Describe the structure and function of the primary and secondary lymphatic organs
* Discuss the cells of the immune system, how they function, and their relationship with the lymphatic system

Functions of the Lymphatic System

A major function of the lymphatic system is to drain body fluids and return them to the bloodstream. Blood pressure causes leakage of fluid from the capillaries, resulting in the accumulation of fluid in the interstitial space—that is, spaces between individual cells in the tissues. In humans, 20 liters of plasma is released into the interstitial space of the tissues each day due to capillary filtration. Once this filtrate is out of the bloodstream and in the tissue spaces, it is referred to as interstitial fluid. Of this, 17 liters is reabsorbed directly by the blood vessels. But what happens to the remaining three liters? This is where the lymphatic system comes into play. It drains the excess fluid and empties it back into the bloodstream via a series of vessels, trunks, and ducts. Lymph is the term used to describe interstitial fluid once it has entered the lymphatic system. When the lymphatic system is damaged in some way, such as by being blocked by cancer cells or destroyed by injury, protein-rich interstitial fluid accumulates (sometimes “backs up” from the lymph vessels) in the tissue spaces. This inappropriate accumulation of fluid referred to as lymphedema may lead to serious medical consequences.

Structure of the Lymphatic System

The lymphatic vessels begin as a blind ending, or closed at one end, capillaries, which feed into larger and larger lymphatic vessels, and eventually empty into the bloodstream by a series of ducts. Along the way, the lymph travels through the lymph nodes, which are commonly found near the groin, armpits, neck, chest, and abdomen. Humans have about 500–600 lymph nodes throughout the body ([link]).

The Organization of Immune Function

The immune system is a collection of barriers, cells, and soluble proteins that interact and communicate with each other in extraordinarily complex ways. The modern model of immune function is organized into three phases based on the timing of their effects. The three temporal phases consist of the following:

Lymphocytes: B Cells, T Cells, Plasma Cells, and Natural Killer Cells

As stated above, lymphocytes are the primary cells of adaptive immune responses ([link]). The two basic types of lymphocytes, B cells and T cells, are identical morphologically with a large central nucleus surrounded by a thin layer of cytoplasm. They are distinguished from each other by their surface protein markers as well as by the molecules they secrete. While B cells mature in red bone marrow and T cells mature in the thymus, they both initially develop from bone marrow. T cells migrate from bone marrow to the thymus gland where they further mature. B cells and T cells are found in many parts of the body, circulating in the bloodstream and lymph, and residing in secondary lymphoid organs, including the spleen and lymph nodes, which will be described later in this section. The human body contains approximately 1012 lymphocytes.

Primary Lymphoid Organs and Lymphocyte Development

Understanding the differentiation and development of B and T cells is critical to the understanding of the adaptive immune response. It is through this process that the body (ideally) learns to destroy only pathogens and leaves the body’s own cells relatively intact. The primary lymphoid organs are the bone marrow and thymus gland. The lymphoid organs are where lymphocytes mature, proliferate, and are selected, which enables them to attack pathogens without harming the cells of the body.

Secondary Lymphoid Organs and their Roles in Active Immune Responses

Lymphocytes develop and mature in the primary lymphoid organs, but they mount immune responses from the secondary lymphoid organs. A naïve lymphocyte is one that has left the primary organ and entered a secondary lymphoid organ. Naïve lymphocytes are fully functional immunologically, but have yet to encounter an antigen to respond to. In addition to circulating in the blood and lymph, lymphocytes concentrate in secondary lymphoid organs, which include the lymph nodes, spleen, and lymphoid nodules. All of these tissues have many features in common, including the following:

Barrier Defenses and the Innate Immune Response

Abstract:
By the end of this section, you will be able to:

* Describe the barrier defenses of the body
* Show how the innate immune response is important and how it helps guide and prepare the body for adaptive immune responses
* Describe various soluble factors that are part of the innate immune response
* Explain the steps of inflammation and how they lead to destruction of a pathogen
* Discuss early induced immune responses and their level of effectiveness

Cells of the Innate Immune Response

A phagocyte is a cell that is able to surround and engulf a particle or cell, a process called phagocytosis. The phagocytes of the immune system engulf other particles or cells, either to clean an area of debris, old cells, or to kill pathogenic organisms such as bacteria. The phagocytes are the body’s fast acting, first line of immunological defense against organisms that have breached barrier defenses and have entered the vulnerable tissues of the body.

Recognition of Pathogens

Cells of the innate immune response, the phagocytic cells, and the cytotoxic NK cells recognize patterns of pathogen-specific molecules, such as bacterial cell wall components or bacterial flagellar proteins, using pattern recognition receptors. A pattern recognition receptor (PRR) is a membrane-bound receptor that recognizes characteristic features of a pathogen and molecules released by stressed or damaged cells.

Soluble Mediators of the Innate Immune Response

The previous discussions have alluded to chemical signals that can induce cells to change various physiological characteristics, such as the expression of a particular receptor. These soluble factors are secreted during innate or early induced responses, and later during adaptive immune responses.

Inflammatory Response

The hallmark of the innate immune response is inflammation. Inflammation is something everyone has experienced. Stub a toe, cut a finger, or do any activity that causes tissue damage and inflammation will result, with its four characteristics: heat, redness, pain, and swelling (“loss of function” is sometimes mentioned as a fifth characteristic). It is important to note that inflammation does not have to be initiated by an infection, but can also be caused by tissue injuries. The release of damaged cellular contents into the site of injury is enough to stimulate the response, even in the absence of breaks in physical barriers that would allow pathogens to enter (by hitting your thumb with a hammer, for example). The inflammatory reaction brings in phagocytic cells to the damaged area to clear cellular debris and to set the stage for wound repair ([link]).

The Adaptive Immune Response: T lymphocytes and Their Functional Types

Abstract:
By the end of this section, you will be able to:

* Explain the advantages of the adaptive immune response over the innate immune response
* List the various characteristics of an antigen
* Describe the types of T cell antigen receptors
* Outline the steps of T cell development
* Describe the major T cell types and their functions

The Benefits of the Adaptive Immune Response

The specificity of the adaptive immune response—its ability to specifically recognize and make a response against a wide variety of pathogens—is its great strength. Antigens, the small chemical groups often associated with pathogens, are recognized by receptors on the surface of B and T lymphocytes. The adaptive immune response to these antigens is so versatile that it can respond to nearly any pathogen. This increase in specificity comes because the adaptive immune response has a unique way to develop as many as 1012, or 100 trillion, different receptors to recognize nearly every conceivable pathogen. How could so many different types of antibodies be encoded? And what about the many specificities of T cells? There is not nearly enough DNA in a cell to have a separate gene for each specificity. The mechanism was finally worked out in the 1970s and 1980s using the new tools of molecular genetics.

T Cell-Mediated Immune Responses

The primary cells that control the adaptive immune response are the lymphocytes, the T and B cells. T cells are particularly important, as they not only control a multitude of immune responses directly, but also control B cell immune responses in many cases as well. Thus, many of the decisions about how to attack a pathogen are made at the T cell level, and knowledge of their functional types is crucial to understanding the functioning and regulation of adaptive immune responses as a whole.

Antigens

Antigens on pathogens are usually large and complex, and consist of many antigenic determinants. An antigenic determinant (epitope) is one of the small regions within an antigen to which a receptor can bind, and antigenic determinants are limited by the size of the receptor itself. They usually consist of six or fewer amino acid residues in a protein, or one or two sugar moieties in a carbohydrate antigen. Antigenic determinants on a carbohydrate antigen are usually less diverse than on a protein antigen. Carbohydrate antigens are found on bacterial cell walls and on red blood cells (the ABO blood group antigens). Protein antigens are complex because of the variety of three-dimensional shapes that proteins can assume, and are especially important for the immune responses to viruses and worm parasites. It is the interaction of the shape of the antigen and the complementary shape of the amino acids of the antigen-binding site that accounts for the chemical basis of specificity ([link]).

T Cell Development and Differentiation

The process of eliminating T cells that might attack the cells of one’s own body is referred to as T cell tolerance. While thymocytes are in the cortex of the thymus, they are referred to as “double negatives,” meaning that they do not bear the CD4 or CD8 molecules that you can use to follow their pathways of differentiation ([link]). In the cortex of the thymus, they are exposed to cortical epithelial cells. In a process known as positive selection, double-negative thymocytes bind to the MHC molecules they observe on the thymic epithelia, and the MHC molecules of “self” are selected. This mechanism kills many thymocytes during T cell differentiation. In fact, only two percent of the thymocytes that enter the thymus leave it as mature, functional T cells.

Mechanisms of T Cell-mediated Immune Responses

Mature T cells become activated by recognizing processed foreign antigen in association with a self-MHC molecule and begin dividing rapidly by mitosis. This proliferation of T cells is called clonal expansion and is necessary to make the immune response strong enough to effectively control a pathogen. How does the body select only those T cells that are needed against a specific pathogen? Again, the specificity of a T cell is based on the amino acid sequence and the three-dimensional shape of the antigen-binding site formed by the variable regions of the two chains of the T cell receptor ([link]). Clonal selection is the process of antigen binding only to those T cells that have receptors specific to that antigen. Each T cell that is activated has a specific receptor “hard-wired” into its DNA, and all of its progeny will have identical DNA and T cell receptors, forming clones of the original T cell.

Clonal Selection and Expansion

The clonal selection theory was proposed by Frank Burnet in the 1950s. However, the term clonal selection is not a complete description of the theory, as clonal expansion goes hand in glove with the selection process. The main tenet of the theory is that a typical individual has a multitude (1011) of different types of T cell clones based on their receptors. In this use, a clone is a group of lymphocytes that share the same antigen receptor. Each clone is necessarily present in the body in low numbers. Otherwise, the body would not have room for lymphocytes with so many specificities.

The Cellular Basis of Immunological Memory

As already discussed, one of the major features of an adaptive immune response is the development of immunological memory.

T Cell Types and their Functions

In the discussion of T cell development, you saw that mature T cells express either the CD4 marker or the CD8 marker, but not both. These markers are cell adhesion molecules that keep the T cell in close contact with the antigen-presenting cell by directly binding to the MHC molecule (to a different part of the molecule than does the antigen). Thus, T cells and antigen-presenting cells are held together in two ways: by CD4 or CD8 attaching to MHC and by the T cell receptor binding to antigen ([link]).

The Adaptive Immune Response: B-lymphocytes and Antibodies

Abstract:
By the end of this section, you will be able to:

* Explain how B cells mature and how B cell tolerance develops
* Discuss how B cells are activated and differentiate into plasma cells
* Describe the structure of the antibody classes and their functions

B Cell Differentiation and Activation

B cells differentiate in the bone marrow. During the process of maturation, up to 100 trillion different clones of B cells are generated, which is similar to the diversity of antigen receptors seen in T cells.

Antibody Structure

Antibodies are glycoproteins consisting of two types of polypeptide chains with attached carbohydrates. The heavy chain and the light chain are the two polypeptides that form the antibody. The main differences between the classes of antibodies are in the differences between their heavy chains, but as you shall see, the light chains have an important role, forming part of the antigen-binding site on the antibody molecules.

Active versus Passive Immunity

Immunity to pathogens, and the ability to control pathogen growth so that damage to the tissues of the body is limited, can be acquired by (1) the active development of an immune response in the infected individual or (2) the passive transfer of immune components from an immune individual to a nonimmune one. Both active and passive immunity have examples in the natural world and as part of medicine.

T cell-dependent versus T cell-independent Antigens

As discussed previously, Th2 cells secrete cytokines that drive the production of antibodies in a B cell, responding to complex antigens such as those made by proteins. On the other hand, some antigens are T cell independent. A T cell-independent antigen usually is in the form of repeated carbohydrate moieties found on the cell walls of bacteria. Each antibody on the B cell surface has two binding sites, and the repeated nature of T cell-independent antigen leads to crosslinking of the surface antibodies on the B cell. The crosslinking is enough to activate it in the absence of T cell cytokines.

The Immune Response against Pathogens

Abstract:
By the end of this section, you will be able to:

* Explain the development of immunological competence
* Describe the mucosal immune response
* Discuss immune responses against bacterial, viral, fungal, and animal pathogens
* Describe different ways pathogens evade immune responses

The Mucosal Immune Response

Mucosal tissues are major barriers to the entry of pathogens into the body. The IgA (and sometimes IgM) antibodies in mucus and other secretions can bind to the pathogen, and in the cases of many viruses and bacteria, neutralize them. Neutralization is the process of coating a pathogen with antibodies, making it physically impossible for the pathogen to bind to receptors. Neutralization, which occurs in the blood, lymph, and other body fluids and secretions, protects the body constantly. Neutralizing antibodies are the basis for the disease protection offered by vaccines. Vaccinations for diseases that commonly enter the body via mucous membranes, such as influenza, are usually formulated to enhance IgA production.

Defenses against Bacteria and Fungi

The body fights bacterial pathogens with a wide variety of immunological mechanisms, essentially trying to find one that is effective. Bacteria such as *Mycobacterium leprae*, the cause of leprosy, are resistant to lysosomal enzymes and can persist in macrophage organelles or escape into the cytosol. In such situations, infected macrophages receiving cytokine signals from Th1 cells turn on special metabolic pathways. Macrophage oxidative metabolism is hostile to intracellular bacteria, often relying on the production of nitric oxide to kill the bacteria inside the macrophage.

Defenses against Parasites

Worm parasites such as helminths are seen as the primary reason why the mucosal immune response, IgE-mediated allergy and asthma, and eosinophils evolved. These parasites were at one time very common in human society. When infecting a human, often via contaminated food, some worms take up residence in the gastrointestinal tract. Eosinophils are attracted to the site by T cell cytokines, which release their granule contents upon their arrival. Mast cell degranulation also occurs, and the fluid leakage caused by the increase in local vascular permeability is thought to have a flushing action on the parasite, expelling its larvae from the body. Furthermore, if IgE labels the parasite, the eosinophils can bind to it by its Fc receptor.

Defenses against Viruses

The primary mechanisms against viruses are NK cells, interferons, and cytotoxic T cells. Antibodies are effective against viruses mostly during protection, where an immune individual can neutralize them based on a previous exposure. Antibodies have no effect on viruses or other intracellular pathogens once they enter the cell, since antibodies are not able to penetrate the plasma membrane of the cell. Many cells respond to viral infections by downregulating their expression of MHC class I molecules. This is to the advantage of the virus, because without class I expression, cytotoxic T cells have no activity. NK cells, however, can recognize virally infected class I-negative cells and destroy them. Thus, NK and cytotoxic T cells have complementary activities against virally infected cells.

Evasion of the Immune System by Pathogens

It is important to keep in mind that although the immune system has evolved to be able to control many pathogens, pathogens themselves have evolved ways to evade the immune response. An example already mentioned is in *Mycobacterium tuberculosis*, which has evolved a complex cell wall that is resistant to the digestive enzymes of the macrophages that ingest them, and thus persists in the host, causing the chronic disease tuberculosis. This section briefly summarizes other ways in which pathogens can “outwit” immune responses. But keep in mind, although it seems as if pathogens have a will of their own, they do not. All of these evasive “strategies” arose strictly by evolution, driven by selection.

Diseases Associated with Depressed or Overactive Immune Responses

Abstract:
By the end of this section, you will be able to:

* Discuss inherited and acquired immunodeficiencies
* Explain the four types of hypersensitivity and how they differ
* Give an example of how autoimmune disease breaks tolerance

Immunodeficiencies

As you have seen, the immune system is quite complex. It has many pathways using many cell types and signals. Because it is so complex, there are many ways for it to go wrong. Inherited immunodeficiencies arise from gene mutations that affect specific components of the immune response. There are also acquired immunodeficiencies with potentially devastating effects on the immune system, such as HIV.

Hypersensitivities

The word “hypersensitivity” simply means sensitive beyond normal levels of activation. Allergies and inflammatory responses to nonpathogenic environmental substances have been observed since the dawn of history. Hypersensitivity is a medical term describing symptoms that are now known to be caused by unrelated mechanisms of immunity. Still, it is useful for this discussion to use the four types of hypersensitivities as a guide to understand these mechanisms ([link]).

Autoimmune Responses

The worst cases of the immune system over-reacting are autoimmune diseases. Somehow, tolerance breaks down and the immune systems in individuals with these diseases begin to attack their own bodies, causing significant damage. The trigger for these diseases is, more often than not, unknown, and the treatments are usually based on resolving the symptoms using immunosuppressive and anti-inflammatory drugs such as steroids. These diseases can be localized and crippling, as in rheumatoid arthritis, or diffuse in the body with multiple symptoms that differ in different individuals, as is the case with systemic lupus erythematosus ([link]).

Transplantation and Cancer Immunology

Abstract:
By the end of this section, you will be able to:

* Explain why blood typing is important and what happens when mismatched blood is used in a transfusion
* Describe how tissue typing is done during organ transplantation and the role of transplant anti-rejection drugs
* Show how the immune response is able to control some cancers and how this immune response might be enhanced by cancer vaccines

The Rh Factor

Red blood cells can be typed based on their surface antigens. ABO blood type, in which individuals are type A, B, AB, or O according to their genetics, is one example. A separate antigen system seen on red blood cells is the Rh antigen. When someone is “A positive” for example, the positive refers to the presence of the Rh antigen, whereas someone who is “A negative” would lack this molecule.

Tissue Transplantation

Tissue transplantation is more complicated than blood transfusions because of two characteristics of MHC molecules. These molecules are the major cause of transplant rejection (hence the name “histocompatibility”). MHC polygeny refers to the multiple MHC proteins on cells, and MHC polymorphism refers to the multiple alleles for each individual MHC locus. Thus, there are many alleles in the human population that can be expressed ([link] and [link]). When a donor organ expresses MHC molecules that are different from the recipient, the latter will often mount a cytotoxic T cell response to the organ and reject it. Histologically, if a biopsy of a transplanted organ exhibits massive infiltration of T lymphocytes within the first weeks after transplant, it is a sign that the transplant is likely to fail. The response is a classical, and very specific, primary T cell immune response. As far as medicine is concerned, the immune response in this scenario does the patient no good at all and causes significant harm.

Immune Responses Against Cancer

It is clear that with some cancers, for example Kaposi’s sarcoma, a healthy immune system does a good job at controlling them ([link]). This disease, which is caused by the human herpesvirus, is almost never observed in individuals with strong immune systems, such as the young and immunocompetent. Other examples of cancers caused by viruses include liver cancer caused by the hepatitis B virus and cervical cancer caused by the human papilloma virus. As these last two viruses have vaccines available for them, getting vaccinated can help prevent these two types of cancer by stimulating the immune response.

Energy, Maintenance, and Environmental Exchange

The Respiratory System

Introduction

Organs and Structures of the Respiratory System

Abstract:
By the end of this section, you will be able to:

* List the structures that make up the respiratory system
* Describe how the respiratory system processes oxygen and CO2
* Compare and contrast the functions of upper respiratory tract with the lower respiratory tract

Conducting Zone

The major functions of the conducting zone are to provide a route for incoming and outgoing air, remove debris and pathogens from the incoming air, and warm and humidify the incoming air. Several structures within the conducting zone perform other functions as well. The epithelium of the nasal passages, for example, is essential to sensing odors, and the bronchial epithelium that lines the lungs can metabolize some airborne carcinogens.

Respiratory Zone

In contrast to the conducting zone, the respiratory zone includes structures that are directly involved in gas exchange. The respiratory zone begins where the terminal bronchioles join a respiratory bronchiole, the smallest type of bronchiole ([link]), which then leads to an alveolar duct, opening into a cluster of alveoli.

The Lungs

Abstract:
By the end of this section, you will be able to:

* Describe the overall function of the lung
* Summarize the blood flow pattern associated with the lungs
* Outline the anatomy of the blood supply to the lungs
* Describe the pleura of the lungs and their function

Gross Anatomy of the Lungs

The lungs are pyramid-shaped, paired organs that are connected to the trachea by the right and left bronchi; on the inferior surface, the lungs are bordered by the diaphragm. The diaphragm is a dome-shaped muscle located at the base of the lungs and thoracic cavity. The lungs are enclosed by the pleurae, which are attached to the mediastinum. The right lung is shorter and wider than the left lung, and the left lung occupies a smaller volume than the right. The cardiac notch is an indentation on the surface of the left lung, and it allows space for the heart ([link]). The apex of the lung is the superior region, whereas the base is the opposite region near the diaphragm. The costal surface of the lung borders the ribs. The mediastinal surface faces the midline.

Blood Supply and Nervous Innervation of the Lungs

The blood supply of the lungs plays an important role in gas exchange and serves as a transport system for gases throughout the body. In addition, innervation by the both the parasympathetic and sympathetic nervous systems provides an important level of control through dilation and constriction of the airway.

Pleura of the Lungs

Each lung is enclosed within a cavity that is surrounded by the pleura. The pleura (plural = pleurae) is a serous membrane that surrounds the lung. The right and left pleurae, which enclose the right and left lungs, respectively, are separated by the mediastinum. The pleurae consist of two layers. The visceral pleura is the layer that is superficial to the lungs, and extends into and lines the lung fissures ([link]). In contrast, the parietal pleura is the outer layer that connects to the thoracic wall, the mediastinum, and the diaphragm. The visceral and parietal pleurae connect to each other at the hilum. The pleural cavity is the space between the visceral and parietal layers.

The Process of Breathing

Abstract:
By the end of this section, you will be able to:

* Describe the mechanisms that drive breathing
* Discuss how pressure, volume, and resistance are related
* List the steps involved in pulmonary ventilation
* Discuss the physical factors related to breathing
* Discuss the meaning of respiratory volume and capacities
* Define respiratory rate
* Outline the mechanisms behind the control of breathing
* Describe the respiratory centers of the medulla oblongata
* Describe the respiratory centers of the pons
* Discuss factors that can influence the respiratory rate

Mechanisms of Breathing

The intra-alveolar and intrapleural pressures are dependent on certain physical features of the lung. However, the ability to breathe—to have air enter the lungs during inspiration and air leave the lungs during expiration—is dependent on the air pressure of the atmosphere and the air pressure within the lungs.

Pulmonary Ventilation

The difference in pressures drives pulmonary ventilation because air flows down a pressure gradient, that is, air flows from an area of higher pressure to an area of lower pressure. Air flows into the lungs largely due to a difference in pressure; atmospheric pressure is greater than intra-alveolar pressure, and intra-alveolar pressure is greater than intrapleural pressure. Air flows out of the lungs during expiration based on the same principle; pressure within the lungs becomes greater than the atmospheric pressure.

Respiratory Volumes and Capacities

Respiratory volume is the term used for various volumes of air moved by or associated with the lungs at a given point in the respiratory cycle. There are four major types of respiratory volumes: tidal, residual, inspiratory reserve, and expiratory reserve ([link]). Tidal volume (TV) is the amount of air that normally enters the lungs during quiet breathing, which is about 500 milliliters. Expiratory reserve volume (ERV) is the amount of air you can forcefully exhale past a normal tidal expiration, up to 1200 milliliters for males. Inspiratory reserve volume (IRV) is produced by a deep inhalation, past a tidal inspiration. This is the extra volume that can be brought into the lungs during a forced inspiration. Residual volume (RV) is the air left in the lungs if you exhale as much air as possible. The residual volume makes breathing easier by preventing the alveoli from collapsing. Respiratory volume is dependent on a variety of factors, and measuring the different types of respiratory volumes can provide important clues about a person’s respiratory health ([link]).

Respiratory Rate and Control of Ventilation

Breathing usually occurs without thought, although at times you can consciously control it, such as when you swim under water, sing a song, or blow bubbles. The respiratory rate is the total number of breaths, or respiratory cycles, that occur each minute. Respiratory rate can be an important indicator of disease, as the rate may increase or decrease during an illness or in a disease condition. The respiratory rate is controlled by the respiratory center located within the medulla oblongata in the brain, which responds primarily to changes in carbon dioxide, oxygen, and pH levels in the blood.

Gas Exchange

Abstract:
By the end of this section, you will be able to:

* Compare the composition of atmospheric air and alveolar air
* Describe the mechanisms that drive gas exchange
* Discuss the importance of sufficient ventilation and perfusion, and how the body adapts when they are insufficient
* Discuss the process of external respiration
* Describe the process of internal respiration

Gas Exchange

In order to understand the mechanisms of gas exchange in the lung, it is important to understand the underlying principles of gases and their behavior. In addition to Boyle’s law, several other gas laws help to describe the behavior of gases.

Gas Exchange

Gas exchange occurs at two sites in the body: in the lungs, where oxygen is picked up and carbon dioxide is released at the respiratory membrane, and at the tissues, where oxygen is released and carbon dioxide is picked up. External respiration is the exchange of gases with the external environment, and occurs in the alveoli of the lungs. Internal respiration is the exchange of gases with the internal environment, and occurs in the tissues. The actual exchange of gases occurs due to simple diffusion. Energy is not required to move oxygen or carbon dioxide across membranes. Instead, these gases follow pressure gradients that allow them to diffuse. The anatomy of the lung maximizes the diffusion of gases: The respiratory membrane is highly permeable to gases; the respiratory and blood capillary membranes are very thin; and there is a large surface area throughout the lungs.

Transport of Gases

Abstract:
By the end of this section, you will be able to:

* Describe the principles of oxygen transport
* Describe the structure of hemoglobin
* Compare and contrast fetal and adult hemoglobin
* Describe the principles of carbon dioxide transport

Oxygen Transport in the Blood

Even though oxygen is transported via the blood, you may recall that oxygen is not very soluble in liquids. A small amount of oxygen does dissolve in the blood and is transported in the bloodstream, but it is only about 1.5% of the total amount. The majority of oxygen molecules are carried from the lungs to the body’s tissues by a specialized transport system, which relies on the erythrocyte—the red blood cell. Erythrocytes contain a metalloprotein, hemoglobin, which serves to bind oxygen molecules to the erythrocyte ([link]). Heme is the portion of hemoglobin that contains iron, and it is heme that binds oxygen. Each hemoglobin molecule contains four iron-containing heme molecules, and because of this, one hemoglobin molecule is capable of carrying up to four molecules of oxygen. As oxygen diffuses across the respiratory membrane from the alveolus to the capillary, it also diffuses into the red blood cell and is bound by hemoglobin. The following reversible chemical reaction describes the production of the final product, oxyhemoglobin (HbO2), which is formed when oxygen binds to hemoglobin. Oxyhemoglobin is a bright red-colored molecule that contributes to the bright red color of oxygenated blood.

Carbon Dioxide Transport in the Blood

Carbon dioxide is transported by three major mechanisms. The first mechanism of carbon dioxide transport is by blood plasma, as some carbon dioxide molecules dissolve in the blood. The second mechanism is transport in the form of bicarbonate (HCO3–), which also dissolves in plasma. The third mechanism of carbon dioxide transport is similar to the transport of oxygen by erythrocytes ([link]).

Modifications in Respiratory Functions

Abstract:
By the end of this section, you will be able to:

* Define the terms hyperpnea and hyperventilation
* Describe the effect of exercise on the respiratory system
* Describe the effect of high altitude on the respiratory system
* Discuss the process of acclimatization

Hyperpnea

Hyperpnea is an increased depth and rate of ventilation to meet an increase in oxygen demand as might be seen in exercise or disease, particularly diseases that target the respiratory or digestive tracts. This does not significantly alter blood oxygen or carbon dioxide levels, but merely increases the depth and rate of ventilation to meet the demand of the cells. In contrast, hyperventilation is an increased ventilation rate that is independent of the cellular oxygen needs and leads to abnormally low blood carbon dioxide levels and high (alkaline) blood pH.

High Altitude Effects

An increase in altitude results in a decrease in atmospheric pressure. Although the proportion of oxygen relative to gases in the atmosphere remains at 21 percent, its partial pressure decreases ([link]). As a result, it is more difficult for a body to achieve the same level of oxygen saturation at high altitude than at low altitude, due to lower atmospheric pressure. In fact, hemoglobin saturation is lower at high altitudes compared to hemoglobin saturation at sea level. For example, hemoglobin saturation is about 67 percent at 19,000 feet above sea level, whereas it reaches about 98 percent at sea level.

Embryonic Development of the Respiratory System

Abstract:
By the end of this section, you will be able to:

* Create a timeline of the phases of respiratory development in the fetus
* Propose reasons for fetal breathing movements
* Explain how the lungs become inflated after birth

Time Line

The development of the respiratory system begins at about week 4 of gestation. By week 28, enough alveoli have matured that a baby born prematurely at this time can usually breathe on its own. The respiratory system, however, is not fully developed until early childhood, when a full complement of mature alveoli is present.

Fetal “Breathing”

Although the function of fetal breathing movements is not entirely clear, they can be observed starting at 20–21 weeks of development. Fetal breathing movements involve muscle contractions that cause the inhalation of amniotic fluid and exhalation of the same fluid, with pulmonary surfactant and mucus. Fetal breathing movements are not continuous and may include periods of frequent movements and periods of no movements. Maternal factors can influence the frequency of breathing movements. For example, high blood glucose levels, called hyperglycemia, can boost the number of breathing movements. Conversely, low blood glucose levels, called hypoglycemia, can reduce the number of fetal breathing movements. Tobacco use is also known to lower fetal breathing rates. Fetal breathing may help tone the muscles in preparation for breathing movements once the fetus is born. It may also help the alveoli to form and mature. Fetal breathing movements are considered a sign of robust health.

Birth

Prior to birth, the lungs are filled with amniotic fluid, mucus, and surfactant. As the fetus is squeezed through the birth canal, the fetal thoracic cavity is compressed, expelling much of this fluid. Some fluid remains, however, but is rapidly absorbed by the body shortly after birth. The first inhalation occurs within 10 seconds after birth and not only serves as the first inspiration, but also acts to inflate the lungs. Pulmonary surfactant is critical for inflation to occur, as it reduces the surface tension of the alveoli. Preterm birth around 26 weeks frequently results in severe respiratory distress, although with current medical advancements, some babies may survive. Prior to 26 weeks, sufficient pulmonary surfactant is not produced, and the surfaces for gas exchange have not formed adequately; therefore, survival is low.

The Digestive System

Introduction

Overview of the Digestive System

Abstract:
By the end of this section, you will be able to:

* Identify the organs of the alimentary canal from proximal to distal, and briefly state their function
* Identify the accessory digestive organs and briefly state their function
* Describe the four fundamental tissue layers of the alimentary canal
* Contrast the contributions of the enteric and autonomic nervous systems to digestive system functioning
* Explain how the peritoneum anchors the digestive organs

Digestive System Organs

The easiest way to understand the digestive system is to divide its organs into two main categories. The first group is the organs that make up the alimentary canal. Accessory digestive organs comprise the second group and are critical for orchestrating the breakdown of food and the assimilation of its nutrients into the body. Accessory digestive organs, despite their name, are critical to the function of the digestive system.

Histology of the Alimentary Canal

Throughout its length, the alimentary tract is composed of the same four tissue layers; the details of their structural arrangements vary to fit their specific functions. Starting from the lumen and moving outwards, these layers are the mucosa, submucosa, muscularis, and serosa, which is continuous with the mesentery (see [link]).

Nerve Supply

As soon as food enters the mouth, it is detected by receptors that send impulses along the sensory neurons of cranial nerves. Without these nerves, not only would your food be without taste, but you would also be unable to feel either the food or the structures of your mouth, and you would be unable to avoid biting yourself as you chew, an action enabled by the motor branches of cranial nerves.

Blood Supply

The blood vessels serving the digestive system have two functions. They transport the protein and carbohydrate nutrients absorbed by mucosal cells after food is digested in the lumen. Lipids are absorbed via lacteals, tiny structures of the lymphatic system. The blood vessels’ second function is to supply the organs of the alimentary canal with the nutrients and oxygen needed to drive their cellular processes.

The Peritoneum

The digestive organs within the abdominal cavity are held in place by the peritoneum, a broad serous membranous sac made up of squamous epithelial tissue surrounded by connective tissue. It is composed of two different regions: the parietal peritoneum, which lines the abdominal wall, and the visceral peritoneum, which envelopes the abdominal organs ([link]). The peritoneal cavity is the space bounded by the visceral and parietal peritoneal surfaces. A few milliliters of watery fluid act as a lubricant to minimize friction between the serosal surfaces of the peritoneum.

Digestive System Processes and Regulation

Abstract:
By the end of this section, you will be able to:

* Discuss six fundamental activities of the digestive system, giving an example of each
* Compare and contrast the neural and hormonal controls involved in digestion

Digestive Processes

The processes of digestion include six activities: ingestion, propulsion, mechanical or physical digestion, chemical digestion, absorption, and defecation.

Regulatory Mechanisms

Neural and endocrine regulatory mechanisms work to maintain the optimal conditions in the lumen needed for digestion and absorption. These regulatory mechanisms, which stimulate digestive activity through mechanical and chemical activity, are controlled both extrinsically and intrinsically.

The Mouth, Pharynx, and Esophagus

Abstract:
By the end of this section, you will be able to:

* Describe the structures of the mouth, including its three accessory digestive organs
* Group the 32 adult teeth according to name, location, and function
* Describe the process of swallowing, including the roles of the tongue, upper esophageal sphincter, and epiglottis
* Trace the pathway food follows from ingestion into the mouth through release into the stomach

The Mouth

The cheeks, tongue, and palate frame the mouth, which is also called the oral cavity (or buccal cavity). The structures of the mouth are illustrated in [link].

The Tongue

Perhaps you have heard it said that the tongue is the strongest muscle in the body. Those who stake this claim cite its strength proportionate to its size. Although it is difficult to quantify the relative strength of different muscles, it remains indisputable that the tongue is a workhorse, facilitating ingestion, mechanical digestion, chemical digestion (lingual lipase), sensation (of taste, texture, and temperature of food), swallowing, and vocalization.

The Salivary Glands

Many small salivary glands are housed within the mucous membranes of the mouth and tongue. These minor exocrine glands are constantly secreting saliva, either directly into the oral cavity or indirectly through ducts, even while you sleep. In fact, an average of 1 to 1.5 liters of saliva is secreted each day. Usually just enough saliva is present to moisten the mouth and teeth. Secretion increases when you eat, because saliva is essential to moisten food and initiate the chemical breakdown of carbohydrates. Small amounts of saliva are also secreted by the labial glands in the lips. In addition, the buccal glands in the cheeks, palatal glands in the palate, and lingual glands in the tongue help ensure that all areas of the mouth are supplied with adequate saliva.

The Teeth

The teeth, or dentes (singular = dens), are organs similar to bones that you use to tear, grind, and otherwise mechanically break down food.

The Pharynx

The pharynx (throat) is involved in both digestion and respiration. It receives food and air from the mouth, and air from the nasal cavities. When food enters the pharynx, involuntary muscle contractions close off the air passageways.

The Esophagus

The esophagus is a muscular tube that connects the pharynx to the stomach. It is approximately 25.4 cm (10 in) in length, located posterior to the trachea, and remains in a collapsed form when not engaged in swallowing. As you can see in [link], the esophagus runs a mainly straight route through the mediastinum of the thorax. To enter the abdomen, the esophagus penetrates the diaphragm through an opening called the esophageal hiatus.

Deglutition

Deglutition is another word for swallowing—the movement of food from the mouth to the stomach. The entire process takes about 4 to 8 seconds for solid or semisolid food, and about 1 second for very soft food and liquids. Although this sounds quick and effortless, deglutition is, in fact, a complex process that involves both the skeletal muscle of the tongue and the muscles of the pharynx and esophagus. It is aided by the presence of mucus and saliva. There are three stages in deglutition: the voluntary phase, the pharyngeal phase, and the esophageal phase ([link]). The autonomic nervous system controls the latter two phases.

The Stomach

Abstract:
By the end of this section, you will be able to:

* Label on a diagram the four main regions of the stomach, its curvatures, and its sphincter
* Identify the four main types of secreting cells in gastric glands, and their important products
* Explain why the stomach does not digest itself
* Describe the mechanical and chemical digestion of food entering the stomach

Structure

There are four main regions in the stomach: the cardia, fundus, body, and pylorus ([link]). The cardia (or cardiac region) is the point where the esophagus connects to the stomach and through which food passes into the stomach. Located inferior to the diaphragm, above and to the left of the cardia, is the dome-shaped fundus. Below the fundus is the body, the main part of the stomach. The funnel-shaped pylorus connects the stomach to the duodenum. The wider end of the funnel, the pyloric antrum, connects to the body of the stomach. The narrower end is called the pyloric canal, which connects to the duodenum. The smooth muscle pyloric sphincter is located at this latter point of connection and controls stomach emptying. In the absence of food, the stomach deflates inward, and its mucosa and submucosa fall into a large fold called a ruga.

Histology

The wall of the stomach is made of the same four layers as most of the rest of the alimentary canal, but with adaptations to the mucosa and muscularis for the unique functions of this organ. In addition to the typical circular and longitudinal smooth muscle layers, the muscularis has an inner oblique smooth muscle layer ([link]). As a result, in addition to moving food through the canal, the stomach can vigorously churn food, mechanically breaking it down into smaller particles.

Gastric Secretion

The secretion of gastric juice is controlled by both nerves and hormones. Stimuli in the brain, stomach, and small intestine activate or inhibit gastric juice production. This is why the three phases of gastric secretion are called the cephalic, gastric, and intestinal phases ([link]). However, once gastric secretion begins, all three phases can occur simultaneously.

The Mucosal Barrier

The mucosa of the stomach is exposed to the highly corrosive acidity of gastric juice. Gastric enzymes that can digest protein can also digest the stomach itself. The stomach is protected from self-digestion by the mucosal barrier. This barrier has several components. First, the stomach wall is covered by a thick coating of bicarbonate-rich mucus. This mucus forms a physical barrier, and its bicarbonate ions neutralize acid. Second, the epithelial cells of the stomach's mucosa meet at tight junctions, which block gastric juice from penetrating the underlying tissue layers. Finally, stem cells located where gastric glands join the gastric pits quickly replace damaged epithelial mucosal cells, when the epithelial cells are shed. In fact, the surface epithelium of the stomach is completely replaced every 3 to 6 days.

Digestive Functions of the Stomach

The stomach participates in virtually all the digestive activities with the exception of ingestion and defecation. Although almost all absorption takes place in the small intestine, the stomach does absorb some drugs, such as alcohol and aspirin.

The Small and Large Intestines

Abstract:
By the end of this section, you will be able to:

* Compare and contrast the location and gross anatomy of the small and large intestines
* Identify three main adaptations of the small intestine wall that increase its absorptive capacity
* Describe the mechanical and chemical digestion of chyme upon its release into the small intestine
* List three features unique to the wall of the large intestine and identify their contributions to its function
* Identify the beneficial roles of the bacterial flora in digestive system functioning
* Trace the pathway of food waste from its point of entry into the large intestine through its exit from the body as feces

The Small Intestine

Chyme released from the stomach enters the small intestine, which is the primary digestive organ in the body. Not only is this where most digestion occurs, it is also where practically all absorption occurs. The longest part of the alimentary canal, the small intestine is about 3.05 meters (10 feet) long in a living person (but about twice as long in a cadaver due to the loss of muscle tone). Since this makes it about five times longer than the large intestine, you might wonder why it is called “small.” In fact, its name derives from its relatively smaller diameter of only about 2.54 cm (1 in), compared with 7.62 cm (3 in) for the large intestine. As we’ll see shortly, in addition to its length, the folds and projections of the lining of the small intestine work to give it an enormous surface area, which is approximately 200 m2, more than 100 times the surface area of your skin. This large surface area is necessary for complex processes of digestion and absorption that occur within it.

The Large Intestine

The large intestine is the terminal part of the alimentary canal. The primary function of this organ is to finish absorption of nutrients and water, synthesize certain vitamins, form feces, and eliminate feces from the body.

Accessory Organs in Digestion: The Liver, Pancreas, and Gallbladder

Abstract:
By the end of this section, you will be able to:

* State the main digestive roles of the liver, pancreas, and gallbladder
* Identify three main features of liver histology that are critical to its function
* Discuss the composition and function of bile
* Identify the major types of enzymes and buffers present in pancreatic juice

The Liver

The liver is the largest gland in the body, weighing about three pounds in an adult. It is also one of the most important organs. In addition to being an accessory digestive organ, it plays a number of roles in metabolism and regulation. The liver lies inferior to the diaphragm in the right upper quadrant of the abdominal cavity and receives protection from the surrounding ribs.

The Pancreas

The soft, oblong, glandular pancreas lies transversely in the retroperitoneum behind the stomach. Its head is nestled into the “c-shaped” curvature of the duodenum with the body extending to the left about 15.2 cm (6 in) and ending as a tapering tail in the hilum of the spleen. It is a curious mix of exocrine (secreting digestive enzymes) and endocrine (releasing hormones into the blood) functions ([link]).

The Gallbladder

The gallbladder is 8–10 cm (~3–4 in) long and is nested in a shallow area on the posterior aspect of the right lobe of the liver. This muscular sac stores, concentrates, and, when stimulated, propels the bile into the duodenum via the common bile duct. It is divided into three regions. The fundus is the widest portion and tapers medially into the body, which in turn narrows to become the neck. The neck angles slightly superiorly as it approaches the hepatic duct. The cystic duct is 1–2 cm (less than 1 in) long and turns inferiorly as it bridges the neck and hepatic duct.

Chemical Digestion and Absorption: A Closer Look

Abstract:
By the end of this section, you will be able to:

* Identify the locations and primary secretions involved in the chemical digestion of carbohydrates, proteins, lipids, and nucleic acids
* Compare and contrast absorption of the hydrophilic and hydrophobic nutrients

Chemical Digestion

Large food molecules (for example, proteins, lipids, nucleic acids, and starches) must be broken down into subunits that are small enough to be absorbed by the lining of the alimentary canal. This is accomplished by enzymes through hydrolysis. The many enzymes involved in chemical digestion are summarized in [link].

Absorption

The mechanical and digestive processes have one goal: to convert food into molecules small enough to be absorbed by the epithelial cells of the intestinal villi. The absorptive capacity of the alimentary canal is almost endless. Each day, the alimentary canal processes up to 10 liters of food, liquids, and GI secretions, yet less than one liter enters the large intestine. Almost all ingested food, 80 percent of electrolytes, and 90 percent of water are absorbed in the small intestine. Although the entire small intestine is involved in the absorption of water and lipids, most absorption of carbohydrates and proteins occurs in the jejunum. Notably, bile salts and vitamin B12 are absorbed in the terminal ileum. By the time chyme passes from the ileum into the large intestine, it is essentially indigestible food residue (mainly plant fibers like cellulose), some water, and millions of bacteria ([link]).

Metabolism and Nutrition

Introduction

Overview of Metabolic Reactions

Abstract:
By the end of this section, you will be able to:

* Describe the process by which polymers are broken down into monomers
* Describe the process by which monomers are combined into polymers
* Discuss the role of ATP in metabolism
* Explain oxidation-reduction reactions
* Describe the hormones that regulate anabolic and catabolic reactions

Catabolic Reactions

Catabolic reactions break down large organic molecules into smaller molecules, releasing the energy contained in the chemical bonds. These energy releases (conversions) are not 100 percent efficient. The amount of energy released is less than the total amount contained in the molecule. Approximately 40 percent of energy yielded from catabolic reactions is directly transferred to the high-energy molecule adenosine triphosphate (ATP). ATP, the energy currency of cells, can be used immediately to power molecular machines that support cell, tissue, and organ function. This includes building new tissue and repairing damaged tissue. ATP can also be stored to fulfill future energy demands. The remaining 60 percent of the energy released from catabolic reactions is given off as heat, which tissues and body fluids absorb.

Anabolic Reactions

In contrast to catabolic reactions, anabolic reactions involve the joining of smaller molecules into larger ones. Anabolic reactions combine monosaccharides to form polysaccharides, fatty acids to form triglycerides, amino acids to form proteins, and nucleotides to form nucleic acids. These processes require energy in the form of ATP molecules generated by catabolic reactions. Anabolic reactions, also called biosynthesis reactions, create new molecules that form new cells and tissues, and revitalize organs.

Hormonal Regulation of Metabolism

Catabolic and anabolic hormones in the body help regulate metabolic processes. Catabolic hormones stimulate the breakdown of molecules and the production of energy. These include cortisol, glucagon, adrenaline/epinephrine, and cytokines. All of these hormones are mobilized at specific times to meet the needs of the body. Anabolic hormones are required for the synthesis of molecules and include growth hormone, insulin-like growth factor, insulin, testosterone, and estrogen. [link] summarizes the function of each of the catabolic hormones and [link] summarizes the functions of the anabolic hormones.

Oxidation-Reduction Reactions

The chemical reactions underlying metabolism involve the transfer of electrons from one compound to another by processes catalyzed by enzymes. The electrons in these reactions commonly come from hydrogen atoms, which consist of an electron and a proton. A molecule gives up a hydrogen atom, in the form of a hydrogen ion (H+) and an electron, breaking the molecule into smaller parts. The loss of an electron, or oxidation, releases a small amount of energy; both the electron and the energy are then passed to another molecule in the process of reduction, or the gaining of an electron. These two reactions always happen together in an oxidation-reduction reaction (also called a redox reaction)—when an electron is passed between molecules, the donor is oxidized and the recipient is reduced. Oxidation-reduction reactions often happen in a series, so that a molecule that is reduced is subsequently oxidized, passing on not only the electron it just received but also the energy it received. As the series of reactions progresses, energy accumulates that is used to combine Pi and ADP to form ATP, the high-energy molecule that the body uses for fuel.

Carbohydrate Metabolism

Abstract:
By the end of this section, you will be able to:

* Explain the processes of glycolysis
* Describe the pathway of a pyruvate molecule through the Krebs cycle
* Explain the transport of electrons through the electron transport chain
* Describe the process of ATP production through oxidative phosphorylation
* Summarize the process of gluconeogenesis

Glycolysis

Glucose is the body’s most readily available source of energy. After digestive processes break polysaccharides down into monosaccharides, including glucose, the monosaccharides are transported across the wall of the small intestine and into the circulatory system, which transports them to the liver. In the liver, hepatocytes either pass the glucose on through the circulatory system or store excess glucose as glycogen. Cells in the body take up the circulating glucose in response to insulin and, through a series of reactions called glycolysis, transfer some of the energy in glucose to ADP to form ATP ([link]). The last step in glycolysis produces the product pyruvate.

Krebs Cycle/Citric Acid Cycle/Tricarboxylic Acid Cycle

The pyruvate molecules generated during glycolysis are transported across the mitochondrial membrane into the inner mitochondrial matrix, where they are metabolized by enzymes in a pathway called the Krebs cycle ([link]). The Krebs cycle is also commonly called the citric acid cycle or the tricarboxylic acid (TCA) cycle. During the Krebs cycle, high-energy molecules, including ATP, NADH, and FADH2, are created. NADH and FADH2 then pass electrons through the electron transport chain in the mitochondria to generate more ATP molecules.

Oxidative Phosphorylation and the Electron Transport Chain

The electron transport chain (ETC) uses the NADH and FADH2 produced by the Krebs cycle to generate ATP. Electrons from NADH and FADH2 are transferred through protein complexes embedded in the inner mitochondrial membrane by a series of enzymatic reactions. The electron transport chain consists of a series of four enzyme complexes (Complex I – Complex IV) and two coenzymes (ubiquinone and Cytochrome c), which act as electron carriers and proton pumps used to transfer H+ ions into the space between the inner and outer mitochondrial membranes ([link]). The ETC couples the transfer of electrons between a donor (like NADH) and an electron acceptor (like O2) with the transfer of protons (H+ ions) across the inner mitochondrial membrane, enabling the process of oxidative phosphorylation. In the presence of oxygen, energy is passed, stepwise, through the electron carriers to collect gradually the energy needed to attach a phosphate to ADP and produce ATP. The role of molecular oxygen, O2, is as the terminal electron acceptor for the ETC. This means that once the electrons have passed through the entire ETC, they must be passed to another, separate molecule. These electrons, O2, and H+ ions from the matrix combine to form new water molecules. This is the basis for your need to breathe in oxygen. Without oxygen, electron flow through the ETC ceases.

Gluconeogenesis

Gluconeogenesis is the synthesis of new glucose molecules from pyruvate, lactate, glycerol, or the amino acids alanine or glutamine. This process takes place primarily in the liver during periods of low glucose, that is, under conditions of fasting, starvation, and low carbohydrate diets. So, the question can be raised as to why the body would create something it has just spent a fair amount of effort to break down? Certain key organs, including the brain, can use only glucose as an energy source; therefore, it is essential that the body maintain a minimum blood glucose concentration. When the blood glucose concentration falls below that certain point, new glucose is synthesized by the liver to raise the blood concentration to normal.

Lipid Metabolism

Abstract:
By the end of this section, you will be able to:

* Explain how energy can be derived from fat
* Explain the purpose and process of ketogenesis
* Describe the process of ketone body oxidation
* Explain the purpose and the process of lipogenesis

Lipolysis

To obtain energy from fat, triglycerides must first be broken down by hydrolysis into their two principal components, fatty acids and glycerol. This process, called lipolysis, takes place in the cytoplasm. The resulting fatty acids are oxidized by β-oxidation into acetyl CoA, which is used by the Krebs cycle. The glycerol that is released from triglycerides after lipolysis directly enters the glycolysis pathway as DHAP. Because one triglyceride molecule yields three fatty acid molecules with as much as 16 or more carbons in each one, fat molecules yield more energy than carbohydrates and are an important source of energy for the human body. Triglycerides yield more than twice the energy per unit mass when compared to carbohydrates and proteins. Therefore, when glucose levels are low, triglycerides can be converted into acetyl CoA molecules and used to generate ATP through aerobic respiration.

Ketogenesis

If excessive acetyl CoA is created from the oxidation of fatty acids and the Krebs cycle is overloaded and cannot handle it, the acetyl CoA is diverted to create ketone bodies. These ketone bodies can serve as a fuel source if glucose levels are too low in the body. Ketones serve as fuel in times of prolonged starvation or when patients suffer from uncontrolled diabetes and cannot utilize most of the circulating glucose. In both cases, fat stores are liberated to generate energy through the Krebs cycle and will generate ketone bodies when too much acetyl CoA accumulates.

Ketone Body Oxidation

Organs that have classically been thought to be dependent solely on glucose, such as the brain, can actually use ketones as an alternative energy source. This keeps the brain functioning when glucose is limited. When ketones are produced faster than they can be used, they can be broken down into CO2 and acetone. The acetone is removed by exhalation. One symptom of ketogenesis is that the patient’s breath smells sweet like alcohol. This effect provides one way of telling if a person with diabetes is properly controlling the disease. The carbon dioxide produced can acidify the blood, leading to diabetic ketoacidosis, a dangerous condition in people with diabetes.

Lipogenesis

When glucose levels are plentiful, the excess acetyl CoA generated by glycolysis can be converted into fatty acids, triglycerides, cholesterol, steroids, and bile salts. This process, called lipogenesis, creates lipids (fat) from the acetyl CoA and takes place in the cytoplasm of adipocytes (fat cells) and hepatocytes (liver cells). When you eat more glucose or carbohydrates than your body needs, your system uses acetyl CoA to turn the excess into fat. Although there are several metabolic sources of acetyl CoA, it is most commonly derived from glycolysis. Acetyl CoA availability is significant, because it initiates lipogenesis. Lipogenesis begins with acetyl CoA and advances by the subsequent addition of two carbon atoms from another acetyl CoA; this process is repeated until fatty acids are the appropriate length. Because this is a bond-creating anabolic process, ATP is consumed. However, the creation of triglycerides and lipids is an efficient way of storing the energy available in carbohydrates. Triglycerides and lipids, high-energy molecules, are stored in adipose tissue until they are needed.

Protein Metabolism

Abstract:
By the end of this section, you will be able to:

* Describe how the body digests proteins
* Explain how the urea cycle prevents toxic concentrations of nitrogen
* Differentiate between glucogenic and ketogenic amino acids
* Explain how protein can be used for energy

Urea Cycle

The urea cycle is a set of biochemical reactions that produces urea from ammonium ions in order to prevent a toxic level of ammonium in the body. It occurs primarily in the liver and, to a lesser extent, in the kidney. Prior to the urea cycle, ammonium ions are produced from the breakdown of amino acids. In these reactions, an amine group, or ammonium ion, from the amino acid is exchanged with a keto group on another molecule. This transamination event creates a molecule that is necessary for the Krebs cycle and an ammonium ion that enters into the urea cycle to be eliminated.

Metabolic States of the Body

Abstract:
By the end of this section, you will be able to:

* Describe what defines each of the three metabolic states
* Describe the processes that occur during the absorptive state of metabolism
* Describe the processes that occur during the postabsorptive state of metabolism
* Explain how the body processes glucose when the body is starved of fuel

The Absorptive State

The absorptive state, or the fed state, occurs after a meal when your body is digesting the food and absorbing the nutrients (anabolism exceeds catabolism). Digestion begins the moment you put food into your mouth, as the food is broken down into its constituent parts to be absorbed through the intestine. The digestion of carbohydrates begins in the mouth, whereas the digestion of proteins and fats begins in the stomach and small intestine. The constituent parts of these carbohydrates, fats, and proteins are transported across the intestinal wall and enter the bloodstream (sugars and amino acids) or the lymphatic system (fats). From the intestines, these systems transport them to the liver, adipose tissue, or muscle cells that will process and use, or store, the energy.

The Postabsorptive State

The postabsorptive state, or the fasting state, occurs when the food has been digested, absorbed, and stored. You commonly fast overnight, but skipping meals during the day puts your body in the postabsorptive state as well. During this state, the body must rely initially on stored glycogen. Glucose levels in the blood begin to drop as it is absorbed and used by the cells. In response to the decrease in glucose, insulin levels also drop. Glycogen and triglyceride storage slows. However, due to the demands of the tissues and organs, blood glucose levels must be maintained in the normal range of 80–120 mg/dL. In response to a drop in blood glucose concentration, the hormone glucagon is released from the alpha cells of the pancreas. Glucagon acts upon the liver cells, where it inhibits the synthesis of glycogen and stimulates the breakdown of stored glycogen back into glucose. This glucose is released from the liver to be used by the peripheral tissues and the brain. As a result, blood glucose levels begin to rise. Gluconeogenesis will also begin in the liver to replace the glucose that has been used by the peripheral tissues.

Starvation

When the body is deprived of nourishment for an extended period of time, it goes into “survival mode.” The first priority for survival is to provide enough glucose or fuel for the brain. The second priority is the conservation of amino acids for proteins. Therefore, the body uses ketones to satisfy the energy needs of the brain and other glucose-dependent organs, and to maintain proteins in the cells (see [link]). Because glucose levels are very low during starvation, glycolysis will shut off in cells that can use alternative fuels. For example, muscles will switch from using glucose to fatty acids as fuel. As previously explained, fatty acids can be converted into acetyl CoA and processed through the Krebs cycle to make ATP. Pyruvate, lactate, and alanine from muscle cells are not converted into acetyl CoA and used in the Krebs cycle, but are exported to the liver to be used in the synthesis of glucose. As starvation continues, and more glucose is needed, glycerol from fatty acids can be liberated and used as a source for gluconeogenesis.

Energy and Heat Balance

Abstract:
By the end of this section, you will be able to:

* Describe how the body regulates temperature
* Explain the significance of the metabolic rate

Mechanisms of Heat Exchange

When the environment is not thermoneutral, the body uses four mechanisms of heat exchange to maintain homeostasis: conduction, convection, radiation, and evaporation. Each of these mechanisms relies on the property of heat to flow from a higher concentration to a lower concentration; therefore, each of the mechanisms of heat exchange varies in rate according to the temperature and conditions of the environment.

Metabolic Rate

The metabolic rate is the amount of energy consumed minus the amount of energy expended by the body. The basal metabolic rate (BMR) describes the amount of daily energy expended by humans at rest, in a neutrally temperate environment, while in the postabsorptive state. It measures how much energy the body needs for normal, basic, daily activity. About 70 percent of all daily energy expenditure comes from the basic functions of the organs in the body. Another 20 percent comes from physical activity, and the remaining 10 percent is necessary for body thermoregulation or temperature control. This rate will be higher if a person is more active or has more lean body mass. As you age, the BMR generally decreases as the percentage of muscle mass decreases.

Nutrition and Diet

Abstract:
By the end of this section, you will be able to:

* Explain how different foods can affect metabolism
* Describe a healthy diet, as recommended by the U.S. Department of Agriculture (USDA)
* List reasons why vitamins and minerals are critical to a healthy diet

Food and Metabolism

The amount of energy that is needed or ingested per day is measured in calories. The nutritional Calorie (C) is the amount of heat it takes to raise 1 kg (1000 g) of water by 1 °C. This is different from the calorie (c) used in the physical sciences, which is the amount of heat it takes to raise 1 g of water by 1 °C. When we refer to "calorie," we are referring to the nutritional Calorie.

Vitamins

Vitamins are organic compounds found in foods and are a necessary part of the biochemical reactions in the body. They are involved in a number of processes, including mineral and bone metabolism, and cell and tissue growth, and they act as cofactors for energy metabolism. The B vitamins play the largest role of any vitamins in metabolism ([link] and [link]).

Minerals

Minerals in food are inorganic compounds that work with other nutrients to ensure the body functions properly. Minerals cannot be made in the body; they come from the diet. The amount of minerals in the body is small—only 4 percent of the total body mass—and most of that consists of the minerals that the body requires in moderate quantities: potassium, sodium, calcium, phosphorus, magnesium, and chloride.

The Urinary System

Introduction

Physical Characteristics of Urine

Abstract:
By the end of this section, you will be able to:

* Compare and contrast blood plasma, glomerular filtrate, and urine characteristics
* Describe the characteristics of a normal urine sample, including normal range of pH, osmolarity, and volume

Gross Anatomy of Urine Transport

Abstract:
By the end of this section, you will be able to:

* Identify the ureters, urinary bladder, and urethra, as well as their location, structure, histology, and function
* Compare and contrast male and female urethras
* Describe the micturition reflex
* Describe voluntary and involuntary neural control of micturition

Urethra

The urethra transports urine from the bladder to the outside of the body for disposal. The urethra is the only urologic organ that shows any significant anatomic difference between males and females; all other urine transport structures are identical ([link]).

Bladder

The urinary bladder collects urine from both ureters ([link]). The bladder lies anterior to the uterus in females, posterior to the pubic bone and anterior to the rectum. During late pregnancy, its capacity is reduced due to compression by the enlarging uterus, resulting in increased frequency of urination. In males, the anatomy is similar, minus the uterus, and with the addition of the prostate inferior to the bladder. The bladder is a retroperitoneal organ whose "dome" distends superiorly when the bladder is filling with urine.

Ureters

The kidneys and ureters are completely retroperitoneal, and the bladder has a peritoneal covering only over the dome. As urine is formed, it drains into the calyces of the kidney, which merge to form the funnel-shaped renal pelvis in the hilum of each kidney. The renal pelvis narrows to become the ureter of each kidney. As urine passes through the ureter, it does not passively drain into the bladder but rather is propelled by waves of peristalsis. As the ureters enter the pelvis, they sweep laterally, hugging the pelvic walls. As they approach the bladder, they turn medially and pierce the bladder wall obliquely. This is important because it creates a one-way valve (a physiological sphincter rather than an anatomical sphincter) that allows urine into the bladder but prevents reflux of urine from the bladder back into the ureter. Children born lacking this oblique course of the ureter through the bladder wall are susceptible to “vesicoureteral reflux,” which dramatically increases their risk of serious UTI. Pregnancy also increases the likelihood of reflux and UTI.

Gross Anatomy of the Kidney

Abstract:
By the end of this section, you will be able to:

* Describe the external structure of the kidney, including its location, support structures, and covering
* Identify the major internal divisions and structures of the kidney
* Identify the major blood vessels associated with the kidney and trace the path of blood through the kidney
* Compare and contrast the cortical and juxtamedullary nephrons
* Name structures found in the cortex and medulla
* Describe the physiological characteristics of the cortex and medulla

External Anatomy

The left kidney is located at about the T12 to L3 vertebrae, whereas the right is lower due to slight displacement by the liver. Upper portions of the kidneys are somewhat protected by the eleventh and twelfth ribs ([link]). Each kidney weighs about 125–175 g in males and 115–155 g in females. They are about 11–14 cm in length, 6 cm wide, and 4 cm thick, and are directly covered by a fibrous capsule composed of dense, irregular connective tissue that helps to hold their shape and protect them. This capsule is covered by a shock-absorbing layer of adipose tissue called the renal fat pad, which in turn is encompassed by a tough renal fascia. The fascia and, to a lesser extent, the overlying peritoneum serve to firmly anchor the kidneys to the posterior abdominal wall in a retroperitoneal position.

Internal Anatomy

A frontal section through the kidney reveals an outer region called the renal cortex and an inner region called the medulla ([link]). The renal columns are connective tissue extensions that radiate downward from the cortex through the medulla to separate the most characteristic features of the medulla, the renal pyramids and renal papillae. The papillae are bundles of collecting ducts that transport urine made by nephrons to the calyces of the kidney for excretion. The renal columns also serve to divide the kidney into 6–8 lobes and provide a supportive framework for vessels that enter and exit the cortex. The pyramids and renal columns taken together constitute the kidney lobes.

Renal Hilum

The renal hilum is the entry and exit site for structures servicing the kidneys: vessels, nerves, lymphatics, and ureters. The medial-facing hila are tucked into the sweeping convex outline of the cortex. Emerging from the hilum is the renal pelvis, which is formed from the major and minor calyxes in the kidney. The smooth muscle in the renal pelvis funnels urine via peristalsis into the ureter. The renal arteries form directly from the descending aorta, whereas the renal veins return cleansed blood directly to the inferior vena cava. The artery, vein, and renal pelvis are arranged in an anterior-to-posterior order.

Microscopic Anatomy of the Kidney

Abstract:
By the end of this section, you will be able to:

* Distinguish the histological differences between the renal cortex and medulla
* Describe the structure of the filtration membrane
* Identify the major structures and subdivisions of the renal corpuscles, renal tubules, and renal capillaries
* Discuss the function of the peritubular capillaries and vasa recta
* Identify the location of the juxtaglomerular apparatus and describe the cells that line it
* Describe the histology of the proximal convoluted tubule, loop of Henle, distal convoluted tubule, and collecting ducts

Nephrons: The Functional Unit

Nephrons take a simple filtrate of the blood and modify it into urine. Many changes take place in the different parts of the nephron before urine is created for disposal. The term forming urine will be used hereafter to describe the filtrate as it is modified into true urine. The principle task of the nephron population is to balance the plasma to homeostatic set points and excrete potential toxins in the urine. They do this by accomplishing three principle functions—filtration, reabsorption, and secretion. They also have additional secondary functions that exert control in three areas: blood pressure (via production of renin), red blood cell production (via the hormone EPO), and calcium absorption (via conversion of calcidiol into calcitriol, the active form of vitamin D).

Physiology of Urine Formation

Abstract:
By the end of this section, you will be able to:

* Describe the hydrostatic and colloid osmotic forces that favor and oppose filtration
* Describe glomerular filtration rate (GFR), state the average value of GFR, and explain how clearance rate can be used to measure GFR
* Predict specific factors that will increase or decrease GFR
* State the percent of the filtrate that is normally reabsorbed and explain why the process of reabsorption is so important
* Calculate daily urine production
* List common symptoms of kidney failure

Glomerular Filtration Rate (GFR)

The volume of filtrate formed by both kidneys per minute is termed the glomerular filtration rate (GFR). The heart pumps about 5 L blood per min under resting conditions. Approximately 20 percent or one liter enters the kidneys to be filtered. On average, this liter results in the production of about 125 mL/min filtrate produced in males (range of 90 to 140 mL/min) and 105 mL/min filtrate produced in females (range of 80 to 125 mL/min). This amount equates to a volume of about 180 L/day in males and 150 L/day in females. Ninety-nine percent of this filtrate is returned to the circulation by reabsorption so that only about 1–2 liters of urine are produced per day ([link]).

Net Filtration Pressure (NFP)

NFP determines filtration rates through the kidney. It is determined as follows:

Tubular Reabsorption

Abstract:
By the end of this section, you will be able to:

* List specific transport mechanisms occurring in different parts of the nephron, including active transport, osmosis, facilitated diffusion, and passive electrochemical gradients
* List the different membrane proteins of the nephron, including channels, transporters, and ATPase pumps
* Compare and contrast passive and active tubular reabsorption
* Explain why the differential permeability or impermeability of specific sections of the nephron tubules is necessary for urine formation
* Describe how and where water, organic compounds, and ions are reabsorbed in the nephron
* Explain the role of the loop of Henle, the vasa recta, and the countercurrent multiplication mechanisms in the concentration of urine
* List the locations in the nephron where tubular secretion occurs

Mechanisms of Recovery

Mechanisms by which substances move across membranes for reabsorption or secretion include active transport, diffusion, facilitated diffusion, secondary active transport, and osmosis. These were discussed in an earlier chapter, and you may wish to review them.

Reabsorption and Secretion in the PCT

The renal corpuscle filters the blood to create a filtrate that differs from blood mainly in the absence of cells and large proteins. From this point to the ends of the collecting ducts, the filtrate or forming urine is undergoing modification through secretion and reabsorption before true urine is produced. The first point at which the forming urine is modified is in the PCT. Here, some substances are reabsorbed, whereas others are secreted. Note the use of the term “reabsorbed.” All of these substances were “absorbed” in the digestive tract—99 percent of the water and most of the solutes filtered by the nephron must be reabsorbed. Water and substances that are reabsorbed are returned to the circulation by the peritubular and vasa recta capillaries. It is important to understand the difference between the glomerulus and the peritubular and vasa recta capillaries. The glomerulus has a relatively high pressure inside its capillaries and can sustain this by dilating the afferent arteriole while constricting the efferent arteriole. This assures adequate filtration pressure even as the systemic blood pressure varies. Movement of water into the peritubular capillaries and vasa recta will be influenced primarily by osmolarity and concentration gradients. Sodium is actively pumped out of the PCT into the interstitial spaces between cells and diffuses down its concentration gradient into the peritubular capillary. As it does so, water will follow passively to maintain an isotonic fluid environment inside the capillary. This is called obligatory water reabsorption, because water is “obliged” to follow the Na+ ([link]).

Reabsorption and Secretion in the Loop of Henle

The loop of Henle consists of two sections: thick and thin descending and thin and thick ascending sections. The loops of cortical nephrons do not extend into the renal medulla very far, if at all. Juxtamedullary nephrons have loops that extend variable distances, some very deep into the medulla. The descending and ascending portions of the loop are highly specialized to enable recovery of much of the Na+ and water that were filtered by the glomerulus. As the forming urine moves through the loop, the osmolarity will change from isosmotic with blood (about 278–300 mOsmol/kg) to both a very hypertonic solution of about 1200 mOsmol/kg and a very hypotonic solution of about 100 mOsmol/kg. These changes are accomplished by osmosis in the descending limb and active transport in the ascending limb. Solutes and water recovered from these loops are returned to the circulation by way of the vasa recta.

Reabsorption and Secretion in the Distal Convoluted Tubule

Approximately 80 percent of filtered water has been recovered by the time the dilute forming urine enters the DCT. The DCT will recover another 10–15 percent before the forming urine enters the collecting ducts. Aldosterone increases the amount of Na+/K+ ATPase in the basal membrane of the DCT and collecting duct. The movement of Na+ out of the lumen of the collecting duct creates a negative charge that promotes the movement of Cl– out of the lumen into the interstitial space by a paracellular route across tight junctions. Peritubular capillaries receive the solutes and water, returning them to the circulation.

Collecting Ducts and Recovery of Water

Solutes move across the membranes of the collecting ducts, which contain two distinct cell types, principal cells and intercalated cells. A principal cell possesses channels for the recovery or loss of sodium and potassium. An intercalated cell secretes or absorbs acid or bicarbonate. As in other portions of the nephron, there is an array of micromachines (pumps and channels) on display in the membranes of these cells.

Regulation of Renal Blood Flow

Abstract:
By the end of this section, you will be able to:

* Describe the myogenic and tubuloglomerular feedback mechanisms and explain how they affect urine volume and composition
* Describe the function of the juxtaglomerular apparatus

Sympathetic Nerves

The kidneys are innervated by the sympathetic neurons of the autonomic nervous system via the celiac plexus and splanchnic nerves. Reduction of sympathetic stimulation results in vasodilation and increased blood flow through the kidneys during resting conditions. When the frequency of action potentials increases, the arteriolar smooth muscle constricts (vasoconstriction), resulting in diminished glomerular flow, so less filtration occurs. Under conditions of stress, sympathetic nervous activity increases, resulting in the direct vasoconstriction of afferent arterioles (norepinephrine effect) as well as stimulation of the adrenal medulla. The adrenal medulla, in turn, produces a generalized vasoconstriction through the release of epinephrine. This includes vasoconstriction of the afferent arterioles, further reducing the volume of blood flowing through the kidneys. This process redirects blood to other organs with more immediate needs. If blood pressure falls, the sympathetic nerves will also stimulate the release of renin. Additional renin increases production of the powerful vasoconstrictor angiotensin II. Angiotensin II, as discussed above, will also stimulate aldosterone production to augment blood volume through retention of more Na+ and water. Only a 10 mm Hg pressure differential across the glomerulus is required for normal GFR, so very small changes in afferent arterial pressure significantly increase or decrease GFR.

Autoregulation

The kidneys are very effective at regulating the rate of blood flow over a wide range of blood pressures. Your blood pressure will decrease when you are relaxed or sleeping. It will increase when exercising. Yet, despite these changes, the filtration rate through the kidney will change very little. This is due to two internal autoregulatory mechanisms that operate without outside influence: the myogenic mechanism and the tubuloglomerular feedback mechanism.

Endocrine Regulation of Kidney Function

Abstract:
By the end of this section, you will be able to:

* Describe how each of the following functions in the extrinsic control of GFR: renin–angiotensin mechanism, natriuretic peptides, and sympathetic adrenergic activity
* Describe how each of the following works to regulate reabsorption and secretion, so as to affect urine volume and composition: renin–angiotensin system, aldosterone, antidiuretic hormone, and natriuretic peptides
* Name and define the roles of other hormones that regulate kidney control

Renin–Angiotensin–Aldosterone

Renin is an enzyme that is produced by the juxtaglomerular (JG) cells of the afferent arteriole at the JGA. It enzymatically converts angiotensinogen (made by the liver, freely circulating) into angiotensin I. Its release is stimulated by prostaglandins and NO from the JGA in response to decreased extracellular fluid volume.

Antidiuretic Hormone (ADH)

Diuretics are drugs that can increase water loss by interfering with the recapture of solutes and water from the forming urine. They are often prescribed to lower blood pressure. Coffee, tea, and alcoholic beverages are familiar diuretics. ADH, a 9-amino acid peptide released by the posterior pituitary, works to do the exact opposite. It promotes the recovery of water, decreases urine volume, and maintains plasma osmolarity and blood pressure. It does so by stimulating the movement of aquaporin proteins into the apical cell membrane of principal cells of the collecting ducts to form water channels, allowing the transcellular movement of water from the lumen of the collecting duct into the interstitial space in the medulla of the kidney by osmosis. From there, it enters the vasa recta capillaries to return to the circulation. Water is attracted by the high osmotic environment of the deep kidney medulla.

Endothelin

Endothelins, 21-amino acid peptides, are extremely powerful vasoconstrictors. They are produced by endothelial cells of the renal blood vessels, mesangial cells, and cells of the DCT. Hormones stimulating endothelin release include angiotensin II, bradykinin, and epinephrine. They do not typically influence blood pressure in healthy people. On the other hand, in people with diabetic kidney disease, endothelin is chronically elevated, resulting in sodium retention. They also diminish GFR by damaging the podocytes and by potently vasoconstricting both the afferent and efferent arterioles.

Natriuretic Hormones

Natriuretic hormones are peptides that stimulate the kidneys to excrete sodium—an effect opposite that of aldosterone. Natriuretic hormones act by inhibiting aldosterone release and therefore inhibiting Na+ recovery in the collecting ducts. If Na+ remains in the forming urine, its osmotic force will cause a concurrent loss of water. Natriuretic hormones also inhibit ADH release, which of course will result in less water recovery. Therefore, natriuretic peptides inhibit both Na+ and water recovery. One example from this family of hormones is atrial natriuretic hormone (ANH), a 28-amino acid peptide produced by heart atria in response to over-stretching of the atrial wall. The over-stretching occurs in persons with elevated blood pressure or heart failure. It increases GFR through concurrent vasodilation of the afferent arteriole and vasoconstriction of the efferent arteriole. These events lead to an increased loss of water and sodium in the forming urine. It also decreases sodium reabsorption in the DCT. There is also B-type natriuretic peptide (BNP) of 32 amino acids produced in the ventricles of the heart. It has a 10-fold lower affinity for its receptor, so its effects are less than those of ANH. Its role may be to provide “fine tuning” for the regulation of blood pressure. BNP’s longer biologic half-life makes it a good diagnostic marker of congestive heart failure ([link]).

Parathyroid Hormone

Parathyroid hormone (PTH) is an 84-amino acid peptide produced by the parathyroid glands in response to decreased circulating Ca++ levels. Among its targets is the PCT, where it stimulates the hydroxylation of calcidiol to calcitriol (1,25-hydroxycholecalciferol, the active form of vitamin D). It also blocks reabsorption of phosphate (PO3–), causing its loss in the urine. The retention of phosphate would result in the formation of calcium phosphate in the plasma, reducing circulating Ca++ levels. By ridding the blood of phosphate, higher circulating Ca++ levels are permitted.

Regulation of Fluid Volume and Composition

Abstract:
By the end of this section, you will be able to:

* Explain the mechanism of action of diuretics
* Explain why the differential permeability or impermeability of specific sections of the nephron tubules is necessary for urine formation

Volume-sensing Mechanisms

The body cannot directly measure blood volume, but blood pressure can be measured. Blood pressure often reflects blood volume and is measured by baroreceptors in the aorta and carotid sinuses. When blood pressure increases, baroreceptors send more frequent action potentials to the central nervous system, leading to widespread vasodilation. Included in this vasodilation are the afferent arterioles supplying the glomerulus, resulting in increased GFR, and water loss by the kidneys. If pressure decreases, fewer action potentials travel to the central nervous system, resulting in more sympathetic stimulation-producing vasoconstriction, which will result in decreased filtration and GFR, and water loss.

Diuretics and Fluid Volume

A diuretic is a compound that increases urine volume. Three familiar drinks contain diuretic compounds: coffee, tea, and alcohol. The caffeine in coffee and tea works by promoting vasodilation in the nephron, which increases GFR. Alcohol increases GFR by inhibiting ADH release from the posterior pituitary, resulting in less water recovery by the collecting duct. In cases of high blood pressure, diuretics may be prescribed to reduce blood volume and, thereby, reduce blood pressure. The most frequently prescribed anti-hypertensive diuretic is hydrochlorothiazide. It inhibits the Na+/ Cl– symporter in the DCT and collecting duct. The result is a loss of Na+ with water following passively by osmosis.

Regulation of Extracellular Na+

Sodium has a very strong osmotic effect and attracts water. It plays a larger role in the osmolarity of the plasma than any other circulating component of the blood. If there is too much Na+ present, either due to poor control or excess dietary consumption, a series of metabolic problems ensue. There is an increase in total volume of water, which leads to hypertension (high blood pressure). Over a long period, this increases the risk of serious complications such as heart attacks, strokes, and aneurysms. It can also contribute to system-wide edema (swelling).

Regulation of Extracellular K+

Potassium is present in a 30-fold greater concentration inside the cell than outside the cell. A generalization can be made that K+ and Na+ concentrations will move in opposite directions. When more Na+ is reabsorbed, more K+ is secreted; when less Na+ is reabsorbed (leading to excretion by the kidney), more K+ is retained. When aldosterone causes a recovery of Na+ in the nephron, a negative electrical gradient is created that promotes the secretion of K+ and Cl– into the lumen.

Regulation of Cl–

Chloride is important in acid–base balance in the extracellular space and has other functions, such as in the stomach, where it combines with hydrogen ions in the stomach lumen to form hydrochloric acid, aiding digestion. Its close association with Na+ in the extracellular environment makes it the dominant anion of this compartment, and its regulation closely mirrors that of Na+.

Regulation of Ca++ and Phosphate

The parathyroid glands monitor and respond to circulating levels of Ca++ in the blood. When levels drop too low, PTH is released to stimulate the DCT to reabsorb Ca++ from the forming urine. When levels are adequate or high, less PTH is released and more Ca++ remains in the forming urine to be lost. Phosphate levels move in the opposite direction. When Ca++ levels are low, PTH inhibits reabsorption of ${\text{HPO}}_{4}^{2-}$
 so that its blood level drops, allowing Ca++ levels to rise. PTH also stimulates the renal conversion of calcidiol into calcitriol, the active form of vitamin D. Calcitriol then stimulates the intestines to absorb more Ca++ from the diet.

Regulation of H+, Bicarbonate, and pH

The acid–base homeostasis of the body is a function of chemical buffers and physiologic buffering provided by the lungs and kidneys. Buffers, especially proteins, ${{\text{HCO}}_{3}}^{-}$, and ammonia have a very large capacity to absorb or release H+ as needed to resist a change in pH. They can act within fractions of a second. The lungs can rid the body of excess acid very rapidly (seconds to minutes) through the conversion of HCO3– into CO2, which is then exhaled. It is rapid but has limited capacity in the face of a significant acid challenge. The kidneys can rid the body of both acid and base. The renal capacity is large but slow (minutes to hours). The cells of the PCT actively secrete H+ into the forming urine as Na+ is reabsorbed. The body rids itself of excess H+ and raises blood pH. In the collecting ducts, the apical surfaces of intercalated cells have proton pumps that actively secrete H+ into the luminal, forming urine to remove it from the body.

Regulation of Nitrogen Wastes

Nitrogen wastes are produced by the breakdown of proteins during normal metabolism. Proteins are broken down into amino acids, which in turn are deaminated by having their nitrogen groups removed. Deamination converts the amino (NH2) groups into ammonia (NH3), ammonium ion (NH4+), urea, or uric acid ([link]). Ammonia is extremely toxic, so most of it is very rapidly converted into urea in the liver. Human urinary wastes typically contain primarily urea with small amounts of ammonium and very little uric acid.

Elimination of Drugs and Hormones

Water-soluble drugs may be excreted in the urine and are influenced by one or all of the following processes: glomerular filtration, tubular secretion, or tubular reabsorption. Drugs that are structurally small can be filtered by the glomerulus with the filtrate. Large drug molecules such as heparin or those that are bound to plasma proteins cannot be filtered and are not readily eliminated. Some drugs can be eliminated by carrier proteins that enable secretion of the drug into the tubule lumen. There are specific carriers that eliminate basic (such as dopamine or histamine) or acidic drugs (such as penicillin or indomethacin). As is the case with other substances, drugs may be both filtered and reabsorbed passively along a concentration gradient.

The Urinary System and Homeostasis

Abstract:
By the end of this section, you will be able to:

* Describe the role of the kidneys in vitamin D activation
* Describe the role of the kidneys in regulating erythropoiesis
* Provide specific examples to demonstrate how the urinary system responds to maintain homeostasis in the body
* Explain how the urinary system relates to other body systems in maintaining homeostasis
* Predict factors or situations affecting the urinary system that could disrupt homeostasis
* Predict the types of problems that would occur in the body if the urinary system could not maintain homeostasis

Vitamin D Synthesis

In order for vitamin D to become active, it must undergo a hydroxylation reaction in the kidney, that is, an –OH group must be added to calcidiol to make calcitriol (1,25-dihydroxycholecalciferol). Activated vitamin D is important for absorption of Ca++ in the digestive tract, its reabsorption in the kidney, and the maintenance of normal serum concentrations of Ca++ and phosphate. Calcium is vitally important in bone health, muscle contraction, hormone secretion, and neurotransmitter release. Inadequate Ca++ leads to disorders like osteoporosis and osteomalacia in adults and rickets in children. Deficits may also result in problems with cell proliferation, neuromuscular function, blood clotting, and the inflammatory response. Recent research has confirmed that vitamin D receptors are present in most, if not all, cells of the body, reflecting the systemic importance of vitamin D. Many scientists have suggested it be referred to as a hormone rather than a vitamin.

Erythropoiesis

EPO is a 193-amino acid protein that stimulates the formation of red blood cells in the bone marrow. The kidney produces 85 percent of circulating EPO; the liver, the remainder. If you move to a higher altitude, the partial pressure of oxygen is lower, meaning there is less pressure to push oxygen across the alveolar membrane and into the red blood cell. One way the body compensates is to manufacture more red blood cells by increasing EPO production. If you start an aerobic exercise program, your tissues will need more oxygen to cope, and the kidney will respond with more EPO. If erythrocytes are lost due to severe or prolonged bleeding, or under produced due to disease or severe malnutrition, the kidneys come to the rescue by producing more EPO. Renal failure (loss of EPO production) is associated with anemia, which makes it difficult for the body to cope with increased oxygen demands or to supply oxygen adequately even under normal conditions. Anemia diminishes performance and can be life threatening.

Blood Pressure Regulation

Due to osmosis, water follows where Na+ leads. Much of the water the kidneys recover from the forming urine follows the reabsorption of Na+. ADH stimulation of aquaporin channels allows for regulation of water recovery in the collecting ducts. Normally, all of the glucose is recovered, but loss of glucose control (diabetes mellitus) may result in an osmotic dieresis severe enough to produce severe dehydration and death. A loss of renal function means a loss of effective vascular volume control, leading to hypotension (low blood pressure) or hypertension (high blood pressure), which can lead to stroke, heart attack, and aneurysm formation.

Regulation of Osmolarity

Blood pressure and osmolarity are regulated in a similar fashion. Severe hypo-osmolarity can cause problems like lysis (rupture) of blood cells or widespread edema, which is due to a solute imbalance. Inadequate solute concentration (such as protein) in the plasma results in water moving toward an area of greater solute concentration, in this case, the interstitial space and cell cytoplasm. If the kidney glomeruli are damaged by an autoimmune illness, large quantities of protein may be lost in the urine. The resultant drop in serum osmolarity leads to widespread edema that, if severe, may lead to damaging or fatal brain swelling. Severe hypertonic conditions may arise with severe dehydration from lack of water intake, severe vomiting, or uncontrolled diarrhea. When the kidney is unable to recover sufficient water from the forming urine, the consequences may be severe (lethargy, confusion, muscle cramps, and finally, death) .

Recovery of Electrolytes

Sodium, calcium, and potassium must be closely regulated. The role of Na+ and Ca++ homeostasis has been discussed at length. Failure of K+ regulation can have serious consequences on nerve conduction, skeletal muscle function, and most significantly, on cardiac muscle contraction and rhythm.

pH Regulation

Recall that enzymes lose their three-dimensional conformation and, therefore, their function if the pH is too acidic or basic. This loss of conformation may be a consequence of the breaking of hydrogen bonds. Move the pH away from the optimum for a specific enzyme and you may severely hamper its function throughout the body, including hormone binding, central nervous system signaling, or myocardial contraction. Proper kidney function is essential for pH homeostasis.

Fluid, Electrolyte, and Acid-Base Balance

Introduction

Body Fluids and Fluid Compartments

Abstract:
By the end of this section, you will be able to:

* Explain the importance of water in the body
* Contrast the composition of the intracellular fluid with that of the extracellular fluid
* Explain the importance of protein channels in the movement of solutes
* Identify the causes and symptoms of edema

Body Water Content

Human beings are mostly water, ranging from about 75 percent of body mass in infants to about 50–60 percent in adults, to as low as 45 percent in old age. The percent of body water changes with development, because the proportions of the body given over to each organ and to muscles, fat, bone, and other tissues change from infancy to adulthood ([link]). Your brain and kidneys have the highest proportions of water, which composes 80–85 percent of their masses. In contrast, teeth have the lowest proportion of water, at 8–10 percent.

Fluid Compartments

Body fluids can be discussed in terms of their specific fluid compartment, a location that is largely separate from another compartment by some form of a physical barrier. The intracellular fluid (ICF) compartment is the system that includes all fluid enclosed in cells by their plasma membranes. Extracellular fluid (ECF) surrounds all cells in the body. Extracellular fluid has two primary constituents: the fluid component of the blood (called plasma) and the interstitial fluid (IF) that surrounds all cells not in the blood ([link]).

Composition of Body Fluids

The compositions of the two components of the ECF—plasma and IF—are more similar to each other than either is to the ICF ([link]). Blood plasma has high concentrations of sodium, chloride, bicarbonate, and protein. The IF has high concentrations of sodium, chloride, and bicarbonate, but a relatively lower concentration of protein. In contrast, the ICF has elevated amounts of potassium, phosphate, magnesium, and protein. Overall, the ICF contains high concentrations of potassium and phosphate (${\text{HPO}}_{4}^{2-}$), whereas both plasma and the ECF contain high concentrations of sodium and chloride.

Fluid Movement between Compartments

Hydrostatic pressure, the force exerted by a fluid against a wall, causes movement of fluid between compartments. The hydrostatic pressure of blood is the pressure exerted by blood against the walls of the blood vessels by the pumping action of the heart. In capillaries, hydrostatic pressure (also known as capillary blood pressure) is higher than the opposing “colloid osmotic pressure” in blood—a “constant” pressure primarily produced by circulating albumin—at the arteriolar end of the capillary ([link]). This pressure forces plasma and nutrients out of the capillaries and into surrounding tissues. Fluid and the cellular wastes in the tissues enter the capillaries at the venule end, where the hydrostatic pressure is less than the osmotic pressure in the vessel. Filtration pressure squeezes fluid from the plasma in the blood to the IF surrounding the tissue cells. The surplus fluid in the interstitial space that is not returned directly back to the capillaries is drained from tissues by the lymphatic system, and then re-enters the vascular system at the subclavian veins.

Solute Movement between Compartments

The movement of some solutes between compartments is active, which consumes energy and is an active transport process, whereas the movement of other solutes is passive, which does not require energy. Active transport allows cells to move a specific substance against its concentration gradient through a membrane protein, requiring energy in the form of ATP. For example, the sodium-potassium pump employs active transport to pump sodium out of cells and potassium into cells, with both substances moving against their concentration gradients.

Water Balance

Abstract:
By the end of this section, you will be able to:

* Explain how water levels in the body influence the thirst cycle
* Identify the main route by which water leaves the body
* Describe the role of ADH and its effect on body water levels
* Define dehydration and identify common causes of dehydration

Regulation of Water Intake

Osmolality is the ratio of solutes in a solution to a volume of solvent in a solution. Plasma osmolality is thus the ratio of solutes to water in blood plasma. A person’s plasma osmolality value reflects the state of hydration. A healthy body maintains plasma osmolality within a narrow range, by employing several mechanisms that regulate both water intake and output.

Regulation of Water Output

Water loss from the body occurs predominantly through the renal system. A person produces an average of 1.5 liters (1.6 quarts) of urine per day. Although the volume of urine varies in response to hydration levels, there is a minimum volume of urine production required for proper bodily functions. The kidney excretes 100 to 1200 milliosmoles of solutes per day to rid the body of a variety of excess salts and other water-soluble chemical wastes, most notably creatinine, urea, and uric acid. Failure to produce the minimum volume of urine means that metabolic wastes cannot be effectively removed from the body, a situation that can impair organ function. The minimum level of urine production necessary to maintain normal function is about 0.47 liters (0.5 quarts) per day.

Role of ADH

Antidiuretic hormone (ADH), also known as vasopressin, controls the amount of water reabsorbed from the collecting ducts and tubules in the kidney. This hormone is produced in the hypothalamus and is delivered to the posterior pituitary for storage and release ([link]). When the osmoreceptors in the hypothalamus detect an increase in the concentration of blood plasma, the hypothalamus signals the release of ADH from the posterior pituitary into the blood.

Electrolyte Balance

Abstract:
By the end of this section, you will be able to:

* List the role of the six most important electrolytes in the body
* Name the disorders associated with abnormally high and low levels of the six electrolytes
* Identify the predominant extracellular anion
* Describe the role of aldosterone on the level of water in the body

Roles of Electrolytes

These six ions aid in nerve excitability, endocrine secretion, membrane permeability, buffering body fluids, and controlling the movement of fluids between compartments. These ions enter the body through the digestive tract. More than 90 percent of the calcium and phosphate that enters the body is incorporated into bones and teeth, with bone serving as a mineral reserve for these ions. In the event that calcium and phosphate are needed for other functions, bone tissue can be broken down to supply the blood and other tissues with these minerals. Phosphate is a normal constituent of nucleic acids; hence, blood levels of phosphate will increase whenever nucleic acids are broken down.

Regulation of Sodium and Potassium

Sodium is reabsorbed from the renal filtrate, and potassium is excreted into the filtrate in the renal collecting tubule. The control of this exchange is governed principally by two hormones—aldosterone and angiotensin II.

Regulation of Calcium and Phosphate

Calcium and phosphate are both regulated through the actions of three hormones: parathyroid hormone (PTH), dihydroxyvitamin D (calcitriol), and calcitonin. All three are released or synthesized in response to the blood levels of calcium.

Acid-Base Balance

Abstract:
By the end of this section, you will be able to:

* Identify the most powerful buffer system in the body
* Explain the way in which the respiratory system affects blood pH

Buffer Systems in the Body

The buffer systems in the human body are extremely efficient, and different systems work at different rates. It takes only seconds for the chemical buffers in the blood to make adjustments to pH. The respiratory tract can adjust the blood pH upward in minutes by exhaling CO2 from the body. The renal system can also adjust blood pH through the excretion of hydrogen ions (H+) and the conservation of bicarbonate, but this process takes hours to days to have an effect.

Respiratory Regulation of Acid-Base Balance

The respiratory system contributes to the balance of acids and bases in the body by regulating the blood levels of carbonic acid ([link]). CO2 in the blood readily reacts with water to form carbonic acid, and the levels of CO2 and carbonic acid in the blood are in equilibrium. When the CO2 level in the blood rises (as it does when you hold your breath), the excess CO2 reacts with water to form additional carbonic acid, lowering blood pH. Increasing the rate and/or depth of respiration (which you might feel the “urge” to do after holding your breath) allows you to exhale more CO2. The loss of CO2 from the body reduces blood levels of carbonic acid and thereby adjusts the pH upward, toward normal levels. As you might have surmised, this process also works in the opposite direction. Excessive deep and rapid breathing (as in hyperventilation) rids the blood of CO2 and reduces the level of carbonic acid, making the blood too alkaline. This brief alkalosis can be remedied by rebreathing air that has been exhaled into a paper bag. Rebreathing exhaled air will rapidly bring blood pH down toward normal.

Renal Regulation of Acid-Base Balance

The renal regulation of the body’s acid-base balance addresses the metabolic component of the buffering system. Whereas the respiratory system (together with breathing centers in the brain) controls the blood levels of carbonic acid by controlling the exhalation of CO2, the renal system controls the blood levels of bicarbonate. A decrease of blood bicarbonate can result from the inhibition of carbonic anhydrase by certain diuretics or from excessive bicarbonate loss due to diarrhea. Blood bicarbonate levels are also typically lower in people who have Addison’s disease (chronic adrenal insufficiency), in which aldosterone levels are reduced, and in people who have renal damage, such as chronic nephritis. Finally, low bicarbonate blood levels can result from elevated levels of ketones (common in unmanaged diabetes mellitus), which bind bicarbonate in the filtrate and prevent its conservation.

Disorders of Acid-Base Balance

Abstract:
By the end of this section, you will be able to:

* Identify the three blood variables considered when making a diagnosis of acidosis or alkalosis
* Identify the source of compensation for blood pH problems of a respiratory origin
* Identify the source of compensation for blood pH problems of a metabolic/renal origin

Metabolic Acidosis: Primary Bicarbonate Deficiency

Metabolic acidosis occurs when the blood is too acidic (pH below 7.35) due to too little bicarbonate, a condition called primary bicarbonate deficiency. At the normal pH of 7.40, the ratio of bicarbonate to carbonic acid buffer is 20:1. If a person’s blood pH drops below 7.35, then the person is in metabolic acidosis. The most common cause of metabolic acidosis is the presence of organic acids or excessive ketone bodies in the blood. [link] lists some other causes of metabolic acidosis.

Metabolic Alkalosis: Primary Bicarbonate Excess

Metabolic alkalosis is the opposite of metabolic acidosis. It occurs when the blood is too alkaline (pH above 7.45) due to too much bicarbonate (called primary bicarbonate excess).

Respiratory Acidosis: Primary Carbonic Acid/CO2 Excess

Respiratory acidosis occurs when the blood is overly acidic due to an excess of carbonic acid, resulting from too much CO2 in the blood. Respiratory acidosis can result from anything that interferes with respiration, such as pneumonia, emphysema, or congestive heart failure.

Respiratory Alkalosis: Primary Carbonic Acid/CO2 Deficiency

Respiratory alkalosis occurs when the blood is overly alkaline due to a deficiency in carbonic acid and CO2 levels in the blood. This condition usually occurs when too much CO2 is exhaled from the lungs, as occurs in hyperventilation, which is breathing that is deeper or more frequent than normal. An elevated respiratory rate leading to hyperventilation can be due to extreme emotional upset or fear, fever, infections, hypoxia, or abnormally high levels of catecholamines, such as epinephrine and norepinephrine. Surprisingly, aspirin overdose—salicylate toxicity—can result in respiratory alkalosis as the body tries to compensate for initial acidosis.

Compensation Mechanisms

Various compensatory mechanisms exist to maintain blood pH within a narrow range, including buffers, respiration, and renal mechanisms. Although compensatory mechanisms usually work very well, when one of these mechanisms is not working properly (like kidney failure or respiratory disease), they have their limits. If the pH and bicarbonate to carbonic acid ratio are changed too drastically, the body may not be able to compensate. Moreover, extreme changes in pH can denature proteins. Extensive damage to proteins in this way can result in disruption of normal metabolic processes, serious tissue damage, and ultimately death.

Human Development and the Continuity of Life

The Reproductive System

Introduction

Anatomy and Physiology of the Testicular Reproductive System

Abstract:
By the end of this section, you will be able to:

* Describe the structure and function of the organs of the testicular reproductive system
* Describe the structure and function of the sperm cell
* Explain the events during spermatogenesis that produce haploid sperm from diploid cells
* Identify the importance of testosterone in reproductive function

Scrotum

The testes are located in a skin-covered, highly pigmented, muscular sack called the scrotum that extends from the body behind the penis (see [link]). This location is important in sperm production, which occurs within the testes, and proceeds more efficiently when the testes are kept 2 to 4°C below core body temperature.

Testes

The testes (singular = testis) are the male gonads—that is, the male reproductive organs. They produce both sperm and androgens, such as testosterone, and are active throughout the reproductive lifespan.

Structure of Formed Sperm

Sperm are smaller than most cells in the body; in fact, the volume of a sperm cell is 85,000 times less than that of the female gamete. Approximately 100 to 300 million sperm are produced each day, whereas females typically ovulate only one oocyte per month. As is true for most cells in the body, the structure of sperm cells speaks to their function. Sperm have a distinctive head, mid-piece, and tail region ([link]). The head of the sperm contains the extremely compact haploid nucleus with very little cytoplasm. These qualities contribute to the overall small size of the sperm (the head is only 5 *μ*m long). A structure called the acrosome covers most of the head of the sperm cell as a “cap” that is filled with lysosomal enzymes important for preparing sperm to participate in fertilization. Tightly packed mitochondria fill the mid-piece of the sperm. ATP produced by these mitochondria will power the flagellum, which extends from the neck and the mid-piece through the tail of the sperm, enabling it to move the entire sperm cell. The central strand of the flagellum, the axial filament, is formed from one centriole inside the maturing sperm cell during the final stages of spermatogenesis.

Sperm Transport

To fertilize an egg without medical intervention, sperm must be moved from the seminiferous tubules in the testes, through the epididymis, and—later during ejaculation—along the length of the penis and out into the female reproductive tract.

The Penis

The penis is the male organ of copulation (sexual intercourse). It is flaccid for non-sexual actions, such as urination, and turgid and rod-like with sexual arousal. When erect, the stiffness of the organ allows it to penetrate into the vagina and deposit semen into the female reproductive tract.

Testosterone

Testosterone, an androgen, is a steroid hormone produced by Leydig cells. The alternate term for Leydig cells, interstitial cells, reflects their location between the seminiferous tubules in the testes. In male embryos, testosterone is secreted by Leydig cells by the seventh week of development, with peak concentrations reached in the second trimester. This early release of testosterone results in the anatomical differentiation of the male sexual organs. In childhood, testosterone concentrations are low. They increase during puberty, activating characteristic physical changes and initiating spermatogenesis.

Anatomy and Physiology of the Ovarian Reproductive System

Abstract:
By the end of this section, you will be able to:

* Describe the structure and function of the organs of the ovarian reproductive system
* List the steps of oogenesis
* Describe the hormonal changes that occur during the ovarian and menstrual cycles
* Trace the path of an oocyte from ovary to fertilization

External Female Genitals

The external female reproductive structures are referred to collectively as the vulva ([link]). The mons pubis is a pad of fat that is located at the anterior, over the pubic bone. After puberty, it becomes covered in pubic hair. The labia majora (labia = “lips”; majora = “larger”) are folds of hair-covered skin that begin just posterior to the mons pubis. The thinner and more pigmented labia minora (labia = “lips”; minora = “smaller”) extend medial to the labia majora. Although they naturally vary in shape and size from person to person, the labia minora serve to protect the urethra and the entrance to the reproductive tract.

Vagina

The vagina, shown at the bottom of [link] and [link], is a muscular canal (approximately 10 cm long) that serves as the entrance to the reproductive tract. It also serves as the exit from the uterus during menses and childbirth. The outer walls of the anterior and posterior vagina are formed into longitudinal columns, or ridges, and the superior portion of the vagina—called the fornix—meets the protruding uterine cervix. The walls of the vagina are lined with an outer, fibrous adventitia; a middle layer of smooth muscle; and an inner mucous membrane with transverse folds called rugae. Together, the middle and inner layers allow the expansion of the vagina to accommodate intercourse and childbirth. The thin, perforated hymen can partially surround the opening to the vaginal orifice. The hymen can be ruptured with strenuous physical exercise, penile–vaginal intercourse, and childbirth. The Bartholin’s glands and the lesser vestibular glands (located near the clitoris) secrete mucus, which keeps the vestibular area moist.

Ovaries

The ovaries are the female gonads (see [link]). Paired ovals, they are each about 2 to 3 cm in length, about the size of an almond. The ovaries are located within the pelvic cavity, and are supported by the mesovarium, an extension of the peritoneum that connects the ovaries to the broad ligament. Extending from the mesovarium itself is the suspensory ligament that contains the ovarian blood and lymph vessels. Finally, the ovary itself is attached to the uterus via the ovarian ligament.

The Ovarian Cycle

The ovarian cycle is a set of predictable changes in oocytes and ovarian follicles. During the reproductive years, it is a roughly 28-day cycle that can be correlated with, but is not the same as, the menstrual cycle (discussed shortly). The cycle includes two interrelated processes: oogenesis (the production of gametes) and folliculogenesis (the growth and development of ovarian follicles).

The Uterine Tubes

The uterine tubes (also called fallopian tubes or oviducts) serve as the conduit of the oocyte from the ovary to the uterus ([link]). Each of the two uterine tubes is close to, but not directly connected to, the ovary and divided into sections. The isthmus is the narrow medial end of each uterine tube that is connected to the uterus. The wide distal infundibulum flares out with slender, finger-like projections called fimbriae. The middle region of the tube, called the ampulla, is where fertilization often occurs. The uterine tubes also have three layers: an outer serosa, a middle smooth muscle layer, and an inner mucosal layer. In addition to its mucus-secreting cells, the inner mucosa contains ciliated cells that beat in the direction of the uterus, producing a current that will be critical to move the oocyte.

The Uterus and Cervix

The uterus is the muscular organ that nourishes and supports the growing embryo (see [link]). Its average size is approximately 5 cm wide by 7 cm long (approximately 2 in by 3 in) when a female is not pregnant. It has three sections. The portion of the uterus superior to the opening of the uterine tubes is called the fundus. The middle section of the uterus is called the body of uterus (or corpus). The cervix is the narrow inferior portion of the uterus that projects into the vagina. The cervix produces mucus secretions that become thin and stringy under the influence of high systemic plasma estrogen concentrations, and these secretions can facilitate sperm movement through the reproductive tract.

The Menstrual Cycle

Now that we have discussed the maturation of the cohort of tertiary follicles in the ovary, the build-up and then shedding of the endometrial lining in the uterus, and the function of the uterine tubes and vagina, we can put everything together to talk about the three phases of the menstrual cycle—the series of changes in which the uterine lining is shed, rebuilds, and prepares for implantation.

The Breasts

Whereas the breasts are located far from the other female reproductive organs, they are considered accessory organs of the female reproductive system. The function of the breasts is to supply milk to an infant in a process called lactation. The external features of the breast include a nipple surrounded by a pigmented areola ([link]), whose coloration may deepen during pregnancy. The areola is typically circular and can vary in size from 25 to 100 mm in diameter. The areolar region is characterized by small, raised areolar glands that secrete lubricating fluid during lactation to protect the nipple from chafing. When a baby nurses, or draws milk from the breast, the entire areolar region is taken into the mouth.

Hormonal Birth Control

Birth control pills take advantage of the negative feedback system that regulates the ovarian and menstrual cycles to stop ovulation and prevent pregnancy. Typically they work by providing a constant level of both estrogen and progesterone, which negatively feeds back onto the hypothalamus and pituitary, thus preventing the release of FSH and LH. Without FSH, the follicles do not mature, and without the LH surge, ovulation does not occur. Although the estrogen in birth control pills does stimulate some thickening of the endometrial wall, it is reduced compared with a normal cycle and is less likely to support implantation.

Development of the Male and Female Reproductive Systems

Abstract:
By the end of this section, you will be able to:

* Explain how bipotential tissues are directed to develop into male or female sex organs
* Name the rudimentary duct systems in the embryo that are precursors to male or female internal sex organs
* Describe the hormonal changes that bring about puberty, and the secondary sex characteristics

Development of the Sexual Organs in the Embryo and Fetus

Mammalian sex determination is generally determined by X and Y chromosomes. Individuals homozygous for X (XX) are female in sex and heterozygous individuals (XY) are male. The presence of a Y chromosome triggers the development of a certain set of male characteristics and its absence results in female characteristics. Nondisjunction during meiosis can produce other combinations such as XXY, XYY, and XO which are called chromosomal intersex.

Further Sexual Development Occurs at Puberty

Puberty is the stage of development at which individuals become sexually mature. Though the outcomes of puberty for different sexes are very different, the hormonal control of the process is very similar. In addition, though the timing of these events varies between individuals, the sequence of changes that occur is predictable for male and female adolescents. As shown in [link], a concerted release of hormones from the hypothalamus (GnRH), the anterior pituitary (LH and FSH), and the gonads (either testosterone or estrogen) is responsible for the maturation of the reproductive systems and the development of secondary sex characteristics, which are physical changes that serve auxiliary roles in reproduction.

Development and Inheritance

Introduction

Fertilization

Abstract:
By the end of this section, you will be able to:

* Describe the obstacles that sperm must overcome to reach an oocyte
* Explain capacitation and its importance in fertilization
* Summarize the events that occur as a sperm fertilizes an oocyte

Transit of Sperm

Fertilization is a numbers game. During ejaculation, hundreds of millions of sperm (spermatozoa) are released into the vagina. Almost immediately, millions of these sperm are overcome by the acidity of the vagina (approximately pH 3.8), and millions more may be blocked from entering the uterus by thick cervical mucus. Of those that do enter, thousands are destroyed by phagocytic uterine leukocytes. Thus, the race into the uterine tubes, which is the most typical site for sperm to encounter the oocyte, is reduced to a few thousand contenders. Their journey—thought to be facilitated by uterine contractions—usually takes from 30 minutes to 2 hours. If the sperm do not encounter an oocyte immediately, they can survive in the uterine tubes for another 3–5 days. Thus, fertilization can still occur if intercourse takes place a few days before ovulation. In comparison, an oocyte can survive independently for only approximately 24 hours following ovulation. Intercourse more than a day after ovulation will therefore usually not result in fertilization.

Contact Between Sperm and Oocyte

Upon ovulation, the oocyte released by the ovary is swept into—and along—the uterine tube. Fertilization must occur in the distal uterine tube because an unfertilized oocyte cannot survive the 72-hour journey to the uterus. As you will recall from your study of the oogenesis, this oocyte (specifically a secondary oocyte) is surrounded by two protective layers. The corona radiata is an outer layer of follicular (granulosa) cells that form around a developing oocyte in the ovary and remain with it upon ovulation. The underlying zona pellucida (pellucid = “transparent”) is a transparent, but thick, glycoprotein membrane that surrounds the cell’s plasma membrane.

The Zygote

Recall that at the point of fertilization, the oocyte has not yet completed meiosis; all secondary oocytes remain arrested in metaphase of meiosis II until fertilization. Only upon fertilization does the oocyte complete meiosis. The unneeded complement of genetic material that results is stored in a second polar body that is eventually ejected. At this moment, the oocyte has become an ovum, the female haploid gamete. The two haploid nuclei derived from the sperm and oocyte and contained within the egg are referred to as pronuclei. They decondense, expand, and replicate their DNA in preparation for mitosis. The pronuclei then migrate toward each other, their nuclear envelopes disintegrate, and the male- and female-derived genetic material intermingles. This step completes the process of fertilization and results in a single-celled diploid zygote with all the genetic instructions it needs to develop into a human.

Embryonic Development

Abstract:
By the end of this section, you will be able to:

* Distinguish the stages of embryonic development that occur before implantation
* Describe the process of implantation
* List and describe four embryonic membranes
* Explain gastrulation
* Describe how the placenta is formed and identify its functions
* Explain how an embryo transforms from a flat disc of cells into a three-dimensional shape resembling a human
* Summarize the process of organogenesis

Pre-implantation Embryonic Development

Following fertilization, the zygote and its associated membranes, together referred to as the conceptus, continue to be projected toward the uterus by peristalsis and beating cilia of the epithelial cells of the Fallopian tube. During its journey to the uterus, the zygote undergoes five or six rapid mitotic cell divisions. Although each cleavage results in more cells, it does not increase the total volume of the conceptus ([link]). Each daughter cell produced by cleavage is called a blastomere (blastos = “germ,” in the sense of a seed or sprout).

Implantation

At the end of the first week, the blastocyst comes in contact with the uterine wall and adheres to it, embedding itself in the uterine lining via the trophoblast cells. Thus begins the process of implantation, which signals the end of the pre-embryonic stage of development ([link]). Implantation can be accompanied by minor bleeding. The blastocyst typically implants in the fundus of the uterus or on the posterior wall. However, if the endometrium is not fully developed and ready to receive the blastocyst, the blastocyst will detach and find a better spot. A significant percentage (50–75 percent) of blastocysts fail to implant; when this occurs, the blastocyst is shed with the endometrium during menses. The high rate of implantation failure is one reason why pregnancy typically requires several ovulation cycles to achieve.

Embryonic Membranes

During the second week of development, with the embryo implanted in the uterus, cells within the blastocyst start to organize into layers. Some grow to form the extra-embryonic membranes needed to support and protect the growing embryo: the amnion, the yolk sac, the allantois, and the chorion.

Embryogenesis

As the third week of development begins, the two-layered disc of cells becomes a three-layered disc through the process of gastrulation, during which the cells transition from totipotency to multipotency. The embryo, which takes the shape of an oval-shaped disc, forms an indentation called the primitive streak along the dorsal surface of the epiblast. A node at the caudal or “tail” end of the primitive streak emits growth factors that direct cells to multiply and migrate. Cells migrate toward and through the primitive streak and then move laterally to create two new layers of cells. The first layer is the endoderm, a sheet of cells that displaces the hypoblast and lies adjacent to the yolk sac. The second layer of cells fills in as the middle layer, or mesoderm. The cells of the epiblast that remain (not having migrated through the primitive streak) become the ectoderm ([link]).

Development of the Placenta

During the first several weeks of development, the cells of the endometrium—referred to as decidual cells—nourish the nascent embryo. During prenatal weeks 4–12, the developing placenta gradually takes over the role of feeding the embryo, and the decidual cells are no longer needed. The mature placenta is composed of tissues derived from the embryo, as well as maternal tissues of the endometrium. The placenta connects to the conceptus via the umbilical cord, which carries deoxygenated blood and wastes from the fetus through two umbilical arteries; nutrients and oxygen are carried from the pregnant person to the fetus through the single umbilical vein. The umbilical cord is surrounded by the amnion, and the spaces within the cord around the blood vessels are filled with Wharton’s jelly, a mucous connective tissue.

Organogenesis

Following gastrulation, rudiments of the central nervous system develop from the ectoderm in the process of neurulation ([link]). Specialized neuroectodermal tissues along the length of the embryo thicken into the neural plate. During the fourth week, tissues on either side of the plate fold upward into a neural fold. The two folds converge to form the neural tube. The tube lies atop a rod-shaped, mesoderm-derived notochord, which eventually becomes the nucleus pulposus of intervertebral discs. Block-like structures called somites form on either side of the tube, eventually differentiating into the axial skeleton, skeletal muscle, and dermis. During the fourth and fifth weeks, the anterior neural tube dilates and subdivides to form vesicles that will become the brain structures.

Fetal Development

Abstract:
By the end of this section, you will be able to:

* Differentiate between the embryonic period and the fetal period
* Briefly describe the process of sexual differentiation
* Describe the fetal circulatory system and explain the role of the shunts
* Trace the development of a fetus from the end of the embryonic period to birth

Sexual Differentiation

Sexual differentiation does not begin until the fetal period, during weeks 9–12. Embryonic males and females, though genetically distinguishable, are morphologically identical ([link]). Bipotential gonads, or gonads that can develop into male or female sexual organs, are connected to a central cavity called the cloaca via Müllerian ducts and Wolffian ducts. (The cloaca is an extension of the primitive gut.) Several events lead to sexual differentiation during this period.

The Fetal Circulatory System

During prenatal development, the fetal circulatory system is integrated with the placenta via the umbilical cord so that the fetus receives both oxygen and nutrients from the placenta. However, after childbirth, the umbilical cord is severed, and the newborn’s circulatory system must be reconfigured. When the heart first forms in the embryo, it exists as two parallel tubes derived from mesoderm and lined with endothelium, which then fuse together. As the embryo develops into a fetus, the tube-shaped heart folds and further differentiates into the four chambers present in a mature heart. Unlike a mature cardiovascular system, however, the fetal cardiovascular system also includes circulatory shortcuts, or shunts. A shunt is an anatomical (or sometimes surgical) diversion that allows blood flow to bypass immature organs such as the lungs and liver until childbirth.

Other Organ Systems

During weeks 9–12 of fetal development, the brain continues to expand, the body elongates, and ossification continues. Fetal movements are frequent during this period, but are jerky and not well-controlled. The bone marrow begins to take over the process of erythrocyte production—a task that the liver performed during the embryonic period. The liver now secretes bile. The fetus circulates amniotic fluid by swallowing it and producing urine. The eyes are well-developed by this stage, but the eyelids are fused shut. The fingers and toes begin to develop nails. By the end of week 12, the fetus measures approximately 9 cm (3.5 in) from crown to rump.

Changes During Pregnancy, Labor, and Birth

Abstract:
By the end of this section, you will be able to:

* Explain how estrogen, progesterone, and hCG are involved in maintaining pregnancy
* List the contributors to weight gain during pregnancy
* Describe the major changes to the maternal digestive, circulatory, and integumentary systems during pregnancy
* Summarize the events leading to labor
* Identify and describe each of the three stages of childbirth

Effects of Hormones

Virtually all of the effects of pregnancy can be attributed in some way to the influence of hormones—particularly estrogens, progesterone, and hCG. During weeks 7–12 from the LMP, the pregnancy hormones are primarily generated by the corpus luteum. Progesterone secreted by the corpus luteum stimulates the production of decidual cells of the endometrium that nourish the blastocyst before placentation. As the placenta develops and the corpus luteum degenerates during weeks 12–17, the placenta gradually takes over as the endocrine organ of pregnancy.

Weight Gain

The second and third trimesters of pregnancy are associated with dramatic changes in maternal anatomy and physiology. The most obvious anatomical sign of pregnancy is the dramatic enlargement of the abdominal region, coupled with weight gain. This weight results from the growing fetus as well as the enlarged uterus, amniotic fluid, and placenta. Additional breast tissue and dramatically increased blood volume also contribute to weight gain ([link]). Surprisingly, fat storage accounts for only approximately 2.3 kg (5 lbs) in a normal pregnancy and serves as a reserve for the increased metabolic demand of breastfeeding.

Changes in Organ Systems During Pregnancy

As the body adapts to pregnancy, characteristic physiologic changes occur. These changes can sometimes prompt symptoms often referred to collectively as the common discomforts of pregnancy.

Physiology of Labor

Childbirth, or parturition, typically occurs within a week of the due date, unless the pregnancy involves more than one fetus, which usually causes labor to begin early. As a pregnancy progresses into its final weeks, several physiological changes occur in response to hormones that trigger labor.

Stages of Childbirth

The process of childbirth can be divided into three stages: cervical dilation, expulsion of the newborn, and afterbirth ([link]).

Adjustments of the Infant at Birth and Postnatal Stages

Abstract:
By the end of this section, you will be able to:

* Discuss the importance of an infant’s first breath
* Explain the closing of the cardiac shunts
* Describe thermoregulation in the newborn
* Summarize the importance of intestinal flora in the newborn

Respiratory Adjustments

Although the fetus “practices” breathing by inhaling amniotic fluid in utero, there is no air in the uterus and thus no true opportunity to breathe. (There is also no need to breathe because the placenta supplies the fetus with all the oxygenated blood it needs.) During gestation, the partially collapsed lungs are filled with amniotic fluid and exhibit very little metabolic activity. Several factors stimulate newborns to take their first breath at birth. First, labor contractions temporarily constrict umbilical blood vessels, reducing oxygenated blood flow to the fetus and elevating carbon dioxide levels in the blood. High carbon dioxide levels cause acidosis and stimulate the respiratory center in the brain, triggering the newborn to take a breath.

Circulatory Adjustments

The process of clamping and cutting the umbilical cord collapses the umbilical blood vessels. In the absence of medical assistance, this occlusion would occur naturally within 20 minutes of birth because the Wharton’s jelly within the umbilical cord would swell in response to the lower temperature outside of the mother’s body, and the blood vessels would constrict. Natural occlusion has occurred when the umbilical cord is no longer pulsating. For the most part, the collapsed vessels atrophy and become fibrotic remnants, existing in the mature circulatory system as ligaments of the abdominal wall and liver. The ductus venosus degenerates to become the ligamentum venosum beneath the liver. Only the proximal sections of the two umbilical arteries remain functional, taking on the role of supplying blood to the upper part of the bladder ([link]).

Thermoregulatory Adjustments

The fetus floats in warm amniotic fluid that is maintained at a temperature of approximately 98.6°F with very little fluctuation. Birth exposes newborns to a cooler environment in which they have to regulate their own body temperature. Newborns have a higher ratio of surface area to volume than adults. This means that their body has less volume throughout which to produce heat, and more surface area from which to lose heat. As a result, newborns produce heat more slowly and lose it more quickly. Newborns also have immature musculature that limits their ability to generate heat by shivering. Moreover, their nervous systems are underdeveloped, so they cannot quickly constrict superficial blood vessels in response to cold. They also have little subcutaneous fat for insulation. All these factors make it harder for newborns to maintain their body temperature.

Gastrointestinal and Urinary Adjustments

In adults, the gastrointestinal tract harbors bacterial flora—trillions of bacteria that aid in digestion, produce vitamins, and protect from the invasion or replication of pathogens. In stark contrast, the fetal intestine is sterile. The first consumption of breast milk or formula floods the neonatal gastrointestinal tract with beneficial bacteria that begin to establish the bacterial flora.

Lactation

Abstract:
By the end of this section, you will be able to:

* Describe the structure of the lactating breast
* Summarize the process of lactation
* Explain how the composition of breast milk changes during the first days of lactation and in the course of a single feeding

Structure of the Lactating Breast

Mammary glands are modified sweat glands. The non-pregnant and non-lactating female breast is composed primarily of adipose and collagenous tissue, with mammary glands making up a very minor proportion of breast volume. The mammary gland is composed of milk-transporting lactiferous ducts, which expand and branch extensively during pregnancy in response to estrogen, growth hormone, cortisol, and prolactin. Moreover, in response to progesterone, clusters of breast alveoli bud from the ducts and expand outward toward the chest wall. Breast alveoli are balloon-like structures lined with milk-secreting cuboidal cells, or lactocytes, that are surrounded by a net of contractile myoepithelial cells. Milk is secreted from the lactocytes, fills the alveoli, and is squeezed into the ducts. Clusters of alveoli that drain to a common duct are called lobules; the lactating female has 12–20 lobules organized radially around the nipple. Milk drains from lactiferous ducts into lactiferous sinuses that meet at 4 to 18 perforations in the nipple, called nipple pores. The small bumps of the areola (the darkened skin around the nipple) are called Montgomery glands. They secrete oil to cleanse the nipple opening and prevent chapping and cracking of the nipple during breastfeeding.

The Process of Lactation

The pituitary hormone prolactin is instrumental in the establishment and maintenance of breast milk supply. It also is important for the mobilization of maternal micronutrients for breast milk.

Changes in the Composition of Breast Milk

In the final weeks of pregnancy, the alveoli swell with colostrum, a thick, yellowish substance that is high in protein but contains less fat and glucose than mature breast milk ([link]). Before childbirth, some people experience leakage of colostrum from the nipples. In contrast, mature breast milk does not leak during pregnancy and is not secreted until several days after childbirth.

Patterns of Inheritance

Abstract:
By the end of this section, you will be able to:

* Differentiate between genotype and phenotype
* Describe how alleles determine a person’s traits
* Summarize Mendel’s experiments and relate them to human genetics
* Explain the inheritance of autosomal dominant and recessive and sex-linked genetic disorders

From Genotype to Phenotype

Each human body cell has a full complement of DNA stored in 23 pairs of chromosomes. [link] shows the pairs in a systematic arrangement called a karyotype. Among these is one pair of chromosomes, called the sex chromosomes, that determines the sex of the individual (XX in females, XY in males). The remaining 22 chromosome pairs are called autosomal chromosomes. Each of these chromosomes carries hundreds or even thousands of genes, each of which codes for the assembly of a particular protein—that is, genes are “expressed” as proteins. An individual’s complete genetic makeup is referred to as their genotype. The characteristics that the genes express, whether they are physical, behavioral, or biochemical, are a person’s phenotype.

Mendel’s Theory of Inheritance

Our contemporary understanding of genetics rests on the work of a nineteenth-century monk. Working in the mid-1800s, long before anyone knew about genes or chromosomes, Gregor Mendel discovered that garden peas transmit their physical characteristics to subsequent generations in a discrete and predictable fashion. When he mated, or crossed, two pure-breeding pea plants that differed by a certain characteristic, the first-generation offspring all looked like one of the parents. For instance, when he crossed tall and dwarf pure-breeding pea plants, all of the offspring were tall. Mendel called tallness dominant because it was expressed in offspring when it was present in a purebred parent. He called dwarfism recessive because it was masked in the offspring if one of the purebred parents possessed the dominant characteristic. Note that tallness and dwarfism are variations on the characteristic of height. Mendel called such a variation a trait. We now know that these traits are the expression of different alleles of the gene encoding height.

Autosomal Dominant Inheritance

In the case of cystic fibrosis, the disorder is recessive to the normal phenotype. However, a genetic abnormality may be dominant to the normal phenotype. When the dominant allele is located on one of the 22 pairs of autosomes (non-sex chromosomes), we refer to its inheritance pattern as autosomal dominant. An example of an autosomal dominant disorder is neurofibromatosis type I, a disease that induces tumor formation within the nervous system that leads to skin and skeletal deformities. Consider a couple in which one parent is heterozygous for this disorder (and who therefore has neurofibromatosis), *Nn*, and one parent is homozygous for the normal gene, *nn*. The heterozygous parent would have a 50 percent chance of passing the dominant allele for this disorder to their offspring, and the homozygous parent would always pass the normal allele. Therefore, four possible offspring genotypes are equally likely to occur: *Nn*, *Nn*, *nn*, and *nn*. That is, every child of this couple would have a 50 percent chance of inheriting neurofibromatosis. This inheritance pattern is shown in [link], in a form called a Punnett square, named after its creator, the British geneticist Reginald Punnett.

Autosomal Recessive Inheritance

When a genetic disorder is inherited in an autosomal recessive pattern, the disorder corresponds to the recessive phenotype. Heterozygous individuals will not display symptoms of this disorder, because their unaffected gene will compensate. Such an individual is called a carrier. Carriers for an autosomal recessive disorder may never know their genotype unless they have a child with the disorder.

X-linked Dominant or Recessive Inheritance

An X-linked transmission pattern involves genes located on the X chromosome of the 23rd pair ([link]). Recall that a male has one X and one Y chromosome. When a male transmits a Y chromosome, the child is male, and when a male parent transmits an X chromosome, the child is female. A female can transmit only an X chromosome, as both her sex chromosomes are X chromosomes.

Other Inheritance Patterns: Incomplete Dominance, Codominance, and Lethal Alleles

Not all genetic disorders are inherited in a dominant–recessive pattern. In incomplete dominance, the offspring express a heterozygous phenotype that is intermediate between one parent’s homozygous dominant trait and the other parent’s homozygous recessive trait. An example of this can be seen in snapdragons when red-flowered plants and white-flowered plants are crossed to produce pink-flowered plants. In humans, incomplete dominance occurs with one of the genes for hair texture. When one parent passes a curly hair allele (the incompletely dominant allele) and the other parent passes a straight-hair allele, the effect on the offspring will be intermediate, resulting in hair that is wavy.

Mutations

A mutation is a change in the sequence of DNA nucleotides that may or may not affect a person’s phenotype. Mutations can arise spontaneously from errors during DNA replication, or they can result from environmental insults such as radiation, certain viruses, or exposure to tobacco smoke or other toxic chemicals. Because genes encode for the assembly of proteins, a mutation in the nucleotide sequence of a gene can change amino acid sequence and, consequently, a protein’s structure and function. Spontaneous mutations occurring during meiosis are thought to account for many spontaneous abortions (miscarriages).

Chromosomal Disorders

Sometimes a genetic disease is not caused by a mutation in a gene, but by the presence of an incorrect number of chromosomes. For example, Down syndrome is caused by having three copies of chromosome 21. This is known as trisomy 21. The most common cause of trisomy 21 is chromosomal nondisjunction during meiosis. The frequency of nondisjunction events appears to increase with age, so the frequency of bearing a child with Down syndrome increases in females over 36. The age of the male parent matters less because nondisjunction is much less likely to occur in a sperm than in an egg.