UNIT 1 LEVELS OF ORGANIZATION - Hazleton Area High School · 2011-01-18 · 1 UNIT 1 LEVELS OF...

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UNIT 1LEVELS OFORGANIZATIONThe sciences of anatomy and physiology consider the struc-tural and functional characteristics of living things, andthis unit introduces basic concepts related to the diagno-sis and treatment of human diseases. This unit begins theprocess by considering the way clinical information is col-lected and evaluated. It discusses the way disease process-es interfere with homeostasis, the key to physiologicalregulation, and how this interference threatens survival ina changing environment. The rest of this unit follows a“levels of organization” theme and relates events andprocesses at the chemical, cellular, and tissue levels to rep-resentative disorders and to clinical procedures useful indiagnosis.

Major sections included within this unit:

AN INTRODUCTION TO CLINICALANATOMY AND PHYSIOLOGY

THE CHEMICAL LEVEL OF ORGANIZATION

THE CELLULAR LEVEL OF ORGANIZATION

THE TISSUE LEVEL OF ORGANIZATION

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AN INTRODUCTION TOCLINICAL ANATOMY ANDPHYSIOLOGY

DISEASE, PATHOLOGY, ANDDIAGNOSISThe formal name for the study of disease is pathology; the studyof functional changes caused by disease processes is calledpathophysiology. Different diseases typically produce similar signsand symptoms. For example, a person whose lips are paler thannormal and who complains of a lack of energy and breathlessnessmight have (1) respiratory problems that prevent normal oxygentransfer to the blood (as in COPD); (2) cardiovascular problemsthat interfere with normal blood circulation to all parts of the body(heart failure); or (3) a reduced oxygen-carrying capacity of theblood (anemia). In such cases, doctors must ask questions and col-lect information to determine the source of the problem. The pa-tient’s history and physical exam may be enough for diagnosis inmany cases, but laboratory testing and imaging studies such as x-rays are often needed.

A diagnosis is a decision about the nature of an illness. The di-agnostic process is often a process of elimination, in which sev-eral potential causes are evaluated and the most likely one isselected. If tests indicate that, for example, anemia is responsiblefor the patient’s symptoms, then the specific type of anemia mustbe identified before effective treatment can begin. After all, thetreatment for anemia due to a dietary iron deficiency is very dif-ferent from the treatment for anemia due to internal bleeding.You could not hope to identify the probable type of anemia un-less you were already familiar with the physical and chemicalstructure of red blood cells and with their role in the transport ofoxygen. This brings us to a key concept: All diagnostic procedurespresuppose an understanding of the normal structure and functionof the human body.

� THE SCIENTIFIC METHODYour course in anatomy and physiology should do more than sim-ply teach you the names and functions of different body parts; itshould also provide you with a frame of reference that will enableyou to understand new information, draw logical conclusions, andmake intelligent decisions. A great deal of confusion and misin-formation exists about just how medical science “works,” and peo-ple make unwise and even dangerous decisions as a result. Nowhereis this more apparent than when a discussion drifts to health, nu-trition, or cancer. Whether you are planning to work in a health-related profession or are just trying to make sound decisions aboutyour own life, you will benefit from learning how to organize in-formation, evaluate evidence, and draw logical conclusions.

Logical analysis, a process often called critical thinking, doesnot come naturally; it is too easy to become distracted or mis-led and then to make a hasty or incorrect decision. Criticalthinking is a learned skill that follows rules designed to minimizethe chances of error. Critical thinking is important in daily life,but it is absolutely vital in the sciences, especially the medical sci-ences. In applying critical thinking to scientific investigation,we follow what is called the scientific method, a standardizedmeans of organizing and evaluating information to reach validconclusions.

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Disease, Pathology, and Diagnosis 3

FORMING A HYPOTHESISScience involves a lot more than just the collection of informa-tion. You could spend the rest of your life carefully observing theworld around you, but such a task wouldn’t reveal very much,unless you could see some kind of pattern and come up with ahypothesis—an idea that explains your observations.

Hypotheses are ideas that may be correct or incorrect. To eval-uate a hypothesis, you must have relevant data and a reliablemethod of analyzing the data. For example, you might proposethe hypothesis that radiation emitted by planet X confers immor-tality on a living being. Could anyone prove you wrong? Not like-ly, particularly if you didn’t specify the location of the planet orthe type of radiation. Would anyone believe you? If you were a“leading authority” on something (anything), a few people prob-ably would.

That’s not as ridiculous as it might seem. For almost 1500 years,“everyone knew” that inhaled air is transported from the lungsthrough blood vessels to the heart. They“knew”this because the fa-mous Roman physician Galen had said so. But as we now know,Galen and all who agreed with him were quite wrong. Why wereGalen’s statements about the lungs believed? Because Galen was fa-mous and much of what he said was correct, all his statements wereaccepted as true. To avoid making this kind of error, you must al-ways remember to evaluate the hypothesis, not the individual whoproposed it!

In evaluating a hypothesis, we must examine it to see if it makescorrect predictions about the real world. The steps in this processare diagrammed in Figure 1�. A valid hypothesis has three char-acteristics: It is (1) testable, (2) unbiased, and (3) repeatable.

A testable hypothesis is a hypothesis that can be studied by ex-perimentation or data collection. Your assertion about planet Xqualifies as a hypothesis, but it cannot be tested unless we find theplanet and detect the radiation. An example of a testable hypoth-esis would be “left-handed airplane pilots have fewer crashes thando right-handed pilots.” This hypothesis is testable because itmakes a prediction about the world that can be checked—in thiscase, by collecting and analyzing data.

AVOIDING BIASSuppose, then, that you collected information about all the planecrashes in the world and discovered that 80 percent of all airplanesthat crashed were flown by right-handed pilots. “Aha!” you mightshout, “The hypothesis is correct!” The implications are obvious:Ban all right-handed airline pilots, eliminate four-fifths of all crash-es, and sit back and wait for your prize from the Air Traffic SafetyAssociation.

Unfortunately, you would be acting prematurely, because yourdata collection was biased. To test your hypothesis adequately, youneed to know not only how many crashes involved right-handedor left-handed pilots, but also how many right-handed and left-handed pilots were flying. If 90 percent of the pilots were righthanded, but they accounted for only 80 percent of the crashes, thenleft-handed pilots are the dangerous ones! Eliminating bias in thiscase is relatively easy, but health studies can have all kinds of com-plicating factors. Because 25 percent of us will probably developcancer at some point in our lives, we will use cancer studies to ex-emplify the problems encountered.

Our first example of bias in action concerns cancer statistics,which indicate that cancer rates in the United States and abroadvary by region. For example, although the estimated age-adjustedyearly cancer death rate in the United States was 202 per 100,000population from 1996 to 2000, the rate in Utah was only 152 per100,000, whereas the rate in the District of Columbia was 244 per100,000. It would be very easy to assume that this difference is thedirect result of rural versus urban living. But these data aloneshould not convince you that moving from the District of Co-lumbia to Utah would lower your risk of developing cancer. Todraw that conclusion, you would have to be sure that the observedrates were the direct result of just a single factor: the difference inphysical location. As you will find in later sections, many factorspromote the development of cancer. To exclude all possibilitiesother than geography, you would have to be certain that the pop-ulations were alike in all other respects. Here are a few possiblesources of variation that could affect that conclusion:

• Different population profiles. Cancer rates vary betweenmales and females, among racial groups, and among age groups.Therefore, we need to know how the populations of Utah andthe District of Columbia differ in each of these respects. The

Observation

Proposealternativehypothesis

Redesignexperiment

Yes

Results notrepeatable

Proposehypothesis

Designexperiment

Determine ifdata are biased

No

Refinehypothesis

Repeatexperiments

If results areconsistent

Accept astheory

Collectand analyze

data

� FIGURE 1The Scientific Method. The basic sequence of steps involved in the de-velopment and acceptance of a scientific theory.

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N4 AN INTRODUCTION TO CLINICAL ANATOMY AND PHYSIOLOGY

age distribution of the population is so critical for cancer thatmost statistics are age adjusted, which means that the averageage of a state’s population is used to adjust the absolute num-ber of cases to arrive at the numbers quoted above.

• Different lifestyles. Because tobacco and alcohol use are lead-ing causes of lung and other cancers, we need to know how thepopulations differ in their patterns of smoking and drinking.

• Different occupations. Because chemicals used in the work-place are implicated in many cancers, we need to know how thepopulations of each region are employed and what occupation-al hazards they face.

• Different mobilities. The region in which a person dies maynot be the region in which he or she developed cancer, so weneed to know whether people with cancer in Utah stay in thestate or go elsewhere for critical care and whether people withcancer travel to the District of Columbia to seek treatment.

• Different health care and habits. Because cancer death ratesreflect differences in patterns of health care, we need to knowwhether residents of Utah pay more attention to preventive healthcare and have more regular checkups, whether their medical fa-cilities are better, and whether they devote a larger proportionof their annual income to health services than do residents in theDistrict of Columbia.

You can probably think of additional factors, but the point isthat avoiding experimental bias can be quite difficult!

A second example of the problem of bias comes from the col-lection of “miracle cures” that continue to appear and disappear atregular intervals. Pyramid power, coffee enemas, crystals, magnetic-energy fields, and psychic healers come and go in the news. Won-der drugs are equally common, whether they are“secret formulas”or South American plant extracts discovered by colonists fromother planets. The proponents of each new procedure or drug re-port glowing successes with patients who would otherwise havesurely succumbed to the disease—and most of these remedies aresaid to have been suppressed or willfully ignored by the “medicalestablishment.”

Even accepting that the claims aren’t exaggerated, does the factthat 1, or 100, or even 1000 patients have been cured prove any-thing? No, because a list of successes doesn’t mean much. To un-derstand why, consider the questions you might pose to aninstructor who announced on the first day of class that he or shehad given 20 A’s last semester. You would want to know how manystudents were in the class: only 20, or several hundred? You wouldalso want to find out how the rest of the class performed—20 A’sand 200 D’s might be rather discouraging. You might want to seehow the students were selected. If only students with A averagesin other courses had enrolled, your opinion should change ac-cordingly. Finally, you might check with the students and comparetheir grades with those given by other instructors who teach thesame course.

With just a couple of modifications, the same questions couldbe asked about a potential cancer cure:

• How many patients were treated, how many were cured, and howmany died?

• How were the patients selected? If selection depended onwealth, degree of illness, or previous exposure to other thera-

peutic techniques, then the experimental procedure was biasedfrom the start.

• How many might have recovered regardless of the treatment?Even “terminal” cancers sometimes simply disappear for no ap-parent reason. Such occurrences are rare, but they do happen.Thus, any treatment, however bizarre, will in some cases appearto work. If the frequency of recovery is lower than that amongother patient groups, the treatment might actually be harmfuldespite the reported “cures.”

• How do the foregoing statistics compare with those of traditionaltherapies when both are subjected to the same unbiased tests?

THE NEED FOR REPEATABILITYFinally, let’s examine the criterion of repeatability. It’s not enoughto develop a reasonable, testable hypothesis and collect unbiaseddata. Consider the hypothesis that every time a coin is tossed, itwill come up heads. You could build a coin-tossing machine, turnit on, and find that in the first experiment of 10 tosses, the coincame up heads every time. Does this result prove the hypothesis?

No, despite the fact that it was an honest experiment and thedata supported the hypothesis. The problem here is one of sta-tistics, sample size, and luck. The odds that a coin will come upheads on any given toss are 50 percent, or 1 in 2—the same as theodds that it will come up tails. The odds that it will come up heads10 times in a row are about 1 chance in (1 in 1024)—small, but certainly not inconceivable. If that coin is tossed 50times, however, the chance of getting 50 heads drops to 1 in

(less than 1 chance in a thousand trillion), a figure thatmost people would accept as vanishingly small. Proving that thehypothesis “a tossed coin always lands heads up” is false requiresthat the coin come up tails only once. So the truth could be re-vealed by running the experiment with more coin tosses or byletting other people set up identical experiments and toss theirown coins.

For a hypothesis to be correct, anyone and everyone must getthe same results when the experiment is performed. If the exper-iment isn’t repeatable, you have to doubt the conclusion even whenyou have complete confidence in the abilities and integrity of theoriginal investigator.

If a hypothesis satisfies all these criteria—it is testable, unbi-ased, and repeatable—it can be accepted as a scientific theory.The scientific use of this term differs from its use in general con-versation. When people discuss “wild-eyed theories,” they are usu-ally referring to untested hypotheses. Hypotheses may be true orfalse, but by definition, theories describe real phenomena andmake accurate predictions about the world. Examples of scientif-ic theories include the theory of gravity and the theory of evolu-tion. The “fact” of gravity is not in question, and the theory ofgravity accounts for the available data. But this does not meanthat theories cannot change over time. Newton’s original theoryof gravity, though used successfully for more than two centuries,was profoundly modified and extended by Albert Einstein. Simi-larly, the theory of evolution has been greatly elaborated since itwas first proposed by Charles Darwin in the middle of the 19thcentury. No one theory can tell the whole story, and all theoriesare continuously being modified and improved as we learn moreabout our universe.

1 * 250

1 * 210

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� HOMEOSTASIS AND DISEASEThe ability to maintain homeostasis depends on two interactingfactors: the status of the physiological systems involved and thenature of the stress imposed. Homeostasis is a balancing act, andeach of us is like a tightrope walker. Homeostatic systems mustadapt to sudden or gradual changes in our environment, the arrivalof pathogens, injuries, and many other factors, just as a tightropewalker must make allowances for gusts of wind, frayed segmentsof the rope, and thrown popcorn.

The ability to maintain homeostasis varies with one’s age, gen-eral health, and genetic makeup. The geriatric patient or young in-fant with the flu is in much greater danger than an otherwisehealthy young adult with the same viral infection. If homeostaticmechanisms cannot cope with a particular stress, physiological val-ues will drift outside the normal range. This change can ultimate-ly affect all other systems, with potentially fatal results. After all, aperson unable to maintain balance will eventually fall off thetightrope.

Consider a person who is exercising heavily and has a heart rateof 180 beats per minute for several minutes. That would be ac-ceptable in a young, healthy adult, but such a heart rate can bedisastrous for an older person with cardiovascular and respirato-ry problems. If it is allowed to continue, cardiac muscle tissue willbe damaged, leading to decreased pumping efficiency and a dan-gerous drop in blood pressure.

These changes represent a serious threat to homeostasis. Othersystems will soon become involved. For example, the drop inblood pressure will suppress kidney function, and waste productswill begin accumulating in the blood. The reduced blood flow inother tissues will result in a generalized hypoxia, or low tissue oxy-gen level. Cells throughout the body then begin to suffer fromoxygen starvation. The person is now in serious trouble: Unlesssteps are taken to correct the situation, his or her survival will bethreatened.

A failure to maintain homeostatic conditions constitutesdisease. The disease process may initially affect a specific tissue, anorgan, or an organ system, but it will ultimately lead to changes inthe function or structure of cells throughout the body. A diseasecan often be overcome through appropriate, automatic adjust-ments in physiological systems. In a case of the flu, the disease de-velops because the immune system cannot defeat the flu virusbefore that virus has infected cells of the respiratory passageways.For most people, the physiological adjustments made in responseto the viral invasion will lead to the elimination of the virus andthe restoration of homeostasis. Some diseases, by contrast, can-not easily be overcome. In the case of the person with acute car-diovascular problems, some outside intervention may be necessaryto restore homeostasis and prevent fatal complications.

Diseases may result from the following:

• Pathogens that invade the body. Examples are the viruses thatcause such diseases as flu, mumps, and measles; the bacteria re-sponsible for diseases like anthrax, Lyme disease, and tuberculo-sis; and the parasites (including protozoans, fungi, and worms)that produce such conditions as malaria, athlete’s foot, and trichi-nosis. The invasion process is called infection. Some parasitesdo not enter the body, but instead attach themselves to its surface.This process is called infestation.

• Inherited genetic conditions that disrupt normal physiologicalmechanisms. These conditions make normal homeostatic con-trol difficult or impossible. Examples include the lysosomal stor-age diseases, cystic fibrosis, and sickle cell anemia.

• The loss of normal regulatory control mechanisms. For ex-ample, cancer involves the rapid, unregulated multiplication ofabnormal cells. Many cancers have been linked to abnormalitiesin genes responsible for controlling rates of cell division. A vari-ety of other diseases, called autoimmune disorders, result whenregulatory mechanisms of the immune system fail and healthytissues are attacked.

• Degenerative changes in vital physiological systems. Many sys-tems become less adaptable and less efficient as part of the agingprocess. For example, we experience significant reductions inbone mass, respiratory capacity, cardiac efficiency, and kidneyfiltration as we age. If the elderly are exposed to stresses that theirweakened systems cannot tolerate, disease results.

• Trauma, toxins, or other environmental hazards. Accidents candamage organs, impairing their function. Toxins consumed inthe diet or absorbed through the skin or lungs can disrupt nor-mal metabolic activities.

• Nutritional factors. Diseases can result from diets that are in-adequate in proteins, essential amino acids, essential fatty acids,vitamins, minerals, or water. Kwashiorkor, a disease caused byprotein deficiency, and scurvy, caused by vitamin C deficiency,are two examples. Excessive consumption of high-calorie foods,fats, or fat-soluble vitamins can also cause diseases, such as coro-nary artery disease, obesity, and diabetes mellitus.

� THE DIAGNOSIS OF DISEASEA person experiencing serious symptoms usually seeks profes-sional help and thereby becomes a patient. The clinician, whethera nurse, a physician, or an emergency medical technician, mustdetermine the need for medical care on the basis of observationand assessment of the patient. This is the process of diagnosis: theidentification of a pathological process by its characteristic symp-toms and signs.

SYMPTOMS AND SIGNSAn accurate diagnosis, or the identification of the disease, is ac-complished through the observation and evaluation of symptomsand signs.

A symptom is the patient’s perception of a change in normalbody function. Examples of symptoms include nausea, fatigue,and pain. Symptoms are difficult to measure, and a clinician mustask appropriate questions, such as the following:

“When did you first notice this symptom?”

“What does it feel like?”

“Does it come and go, or does it always feel the same?”

“Does anything make it feel better or worse?”

The answers provide information about the location, duration,sensations, recurrence, and triggering mechanisms of the symp-toms important to the patient.

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Localized pain Generalized (diffuse) pain

Restricted to one specific area (Example: skin laceration)

Poorly localized, regional, or widespread (Example: abdominal pain)

Localization

Duration

Acute pain

Chronic pain

Sudden onset, intense (Example: wasp sting)

Recurrent or continuous over long period (Example: joint pain, arthritis)

Source

Sensations

Fast (prickling) pain

Intense, sharp, localized

Slow (burning and aching) pain

Deep, aching, poorly localized

Somatic pain

Pain in skeletal muscles, joints, skin, or body wall

Visceral pain

Pain in visceral tissues and organs

Referred pain

Visceral pain perceived as somatic pain in another part of the body (Example: left arm pain during heart attack)

PAIN

� FIGURE 2Methods of Classifying and Describing Pain

Pain,an important symptom of many illnesses, is often an indica-tion of tissue injury. The flowchart in Figure 2� indicates the types ofpain and introduces important related terminology.We shall consid-er the control of pain in related sections of the Applications Manual.

A sign is a physical manifestation of a disease. Unlike symp-toms, signs can be measured and observed through sight, hear-ing, or touch. The yellow color of the skin caused by liverdysfunction and a detectable breast lump are signs of disease. Asign that results from a change in the structure of tissue or cells iscalled a lesion. We shall consider lesions of the skin in detail in alater section dealing with the integumentary system.

THE STEPS IN DIAGNOSISDiagnosis is a lot like assembling a jigsaw puzzle. The more pieces(clues) available, the more complete the picture will be. The process

of diagnosis is one of deduction and follows an orderly sequenceof steps:

1. Obtain the patient’s medical history. The medical history is aconcise summary of past medical disorders, general factors thatmay affect the functioning of body systems, and the health of thepatient’s family. This information provides a framework for con-sidering the individual’s current problem. Probably over half ofall diagnoses are made from the history, with tests being usedchiefly for confirmation.

When taking a history, the examiner gains information aboutthe patient’s concerns by asking specific questions and using goodlistening skills. (Physicians in training are often told,“Listen to thepatient; she (or he) is trying to tell you what’s wrong.”) Physicalassessment also begins here—this is the time for unspoken ques-tions such as “Is this person moving, speaking, and thinking nor-

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mally?” The answers will later be integrated with the results ofmore precise observations.

Other components of the medical history may include thefollowing:

• Chief complaint. The patient is asked to specify the primaryproblem that requires attention. This is recorded as the chiefcomplaint. An example would be the entry “Patient complainsof pain in the abdomen.”

• History of present illness. Which areas of the body are af-fected? What kinds of functional problems have developed?When did the patient first notice the symptoms? The durationand pattern of the disease process is an important factor. Forexample, an infection may have been present for months, onlygradually increasing in severity. This would be called a chronicinfection. A disease process may have been underway for sometime before the person recognizes that a problem exists. Over theinitial period, the individual experiences subclinical symptoms—symptoms so mild that they are usually ignored. Chronic in-fections commonly have different causes and treatments than doacute infections, which produce sudden, intense symptoms.

• Review of systems. The patient is asked questions that focuson the general status of each body system. This process maydetect related problems or causative factors. For example, achief complaint of a headache may be related to visual problems(stars, spots, blurs, or blanks seen in the field of vision) orcaused by visual problems (eyeglasses poorly fitted or madefrom the wrong prescription).

2. Perform a physical examination. The physical examination is a basicand vital part of the diagnostic process. Common techniques usedin physical examination are inspection (viewing), palpation (touch-ing),percussion (tapping and listening),and auscultation (listening):

• Inspection is careful observation. A general inspection in-volves examining body proportions, posture, and patterns ofmovements. Local inspection is the examination of sites or re-gions of suspected disease. Of the four components of the phys-ical exam, inspection is often the most important, because itprovides the largest amount of useful information. Many diag-nostic conclusions can be made on the basis of inspection alone;most skin conditions, for example, are identified in this way. Anumber of endocrine problems and inherited metabolic disor-ders can produce changes in body proportions. Many neuro-logic disorders affect speech and movement in distinctive ways.

• Palpation is the clinician’s use of the hands and fingers to feelthe patient’s body. This procedure provides information aboutskin texture and temperature, the presence and texture of ab-normal tissue masses, the pattern of the pulse, and the loca-tion of tender spots. Once again, the procedure relies on anunderstanding of normal anatomy. In one spot, a small, soft,lumpy mass is a salivary gland; in another location, it could bea tumor. A tender spot is important in diagnosis only if the ob-server knows what organs lie beneath it.

• Percussion is tapping with the fingers or hand to obtain in-formation about the densities of underlying tissues. For ex-ample, when tapped, the chest normally produces a hollowsound, because the lungs are filled with air. That sound changesin pneumonia, when the lungs contain large amounts of fluid.

To get the clearest chest percussions, the fingers must be placedin the right spots.

• Auscultation (aws-kul-TA-shun; auscultare, to listen) is lis-tening to body sounds, typically with a stethoscope. This tech-nique is particularly useful for checking the condition of thelungs during breathing. The wheezing sound heard in peoplewith asthma is caused by a constriction of the airways, andpneumonia produces a gurgling sound, indicating that fluidhas accumulated in the lungs. Auscultation is also important indiagnosing heart conditions. Many cardiac problems affect thesound of the heartbeat or produce abnormal swirling soundsduring blood flow.

Every examination also includes measurements of certain vitalbody functions, such as the body temperature, weight, blood pres-sure, respiratory rate, and heart (pulse) rate. The results, calledvital signs, are recorded on the patient’s chart. Vital signs canvary over a normal range that differs according to the age, gen-der, and general condition of the individual. Table 1 indicates therepresentative ranges of vital signs in infants, children, and adults.

TABLE 1 Normal Range of Values for RestingIndividuals by Age Group

Vital Infant ChildSign (3 months) (10 years) Adult

Blood pressure 90/50 90–125/60 95/60 to (mm Hg) 140/90

Respiratory rate 30–50 18–30 8–18(per minute)

Pulse rate 70–170 70–110 50–95(per minute)

3. If necessary, perform diagnostic procedures. The medical histo-ry and physical examination may not provide enough informa-tion to permit a precise diagnosis. Diagnostic procedures can thenbe used to focus on abnormalities revealed by the history and phys-ical examination. For example, if the chief complaint is knee painafter a fall, and the examination reveals swelling and localized, acutepain on palpation, the preliminary diagnosis may be a torn car-tilage.An x-ray, MRI scan, or both may be performed to determinemore precisely the extent of the injury and to ensure that there areno other problems, such as broken bones or torn ligaments. Withthe information the diagnostic procedure provides, the finaldiagnosis can be made with reasonable confidence. Diagnosticprocedures extend, rather than replace, the physical examination.

Two general categories of diagnostic procedures are performed:

1. Tests performed on the individual. Information about repre-sentative tests of this type is summarized in Table 2. These pro-cedures allow the clinician to

• Visualize internal structures (endoscopy; x-rays; scanning pro-cedures such as CT, MRI, and radionucleotide scans; ultra-sonography; mammography; see Figure 3)

• Monitor physiological processes (EEG, ECG, PET, RAI, pul-monary function tests)

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TABLE 2 Representative Diagnostic Tests, Their Principles, and Their Uses

Procedure Principle Examples of Uses

Endoscopy Insertion of fiber-optic tubing into a body opening Bronchoscopy: bronchi and lungsor through a small incision (laparoscopy and Laparoscopy: abdominopelvic organsarthroscopy); permits visualization of a body cavity Cystoscopy: urinary bladderor the interior of an organ; allows direct Esophagoscopy: esophagusvisualization and biopsy of structures and Gastroscopy: stomachdetection of abnormalities of surrounding Colonoscopy: colonsoft tissue Arthroscopy: joint cavity

Standard x-rays A beam of x-rays passes through the body and Limb bones: to detect fracture, tumor, growth patternsthen strikes a photographic plate; radiodense Chest: to detect tumors, pneumonia, atelectasis, tuberculosistissues block X-ray penetration, leaving unexposed Skull: to detect fractures, sinusitis, metastatic tumors(white) areas on the developed film (Figure 3) Mammogram: x-rays of each breast taken at different angles

for early detection of breast cancer and other masses, such as cysts

Contrast x-rays X-rays taken after infusion or ingestion of Barium swallow (upper GI): series of x-rays after the ingestion radiodense solutions (Figure 3) of barium, to detect abnormalities of esophagus, stomach,

and duodenumBarium enema: series of x-rays after barium enema, to detect abnormalities of colon

IV pyelography: series of x-rays after intravenous injection of radiopaque dye filtered by kidneys; reveals abnormalities of kidneys, ureters, and bladder; allows assessment of renal function

Digital subtraction Produces strikingly clear images of blood vessel Analysis of blood flow to the heart, kidneys, and brain to angiography distribution by computer analysis of images detect blockages and restricted circulation

taken before and after dye infusion (Figure 5)

Computerized Produces cross-sectional images of body area CT scans of the head, abdominal region (liver, pancreas, tomography viewed; together, all sections can produce a kidney), chest, and spine, to assess organ size and position, (CT or CAT) three-dimensional image for detailed examination. to determine progression of a disease, and to detect

(Figure 4) abnormal masses

Spiral CT scans Produce three-dimensional images by computer Often a research tool, but of increasing clinical use at large reconstruction of CT data (Figure 5) regional hospitals and universities

Nuclear scans Radioisotope ingested, inhaled, or injected into the Bone scan: to detect tumors, infections, and degenerative body becomes concentrated in the organ to be diseasesviewed; gamma radiation camera records image on Scans of the brain, heart, thyroid, liver, lung, spleen, and film. Area should appear uniformly shaded; dark or kidney, to assess organ function and the extent of light areas suggest hyperactivity or hypoactivity of many diseasesthe organ. (p. 16)

Radioactive iodine Radioactive labeled iodine compound is given orally; Aids in the determination of hyperthyroidism and uptake test (RAI) thyroid scans are taken to determine percentage hypothyroidism and in detection of thyroid nodules

uptake of radioiodine by thyroid gland

Positron emission Radioisotopes are given by injection or inhalation; Used to measure metabolic activity of heart and brain and to tomography (PET) gamma detectors absorb energy and transmit analyze blood flow through organs.

information to computers to generate Primarily a research tool; rapid functional MRI more widely cross-sectional images. (Figure 5) used in clinical settings

Magnetic resonance A magnetic field is produced to align hydrogen Gives excellent contrast of normal and abnormal tissue; imaging (MRI) protons and is then exposed to radio waves that reveals extent of tumors, demyelination and other brain

cause the aligned atoms to absorb energy. and spinal cord abnormalities, obstructions or aneurysms in The energy is later emitted and captured to produce arteries, and ligaments and cartilages at jointsan image. (Figure 4)

• Assess the patient’s homeostatic responses (stress testing,skin tests)

2. Tests performed in a clinical laboratory on tissue samples, bodyfluids, or other materials collected from the patient. Table 3includes details about a representative sample of these tests.

Many of the diagnostic procedures and disorders noted in thesetables will be unfamiliar to you now. The main purpose here is togive you an overview; you can refer to the tables as needed through-out the course.

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TABLE 3 Laboratory Tests Performed on Samples Taken from the Body

BLOOD TESTS: Serum, plasma, or whole-blood samples can be evaluated. Either venous or arterial blood is taken, depending on the bloodconstituent or chemical being monitored.

Laboratory Test Significance Notes

Complete blood count (CBC): Data from this test series inform the practitioner about a change For more information, RBC count in the number of red blood cells; changes may indicate the presence see Table 27c, p. 125.Hemoglobin (Hb. Hgb) of disease, hemorrhaging, malnutrition, or other problems. A CBC Hematocrit (Hct) is generally performed during a normal physical exam to give the

practitioner more information about the patient’s general health.Changes may indicate blood loss, infections, or other problems.

RBC indices (Mean corpuscular hemoglobin, Provide information about the status of hemoglobin production See Table 27c, p. 125.MCH, and Mean corpuscular hemoglobin and red blood cell maturationconcentration, MCHC, among others)

WBC count and Differential WBC count The white blood cell count and the proportions of various cell types See Table 27c, p. 125.reflect the state of the body’s immune system and the ability to fight infection. An increased white blood cell count could indicate the presence of infection.

Hemostasis tests: A decreased number of platelets could result in uncontrolled See Table 27c, p. 125.Platelet count bleeding. Other constituents, such as fibrinogen, clotting factors, Bleeding time and prothrombin, also contribute to the clotting process, and Factors assay these can be assessed separately.Plasma fibrinogenPlasma prothrombin time (PT) Frequently used to monitor therapeutic use of anticoagulantsPlasminogen

TABLE 2 Representative Diagnostic Tests, Their Principles, and Their Uses (Continued)

Procedure Principle Examples of Uses

Ultrasonography A transducer contacting the skin or other body Avoids X-ray exposure, used to view soft tissues not shielded surface sends out sound waves and then picks up by bone throughout the body. Used in obstetrics to detect the echoes. (Figure 4) ectopic pregnancy, determine size of fetus, and check fetal

rate of growth; upper abdominal ultrasound detects gallstones, visceral abnormalities, and measures kidneys

Echocardiography Ultrasonography of the heart (p. 138) Used to assess the structure and function of the heart and heart valves

Electrocardiography Graphed record of the electrical activity of the heart, Useful in detection of arrhythmias, such as premature (ECG) using electrodes on the skin surface ventricular contractions (PVCs) and fibrillation, and to assess

damage after a heart attack

Electroencepha- Graphed record of electrical activity in the brain Analysis of brain wave frequency and amplitude aids in the lography (EEG) through the use of electrodes on the surface of diagnosis of tumors and seizure disorders

the scalp

Electromyography Graphed record of electrical activity resulting from Determination of neural or muscular origin of muscle (EMG) skeletal muscle contraction, using electrodes disorder; aids in the diagnosis of muscular dystrophy,

inserted into the muscles pressure on spinal nerves, and peripheral neuropathies

Pulmonary Measurement of lung volumes and capacities by a Aids in the differentiation between obstructive and restrictive function tests spirometer or other device lung diseases; used to test for and monitor asthma

Cytology Removal of cells for laboratory analysis Detects precancerous cells or infections; most often used to assess mucosal cells of cervix (Pap smear)

Stress testing Monitoring of blood pressure, pulse rate, and ECG Aids in the determination of the extent of coronary artery during exercise; may include intravenous injection disease, which may not be apparent while the individual is of radioisotopes at rest

Skin tests Injection of a substance under the skin, or placement Tuberculin test: injection of tuberculin protein under skinof a substance on the skin surface, to determine the Allergen test: injection of allergen or application of a patch response of the immune system (p. 160) containing allergen

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TABLE 3 Laboratory Tests Performed on Samples Taken from the Body (Continued)


Electrolytes: Sodium, potassium, and chloride levels are levels of electrolytes See Tables 27b, 37, 39, Sodium that function in nerve transmission, skeletal muscle contraction, pp. 124, 179, 202–203.Potassium and cardiac rhythm.Chloride Abnormal levels of bicarbonate indicate problems with acid–base Bicarbonate balance.

Iron Decreased levels cause iron deficiency anemia; increased levels may cause liver and heart damage.

Arterial blood gases and pH: Respiratory acidosis and alkalosis can be monitored with these See Table 34, p. 167.pH values. Decreased oxygen levels occur in respiratory and

cardiovascular system dysfunction.

Hemoglobin electrophoresis: Electrophoresis separates the types of hemoglobin for quantitative See Table 27c, p. 126.Hemoglobin A measurement.Hemoglobin F Abnormal types of hemoglobin occur in sickle cell anemias and Hemoglobin S thalassemias.

ABO and Rh typing Blood typing is critical for correct matching of blood types prior to See Table 44, p. 232.transfusion. Rh typing during pregnancy is important to determine risk of fetal–maternal Rh incompatibility.

Cholesterol Elevated cholesterol levels reflect the potential for atherosclerosis See Table 27b, p. 124.and coronary artery disease.

Lipoproteins: Electrophoresis is used to separate the LDL fraction of total See Table 27b, p. 124.LDL cholesterol to determine the HDL and LDL levels. High LDL and HDL low HDL are risk factors for coronary artery disease.

Enzymes: Abnormal enzyme levels in the blood are generally due to See Table 27b, p. 124.cellular damage.

Creatine phosphokinase (CPK or CK)

Isoenzymes (CPK-MM, CPK-MB, CPK-BB) CPK-MM is useful in the diagnosis of muscle disease; CPK-MB is used in the diagnosis of heart attacks.

Aspartate aminotransferase (AST) AST levels are important to assess liver damage.

Lactate dehydrogenase (LDH) Different isoenzymes of LDH can be useful in the detection of heart damage, liver problems, and pulmonary dysfunction.

Rheumatoid factor Measures presence of antibodies characteristic of rheumatoid See Table 16, p. 55.arthritis and (less often) other autoimmune diseases

Hormones Varies with age and gender; abnormally increased or decreased See Table 26, levels reflect endocrine system disorders pp. 110–111.

Blood urea nitrogen (BUN) Assesses kidney function, presence of dehydration See Table 39, p. 203.

Creatinine Assess kidney function

Immunoglobin electrophoresis Monitors infections and allergic response See Table 29, p. 000.(IgA, IgG, IgD, IgE, IgM)

Alcohol Determines level of intoxication

Human chorionic gonadotropin (hCG) Detects pregnancy See Table 44, p. 232.

Phenylalanine Detects phenylketonuria (PKU), a genetic disorder of amino acid metabolism

Alpha fetoprotein Identifies probability of fetal defects or presence of twins; elevated levels with liver tumors

Glucose tolerance test Detects hyperglycemia (diabetes mellitus) See Table 26, p. 111.

PO2

PCO2

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THE PURPOSE OF DIAGNOSISTwo hundred years ago, a physician would arrive at a diagnosis andconsider the job virtually done. Once the diagnosis was made andthe physician gave a prognosis (likely outcome), the patient andfamily would know what to expect. In effect, the physician wasmore of an oracle than a healer. Wounds could be closed and limbsamputated, but few effective treatment options were available. Lessobvious diagnoses than trauma often reflected the culture and be-liefs of the era. Curses and bewitching vied with “unbalanced hu-mours”as explanations of disease. Therapy was often a combinationof bleeding (often performed by barbers rather than by surgeons),dietary changes, and herbal medicines (often laxatives). Strong lax-atives might have helped in cases of intestinal parasites, but thecombination of bleeding and laxatives was potentially dangerousbecause it reduced both blood volume and blood pressure.

Fortunately, a vast array of treatment options guided by a ra-tional, accurate diagnosis are available today. A modern physicianaddressing a new problem presented by a patient follows the SOAPprotocol:

S is for subjective. The clinician obtains subjective information fromthe patient and the medical history.

O is for objective. The clinician performs the physical examinationand obtains objective information about the physical condition

of the patient. The examination may include the use of diagnos-tic procedures.

A is for assessment. The clinician arrives at a diagnosis and, if nec-essary, reviews the literature on the condition. A preliminary con-clusion as to the prognosis (probable outcome) is made.

P is for plan. A treatment plan is designed. This can be verysimple (lose weight, exercise, and take two aspirin) or highlycomplex (referral for radiation, chemotherapy, or surgery).If the treatment is complex, one or more treatment optionsare usually reviewed with the patient and, in many cases, thepatient’s family. Treatment begins only after informed deci-sions are made.

The SOAP protocol is both simple to remember and remarkablyeffective.

The primary goal of an introductory anatomy and physiologycourse is to provide you with the foundation for other, more spe-cialized courses. In the unit of this manual that deals with bodysystems, you will be introduced to clinical conditions that demon-strate the relationships between normal and pathological anatomyand physiology. The goal is to acquaint you with the mechanics ofthe process involved. This knowledge will not enable you to makeaccurate clinical diagnoses; situations in the real world are muchmore complicated and variable than the examples provided here.

Disease, Pathology, and Diagnosis 11IN

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TABLE 3 Laboratory Tests Performed on Samples Taken from the Body (Continued)


Blood culture The presence of bacterial pathogens occurs in septicemia, See Tables 27c, 29, 37, pneumonia, and other infectious disorders. pp. 125–126, 149, 181.

URINE TESTS: A single urine sample may be tested, or urine may be collected over a period of time (usually from 2 to 24 hours) and tested. Aroutine urinalysis aids in the detection of kidney dysfunction, as well as metabolic imbalances and other disorders. The presence of abnormalcellular constituents in urine indicates urinary system disorder, including infection, inflammation, or the existence of a tumor.

Creatine clearance Abnormal values indicate reduced renal function.

Urine electrolytes: Abnormal levels reflect fluid or electrolyte imbalances and the See Table 39, p. 202.Sodium effects of hormones on renal function.Potassium

Uric acid Increased levels occur with gout and some kidney disorders. See Table 39, p. 203.

Urine culture Detects pathogens present in urinary tract infections

OTHER LABORATORY TESTS: Additional laboratory tests can be used to monitor other body fluids, excretory products, or tissues. Here areseveral examples:

Cerebrospinal fluid (CSF) Tested for sugar and protein content, and the presence See Table 19, p. 79.of antibodies, pathogens, or blood cells

Stool sample Culturing and microscopic examination of sample to identify See Table 39, p. 203.pathogenic bacteria or parasites. DNA analysis may detect colon tumors.

Semen analysis Useful in diagnosis of male infertility or in assessing success See Table 42, p. 218.of vasectomy

Tissue biopsy The removal of tissue for microscopic examination See Table 17, p. 66.

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(a)

Stomach

Smallintestine

(b)

� FIGURE 3X Rays. (a) An x-ray of the skull, taken from the left side. X-rays are a form of high-energyradiation that can penetrate tissues. In the most familiar procedure, a beam of x-rays travelsthrough the body and strikes a photographic plate. Not all of the projected x-rays reach thefilm; some are absorbed or deflected as they pass through the body. The resistance to X-raypenetration is called radiodensity. Radiodensity increases in the following sequence: air, fat,liver, blood, muscle, bone. The usual result is an image with radiodense tissues, such as bone,appearing in white, and less dense tissues in shades of gray to black. (b) A barium contrastx-ray of a portion of the upper digestive tract. Such an x-ray is produced after a radiodensematerial is introduced into the body. It is used to provide sharp outlines and contrast and tocheck the distribution of fluids or the movements of internal organs. In this instance, thepatient swallowed a solution of barium, an element that is very dense. The contours of thestomach and intestinal linings are clearly indicated by the white of the barium solution.

Making an accurate clinical diagnosis is generally a complex processthat demands a far greater level of experience and training thanthis course can provide.

For similar reasons, we will not discuss detailed treatment plans;the treatment of serious diseases requires current and specializedtraining and competence in advanced biochemistry, pharmacolo-gy, microbiology, pathology, and other clinical disciplines. How-ever, many of the discussions in later sections include informationabout the use of specific drugs and other therapeutic proceduresin the treatment of disease. These are representative examples in-tended to show potential treatment strategies, rather than to en-dorse specific protocols and therapies.

SECTIONAL ANATOMY ANDCLINICAL TECHNOLOGYRadiological procedures are used to provide detailed informationabout internal systems in a living individual. They include(1) scanning techniques that involve the use of beams of radia-tion, such as x-rays, to create a photographic or computer-

generated image of internal structures, and (2) methods that in-volve the administration of radioactive materials. Over the lastdecade, imaging techniques such as MRI scans and sophisticat-ed ultrasounds have reduced the reliance on radiation for diag-nostic imaging. Physicians who specialize in the performance ofthese procedures and the analysis of the resulting images arecalled radiologists.

Figures 3 through 5� compare the views provided by severaltechniques used. The figures include images produced using x-rays, computerized tomography (CT) scans, magnetic resonanceimaging (MRI) scans, ultrasound procedures, spiral-CT scans,digital subtraction angiography (DSA) techniques, and positronemission tomography (PET) scans. These clinical technologies andmore specialized MRI procedures are described and included asfigures later in the text.

Whenever you see anatomical diagrams or clinical proceduresthat present cross-sectional views of the body, remember that eachsection is oriented as though the observer is standing at the feet ofthe subject and looking toward the head. The section is an inferi-or view, with anterior at the top and posterior at the bottom, andstructures on the left side of the body are seen on the right side ofthe image.

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Sectional Anatomy and Clinical Technology 13

(d)

(c)

(b)

(a)

Liver Stomach

Rib

Vertebra

Left kidney

Aorta

Liver

Liver

Kidneys

Vertebra

Kidney

Stomach

Stomach

Stomach

Vertebra AortaLeft kidneyRight kidney

Spleen

Spleen

Spleen

Liver

Rib

� FIGURE 4Common Scanning Techniques

(a) Drawings of the structures and relative position and orientation ofthe scans shown in parts (b)–(d).

(b) A CT scan of the abdomen. Computerized tomography (CT), former-ly called computerized axial tomography (CAT), uses computers to re-construct sectional views. A single X-ray source rotates around the body,and the X-ray beam strikes a sensor monitored by the computer. Thesource completes one revolution around the body every few seconds; itthen moves a short distance and repeats the process. The result is usuallydisplayed as a sectional view in black and white, but it can be colorizedfor visual effect. CT scans show three-dimensional relationships and soft-tissue structure more clearly than do standard x-rays.

(d) An ultrasound scan of the abdomen. In ultrasound procedures, asmall transmitter contacting the skin broadcasts a brief, narrow burst ofhigh-frequency sound and then picks up the echoes. An echogram, orultrasound picture, can be assembled from the pattern of echoes pro-duced when the sound waves are reflected by internal structures.Theseimages lack the clarity of those produced by other procedures, but noadverse effects have been reported, and fetal development can be moni-tored without any known risk of birth defects. Special methods of trans-mission and processing permit analysis of the beating heart, without thecomplications that can accompany injections of a dye. Note the differ-ences in detail among this image, the CT scan, and the MRI image. Im-proved technology is reducing this disparity.

(c) An MRI scan of the abdomen. Magnetic resonance imaging (MRI)surrounds part or all of the body with a magnetic field about 3000 timesas strong as that of Earth. The MRI field affects protons within atomicnuclei throughout the body. The protons line up along the magneticlines of force like compass needles in Earth’s magnetic field. When struckby a radio wave of a certain frequency, a proton will absorb energy.When the wave pulse ends, that energy is released and the source of theradiation is detected. Each element differs in terms of the radio frequen-cy required to affect its protons.

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14 AN INTRODUCTION TO CLINICAL ANATOMY AND PHYSIOLOGYIN

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First rib

Aortic arch

Aorta

Vertebralcolumn

Right scapula

Heart

Arteries ofthe heart

(a) (b)

(c)

AnteriorPosterior

� FIGURE 5Special Scanning Methods. (a) A spiral-CT scan of the chest. Such an image is created by special processing of CT data to permit rapid three-dimensional visualization of internal organs. Spiral-CT scans are becoming increasingly important in clinical settings. (b) Digital subtraction angiography(DSA) is used to monitor blood flow through specific organs, such as the brain, heart, lungs, or kidneys. X-rays are taken before and after a radiopaquedye is administered, and a computer “subtracts” details common to both images. The result is a high-contrast image showing the distribution of thedye. (c) Positron-emission tomography (PET) scans rely on the administration of radioactive isotopes that are later detected by gamma-ray detectorsand interpreted by computers.

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15

MEDICAL USE OF RADIOISOTOPESA radioisotope, or radioactive isotope, is an isotope whose nu-cleus is unstable; that is, the nucleus spontaneously decays, or emitssubatomic particles. Many recent technological advances in med-icine have involved the use of radioisotopes for the diagnosis andtreatment of disease. We will focus on two examples:

1. The use of radioactive tracers in clinical testing, particularlythrough the creation of diagnostic images. Radioisotopes can beattached to organic or inorganic molecules and injected into thebody. There, the labeled molecules emit radiation that allowsclinicians to monitor their distribution and utilization. The ra-diation can often be used to create images that provide infor-mation about tissue structure, tumors, blocked or weakenedblood vessels, and other abnormalities in the body.

2. The use of radiopharmaceuticals to destroy abnormal cells andtissues. If a suitable radioactive compound can be accurately de-livered to a target site, radiation can be used to treat many diseases.

� RADIOISOTOPES AND CLINICAL TESTING

Alpha particles are subatomic particles that consist of a heliumnucleus: two protons and two neutrons. These particles general-ly are emitted by the nuclei of large radioactive atoms, such asuranium. Beta particles are electrons, more typically released byradioisotopes of lighter atoms. Gamma rays are very-high-energyelectromagnetic waves comparable to the x-rays used in clinicaldiagnosis.

The half-life of any radioisotope is the time required for half ofa given amount of the isotope to decay. The half-lives of radioiso-topes range from fractions of a second to billions of years.

Gamma rays, beta particles, and alpha particles—like x-rays—can damage or destroy living tissues. The danger posed by expo-sure to radiation varies with the nature of the emission and theduration of exposure. But radiation also has a variety of beneficialuses in medical research and clinical diagnosis. Weakly radioac-tive isotopes with short half-lives provide a noninvasive means ofchecking the structure and functional state of an organ.

Radioisotopes can be incorporated into specific compoundsthat the body normally processes. These compounds, calledtracers, are said to be labeled: When introduced into the body, la-beled compounds can be traced by the radiation they release. Aftera labeled compound is swallowed, its uptake, distribution, and ex-cretion can be determined by monitoring the radioactivity of sam-ples taken from the digestive tract, body fluids, and waste products,respectively. For example, compounds labeled with radioisotopesof cobalt are used to measure the intestinal absorption of vitamin

Normally, cobalt-58, a radioisotope with a half-life of 71 days,is used.

Radioisotopes can also be injected into the blood or other bodyfluids to provide information about circulatory anatomy and theanatomy and function of specific target organs. In nuclear imag-ing, the radiation emitted by injected radioisotopes creates animage on a special detector. Such a procedure is used to identify re-gions where particular radioactive materials are concentrated or

B12.

THE CHEMICAL LEVEL OFORGANIZATION

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16 THE CHEMICAL LEVEL OF ORGANIZATIONC

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Thyroidgland

Trachea(windpipe)

(c)

� FIGURE 6Imaging Techniques. (a) The position and contours of the normal thy-roid gland as seen in dissection. (b) After it has been labeled with aradioactive tracer, the thyroid can be examined by special imaging tech-niques. In this computer-enhanced image, different intensities indicatedifferent concentrations of the radioactive tracer. (c) A PET scan of thebrain. The different intensities correspond to varying levels of metabolicactivity.

to check the flow of various substances through vital organs. Ra-dioisotopes can produce pictures of specific organs, such as theliver, spleen, thyroid, or bone, where different labeled compoundsare preferentially removed from the bloodstream.

The thyroid gland sits below the larynx (voice box) on the an-terior portion of the neck (Figure 6a�). A normal thyroid gland ab-sorbs iodine, which is then used to produce thyroid hormones. Asa result, the thyroid gland will actively absorb and concentrate

radioactive iodine. The thyroid scan in Figure 6b� was taken fol-lowing the injection of iodine-131, a radioisotope with an 8-dayhalf-life. This procedure, called a thyroid radioactive iodine uptakemeasurement, or RAIU, can provide information about (1) thesize and shape of the thyroid gland and (2) the amount of iodineabsorption. Comparing the rate of iodine uptake with the level ofcirculating hormones allows us to evaluate the functional state ofthe gland.

Radioactive iodine is an obvious choice for imaging the thy-roid gland. For most other tissues and organs, a radioactive labelmust be attached to another compound. Technetium a ver-satile tracer, is the primary radioisotope used in nuclear imagingtoday. The isotope is artificially produced and has a half-life of6 hours. This brief half-life significantly reduces the patient’s ex-posure to radiation. Technetium is used in more than 80 percentof all scanning procedures. The nature of the technetium-labeledcompound varies with the target organ. Technetium scans are per-formed to examine the thyroid gland, spleen, liver, kidneys, di-gestive tract, bone, and a variety of other organs.

PET (positron emission tomography) scans utilize the sameprinciples as standard radioisotope scans, but the analyses are per-formed by computer. The scans are much more sensitive, and thecomputers can reconstruct sections through the body and pro-vide extremely precise localization. Among other things, this pro-cedure can analyze blood flow through organs and assess themetabolic activity in specific portions of an organ as complex asthe human brain.

Figure 6c� is a PET scan of the brain showing its activity at asingle moment in time. The scan is dynamic, however, and chang-ing patterns of activity can be followed in real time. PET scanscan be used to analyze normal brain function, as well as to diag-nose brain disorders. To date, the technique has served primarilyas a research tool. Because the equipment is expensive and bulky,it is available only in large, regional medical centers or universi-ties. The research advantages of PET scans have been challengedby the advent of real-time CT analysis (cine-CT) and the realiza-tion that rapid “functional” MRI scans can be used to monitorsmall changes in blood flow and tissue activity without the use ofradioactive tracers.

� RADIOPHARMACEUTICALSNuclear medicine involving injected radioisotopes has been farmore successful in producing useful images than in treating spe-cific disorders. The problem is that the doses of radiation mustbe relatively large to destroy abnormal or cancerous tissues andit is very difficult to control the distribution of these radioiso-topes in the body with sufficient precision. As a result, radiationexposure can damage normal as well as abnormal tissues. It isalso difficult to control the radiation dosage administered to thetarget tissues: Underexposure can have very little effect on theabnormal cells, whereas overexposure can destroy adjacent nor-mal tissues.

Radioactive drugs, or radiopharmaceuticals, are effective only ifthey are delivered precisely and selectively. One success story hasbeen the treatment of hyperthyroidism (thyroid oversecretion) andthyroid cancer. The thyroid gland selectively concentrates iodine.Large doses of radioactive iodine can be administered to1131I2

199 Tc2,

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Solutions and Concentrations 17C

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TABLE 4 A Comparison of Methods for Report-ing Concentrations of Solutes in Blood*

Solute mg/dl mmol/L mEq/L SI Units

Electrolytes

Sodium 320 140 140 140 mmol/L

Potassium 16.4 4.2 4.2 4.2 mmol/L

Calcium 9.5 2.4 4.8 2.4 mmol/L

Chloride 354 100 100 100 mmol/L

Metabolites

Glucose 90 5 nr 5 mmol/L

Lipids, total 600 nr nr 0.6 g/L

Proteins, total 7 g/dl nr nr 70 g/L

* = not reported in these units.

1Cl-2

1Ca2+2

1K+2

1Na+2

treat hyperthyroidism. The radiation that is released destroys theabnormal thyroid tissue and stops the excessive production of thy-roid hormones. (Following this treatment, most individuals even-tually become hypothyroid—deficient in thyroid hormone—butthis condition can be treated by taking thyroid hormones in tabletform.) The use of radioactive iodine is now the preferred treat-ment method, as opposed to surgery or prolonged anti-thyroidmedication, for most adult hyperthyroid patients.

A relatively new application of nuclear medicine involves the at-tachment of a radioactive isotope to a monoclonal antibody(MoAb). Antibodies are proteins produced in the body to providea selective defense against foreign proteins, toxins, or pathogens.Monoclonal antibodies are produced by immune cells culturedunder laboratory conditions. The antibodies these cells produce arethen labeled with radioactive materials. Injected into the body, theantibodies will bind to their targets and expose the surroundingtissues to radiation. MoAbs specific to certain types of tumor cellshave already been approved by the Food and Drug Administra-tion (FDA). The amount of radiation emitted is low, however, andthe procedure is used to produce diagnostic images rather than totreat disease. Higher radiation levels may damage the MoAbs andaffect binding to target. Experiments continue, with the eventualgoal of using radiolabeled MoAbs to destroy tumor cells.

SOLUTIONS ANDCONCENTRATIONSPhysiologists and clinicians pay particular attention to the dis-tribution of ions across membranes and to the electrolyte com-position of body fluids. Data must be analyzed from severalperspectives, and physiological values can be reported in severalways. One method is to report the concentration of atoms, ions,or molecules in terms of weight per unit volume of solution. Al-though grams per liter (g/L) can be used, values are most oftenexpressed in grams (g), milligrams (mg), or micrograms per100 ml. Because (dl), the abbre-viations most often used in this text are g/ dl (grams per deciliter)and mg/ dl (milligrams per deciliter).

Osmotic concentration, or osmolarity, depends on the totalnumber of individual atoms, ions, and molecules in solution,without regard to molecular weight, electrical charge, or molec-ular identity. As a result, if fluid balance and osmolarity are beingmonitored, concentrations are usually reported in moles per liter(mol/ L, or M) or millimoles per liter (mmol/ L, or mM) ratherthan in g/dl or mg/dl. To convert g/dl to mol/L, multiply by 10and divide by the atomic weight of the element. For example, asample of plasma (blood with the cells removed) contains sodiumions at a concentration of roughly 0.32 g/dl (320 mg/dl). We con-vert this value to mmol/L as follows:

Moles or millimoles per liter can also be used to indicate theconcentration of molecules in solution. We can perform the sameconversion by substituting molecular weight for atomic weight inthe preceding equation. The total solute concentration of a solutioncan be determined by adding together the concentrations of indi-

g/dl * 10

atomic weight=

0.32 * 10

22.99= 0.14 mol/L 1= 140 mmol/L2

100 ml = 0.1 liter = 1 deciliter1mg2

vidual solutes, expressed in moles per liter or millimoles per liter.The resulting value is reported in milliosmoles per liter (mOsm/L).The use of mOsm rather than mmol indicates that multiple solutesare present, each contributing to the total osmolarity.

Because electrolyte concentrations have profound effects oncells, it is often important to know how many positive and nega-tive charges the ions or molecules in a biological solution bear,not just how many ions or molecules are present. For example, asingle calcium ion has twice the electrical charge of a sin-gle sodium ion although the two are identical in terms oftheir effects on osmolarity. One equivalent (Eq) is a mole of pos-itive or negative charges. Physiological concentrations are oftenreported in milliequivalents per liter (mEq/L). You should be-come familiar with both methods of expression. Fortunately, theconversion from millimoles to milliequivalents is relatively easyto perform. For monovalent ions—those with a or charge—millimole and milliequivalent values are identical, so nocalculation is needed. For divalent ions, with a or charge,the number of charges (mEq) is twice the number of ions (mmol).For an ion with a or charge, the number of milliequivalentsis three times the number of millimoles. To convert mEq to mmol,simply divide by the ionic valence (number of charges). Table 4compares the methods of reporting the concentration of majorelectrolytes in plasma in terms of weight, moles, and equivalents.

Physiologists and clinicians surely would benefit from the useof standardized reporting procedures. It can be very frustratingto consult three references and find that the first reports elec-trolyte concentrations in mg/dl, the second in mmol/L, and thethird in mEq/L.

In 1984, the American Medical Association House of Delegatesendorsed a plan to standardize clinical test results through the useof SI (Système Internationale) units, with a target date of July 1,1987, for the switchover. Unfortunately, there was no mechanismfor enforcing compliance, and the standardization attempt ulti-mately failed. As of 1997, all scientific and medical journals aroundthe world report data in SI units, but most U.S. clinical laboratoriesand journals continue to use their traditional reporting methods.

-3+3

-2+2

-1+1

1Na+2,1Ca2+2

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18 THE CHEMICAL LEVEL OF ORGANIZATION

The major problem is that the relationships to values current-ly in use are difficult to remember. Electrolyte concentrations, nowmost often given in mEq/L, are reported in mmol/L in the SI. Thus,the values for sodium and potassium concentrations remain un-changed, but the normal values for calcium and magnesium are re-duced by 50 percent. The situation becomes more confusing interms of metabolite concentrations. Cholesterol and glucose con-centrations are now most often reported in mg/dl, but the SI unitsare mmol/L. However, total lipid concentrations, also currentlyreported as mg/dl, and total protein concentrations, now given asg/dl, are reported in terms of g/L under the SI. For these units tobe useful in a clinical setting, physicians must not only rememberthe definition of each SI unit, but must also convert and relearn thenormal ranges. As a result, it appears unlikely that the conversionto SI units will be completed in the immediate future.

THE PHARMACEUTICAL USE OF ISOMERSA chemical compound is a combination of atoms bonded togeth-er in a particular arrangement. The chemical formula specifies thenumber and types of atoms that combine to form the compound.The arrangement of the atoms, which determines the specific shapeof each molecule, is shown by the molecule’s structural formula.

Isomers are chemical compounds that have the same chemicalformula,but different structural formulas. Isomers called stereoisomersare mirror images of each other. Stereoisomers are analogous to theleft hand and right hand of the human body. The two hands containthe same palm bones (metacarpals) and finger bones (phalanges),but each hand is a mirror image of the other. A glove designed forthe left hand will not fit the right hand,and vice versa.Chemical com-pounds are also said to be left handed or right handed, dependingon their structural configuration. For example, glucose has a left-handed (levo-) isomer and a right-handed (dextro-) isomer. Just as theright hand cannot fit into a left glove, receptors and enzymes in ourcells cannot bind the levo-isomer of glucose. Our cells are thereforeunable to metabolize levo-glucose as an energy source.

This pattern is common: Our cells and tissues will typically re-spond to only one structural form—either levo or dextro—notboth. This feature can pose a problem for pharmaceutical chemists,because many of the chemical reactions used to synthesize a drugproduce a mixture of levo- and dextro-isomers. In some cases, theinactive isomer is simply ignored; in others, it is removed. For ex-ample, the antibiotic chloramphenicol contains both levo- anddextro-isomers, but only the levo form is effective in killing bac-terial pathogens. And only the levo form (the active form) ofephedrine, a drug that dilates the bronchioles of the lungs, is con-tained in the popular tablet Primatene, which is sometimes usedto treat asthma attacks. Finally, birth control pills containing thesteroid Levonorgestre, the levo form of Norgestrel, are effective athalf the dosage of pills containing a mixture of levo- and dextro-isomers.

In some cases, both forms of an isomer are biologically active,but have strikingly different effects, both desired and undesired.The drug thalidomide was given to pregnant women in the 1960s toalleviate symptoms of morning sickness. The sedative effect of oneisomer was well documented, but the medication sold contained

both forms. Unfortunately, the other isomer caused tragic abnor-malities in fetal limb development. (We discuss the mechanismsthat underlie thalidomide’s effects on fetal development on p. 227.)

ARTIFICIAL SWEETENERSSome people cannot tolerate sugar for medical reasons; othersavoid it to comply with recent dietary guidelines that call for re-duced sugar consumption or to lose weight. Thus, many peopletoday use artificial sweeteners in their foods and beverages.

Artificial sweeteners are organic molecules that can stimulate tastebuds and provide a sweet taste to foods without adding substantialamounts of calories to the diet. These molecules have a much greatereffect on the taste receptors than do natural sweeteners, such as fruc-tose or sucrose, so they can be used in minute quantities. For exam-ple, saccharin is about 300 times as sweet as sucrose. The popularityof this sweetener has declined since it was reported that saccharincan promote bladder cancer in rats. However, the risk is very small,even for rats, and saccharin continues to be used. Several other arti-ficial sweeteners, including aspartame (NutraSweet), sucralose, andacesulfame potassium (Ace-K, or Surette), are currently available. Themarket success of an artificial sweetener ultimately depends on itstaste and its chemical properties.Stability in high temperatures (as inbaking) and resistance to breakdown in an acidic pH (as in carbon-ated drinks) are important properties of any artificial sweetener.

Molecules of artificial sweeteners do not resemble those of nat-ural sugars. Saccharin, acesulfame potassium, and sucralose cannotbe broken down by the body, and they have no nutritional value.As-partame consists of a pair of amino acids, the building blocks of pro-teins (as we shall discuss later in this chapter), and they can be brokendown in the body to provide energy. However, because aspartame is200 times as sweet as sucrose, very small quantities are needed, so thisartificial sweetener adds few calories to a meal. Because it does notproduce the bitter aftertaste sometimes attributed to saccharin, as-partame is used in many diet drinks and low-calorie desserts.

Two recent entries into the market for artificial sweeteners,thaumatin-1 and monellin, are proteins extracted from Africanberries. Thaumatin, roughly 100,000 times as sweet as sucrose, hasbeen approved by the FDA for use in chewing gums.

FATTY ACIDS AND HEALTHHumans love fatty foods. The smooth, creamy texture of fatty sub-stances, and their appealing taste, makes fats a welcome part ofour diet. Saturated fats tend to be solid at room temperature, whileunsaturated fats are usually liquid. Unfortunately, a diet contain-ing large amounts of saturated fatty acids has been shown to in-crease the risk of heart disease and other circulatory problems.Saturated fats are found in popular foods like fatty meat and dairyproducts (including such favorites as butter, cheese, and ice cream).

Some unsaturated fats, by contrast, appear to decrease the riskof heart disease. Most vegetable oils contain a mixture of mo-nounsaturated and polyunsaturated fatty acids. Current researchindicates that monounsaturated fats may be more effective thanpolyunsaturated fats in lowering the risk of heart disease. Accord-ing to current research, perhaps the healthiest choice is oleic acid,an 18-carbon monounsaturated fatty acid particularly abundant

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� FIGURE 7Labeling Fat Content. In 2005, the labels will be expanded to include in-formation on the quantity of trans fats as well as saturated and total fats.

in olive and canola oils. Compounds called trans fatty acids, pro-duced during the manufacturing of some margarines and veg-etable shortenings (making the product less liquid), appear toincrease the risk of heart disease. Margarines and prepared foodscontaining these substances may be no healthier for you than but-ter. The labels on most packaged foods now show general infor-mation about the fats they contain (Figure 7�). The amount oftrans fats in products will be included in the nutritional labels onfood in 2005.

Eskimos have lower rates of heart disease than do other popu-lations, even though the Eskimo diet is high in fats and choles-terol. Interestingly, the fatty acids in the Eskimo diet have anunsaturated bond three carbons before the last, or omega, carbon,a position known as “omega minus 3,” or omega-3. Fish flesh andfish oils, a substantial portion of the Eskimo diet, contain omega-3fatty acids. Why does the presence of omega-3 fatty acids (or someother unidentified component of fish) in the diet reduce the risksof heart disease, rheumatoid arthritis, and other inflammatorydiseases? The answer is not yet apparent, but as you can imagine,there is a great deal of interest in this area of research.

FAT SUBSTITUTESThe average diet in the United States contains more fat than dothe diets of people in many other parts of the world. Diets high infat have been linked to heart disease, as well as to certain forms ofcancer. Recent recommendations suggest that lowering the per-centage of calories we derive from fat would benefit our health.This suggestion has led to an increased interest in the develop-ment of fat substitutes.

Fat substitutes provide the texture, taste,and cooking properties ofnatural fats. Two such substitutes, Simplesse and Olestra, are in wide-spread use. Simplesse is made from proteins of egg white and skim

milk or whey. The heated proteins are treated to form small spheri-cal masses that have the taste and texture of fats. Simplesse can beused in place of fats in any application other than baking; it is used inlow-calorie“ice creams”under the trade name Simple Pleasures. Thesefat substitutes can be broken down in the body, but they provide lessenergy than do natural fats. For example, ice cream made with Sim-plesse has half the calories of ice cream that contains natural fats.

Olestra is made by chemically combining sucrose and fatty acids.The resulting compounds cannot be used by the body and so con-tribute no calories. Olestra has been approved as an ingredient inmargarines, baked goods, and other snack foods, despite some con-cerns. One of the problems is that Olestra droplets within the di-gestive tract collect dietary lipids and lipid-soluble materials,including fat-soluble vitamins (A, D, E, and K), and prevent theirabsorption. In addition, if eaten in large quantities, Olestra cancause diarrhea. To prevent vitamin deficiencies among consumers,manufacturers of snack foods prepared with Olestra now fortifythem with fat-soluble vitamins.

One drug, Xenical, is available as an alternative to fat substitutesand is FDA approved to aid in weight loss. This medication blocksthe action of the pancreatic enzymes responsible for fat digestionand prevents the absorption of dietary fats. Side effects of oily di-arrhea and potential vitamin deficiencies may occur, but desirablereductions of weight and blood levels of cholesterol and lipids arebeneficial.

In the 1970s, Dr Atkins, a cardiologist, advocated a high-fat andhigh-protein but restricted carbohydrate diet. Many heart diseaseresearchers initially thought it would be undesirable because theepidemiologic data linked diets high in fat to heart disease. In a re-cent controlled study it has been shown to be more effective forinitial weight loss than a low-fat and calorie-restricted diet, butsustained weight loss at one year was comparable with either diet.A similar number of patients on each diet, 40 percent, were unableto complete a year of dieting. However, the study did show im-proved blood HDL cholesterol and triglyceride levels in the Atkin’sdieters, compared to the low-fat calorie-restricted diet (which im-proved LDL lipid levels more than the Atkin’s diet). Dr Atkins the-orized that his diet induced a state of ketosis, which contributed toweight loss, and that the reduction in carbohydrates improvedblood cholesterol and lipid levels. The study did not find increasedketosis in persons on the Atkin’s diet, and the researchers suggest-ed the unpalatability of a high-fat/protein, carbohydrate-restricteddiet reduced hunger and caloric intake, leading to weight loss.Whatever the mechanism, the high-fat/protein, low-carbohydratediet has helped obese people lose weight, with beneficial results.Because long-term use has not been studied extensively, monitor-ing for heart disease risk factors is warranted for those using thediet. Sustained weight loss, regardless of type of diet, to more nor-mal weights reduces heart disease risk.

METABOLIC ANOMALIESIf enzymes are nonfunctional or are missing, metabolic disordersknown as metabolic anomalies result. The effects are variable, de-pending on the enzyme involved, but in severe cases growth anddevelopment are impaired and vital tissues are damaged or de-stroyed. Additional information about many such conditions isgiven elsewhere in the Applications Manual.

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20 THE CHEMICAL LEVEL OF ORGANIZATION

� PHENYLKETONURIAPersons diagnosed with phenylketonuria (PKU) lack the enzymethat converts the amino acid phenylalanine to the amino acidtyrosine. Without this enzyme, phenylalanine accumulates in theblood and tissues, and large quantities are excreted in the urine.If the condition is not detected shortly after birth, mental retar-dation can occur due to damage to the developing nervous system.Because milk is a major source of phenylalanine, newborns gen-erally undergo a blood test for PKU 48 hours after nursing be-gins. Abnormally high levels of phenylalanine in the bloodstreammay indicate PKU. Once a diagnosis of PKU is made, the diet iscontrolled to avoid foods containing high levels of phenylalanine.The artificial sweetener aspartame contains phenylalanine andcould cause problems for PKU patients. (PKU is discussed fur-ther on pp. 190–191.)

� ALBINISMAlbinism is a genetic disorder that results in a lack of pigment inthe skin. The cause is a defective enzyme involved in the metabo-lism of the amino acid tyrosine. Because of this abnormal enzyme,the protein pigment melanin cannot be synthesized. The skin of aperson afflicted with albinism is white, and the hair and eyes arealso affected. Among its other functions, melanin helps protectthe skin from the effects of ultraviolet (UV) radiation. When out-doors, individuals with albinism must be careful to avoid skindamage from the UV radiation in sunlight.

� HYPERCHOLESTEROLEMIAFamilial hypercholesterolemia is a genetic disorder resulting in areduced ability to remove cholesterol from the bloodstream. Ascirculating levels rise, cholesterol accumulates around tendons,creating yellow deposits called xanthomas beneath the skin. Theworst aspect of the disorder is the deposition of cholesterol in thewalls of blood vessels. This condition, a form of atherosclerosis,can restrict the flow of blood through vital organs such as the heartand brain. Atherosclerosis can develop in individuals with normalcholesterol metabolism, but clinical symptoms do not ordinarilyappear until age 40 or older. Individuals with congenital hyper-cholesterolemia may develop acute coronary artery disease or evensuffer a heart attack at or before 20 years of age. A group of med-icines called the “statins” inhibit an enzyme (HMG–COA reduc-tase) that is a rate limiting step in cholesterol synthesis. Theysignificantly reduce deaths from atherosclerosis.

� GALACTOSEMIAMilk contains the monosaccharide galactose, which can be con-verted to glucose within cells. The genetic disorder galactosemia iscaused by the absence of the enzyme that catalyzes this reaction.Affected individuals have elevated levels of galactose in the bloodand urine. Chronically high levels of galactose during childhoodcan cause abnormalities in the nervous system, jaundice, liver dam-age, and cataracts. Preventive treatment involves the early detectionof galactosemia and a restriction on the dietary intake of galactose.

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21

THE NATURE OF PATHOGENSThe presence of a nucleus is the defining characteristic of eu-karyotic cells (u-kar-e-OT-ik; eu, nucleus). Alleukaryotic cells have similar membranes, organelles, and meth-ods of cell division. All multicellular animals, plants, and fungi(plus many single-celled organisms) are composed of eukary-otic cells.

The eukaryotic plan of organization is not the only one in the liv-ing world, however. Some organisms do not consist of eukaryoticcells. These organisms are of great interest to us, because they in-clude many of the pathogens that are recognized causes of humandiseases. Representative pathogens are introduced in Figure 8�.

� BACTERIAProkaryotic cells do not have nuclei or other membranous or-ganelles. Nor do they have a cytoskeleton, and typically, their cellmembranes are surrounded by a semirigid cell wall made of car-bohydrate and protein.

Bacteria are probably the most familiar prokaryotic cells. Theyare generally less than in diameter. Many bacteria are quiteharmless, and many more—including some that live within ourbodies—are beneficial to us in a variety of ways. Other bacteria aredangerous pathogens that, given the opportunity, will destroy bodytissues. These bacteria are dangerous because they absorb nutri-ents and release enzymes that damage cells and tissues. A few path-ogenic bacteria also release toxic chemicals. Bacterial infections areresponsible for many serious diseases, as indicated in Table 5. Weconsider these and other bacterial infections in other sections of theApplications Manual.

Figure 8a� shows the structure of a representative bacterium.Figure 9� shows the three basic shapes of bacteria: round, rodlike,and spiral. A round bacterium is called a coccus (KOK-us; plural,cocci, KOK-se). A rodlike bacterium is a bacillus (ba-SIL-us; plu-ral, bacilli, ba-SIL-e). Shapes of spiral bacteria vary, and so dotheir names. A vibrio (VIB-re-o) is comma shaped; a spirillum(spi-RIL-um; plural, spirilla) is rigid and wavy; and a spirochete(SPI-ro-ket) is shaped like a corkscrew.

Some cocci and bacilli form groupings of cells. The Latin namesused to describe these groupings are also used to identify specificbacteria. For instance, pairs of cocci are called diplococci (diplo-,double). Streptococci and streptobacilli form twisted chains of cells(strepto-, twisted), and staphylococci look like a bunch of grapes(staphylo-, grapelike).

� VIRUSESAnother type of pathogen conforms neither to the prokaryoticnor to the eukaryotic organizational plan. These tiny pathogens,called viruses, are not cellular. In fact, when free in the environ-ment, they do not show any of the characteristics of living organ-isms. They are classified as infectious agents—factors that causeinfection—because they can enter cells (either prokaryotic or eu-karyotic) and replicate themselves.

Viruses consist of a core of nucleic acid (DNA or RNA) sur-rounded by a protein coat called a capsid. (Some varieties have an

2 mm

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THE CELLULAR LEVEL OFORGANIZATION

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envelope, a membranous outer covering, as well.) The structure ofa representative virus is shown in Figures 8b and 10�. Importantviral diseases include influenza (flu), yellow fever, some leukemias,AIDS, hepatitis, polio, measles, mumps, rabies, herpes, and thecommon cold (Table 6).

To enter a cell, a virus must first attach to the cell membrane.Attachment occurs at one of the normal membrane proteins. Oncethe virus has penetrated the cell membrane, the viral nucleic acidtakes over the cell’s metabolic machinery. In the case of a DNAvirus (Figure 11a�), the viral DNA enters the cell nucleus, wheretranscription begins. The mRNA produced then enters the cyto-plasm and is used in translation, in which the cell’s ribosomesbegin synthesizing viral proteins. The viral DNA replicates in thenucleus,“stealing” the cell’s nucleotides. The replicated viral DNAand the new viral proteins then form new viruses that pass out ofthe cell through the cell membrane or from cell rupture.

In an RNA virus, the situation is somewhat more complicated(Figure 11b�). In the simplest RNA viruses, the viral RNA enter-ing the cell functions as an mRNA strand that carries the infor-mation needed to direct the cell’s ribosomes to synthesize viralproteins. These proteins include enzymes essential to the dupli-cation of viral RNA. When the cell is packed with new viruses, thecell membrane ruptures and the RNA viruses are released into theinterstitial fluid.

In retroviruses, a group that includes HIV (the virus responsi-ble for AIDS), the replication process is even more complex. TheseRNA viruses carry an enzyme called reverse transcriptase, whichdirects “reverse transcription”—the assembly of DNA accordingto the nucleotide sequence of an RNA strand. The DNA createdin this way is then inserted into the infected cell’s chromosomes.The viral genes become activated, and the cell begins producingRNA by normal transcription. The RNA produced includes viral

22 THE CELLULAR LEVEL OF ORGANIZATIONC

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•

••

•

•

•

Ribosomes

Chromosome

Capsule orslime layer

(protein coat)

Cell membrane

Cell wall

Capsid

Membranousenvelope

SpikesNucleic acid(DNA or RNA)

(protein)

Inclusion

Flagellum

•

•

•

•

•

•

(a) Bacterium

(c) Protozoan pathogens

(d) Multicellular parasites

(b) Virus

causes amoebic dysentery

causes sleeping sickness

Liver fluke(Fasciola hepatica)

Trypanosoma;

Amoeba;

Plasmodium

Tapeworm(Taenia)

Roundworm(Ascaris)

(in red blood cell);causes malaria

1 µm

10 µm

1 cm

0.1 µm

Cytoplasm

•

� FIGURE 8Representative Pathogens.(a) A bacterium, with prokary-otic characteristics indicated.(b) A typical virus. Each virushas an inner chamber contain-ing nucleic acid, surrounded bya protein capsid or an innercapsid and an outer membra-nous envelope. The herpesviruses are enveloped DNAviruses; they cause chickenpox, shingles, and herpes.(c) Protozoan pathogens. Pro-tozoa are eukaryotic single-celled organisms, common insoil and water. (d) Multicellularparasites. Several groups oforganisms are humanpathogens, and many havecomplex life cycles.

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The Nature of Pathogens 23

RNA, mRNA carrying the information for the synthesis of re-verse transcriptase, and mRNA controlling the synthesis of viralproteins. These components then combine within the cytoplasm,which gradually becomes filled with viruses. Finally, the new RNAviruses are shed at the cell surface. Two new anti-influenza med-icines, Relenza and Tamiflu, inhibit a key enzyme involved in theassembly of the virus and its release by infected cells.

Even if the host cell is not destroyed by these events, normalcell function is usually disrupted. In effect, the metabolic activ-ity of the cell is diverted to create viral components, rather thanperforming tasks needed for cell maintenance and survival.Some viruses, such as herpes simplex or herpes varicella, can liedormant within infected cells for long periods before replicating.

Viruses are now becoming important as benefactors as well asadversaries. In genetic-engineering procedures (p. 31), viruses whosenucleic acid structure has been intentionally altered can be usedto transfer copies of normal human genes into the cells of indi-viduals with inherited enzymatic disorders. This was the methodused to insert the gene for the missing enzyme (adenosine deam-inase) in persons with severe combined immunodeficiency dis-ease, or SCID (p. 32). The virus integrates the normal gene intothe patient’s chromosomes, presumably in a random matter. Un-fortunately, two of the nine children successfully treated for SCID

TABLE 5 Examples of Bacterial Diseases and the Primary Organ Systems Affected

Organism Disease Affected Organ System

Bacilli

Bacillus anthracis Anthrax Integumentary and respiratory systems

Mycobacterium tuberculosis Tuberculosis Respiratory system

Corynebacterium diphtheriae Diphtheria Respiratory system

Cocci

Staphylococcus aureus Various skin infections Integumentary system

Streptococcus pyogenes Pharyngitis (strep throat) Respiratory system

Neisseria gonorrhoeae Gonorrhea Reproductive system

Vibrios

Vibrio cholerae Cholera Digestive system

Spirochetes

Treponema pallidum Syphilis Reproductive and nervous systems

Borrelia burgdorferi Lyme disease Skeletal system (joints)

Rickettsias

Rickettsia prowazekii Epidemic typhus fever Cardiovascular and integumentary systems

Coxiella burnetii Q fever Respiratory system

Chlamydias

Chlamydia trachomatis Trachoma (eye infections) Integumentary system

PID (pelvic inflammatory disease) Reproductive system

Coccus

Vibrio

Bacillus

Spirillum

Spirochete

� FIGURE 9Common Bacterial Shapes

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Rubella virus(Germanmeasles)

Herpesvirus(fever blisters,chicken pox)

Adenovirus(respiratoryinfections)

Poliovirus(polio)

Paramyxovirus(mumps)

Human liver cell

Humanliver cell

Ribosome

Bacterial cell

� FIGURE 10Viruses. A variety of viruses, shown with a typical bac-terial cell, a human liver cell, and a ribosome for scale.

TABLE 6 Examples of Viral Diseases and the Primary Organ Systems Affected

Nucleic Acid Virus Disease Affected Organ System

RNA Influenza A, B, C Flu Respiratory system

Paromyxovirus Mumps Digestive and reproductive systems

Hepatitis A, C, D, E Infectious hepatitis Digestive system (liver)

Rhinovirus Common cold Respiratory system

Human immunodeficiency virus (HIV) AIDS Lymphatic system

DNA Herpesvirus

Herpes simplex 1 Cold sore/fever blister Integumentary system

Herpes simplex 2 Genital herpes Reproductive system

Varicella-zoster Chicken pox Integumentary system

Varicella-zoster Shingles Nervous system

Hepatitis B Hepatitis Digestive system (liver)

Epstein–Barr Mononucleosis Respiratory and lymphatic systems

this way have developed a form of leukemia from the activation ofother genes in their chromosomes. (The abnormally activatedgenes are called oncogenes). Efforts are under way to understandthe mechanism responsible and to develop different viral thera-pies that will not cause similar problems.

Researchers and clinicians are currently planning to treat cys-tic fibrosis by gene therapy. Cystic fibrosis (CF) is a debilitatinggenetic defect whose most obvious—and potentially deadly—symptoms involve the respiratory system. The underlying problemis an abnormal gene that carries instructions for a chloride ion

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The Nature of Pathogens 25C

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channel that occurs in cell membranes throughout the body.Researchers have recently treated CF in laboratory animals byinserting the normal gene into a virus that infects cells liningthe respiratory passageways.

� PRIONSRecently, it was determined that certain rare and previouslymysterious conditions making up the transmissible spongiformencephalopathic (TSE) diseases are caused by a novel class of in-fectious agents called prions. Prions [from “protein infectious‘ions,”’(particles)] are unique among agents of transmissibledisease, because they contain no nucleic acids (either DNA orRNA). Rather, they appear to be abnormal three-dimensionalforms of the ordinarily harmless protein PrPc found in cells.Apparently, an abnormally folded protein can serve as a tem-plate for converting normal proteins to the pathogenic form.When present in large quantities, these proteins cause degen-erative cellular gaps in brain tissue, which takes on a micro-scopic “spongy” appearance. Partially metabolized fragmentsof abnormal prion proteins may form microscopic depositscalled amyloid plaques in the brain as well.

The same clinical TSE disease can have a genetic, a spo-radic, or an infectious origin. Rare genetic variations in thePrPc protein cause inheritiable forms of TSE. Sporadic casesmay come from spontaneous change of the PrPc protein tothe abnormal shape. In addition, the disease can be transmit-ted from unrecognized infected donor individuals to recipientsof corneal transplants or pituitary hormone extracts. Some

12

3

Envelope Capsid

DNADNA virus

Penetration

Uncoating

Adsorption and fusionwith cell membrane

Host cell membrane

Host cellnuclear membrane

Translation

Viralcoat

proteins (capsid)

Replicationof viral DNA

New virusparticles areassembled

(maturation).

Transcriptionof viral genes

Release

Viruses bud out fromhost cell. Some

become covered byenvelope protein.

Others acquire envelopeas they emerge from

nucleus or while withincytoplasm.

be inserted into host cell or nuclear

membranes or can float within cytoplasm.3

2

Examples: smallpox, herpes, hepatitis, common cold

Envelope proteins fordifferent viruses can

(a)

1

� FIGURE 11Viral Replication. (a) The replication of a DNA virus.(b) The replication of RNA viruses.

HIV and otherretroviruses

Polio, influenza,mumps, and

measles viruses

One strand of DNAserves as template forsynthesis of viral DNA

Replicationof viralRNA

Translation of viralRNA: enzymes and

capsid proteins

Insert into host cell chromosome

Form double strands

Form complementary (�) sense strand ofDNA, using reverse

transcriptase

RNAreplication

(�) senseRNA copy

Directtranslation: enzyme and

capsid proteins

Capsid proteinsassembled with

RNA(maturation)

Capsid proteins

assembledwith RNA

(maturation)

Release of newRNA viruses Release of

new RNA viruses

Capsid

RNA

Adsorption

RNA virus

Penetrationand

uncoating

Cell membraneproteins (recognition

factors)

(b)

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are also known to have contracted TSE diseases from exposure tocontaminated medical instruments or by eating affected tissues.While TSE diseases are not transmitted by normal household in-teractions, they can be acquired by contact with the abnormalproteins.

The first recognized human prion disease was kuru, a deadly dis-ease affecting members of a society in New Guinea that practiced rit-ual cannibalism. The prions were passed from person to personwhen uninfected individuals ate infected brains. The infection,which could lead to death within a year, caused half of all childhoodand adult deaths in the affected part of New Guinea. Other knownprion diseases include inherited and sporadic Creutzfeldt–Jakob dis-ease (which usually affects older people) and fatal familial insomnia.

Prion infections also occur in domesticated animals. In sheep,the condition is called scrapie; in cows, it is called bovine spongiformencephalopathy (BSE). Infected cows ultimately develop an as-sortment of strange neurological symptoms (such as pawing atthe ground and exhibiting difficulty in walking), giving the con-dition the common name “mad-cow disease.”

In 1995, European researchers reported a puzzling variant ofCreutzfeldt–Jakob disease among teenagers and young adults. Anumber of fatal cases in England showed brain changes similar tothose of BSE, leading investigators to attribute the outbreak to theconsumption of meat products from prion-infected cows. Thisdiscovery led to a temporary ban on British beef from the Euro-pean community, the slaughter and destruction of infected andpotentially infected cows, and a change in livestock feeding prac-tices throughout the world. Presumably, many cows became in-fected by eating feed containing beef by-products and bonemealcontaminated with prions from the neural tissue of infected ani-mals. The use of such feed has now been banned, and greater careis taken when butchering to prevent contact of brain and spinal

neural tissue with meat intended for consumption. In 2003 and2004 cows in Canada and the United States were found to haveBSE. Public health measures included quarantine and destructionof herds containing the affected cows, and more widespread test-ing of meat products.

� UNICELLULAR AND MULTICELLULARPARASITES

Bacteria and viruses are the best-known human pathogens, butsome pathogens are eukaryotic. Examples of the most importanttypes are shown in Figure 8c, d. Protozoa (Figure 12�) are unicel-lular eukaryotes that are abundant in soil and water. They are re-sponsible for a variety of serious human diseases, including amoebicdysentery and malaria (Table 7). Protozoa include (1) flagellates,which use flagella for propulsion; (2) amoeboids, among which aremobile, amoebalike forms that engulf their prey; (3) ciliates, whichare covered with cilia; and (4) sporozoans—parasitic forms withcomplex life cycles. Fungi (singular, fungus) are eukaryotic organ-isms that absorb organic materials from the remains of dead cells.Mushrooms are familiar examples of very large fungi. In a mycosis,or fungal infection, a microscopic fungus spreads through livingtissues, killing cells and absorbing nutrients. Several relatively com-mon skin conditions (including athlete’s foot) and a few more se-rious diseases (e.g., histoplasmosis) are the result of fungal infections(Table 8).

Larger multicellular organisms, generally referred to as parasites,can also invade the human body and cause diseases. The multipli-cation of these larger parasitic organisms in or on the body is calledan infestation. Diseases caused by multicellular parasites are list-ed in Table 9. Helminths are parasitic worms that can live within

(a) (b)

(c) (d)

� FIGURE 12Representative Protozoa. (a) Trichonympha, aflagellate from a termite gut. (b) Amoeba proteus,a free-living form found in ponds. (c) Paramecium caudatum, a free-living ciliate.(d) Plasmodium vivax, the parasite that causesmalaria, stained within human blood cells.1LM * 1252

1LM * 3102

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Methods of Microanatomy 27

TABLE 7 Examples of Protozoan Diseases and the Primary Organ Systems Affected

Type of Protozoa Name (Genus) Disease Affected Organ System

Flagellates Trypanosoma African sleeping sickness Cardiovascular system

Leishmania Leishmaniasis Lymphatic system

Giardia Giardiasis Digestive system

Trichomonas Trichomoniasis Reproductive system

Amoeboids Entamoeba Amoebic dysentery Digestive system

Ciliates Balantidium Dysentery Digestive system

Sporozoans Plasmodium Malaria Various systems

Toxoplasma Toxoplasmosis Various systems

TABLE 8 Examples of Fungal Diseases and the Primary Organ Systems Affected

Organism (Genus) Disease Affected Organ System

Aspergillus Aspergillosis (“Farmer’s lung disease”) Respiratory system

Blastomyces Blastomycosis Integumentary system

Histoplasma Histoplasmosis Respiratory system

Epidermophyton, Ringworm Integumentary systemMicrosporum, tinea capitis (scalp)and Trichophyton tinea corporis (body)

tinea cruris (groin)tinea unguium (nails)

Candida Candidiasis Integumentary system

Coccidioides Coccidioidomycosis (“San Joaquin valley fever”) Respiratory system

the body. They include flatworms, such as the flukes andtapeworms, and roundworms, or nematodes. These organisms,which range in size from microscopic flukes to tapeworms a meteror more in length, typically cause weakness and discomfort, butdo not by themselves kill their host. However, complications re-sulting from the parasitic infection, such as malnutrition, chronicbleeding, or secondary infections by bacterial or viral pathogens,can ultimately prove fatal.

Arthropods (Figure 13�) make up the largest and most diversegroup of animals on Earth. The major arthropods that affect hu-mans are the arachnids, including scorpions, spiders, mites, and ticks,and the insects, such as mosquitoes, flies, lice, fleas, and bedbugs.

METHODS OF MICROANATOMYOver the last 50 years, our technological gadgetry has improvedremarkably, enabling us to view the insides and outsides of cells innew ways. Sophisticated equipment has permitted the detailedanalysis of physiological processes within cells. The basic problemsfacing cytologists stem from the considerable difference in size be-tween the investigator and the object of interest. Cytologists (cellbiologists) and histologists (biologists who study tissues) measure

intracellular structures in micrometers also known asmicrons. Although the range of cell sizes is considerable, an “av-erage cell” is a cube roughly To fill acubic millimeter, we would need a million cells. Because the humaneye cannot recognize details smaller than about 0.1 mm, cytologistsrely on special equipment that magnifies cells and their contents.

� LIGHT MICROSCOPYHistorically, most information has been provided by light mi-croscopy, a method in which a beam of light is passed through theobject to be viewed. A light microscope can magnify cellular struc-tures about 1000 times and can show details as fine as Acamera can be attached to the microscope and used to produce aphotograph called a light micrograph (LM). Unfortunately, youcannot simply pick up a cell, slap it onto a microscope slide, andtake a photograph. Because individual cells are so small, you mustwork with large numbers of them. Most tissues have a three-dimensional structure, and small pieces of tissue can be removedfor examination. The component cells are prevented from de-composing by first exposing the tissue sample to a poison that willstop metabolic operations, but will not alter cellular structures.

0.25 mm.

10 mm * 10 mm * 10 mm.

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R28 THE CELLULAR LEVEL OF ORGANIZATION

TABLE 9 Examples of Diseases Caused by Multicellular Parasites and the Primary Organ Systems Affected

Group Organism Disease or Condition Affected Organ System

Helminths

Roundworms Ascaris Intestinal infestation Digestive system

Enterobius Pinworm infestation Digestive system

Flatworms Wuchereria Elephantiasis Lymphatic system

Flukes Fasciola, Clonorchis Fascioliasis Digestive system(liver flukes)

Schistosoma Schistosomiasis Cardiovascular, digestive, urinary systems(blood fluke)

Tapeworms Taenia Tapeworm infestation Digestive system

Arthropods

Arachnids (eight legs) Mites Vectors of bacterial and Various systemsrickettsial diseases

Ticks Vectors of bacterial and Various systemsrickettsial diseases

Spiders, scorpions Inflammation from bites Integumentary system

Insects (six legs) Lice Vectors of bacterial and Various systemsrickettsial diseases

Human lice Pediculosis Integumentary system

Mosquitoes Vectors of bacterial, viral, and Various systemsparasitic diseases

Flies Passive carriers of bacterial diseases Various systems

Wasps, bees Inflammation from stings Various systems

(a)

(b)

(c) (d) (e)

� FIGURE 13Representative Disease-Carrying Arthropods.(a) Dermacentor andersoni, a wood tick.(b) Phthirus pubis, a crab louse, holding onto ahuman pubic hair. (c) Musca domes-tica, the housefly, which can transport microbes onits body. (d) The Aedes mosquito, a vectorfor dengue fever. (e) Ctenocephalides canis, acommon flea. 1*312

1*32

1SEM * 552

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Lysosomal Storage Diseases 29

Even then, you still cannot look at the tissue sample through alight microscope, because a cube only 2 mm (0.078 in.) on a sidewill contain several million cells. You must slice the sample intothin sections. Living cells are relatively thick, and cellular contentsare not transparent. Light can pass through the section only if theslices are thinner than the individual cells. Making a section thatslender poses interesting technical problems. Most tissues are notvery sturdy, so an attempt to slice a fresh piece will destroy thesample. (To appreciate the problem, try to slice a marshmallowinto thin sections.) Thus, before you can make sections, you mustembed the tissue sample in something that will make it more sta-ble, such as wax, plastic, or epoxy. These materials will not inter-act with water molecules, so your sample must first be dehydrated(typically by immersion in 30 percent, 70 percent, 95 percent, and,finally, 100 percent alcohol). If you are embedding the sample inwax, the wax must be hot enough to melt; if you are using plasticor epoxy, the hardening process generates heat on its own.

After embedding the sample, you can section the block witha machine called a microtome, which uses a metal, glass, or di-amond knife. For viewing by light microscopy, a typical sectionis about (0.002 in.) thick. The thin sections are then placedon microscope slides. If the sample was embedded in wax, youcan now remove the wax with a solvent, such as xylene. But youare not done yet: In thin sections, the cell contents are almosttransparent; you cannot yet distinguish intracellular details byusing an ordinary light microscope. You must first add color tothe internal structures by treating the slides with special dyescalled stains. Some stains are dissolved in water and others inalcohol. Not all types of cells pick up a given stain to the samedegree—if they pick it up at all; nor do all types of cellular or-ganelles. For example, in a sample scraped from the inside ofthe cheek, one stain might dye only certain types of bacteria; ina semen sample, another stain might dye only the flagella of thesperm. If you try too many stains at one time, they all run to-gether, and you must start over. Following staining, you can putcoverslips over the sections (generally after you have dehydrat-ed them again) and can see what your labors have accomplished.

Any single section can show you only a part of a cell or tissue.To reconstruct the tissue structure, you must look at a series ofsections made one after the other. After examining dozens or hun-dreds of sections, you can understand the structure of the cellsand the organization of your tissue sample—or can you? Your re-construction has left you with an understanding of what these cellslook like after they have (1) died an unnatural death; (2) been de-hydrated; (3) been impregnated with wax or plastic; (4) been slicedinto thin sections; (5) been rehydrated, dehydrated, and stainedwith various chemicals; and (6) been viewed with the limitationsof your equipment. A good cytologist or histologist is extremelycareful, cautious, and self-critical and realizes that much of thelaboratory preparation is an art as well as a science.

� ELECTRON MICROSCOPYMore elaborate procedures can allow for the examination of finerdetails. In electron microscopy, a beam of electrons is passedthrough or reflected off the surface of a suitably prepared object.In transmission electron microscopy, the electrons pass throughan ultrathin section. Once through the section, they strike a pho-

5 mm

tographic plate and produce an image known as a transmissionelectron micrograph (TEM). Transmission electron microscopycan magnify structures up to approximately 500,000 times, re-vealing details less than a nanometer in size. For instance, with atransmission electron microscope, you can visualize large organicmolecules. In scanning electron microscopy, a beam of electronsreflects off the surface of an object such as a cell, a broken portionof a cell, or an extracellular structure. (The surfaces are speciallycoated to enhance reflectivity.) After bouncing off the surface, theelectrons strike a photographic plate, producing an image knownas a scanning electron micrograph (SEM). Scanning electron mi-croscopy can magnify structures about 50,000 times, but the tech-nique provides a three-dimensional perspective on cellularanatomy that cannot be obtained by other methods.

This level of detail poses problems of its own. At the level ofthe light microscope, if you were to slice a large cell as you wouldslice a loaf of bread, you might produce 10 sections from the onecell. You could review the entire series under a light microscope ina few minutes. If you sliced the same cell for examination underan electron microscope, you would have 1000 sections, each ofwhich could take several hours to inspect! Figure 14a, b� com-pares SEM and TEM views of cells that line the intestinal tract,and Figure 14c� shows a diagrammatic representation of the in-tact cell.

LYSOSOMAL STORAGE DISEASESProblems with lysosomal enzyme production cause more than 30storage diseases. In these conditions, the lack of a specific lysoso-mal enzyme results in the buildup of materials normally removedand recycled by lysosomes. Eventually, the cell cannot continue tofunction. Over time, these conditions are often fatal, so most casesare diagnosed in children. We shall consider three important ex-amples here: Gaucher’s disease, Tay–Sachs disease, and glycogenstorage disease.

Gaucher’s disease, caused by the buildup of cerebrosides—glyco-lipids in cell membranes—is probably the most common type oflysosomal storage disease. The disease takes two forms: (1) an in-fantile form, marked by severe neurological symptoms and end-ing in death, and (2) a juvenile form, with enlargement of thespleen, anemia, pain, and relatively mild neurological symptoms.Gaucher’s disease is most common among Ashkenazic Jews, at afrequency of approximately 1 in 1000 births. Treatment with aform of the enzyme glucocerebrosidase is partially effective but ex-tremely expensive.

Tay–Sachs disease is another hereditary disorder caused by theinability to break down glycolipids. In this case, the glycolipids aregangliosides, which are most abundant in neural tissue. Individualswith the condition develop seizures, blindness, and dementia andgenerally die by age 3–4 years. Like Gaucher’s disease, Tay–Sachsdisease is most common among Ashkenazic Jews, at a frequency of0.3 per 1000 births.

Glycogen storage disease (Type II), also called Pompe’s disease,affects primarily skeletal muscle, cardiac muscle, and liver cells—the cells that synthesize and store glycogen. In people with thiscondition, a deficiency of the enzyme alpha-glucosidase leavescells unable to mobilize glycogen normally, and large numbers ofinsoluble glycogen granules accumulate in the cytoplasm. The

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(a)

(b)

(c)

Microvilli ofbrush border

Apical surfaceof goblet cell

•

•

•

Brush border

Secretoryvesicles

Columnarepithelial cells

Nucleus ofgoblet cell

Lumen

•

•

•

•

•

•

•

Mucins•

•

•

•

•

Goblet cell

Nucleus

Golgiapparatus

Basementmembrane

� FIGURE 14A Comparison of Histological Techniques. (a) Cell surfaces can be seenwith a scanning electron microscope. (b) Cells similar to those in (a), butviewed with a transmission electron microscope. (c) A composite drawingthat summarizes the information provided by both scanning and transmissionelectron microscopy.

granules disrupt the organization of the cytoskeleton, interferingwith transport operations and the synthesis of materials. In skele-tal and heart muscle cells, the buildup leads to muscular weaknessand frequently fatal heart problems.

MITOCHONDRIAL DNA, DISEASE,AND EVOLUTIONSeveral inheritable disorders result from abnormal mitochondrialactivity. The mitochondria involved have defective enzymes thatreduce their ability to generate ATP. Cells throughout the bodymay be affected, but symptoms involving muscle cells, neurons,and the receptor cells in the eye are most common, because thesecells have especially high energy demands normally met by mito-chondrial activity. Disorders caused by defective mitochondriaare called mitochondrial cytopathies. In several instances, the dis-orders have been linked to inherited abnormalities in mitochon-

drial DNA. In some cases, the problem appears in one popula-tion of cells only. For example, abnormal mitochondrial DNA hasbeen found in the motor neurons whose degeneration is respon-sible for Parkinson’s disease, a neurological disorder characterizedby a shuffling gait and uncontrollable tremors.

More commonly, mitochondria throughout the body are in-volved. Examples of conditions caused by mitochondrial dysfunc-tion include one class of epilepsies (myoclonic epilepsy) and a typeof blindness (Leber’s hereditary optic neuropathy). These are in-herited conditions, but the pattern of inheritance is unusual. Al-though men or women may have the disease, only affected womencan pass the condition on to their children. The explanation forthis pattern is that the disorder results from an abnormality in theDNA of mitochondria, not in the DNA of cell nuclei. All themitochondria in the body are produced by the replication of mi-tochondria present in the fertilized ovum. Few, if any, of thosemitochondria were provided by the father; most of the mitochon-dria of the sperm do not remain intact after fertilization takes place.

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Genetic Engineering and Gene Therapy 31

As a result, children can generally inherit myoclonic epilepsy andLeber’s disease only from their mother.

This brings us to an interesting concept: Virtually all your mito-chondria were inherited from your mother, hers from her mother,and so on back through time.The same is true for every other human.Now, it is known that small changes in DNA nucleotide sequences ac-cumulate over long periods of time. Mitochondrial DNA, or mDNA,can therefore be used to estimate the degree of relatedness betweenindividuals. The greater the difference between the mDNA of twoindividuals, the more time has passed since the lifetime of their mostrecent common ancestor, and the more distant is their relationship.On this basis, it has been estimated that all humans now alive shareda common female ancestor roughly 350,000 years ago.Appropriate-ly, that individual has been called“Mitochondrial Eve.”The existenceand history of Mitochondrial Eve remain controversial.

GENETIC ENGINEERING AND GENE THERAPYThe study of the synthesis, structure, and function of macromol-ecules important to life, such as proteins and nucleic acids, isknown as molecular biology. Among the main goals of this fieldare deciphering the genomes of living organisms (especially hu-mans), elucidating the mechanisms that control the transcriptionof genes and the synthesis of proteins, and relating the intricatestructure of a protein to its functions.

Research in molecular biology has greatly enhanced our under-standing of both normal functions and disease processes. In medi-cine, molecular biology has prompted a revolution by uncovering aclear biochemical basis for many complex pathologies. For example,in sickle-cell anemia, red blood cells undergo changes in shape thatlead to blocked blood vessels and subsequent tissue damage due tooxygen starvation. This condition results when an individual car-ries two copies of a defective gene that determines the structure ofhemoglobin, the oxygen-binding protein in red blood cells. The ge-netic defect changes just 2 of the 574 amino acids in this protein,but that is enough to alter the functional properties of the hemo-globin molecule, leading to changes in the properties of the red bloodcells. This type of disorder is often called a molecular disease, becauseit results from abnormalities at the molecular level of organization.

Roughly 2500 inherited disorders have now been identified,and researchers have located the defective genes responsible forover 80 of them, including Huntington’s disease, cystic fibrosis,Duchenne’s muscular dystrophy, and Tay–Sachs disease. Identify-ing the genetic defect is the vital first step toward the developmentof an effective gene therapy or other treatment. Such developmentis an important aspect of the field of genetic engineering, a gen-eral term that encompasses attempts to change the genetic make-up of cells or organisms, including humans.

What are some of the key problems confronting genetic engi-neers? Genes code for proteins; the makeup of each protein is deter-mined by the sequence of codons (nucleotide triplets) in a stretch ofDNA. A human cell has 46 chromosomes, 2 meters of DNA, androughly If all the DNA in the human body were ex-tracted and strung together, the resulting strand would be longenough to make several hundred round-trips between Earth and thesun. Simply finding a particular gene among the approximately40,000 protein-coding genes that each of us carries is an imposing

109 triplets.

task.Yet before a specific gene can be studied, its location must be de-termined. Locating a gene involves preparing a map of the appro-priate chromosome.

� MAPPING THE HUMAN GENOMESeveral techniques can be used to create a map of the chromo-somes. Karyotyping (KAR-e-o-tI-ping; karyon,a mark) is the determination of an individual’s complement ofchromosomes. Figure 15a� shows a set of normal human chro-mosomes. Each chromosome has characteristic banding patterns,and segments can be stained with special dyes. Unusual bandingpatterns can indicate structural abnormalities, which are some-times linked to specific inherited conditions (including one formof leukemia). Down syndrome results from the presence of an extracopy of chromosome 21 (Figure 15b�). Locating the relative posi-tions of protein-coding genes on the chromosomes, a process calledgene mapping, started in the 1990s. By 2003, over 99 percent of thenucleotide sequences of the human genome had been completedin the course of the Human Genome Project.

However, knowing the nucleotide sequence of a gene doesn’tprovide as much information about the associated protein as weoriginally expected. It turns out that while there are roughly 40,000protein-coding genes in the human genome, there are probably2–3 million different proteins in the body. Each gene can direct thesynthesis of a variety of different related proteins, depending onwhich nucleotide segments are removed from the m-RNA strandduring RNA processing. It appears likely that much of the DNApreviously thought to be “useless” may be responsible for regulat-ing this process.

So far, the genomes of 114 organisms have been determined.Most of these were unicellular organisms (yeast and other bacte-ria), but complete nucleotide sequences are available for a nema-tode worm, a fruit fly, several fishes, the laboratory rat and mouseas well as humans and chimpanzees. To paraphrase WinstonChurchill, the accurate sequencing of our genome may be “theend of the beginning” in understanding our genetic selves.

� GENE MANIPULATION ANDMODIFICATION

Suppose that the location of a defective gene has been pinpoint-ed. Before attempting to remedy the defect in an individual, aclinician would have to determine the nature of the genetic ab-normality. For example, the gene could be inactive or overactive,or it could produce an abnormal protein. It could even be missing.Only after understanding what the problem is could the cliniciantry to decide how to remedy the defect. Can the gene be turned on,turned off, modified, supplemented, or replaced?

What’s the problem? This can be a particularly difficult ques-tion to answer. Many of the 2500 inheritable genetic disorders areclassified according to general patterns of symptoms, rather thanany specific protein or enzyme deficiency. In some cases, theapproximate location of the gene has been determined, but theidentity of the protein responsible for the clinical symptoms re-mains a mystery. In cystic fibrosis, many different abnormalities inthe gene and the resulting variations in the protein produced re-sult in different patterns of clinical disease. To complicate things

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(b) Trisomy 21(a) Normal chromosomes

� FIGURE 15Normal and Abnormal Karyotypes. (a) A micrograph of the normal human set of chromosomes; the chromosomes have been arranged in this se-quence for ease of comparison. (b) The chromosomes of an individual with Down syndrome. Notice the extra copy of chromosome 21.

further, several genes contribute to many genetic disorders, andenvironmental factors that influence the timing and amount ofgene function also play a role.

What can be done? If the gene is present, but is overproducing orunderproducing a protein, its activity might be controlled by in-troducing chemical repressors or inducers.Another approach relieson gene manipulation to produce the missing protein or increase itsamount to more normal levels. This process, sometimes called genesplicing, may begin with the localization of the gene, followed by itsisolation. A “healthy” copy of the gene is then spliced into the rela-tively simple DNA strand of a bacterium, creating recombinant DNA(rDNA) (Figure 16�). Bacteria grow and reproduce rapidly underlaboratory conditions, and before long a colony of identical bacte-ria has formed. All the members of the colony carry the introducedgene and will manufacture the corresponding protein. The proteincan then be extracted, concentrated, and administered to individ-uals who are deficient in the activity of the gene in question.Hemophilia (a deficiency of blood-clotting factors) and diabetescaused by insulin deficiency can be treated in this way.

Gene splicing is also used to obtain large quantities of proteinsthat normally are present in an organism only in very small con-centrations. Interferon, an antiviral protein, and human growthhormone are compounds now being produced commercially bymeans of gene-splicing technology.

The most revolutionary strategies involve “fixing” abnormalcells by giving them copies of normal genes. In general, thismethod poses significant targeting problems, because the genemust be introduced into the right kind of cell. For example, plac-ing liver enzymes in fingernails would not correct a metabolic dis-order, but when the target cells can be removed and isolated, as inthe case of bone marrow, the technique is promising. The removal

of a defective gene does not appear to be a practical approach, andthe focus has been on adding genes that can take over normal func-tions. Technical difficulties and unexpected problems, such as ten-dency to develop leukemia following treatment of SCID (p. 23),have slowed progress.

The foregoing procedures attempt to relieve the symptoms ofdisease by producing supplemental gene products as medicine, orby inserting genes into defective somatic cells for the body to pro-duce the gene products for itself. The new genes do not change thegenetic structure of reproductive cells; because oocytes and spermretain the original genetic pattern, the genetic defect would bepassed to future generations. Researchers are much further awayfrom practical methods of changing the genetic characteristics ofreproductive cells. Mouse eggs fertilized outside the body have beentreated and transplanted into the uterus of a second mouse for de-velopment. The gene that was added was one for a growth hor-mone obtained from a rat, and the large“supermouse” that resulteddemonstrated that such manipulations can be performed. The pos-sibilities of manipulating the characteristics of valuable animalstocks, such as cattle, sheep, or chickens, are exciting. The poten-tial for altering the genetic characteristics of humans is intimidat-ing. Before any clinical variations on this theme are tested, oursociety will have to come to grips with some difficult ethical issuesand safety concerns.

DRUGS AND THE CELL MEMBRANEMany clinically important drugs affect cell membranes. Althoughthe mechanisms behind the action of general anesthetics, suchas ether, chloroform, and nitrous oxide, have yet to be complete-

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Telomeres, Aging, and Cancer 33

Bacterial DNA

•

•

Transcription

Translation

Proteinproduct

Gene insertedinto bacterialchromosome

Normal generemoved

•

Human DNA

•Bacterium carrying

human gene

Bacterialreplication

Bacterium

� FIGURE 16Gene Splicing. A gene is re-moved from a human cell nucle-us and is attached to the DNA ina bacterium, where it directs theproduction of a human protein.Bacterial replication creates acolony of bacteria that share theintroduced gene and that canyield large quantities of the pro-tein product.

ly explained, most are lipid-soluble hydrophobic molecules. Thepotency of an anesthetic is directly correlated with its lipid sol-ubility, which may speed the drug’s entry into cells and enhanceits ability to block ion channels or change other properties ofcell membranes. The most important clinical result is a reduc-tion in the sensitivity and responsiveness of neurons and mus-cle cells.

Local anesthetics, such as procaine and lidocaine, as well asalcohol and barbiturate drugs, are also lipid soluble. These com-pounds block sodium channels in the cell membranes of neu-rons, reducing or eliminating the responsiveness of the neuronsto painful (or any other) stimuli. The very powerful toxintetrodotoxin (TTX) is found in some species of puffers (familyTetraodontidae). Eating the internal organs of these fish causesa severe and potentially fatal form of food poisoning, marked bythe disruption of normal neural and muscular activities. (Nev-ertheless, the flesh is considered a delicacy in Japan, where it isprepared by specially licensed chefs and served under the namefugu.)

Other drugs interfere with membrane receptors for hormonesor chemicals that stimulate muscle or nerve cells. Curare is aplant extract that interferes with the chemical stimulation ofmuscle cell membranes. South American Indians use it to coattheir hunting arrows so that wounded prey cannot run away. Toprevent reflexive muscle contractions or twitches while surgeryis being performed, anesthesiologists may administer a curarederivative (d-tubocurarine or a related drug) preoperatively topatients.

TELOMERES, AGING, AND CANCEREach telomere contains a sequence of roughly 8000 nitrogenousbases, but they are multiple copies of the same base sequence,TTAGGG, repeated over and over again. Telomeres are created byan enzyme called telomerase. Telomerase is functional early in life,but by adulthood it has become inactive. As a result, the telomeresegments lost during each mitotic division are not replaced. Even-tually, shortening of the telomere reaches a point at which the cellceases to divide.

This mechanism is clearly a major factor in the aging process,since many of the signs of age result from the gradual loss of func-tional stem cell populations. Experiments are in progress to deter-mine whether activating telomerase (or a suspected alternativerepair enzyme) can forestall or reverse the effects of aging. Thiswould seem to be a very promising area of research. Activate telo-merase, and eliminate aging—sounds good, doesn’t it? Unfortu-nately, there’s always a catch: In adults, telomerase activation is a keystep in the development of cancer.

If for some reason a cell with short telomeres does not respondnormally to repressor genes, it will continue to divide. The resultis mechanical damage to the DNA strands, chromosomal abnor-malities, and mutations. Interestingly, one of the first consequencesof such damage is the abnormal activation of telomerase. Oncethis occurs, the abnormal cells can continue dividing indefinitely.Telomerase is active in at least 90 percent of all cancer cells. Re-search is therefore underway to find out how to turn off telomerasethat has been improperly activated.

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34

THE TISSUE LEVEL OFORGANIZATION

FIBROCARTILAGE ON DEMANDRecent advances in tissue culture have enabled researchers to growfibrocartilage in the laboratory. Chondrocytes removed from theknees of injured patients are cultured in an artificial framework ofcollagen fibers. Eventually, they produce masses of fibrocartilagethat can be inserted into the damaged joints. Over time, the padschange shape and grow, restoring normal joint function. Thislabor-intensive technique has been used to treat severe joint in-juries, particularly in athletes.

PROBLEMS WITH SEROUSMEMBRANESSeveral clinical conditions, including infection and chronic in-flammation, can cause the abnormal buildup of fluid in a bodycavity. Other conditions can reduce the amount of lubrication,causing friction between opposing layers of serous membranes.This can promote the formation of adhesions—fibrous connec-tions that eliminate the friction by locking the membranes to-gether. Adhesions may also severely restrict the movement of theaffected organ or organs and may compress blood vessels or nerves.

Pleuritis, or pleurisy, is an inflammation of the pleural cavities.At first the opposing membranes become drier, and scratch againstone another, producing a sound known as a pleural rub. Adhe-sions seldom form between the serous membranes of the pleuralcavities. More commonly, continued rubbing and inflammationleads to a gradual increase in fluid production to levels well abovenormal. Fluid then accumulates in the pleural cavities, producinga condition known as pleural effusions. Pleural effusions are alsocaused by heart conditions that elevate the pressure within thepulmonary blood vessels. Fluid then leaks into the alveoli and intothe pleural spaces as well, compressing the lungs and makingbreathing difficult. This combination can be lethal.

Pericarditis is an inflammation of the pericardium. This con-dition may lead to pericardial effusion, an abnormal accumulationof the fluid in the pericardial cavity. When sudden or severe, thefluid buildup can seriously reduce the efficiency of the heart andrestrict blood flow through major vessels.

Peritonitis, an inflammation of the peritoneum, can follow in-fection of, or injury to, the peritoneal lining. Peritonitis is a poten-tial complication of any surgical procedure in which the peritonealcavity is opened or a disease that perforates the walls of the intestinesor stomach. Adhesions are common following peritoneal infectionsand may lead to constriction and blockage of the intestinal tract.

Liver disease, kidney disease, or heart failure can cause an ac-cumulation of fluid in the peritoneal cavity. Called ascites(a-SI-tez), this accumulation creates a characteristic abdominalswelling. The pressure and distortion of internal organs by the ex-cess fluid can lead to symptoms such as heartburn, indigestion,shortness of breath, and low-back pain.

CANCER: A CLOSER LOOKIn the United States, the lifetime risk of developing some form ofcancer is 50 percent for males and 33 percent for females. In 2004,an estimated 556,500 people will die of some form of cancer, mak-

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Cancer: A Closer Look 35TISSU

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ing it second only to heart disease as a cause of mortality in theU.S. population. Because both population size and average ageincreased in the twentieth century, just comparing the numbersof deaths from year to year can be misleading. The relevant sta-tistics are better presented in terms of the cancer rate per 100,000population, age adjusted to match the most recent census data(2000), and compared to statistics on other causes of death. Forexample, from 1975 to 2000, the United States has had an increasein cancer incidence of 12.5 percent, while the cancer death rateover this time has not increased, and the absolute death rate hasdeclined at least 18 percent. For those interested in more detaileddata analyses, visit the National Center for Health Statistics athttp://www.cdc.gov/nchs.

� CAUSES OF CANCERRelatively few types of cancer are inherited; only 20 hereditarytypes have been identified to date, and together they account for lessthan 1 percent of cancer cases. By definition, inherited cancer in-volves gene(s) provided by the sperm or oocyte at fertilization; asa result, these genes are in every cell of the individual’s body. Suchpeople have a much higher risk of developing a specific cancer thanthe general population. However, not everyone with these genesgets cancer, and this indicates that other genes and/or environ-mental factors must act as a “trigger.” For the general population,it is the interaction of genetic and environmental factors that caus-es most cancers.

GENETIC FACTORSTwo related genetic factors are involved in the development ofcancer: hereditary predisposition and oncogene activation.

An individual born with genes that increase the likelihood ofcancer is said to have a hereditary predisposition for the disease.Such a person may never develop cancer, but his or her chancesare higher than average. The inherited genes generally affect theabilities of tissues to metabolize toxins, control mitosis and growth,perform repairs after injury, or identify and destroy abnormal tis-sue cells. As a result, body cells become sensitive to local or envi-ronmental factors that would have less effect on cells from personslacking these genes. Roughly 15 percent of cancers “run in families”and reflect a hereditary disposition for cancer of a specific type.

The majority of cancers result from somatic-cell mutations thatmodify genes involved in cell growth, differentiation, or mitosis.As a result, an ordinary cell is converted into a cancer cell. Themodified genes are called oncogenes (ON-ko-jenz); the normalgenes are called proto-oncogenes. Oncogene activation occurs bythe alteration of normal somatic genes. Because these mutationsdo not affect reproductive cells, the cancers caused by active onco-genes are not inherited.

A proto-oncogene, like other genes, has a regulatory compo-nent that turns the gene “on” and “off” and a structural compo-nent that contains the mRNA triplets that determine proteinstructure. Mutations in either portion of the gene may convert itto an active oncogene. A change of just one nucleotide out of achain of 5000 can convert a normal proto-oncogene to an activeoncogene. In some cases, a viral infection can trigger the activa-tion of an oncogene. For example, one of the human papilloma(wart) viruses appears to be responsible for many cases of cervi-

cal cancer. If a person with one form of stomach lymphoma (alymphatic system cancer) is also infected with the bacteriaHeliobacter pylori, eradication of the bacteria has been followed bythe disappearance of the lymphoma.

More than 50 proto-oncogenes have been identified. In addi-tion, a group of anticancer genes has been discovered. Thesegenes, called tumor-suppressing genes (TSGs), or anti-oncogenes,suppress division and growth in normal cells. Mutations that alterTSGs make oncogene activation more likely. Such mutation hasbeen suggested as an important factor in promoting several can-cers, including a number of blood cell cancers, breast cancer, andovarian cancer. Examples of important suppressor genes are thegenes p53 and p16. Mutations affecting the p53 gene are presentin the majority of cancers of the colon, breast, and liver. Abnor-mal p16 gene activity may be involved in as many as half of allcancer cases.

ENVIRONMENTAL FACTORSMany cancers can be directly or indirectly attributed to envi-ronmental factors called carcinogens (kar-SIN-o-jenz). Car-cinogens stimulate the conversion of a normal cell to a cancercell. Some carcinogens are mutagens (MU-ta-jenz)—that is, theydamage DNA strands and may cause chromosomal breakage. Allforms of high-energy radiation, including cosmic rays, x-rays,and UV rays as well as radioisotopes, are mutagens that have car-cinogenic effects.

The environment contains many chemical carcinogens. Plantsmanufacture poisons that protect them from insects and otherpredators, and although their carcinogenic activities are often rel-atively weak, many common spices, vegetables, and beverages con-tain compounds that are carcinogens if consumed in largequantities. Animal tissues may also store or concentrate toxins,and hazardous compounds of many kinds can be swallowed incontaminated food. A variety of laboratory and industrial chem-icals, such as coal tar derivatives and synthetic pesticides, have beenshown to be carcinogenic. From studies that compared cancer in-cidence in twins with other data, it has been estimated that 70–80percent of all cancers are the result of chemical or environmentalfactors, and 40 percent are due to a single source of carcinogens:cigarette smoke.

Specific carcinogens will affect only those cells capable of re-sponding to that particular physical or chemical stimulus. The re-sponses vary because differentiation produces cell types with specificsensitivities.For example,benzene can produce a cancer of the blood,cigarette smoke a lung cancer, and vinyl chloride a liver cancer. Veryfew stimuli can produce cancers throughout the body. Radiation is anotable exception. In general, cells undergoing mitosis are most like-ly to be vulnerable to chemical or radiational carcinogens.As a result,cancer rates are highest in epithelial tissues, like the skin and lining ofthe intestines, where stem cell divisions occur rapidly, and lowest innervous and muscle tissues, where divisions do not normally occur.

� DETECTION AND INCIDENCE OF CANCER

Physicians who specialize in the identification and treatment ofcancers are called oncologists (on-KOL-o-jists; onkos, mass).Pathologists and oncologists classify cancers according to their

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cellular appearance and their sites of origin. More than a hun-dred kinds have been described, but broad categories are used thatindicate the location of the primary tumor. A tumor is defined asa “new growth” resulting from uncontrolled cell division. A tumorcan be malignant or benign and may metastasize (spread) rapidlyor very slowly. Only malignant tumors are called cancers. Table 10summarizes information about benign and malignant tumors(cancers) associated with the major tissues of the body.

A statistical profile of cancer incidences and survival rates inthe United States is shown in Table 11. The numbers from othercountries are different. For example, bladder cancer is common inEgypt, stomach cancer in Japan, and liver cancer in Africa. Varia-tions in the combination of genetic factors and dietary, infectious,and other environmental factors are thought to be responsible forthese differences.

� CLINICAL STAGING AND TUMOR GRADING

The detection of a cancer often begins during a routine physical ex-amination, when the physician notices an abnormal lump orgrowth. Many laboratory and diagnostic tests are necessary for thecorrect diagnosis of cancer. Information is usually obtained by thehistological examination of a tissue sample, or biopsy, typicallysupplemented by medical imaging and blood studies. A biopsy isone of the most significant diagnostic procedures, because it per-mits a direct look at the tumor cells. Not only do malignant cellshave an abnormally high rate of mitosis, but they are also struc-turally distinct from healthy body cells.

If the tissue appears cancerous, other important questions mustbe answered, including the following: What is the measurable sizeof the primary tumor? Has the tumor invaded surrounding tis-sues? Has the cancer already metastasized to develop secondarytumors? Are any regional lymph nodes affected? The answers tothese questions are combined with observations from the physi-cal exam, the biopsy results, and information from any imagingprocedures to arrive at an accurate diagnosis and prognosis.

In an attempt to develop a standard system, national and in-ternational cancer organizations have devised the TNM system forstaging (i.e., identifying the stage of progression of) cancers. Theletters stand for tumor (T) size and invasion, lymph node (N) in-volvement, and degree of metastasis (M):

• Tumor size is graded on a scale of 0 to 4. T0 indicates the ab-sence of a primary tumor, and the largest dimensions and great-est amount of invasion are categorized as T4.

• Lymph nodes filter the tissue fluids from nearby capillary beds.The fluid, called lymph, then returns to the general lymphaticcirculation. Once cancer cells have entered the lymphatic system,they can spread very quickly throughout the body. Lymph nodeinvolvement is graded on a scale of 0 to 3. A designation of N0indicates that no lymph nodes have been invaded by cancer cells.A classification of N1 to N3 indicates the involvement of in-creasing numbers of lymph nodes:

N1 indicates the involvement of a single lymph node less than3 cm in diameter.

N2 includes one medium-sized (3–6 cm) node or multiplenodes smaller than 6 cm.

N3 indicates the presence of a single lymph node larger than 6 cmin diameter, regardless of whether other nodes are involved.

• Metastasis is graded on a scale of 0 to 1. M0 indicates that thereis no evidence of metastasis, whereas M1 indicates that the can-cer cells have produced secondary tumors in other portions ofthe body.

This grading system provides a general overview of the pro-gression of the disease. For example, a tumor classified as T1N1M0has a better prognosis than one classified as T4N2M1. The lattertumor would be much more difficult to treat. The grading systemalone does not provide all the information needed to plan treat-ment, however, because different types of cancer progress in dif-ferent ways. Therapies must vary accordingly. Thus, leukemia, acancer of the blood-forming tissues, is treated differently than

TABLE 10 Benign and Malignant Tumors in theMajor Tissue Types

Tissue Description

Epithelia

Carcinomas Any cancer of epithelial origin

Adenocarcinomas Cancers of glandular epithelia

Angiosarcomas Cancers of endothelial (vascular) cells

Mesotheliomas Cancers of mesothelial cells

Connective tissues

Fibromas Benign tumors of fibroblast origin

Lipomas Benign tumors of adipose tissue

Liposarcomas Cancers of adipose tissue

Leukemias Cancers of blood-forming tissues

Lymphomas Cancers of lymphoid tissues

Chondromas Benign tumors in cartilage

Chondrosarcomas Cancers of cartilage

Osteomas Benign tumors in bone

Osteosarcomas Cancers of bone

Muscle tissues

Myxomas Benign muscle tumors

Myosarcomas Cancers of skeletal muscle tissue

Cardiac sarcomas Cancers of cardiac muscle tissue

Leiomyomas Benign tumors of smooth muscle tissue

Leiomyosarcomas Cancers of smooth muscle tissue

Neural tissues

Gliomas Cancers of neuroglial origin

Neuroblastomas Cancers of neuronal origin

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TABLE 11 Cancer Incidences and Survival Rates in the United States

Five-Year Survival Rates

Estimated Estimated Diagnosis DateSite New Cases (2003) Deaths (2003) 1974–76 1992–98

Digestive tract

Esophagus 13,900 13,000 5% 13%

Stomach 22,400 12,100 15% 22%

Colon and rectum 147,500 57,100 50% 62%

Respiratory tract

Lung and bronchus 171,900 157,200 12% 15%

Urinary tract

Kidney and renal pelvis 31,900 11,900 52% 62%

Urinary bladder 57,400 12,500 73% 82%

Reproductive system

Breast 212,600 40,200 75% 86%

Ovary 25,400 14,300 37% 53%

Testis 7,600 400 79% 95%

Prostate gland 220,900 28,900 67% 97%

Nervous system 18,300 13,100 22% 32%

Skin (melanoma only) 54,200 7,600 80% 89%

Data courtesy of the American Cancer Society

colon cancer. We will consider specific treatments in discussionsdealing with cancers that affect individual body systems; the nextsection provides a general overview of the strategies used to treatcancer.

� CANCER TREATMENTIt is unfortunate that the media tend to describe cancer as thoughit were one disease rather than many. This simplistic perspectivefosters the belief that some dietary change, air ionizer, or wonderdrug will be found that can prevent or cure the affliction. No sin-gle, universally effective cure for cancer is likely, because there aretoo many separate causes, underlying mechanisms, and individ-ual differences.

The goal of cancer treatment is to achieve remission. A tumorin remission either ceases to grow or decreases in size. The treat-ment of malignant tumors must accomplish one of these two ob-jectives to produce remission:

1. The surgical removal or destruction of individual tumors.Tumors containing malignant cells can be surgically removed ordestroyed by radiation, heat, or freezing. These techniques are

highly effective if the treatment is undertaken before metastasishas occurred. For this reason, early detection is important in im-proving survival rates for all forms of cancer.

2. The killing of metastasized cells throughout the body. This ismuch more difficult and potentially dangerous, because healthytissues are likely to be damaged at the same time. At present, themost widely approved treatments are chemotherapy and radiation.

Chemotherapy may involve the administration of drugs thatwill either kill the cancerous tissues or prevent mitotic divisions.These drugs typically affect stem cells in normal tissues, and theside effects are usually unpleasant. For example, because somechemotherapy slows the regeneration and maintenance of epitheliaof the skin and digestive tract, patients often lose their hair andexperience nausea and vomiting. Several drugs are often admin-istered simultaneously or in sequence, because, over time, cancercells can develop a resistance to a single drug. Chemotherapy isused in the treatment of many kinds of metastasized cancer.

Massive doses of total body irradiation are sometimes used totreat advanced cases of lymphoma, a cancer of the immune system.In this rather drastic procedure, enough radiation is administeredto kill all the blood-forming cells in the body. After treatment, newblood cells must be provided by a bone marrow transplant. In later

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TABLE 12 Seven Warning Signs of Cancer

Change in bowel or bladder habits

A sore that does not heal

Unusual bleeding or discharge

Thickening or lump in breast or elsewhere

Indigestion or difficulty in swallowing

Obvious change in a wart or mole

Nagging cough or hoarseness

sections dealing with the lymphatic system, we will discuss marrowtransplants, lymphomas, and other cancers of the blood.

An understanding of molecular mechanisms and cell biologyis leading to new approaches that may revolutionize cancertreatment. One approach focuses on the fact that cancer cells areignored by the immune system. In immunotherapy, chemicals areadministered that help the immune system recognize and attackcancer cells. More elaborate experimental procedures involve thecreation of customized antibodies by the gene-splicing techniquesdiscussed on p. 32. The resulting antibodies are specifically de-signed to attack the tumor cells in each particular patient. Althoughthis technique shows promise, it remains difficult, costly, and verylabor-intensive.

A second approach is targeted “designer” cancer drugs. Onetype of cancer, chronic myelogenous leukemia, involves the activ-ity of an abnormal enzyme. A drug has been developed that inac-tivates this enzyme but has no effect on normal enzymes, and thusdoes not affect normal cells. In early trials of the drug imatinib(Gleevac) complete remission occurred in up to 95 percent of CMLpatients treated. Studies are now in progress to determine whetherGleevac could be effective against other types of cancer.

� CANCER AND SURVIVALAdvances in chemotherapy, radiation procedures, and molecularbiology have produced significant improvements in the survivalrates of several types of cancer patients. However, the improvedsurvival rates indicated in Table 11 reflect advances not only intherapy, but also in early detection. Much of the credit goes to in-creased public awareness and concern about cancer. In general,the odds of survival increase markedly if the cancer is detectedearly, especially before it undergoes metastasis. The AmericanCancer Society has identified seven “warning signs,” which meanthat it’s time to consult a physician. These signs are presented inTable 12.

TISSUE STRUCTURE AND DISEASEPhysicians who specialize in the study of disease processes arecalled pathologists (pa-THOL-o-jists). Diagnosis, rather thantreatment, is usually the main focus of their activities. In theiranalyses, pathologists integrate anatomical and histological

observations to determine the nature and severity of a disease.Because disease processes affect the histological organization oftissues and organs, biopsies, or tissue samples, often play a keyrole in their diagnoses.

Figure 17� diagrams the histological changes induced in therespiratory epithelium by one relatively common irritating stim-ulus, cigarette smoke. The normal respiratory epithelium is shownin Figure 17a�. The first abnormality to be observed in a smoker

Reversible

Reversible

Irreversible

(a) The cilia of respiratoryepithelial cells are damaged and paralyzedby exposure to cigarettesmoke. These changescause the local buildup of mucus and reduce the effectiveness of the epithelium in protecting deeper, more delicate portions of the respiratory tract.

(b) In metaplasia, a tissuechanges its structure. In this case the stressedrespiratory surface converts to a stratifiedepithelium that protectsunderlying connective tissues but does nothingfor other areas of the respiratory tract.

(c) In anaplasia, the tissuecells become tumor cells;anaplasia producesa cancerous tumor.

Irritant chemicals andparticles in smoke

NORMALRESPIRATORY EPITHELIUM

DYSPLASIA

METAPLASIA

ANAPLASIA

� FIGURE 17Changes in a Tissue under Stress

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As metaplasia progresses, the epithelial cells produced by stemcell divisions no longer differentiate into ciliated columnar cells. In-stead, they form a stratified squamous epithelium that providesgreater resistance to drying and chemical irritation (Figure 17c�).This epithelium protects the underlying tissues more effectively,but it eliminates the moisturization and cleaning properties of theepithelium. Cigarette smoke will now have an even greater effect onmore delicate portions of the respiratory tract. Fortunately, meta-plasia is reversible, and unless a malignant tumor has formed, theepithelium will gradually return to normal if the individual quitssmoking.

In anaplasia (a-nuh-PLA-ze-uh), tissue organization breaksdown. Tissue cells change size and shape, typically becoming un-usually large or small (Figure 17d�) and losing any resemblance tomature tissue cells. Anaplasia is characteristic of most if not allcancers; it occurs in smokers who develop one form of lung can-cer. In anaplasia, the cells divide more frequently but not all divi-sions proceed in the normal way. Many of the tumor cells haveabnormal chromosomes. Unlike dysplasia and metaplasia, anapla-sia is irreversible.

Tissue Structure and Disease 39TISSU

E

is dysplasia (dis-PLA-ze-uh), a change in the shape, size, and or-ganization of tissue cells. Dysplasia is generally a response tochronic irritation or inflammation, and the changes are reversible.The normal trachea (windpipe) and its branches are lined by apseudostratified ciliated columnar epithelium. The cilia move amucous layer that traps foreign particles and moistens incomingair. The drying and chemical effects of smoking first paralyze thecilia, halting the movement of mucus (Figure 17b�). As mucusbuilds up, the individual coughs to dislodge it (the well-known“smoker’s cough”). Dysplasia is generally a response to chronicirritation or inflammation, and the changes are reversible. How-ever, dysplasia increases the risk of cancer formation in that tissue;in a tissue not subject to abnormal stresses, dysplasia may be thefirst indication of a developing cancer.

Epithelia and connective tissues may undergo more radicalchanges in structure, caused by the division and differentiation ofstem cells. Metaplasia (me-tuh-PLA-ze-uh) is a structural changethat dramatically alters the character of the tissue. In our exam-ple, over time heavy smoking causes the epithelial cells to lose theircilia altogether.

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UNIT 1 LEVELS OF ORGANIZATION - Hazleton Area High School · 2011-01-18 · 1 UNIT 1 LEVELS OF...

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