human disease

human disease

Introduction

      an impairment of the normal state of a human being that interrupts or modifies its vital functions.

health versus disease
      Before human disease can be discussed, the meanings of the terms health, physical fitness, illness, and disease must be considered. Health could be defined theoretically in terms of certain measured values; for example, a person having normal body temperature, pulse and breathing rates, blood pressure, height, weight, acuity of vision, sensitivity of hearing, and other normal measurable characteristics might be termed healthy. But what does normal mean, and how is it established? It is well known that if the temperatures are taken of a large number of active, presumably healthy, individuals the temperatures will all come close to 98.6° F (37° C). The great preponderance of these values will fall between 98.4° F (36.9° C) and 98.8° F (37.1° C). Thus, health could in part be defined as having a temperature within this narrow range. Similarly, a normal range can be established for pulse, blood pressure, and height. In some healthy individuals, however, the body temperature may range below 98.4° F or above 98.8° F. These low and high temperatures fall outside the limits defined above as normal and are instances of biological variability.

      Biological criteria of normality are based on statistical concepts. Body height may be used as an example. If the heights of every individual in a large sample were plotted on a graph, the many points would fall on a bell-shaped curve. At one end of the curve would be the very short people, and at the other extreme the few very tall people. The majority of the points of the sample population would fall on the dome of the bell-shaped curve. At the peak of the dome would be those individuals whose height approaches the average of all the heights. Scientists use curves in determining what they call normal criteria. By accepted statistical criteria, 95 percent of the population measured would be included in the normal range—that is, 47.5 percent above and 47.5 percent below the mean at the very centre of the bell. Looked at in another way, in any given normal biological distribution 5 percent will be considered outside the normal range. Thus the 7-foot (213-centimetre) basketball player would be considered abnormally tall, but that which is abnormal must be distinguished from that which represents disease. The basketball player might be abnormally tall but still have excellent health. Thus, in any statistical analysis of health, the possibility of biological variation must be recognized.

      A better example than height of how problems can arise with biological variability is heart size. If the heart is subjected to a greater than normal burden over a long period, it can respond by growing larger (the process is known as hypertrophy). This occurs in certain forms of heart disease, especially in those involving long-standing high blood pressure or structural defects of the heart valves. A large heart, therefore, may be a sign of disease. On the other hand, it is not uncommon for athletes to have large hearts. Continuous strenuous exercise requires a greater output of blood to the tissues, and the heart adapts to this demand by becoming larger. In some cases the decision as to whether an abnormally large heart represents evidence of disease or is simply a biological variant may tax the diagnostic abilities of the physician.

      The effects of age (human aging) introduce yet another difficulty in the attempt to define health in theoretical measured norms. It is well known that muscular strength diminishes in the advanced years of life, the bones become more delicate and more easily fractured, vision and hearing become less sharp, and a variety of other retrogressive changes occur. There is some basis for considering this general deterioration as a disease, but, in view of the fact that it affects virtually everyone, it can be accepted as normal. Theoretical criteria for health, then, would have to be set for virtually every year of life. Thus, one would have to say that it is normal for a man of 80 to be breathless after climbing two flights of stairs, while such breathlessness would be distinctly abnormal in an agile child of 10 years of age. Moreover, an individual's general level of physical activity significantly alters his ability to respond to the ordinary demands of daily life. The amount of muscular strength possessed by an 80-year-old man who has remained physically active would be considerably more than that of his fragile friend who has led a confined life because of his dislike of activity. There are, therefore, many difficulties in establishing criteria for health in terms of absolute values.

      Health might be defined better as the ability to function effectively in complete harmony with one's environment. Implied in such a definition is the capability of meeting—physically, emotionally, and mentally—the ordinary stresses of life. In this definition health is interpreted in terms of the individual's environment. Health to the construction worker would have a dimension different from health to the bookkeeper. The healthy construction worker expects to be able to do manual labour all day, while the bookkeeper, although perfectly capable of performing sedentary work, would be totally incapable of such heavy labour and indeed might collapse from the physical strain; yet both individuals might be termed completely healthy in terms of their own way of life.

      The term physical fitness, although frequently used, is also exceedingly difficult to define. In general it refers to the state of optimal maintenance of muscular strength, proper function of the internal organs, and youthful vigour. The champion athlete prepared to cope not only with the commonplace stresses of life but also with the unusual illustrates the concept of physical fitness. To be in good physical condition is to have the ability to swim a mile to save one's life or to slog home through snowdrifts when a car breaks down in a storm. Some experts in fitness insist that the state of health requires that the individual be in prime physical condition. They prefer to divide the spectrum of health and disease into (1) health, (2) absence of disease, and (3) disease. In their view, those who are not in prime condition and are not physically fit cannot be considered as healthy merely because they have no disease.

      Health involves more than physical fitness, since it also implies mental (mental hygiene) and emotional well-being. Should the angry, frustrated, emotionally unstable person in excellent physical condition be called healthy? Certainly this individual could not be characterized as effectively functioning in complete harmony with the environment. Indeed, such an individual is incapable of good judgment and rational response. Health, then, is not merely the absence of illness or disease but involves the ability to function in harmony with one's environment and to meet the usual and sometimes unusual demands of daily life.

      The definitions of illness and disease are equally difficult problems. Despite the fact that these terms are often used interchangeably, illness is not to be equated with disease. A person may have a disease for many years without even being aware of its presence. Although diseased, this person is not ill. Similarly, a person with diabetes who has received adequate insulin treatment is not ill. An individual who has cancer is often totally unaware of having the disorder and is not ill until after many years of growth of the tumour, during which time it has caused no symptoms. The term illness implies discomfort or inability to function optimally. Hence it is a subjective state of lack of well-being produced by disease. Regrettably, many diseases escape detection and possible cure because they remain symptomless for long years before they produce discomfort or impair function.

      Disease, which can be defined at the simplest level as any deviation from normal form and function, may either be associated with illness or be latent. In the latter circumstance, the disease will either become apparent at some later time or will render the individual more susceptible to illness. The person who fractures an ankle has an injury (wound)—a disease—producing immediate illness. Both form and function have been impaired. The illness occurred at the instant of the development of the injury or disease. The child who is infected with measles, on the other hand, does not become ill until approximately 10 days after exposure (the incubation period). During this incubation period the child is not ill but has a viral infectious disease that is incubating and will soon produce discomfort and illness. Some diseases render a person more susceptible to illness only when the person is under stress. Some diseases may consist of only extremely subtle defects in cells that render the cells more susceptible to injury in certain situations. The blood disease known as sickle cell anemia, for example, results from a hereditary abnormality in the production of the red oxygen-carrying pigment (hemoglobin) of the red cells of the blood. The child of a mother and father who both have sickle cell anemia will probably inherit an overt form of sickle cell anemia and will have the same disease as the parents. If only one parent has sickle cell anemia, however, the child may inherit only a tendency to sickle cell anemia. This tendency is referred to by physicians as the sickle cell trait. Individuals having such a trait are not anemic but have a greater likelihood of developing such a disease. When they climb a mountain and are exposed to lower levels of oxygen in the air, red blood cells are destroyed and anemia develops. This can serve as an example of a disease or a disease trait that renders the affected person more susceptible to illness.

      Disease, defined as any deviation from normal form and function, may be trivial if the deviation is minimal. A minor skin infection might be considered trivial, for example. On the eyelid, however, such an infection could produce considerable discomfort or illness. Any departure from the state of health, then, is a disease, whether health be measured in the theoretical terms of normal measured values or in the more pragmatic terms of ability to function effectively in harmony with one's environment.

Maintenance of health
      Health is not a static condition but represents a fluid range of physical and emotional well-being continually subjected to internal and external challenges such as worry, overwork, varying external temperatures, mechanical stresses, and infectious agents. These constantly changing conditions require the adjustment of the function of the various systems within the body. Mechanisms are continually at work to maintain a constant internal environment called by the French scientist Claude Bernard the milieu intérieur. The maintenance of this relatively constant internal environment is known as homeostasis. On a hot summer day, for example, the body is challenged to maintain its normal temperature of 98.6° F (37° C). Sweating (sweat) represents a mechanism by which the skin is kept moist. By the evaporation of the moisture, heat is lost more rapidly. The hot day, therefore, represents a challenge to homeostasis. On a cold day gooseflesh may develop, an example of a homeostatic response that is a throwback to mechanisms in lower animals. In fur-bearing ancestors of humans, cold external environments caused the individual hair shafts to rise and, in effect, produce a heavier, thicker insulation of the body against the external chill. Humans still develop this primitive gooseflesh response but, regrettably, lack the luxuriant pelt to protect themselves.

      Bacteria, viruses, and other microbiological agents are obvious challenges to health. The body is able, to a considerable extent, to protect itself and adjust to challenges, and, to the extent that it is successful, the state of health is maintained. While health is often thought of as fragile and subject to many onslaughts, it is, in fact, a ruggedly guarded state protected by a host of highly efficient internal mechanisms.

      Some of the mechanisms vital to the maintenance of health include (1) the maintenance of the internal environment, or homeostasis, (2) adaptation to stress situations, (3) defense against microbiological agents, such as bacteria and viruses, (4) repair and regeneration of damaged tissue or cells, and (5) clotting of the blood to prevent excessive bleeding. Each of these areas will be discussed briefly. Despite these separate considerations, the commonality of purpose—the preservation and maintenance of health—must not be lost sight of. Insofar as each of these mechanisms works to maintain a constant internal environment, it can be considered as a homeostatic mechanism. Later, when disease is discussed, it will be apparent that to a considerable extent disease represents a failure of homeostasis and the other defensive responses listed above.

Homeostasis
      As noted earlier, the term homeostasis refers to the maintenance of the internal environment of the body within narrow and rigidly controlled limits. The major functions important in the maintenance of homeostasis are fluid and electrolyte balance, acid-base regulation, thermoregulation, and metabolic control.

Fluid and electrolyte balance
 This term refers to the controlled partition of water and major chemical constituents among the cells and the extracellular fluids of the body. The human body is basically a collection of cells grouped together into organ systems and bathed in fluids, most notably the blood. The intracellular fluid is the fluid contained within cells. The extracellular fluid—the fluid outside the cells—is divided into that found within the blood and that found outside the blood; the latter fluid is known as the interstitial fluid. These fluids are not simply water but contain varying amounts of solutes (electrolytes and other bioactive molecules). An electrolyte (sodium chloride, for example) is defined as any molecule that in solution separates into its ionic components and is capable of conducting an electric current. Cations (cation) are electrolytes that migrate toward the negative pole of an electric field; anions (anion) migrate toward the positive pole. The electrolyte composition of the various fluid compartments is summarized in Table 1—>.

 It is apparent from this table that the ionic compositions of the intracellular and extracellular fluids are significantly different. The major cation of extracellular fluid is sodium. The major anion of the extracellular fluid is chloride, while bicarbonate is the second most important. In contrast, the major cation of the intracellular fluid is potassium, and the major anions are proteins (protein) and organic phosphates (phosphate). The marked differences in sodium and potassium concentrations between the intracellular and extracellular fluid of cells are not fortuitous but are due to active transport by energy-dependent ion pumps located in cell membranes. The pumps continuously move sodium ions out of the cell and potassium ions into the cell. The intracellular and extracellular compartments are thus closely integrated and interdependent: changes in one have immediate effects on the other. In clinical medicine most measurements of electrolyte concentration are performed on the extracellular fluid compartment, notably the blood serum (serum). The values given in Table 1—> remain fairly constant on a day-to-day basis, in spite of various dietary intakes of food and water.

      It is the primary task of the kidneys (kidney) to regulate the various ionic concentrations of the body. Any abnormality in these concentrations can produce serious disease; for instance, the normal sodium concentration in the serum (the blood minus its cells and clotting factors) ranges from 136 to 142 milliequivalents per litre, while the normal potassium level in the serum is kept within the narrow range of 3.5 to 5 milliequivalents per litre. A rise in the serum potassium to perhaps 6.2 milliequivalents per litre, as can occur when large numbers of cells are severely injured or die and potassium ions are released, could cause serious abnormalities in the performance of the heart by disturbing the regularity of the nervous impulses that maintain the heart's rhythm.

      The total amount of body water is also maintained at fairly constant levels from day to day by the combined action of the central nervous system and the kidneys. If one were to refrain from drinking any water for a few days, the thirst centre, located in the hypothalamus deep within the brain, would send out messages that would be translated into the feeling of thirst. At the same time a hormone from the posterior pituitary gland known as antidiuretic hormone (ADH; vasopressin) would be secreted. This hormone, released into the bloodstream, would reach the kidneys, where it would signal the kidneys to retain water and not excrete it. Should too much water be ingested, ADH secretion would be turned off, and the kidneys would promptly excrete the excess amount.

Acid-base (acid–base reaction) equilibrium
      The acidity of the body fluids is maintained within narrow limits. This acidity is expressed in terms of the pH of a solution, values exceeding 7 representing alkalinity and less than 7 acidity. The pH of a solution is an expression of the amount of hydrogen ion present. Increases in hydrogen ion concentration cause a lowering of the pH, and, conversely, decreases in the hydrogen ion concentration raise the pH. Any abnormal process raising the hydrogen ion concentration in the body fluids produces a state of disease referred to as acidosis; (acidosis) one that causes the concentration to be lowered results in alkalosis.

      In health the blood (blood disease) is slightly alkaline, being kept at a pH of 7.35 to 7.45, a narrow range which must be maintained for the optimum operation of the many chemical reactions that go on constantly in the body. Alterations in the blood pH occur in many diseases, particularly of the lungs and kidneys, organs whose functions include regulation of the body pH.

      As has been said above, the temperature of the body is kept nearly constant at 98.6° F (37° C). Fluctuations within a few tenths of a degree are perfectly compatible with health. Wider swings in temperature are usually indicative of disease, and thus body temperature is an important factor in assessing health. Body temperature is regulated by a thermostatic control centre in the hypothalamus. A rise in body temperature initiates a chain of events leading to an increase in the rate of breathing and in sweating, two processes that serve to lower the body temperature. Similarly, a decrease in body temperature, perhaps occasioned by a chilly winter walk, leads to increased heat-producing activity such as the muscular contractions of shivering—again mediated by the thermostatic control centre in the hypothalamus.

      In essence, metabolism involves all the physical and chemical processes by which cells are produced and maintained. Included under this broad umbrella are the regulation of fluid and electrolytes, the maintenance of plasma protein levels adequate for the building and repair of cells, and control of the amounts of sugar (glucose) and fats (lipids) in the blood so as to provide sufficient amounts for all the energy-producing activities of the cells. (The main treatment of this subject is contained in the article metabolism.)

      The control of blood glucose levels is a good example of homeostasis. Most of the glucose utilized by the body is derived from the dietary intake of various forms of sugars and starches. These are digested within the intestinal tract into the simplest forms of carbohydrate (monosaccharides). Glucose, galactose, and fructose are the principal monosaccharides. These are absorbed from the intestines into the blood and enter the liver. Here all are eventually converted to glucose. The glucose may be utilized by the liver cells in part as a source of readily available energy, or it may be polymerized and stored as glycogen, but most of it enters the general circulation of the body and contributes to the blood glucose level. Blood glucose may also be derived in times of need by the conversion of the stored glycogen into glucose.

      When food is eaten, there is a temporary rise in the blood glucose level known as alimentary hyperglycemia (high blood glucose level). Mechanisms are activated that stimulate the pancreas to secrete the hormone insulin. This hormone makes it possible for cells to utilize the glucose by facilitating its transport (carriage) across the membranes of cells into their interior, where it can enter the complex chemical reactions that provide the cell with energy. By virtue of insulin secretion, the cells receive adequate amounts of glucose, and the blood glucose levels are returned to the normal range, somewhere between 70 and 110 milligrams per 100 millilitres of blood.

      Metabolic controls are exerted similarly for fats and proteins. As will be noted later on, derangements of these controls can lead to serious disease. The state of health implies proper, smooth-running metabolic machinery.

      Adaptation refers to the ability of cells to adjust to severe stresses and achieve altered states of equilibrium while preserving a healthy state. In the human body the large bulging muscles (muscle) of an individual engaged in heavy labour are a good example of cellular adaptation. Because of the heavy demand for work from these muscles, each of the individual muscle cells within the labourer's arms and legs becomes larger (hypertrophic). This enlargement is caused by the formation of increased numbers of tiny fibres (myofilaments) that provide the contractile power of muscles. Thus, while the normal muscle cell might have 2,000 myofilaments, the hypertrophied cell might have 4,000 myofilaments. The workload can now be divided evenly among twice as many myofilaments, and the muscle cell is capable of more work. The cells are completely normal and, in fact, are more robust than their fragile cousins. The individual can do heavy work all day without excessive fatigue, and no cell injury results from the heavy workload. A new level of equilibrium has been achieved by the process of cellular hypertrophy. A person with this type of muscular development can be considered to be in excellent physical condition, capable of meeting emergency situations such as running from a fire or catching a train without the dangers that might be encountered by a person who has not undergone such a development.

      Inhabitants of high altitudes adapt to the lowered amounts of oxygen within the air by developing an increased number of red blood cells (a condition called secondary polycythemia). The greater number of red cells in the blood are capable of absorbing more oxygen from the air breathed into the lungs, and thus the person who lives in high altitudes makes better use of the slender oxygen content of the air.

      Other examples of adaptation can be given; for example, liver cells, when exposed to drugs (or other chemicals), increase their level of drug-metabolizing enzymes.

      Thus, adaptation is a mechanism by which the body preserves and maintains its health by adjusting to alterations in the conditions under which it functions.

Defense against biotic invasion
      Human beings are surrounded by a microscopic menagerie of organisms, most of which pose no threat and some of which are beneficial. Organisms capable of producing disease are pathogens. The maintenance of health requires defense against biotic invasion. There are four levels of defense in the body: (1) the intact skin and linings of the various orifices of the body (such as the mouth, nose, throat), (2) a widely dispersed system of cells capable of destroying invaders, (3) the capability of mounting an inflammatory reaction that destroys offenders, and (4) the capability of developing an immune response that helps to bring about further neutralization and destroy any attackers.

Maintenance of the integrity of skin and mucosal linings
      With rare exception, pathogenic organisms cannot penetrate the intact covering and linings of the body. Indeed, if one were to take samples of the bacteria found on the skin, one would find large numbers of potentially harmful organisms that represent no threat unless the skin is punctured or the linings of the body are in some way injured. There are exceptions to this generalization, and a few biotic agents probably can penetrate intact mucosal (mucous membrane) surfaces. The bacterium Salmonella typhi that causes typhoid fever is thought to penetrate the normal lining of the gastrointestinal tract. Nevertheless, the intact skin and mucosal linings are primary protective barriers in the maintenance of health. The skin serves as a barrier to the external world, and the mucus-secreting and ciliated membranes of the upper respiratory tract trap inhaled foreign material and bacteria, transporting them to the pharynx where they are either swallowed or expelled by coughing. Potentially harmful bacteria can be introduced into a cut, which thus provides a portal of entry for organisms that may then cause an infection. By adequate washing, at least sufficient numbers of bacteria are flushed out to prevent the infection. Irritation of the skin from any cause or irritation of the throat by habitual smoking of tobacco impairs the integrity of these barriers and predisposes the area to invasion by potentially harmful organisms. The body has ingeniously contrived to place further roadblocks in the way of invaders. The saliva and the secretions in the stomach, for example, contain enzymes and acids that also destroy most organisms. Thus, humans have an effective enclosing barrier that provides protection against biotic attack.

Phagocytic cells of the body
       phagocytosis is the process by which certain cells ingest particulate material. When a phagocytic cell comes in contact with some particle such as a bacterium or even inert material such as dust, the cytoplasm of the cell (the cell substance outside its nucleus) flows around the object and forms a phagocytic vesicle. The phagocytic vesicle containing the particle then fuses with a lysosome (a membrane-enclosed sac that contains digestive enzymes). If the chemical composition of the foreign substance permits its degradation by the enzymes, it is destroyed. If the ingested material is resistant to digestion, it is retained within the phagocyte and is thus effectively removed from further interaction with the host. Phagocytic cells abound in the body; they serve as a second line of defense against most biotic invasion.

      There are two groups of phagocytic cells, white blood cells—polymorphonuclear leukocytes (leukocyte)—and tissue cells. The white blood cells are able to migrate through blood-vessel walls in areas of inflammation or infection, where they may phagocytize foreign material such as bacteria. Moreover, in inflammatory and infectious states, the total number of white cells in the body increases ( leukocytosis). Thus the population of phagocytic cells is expanded when the cells are needed in the body's defense.

      The second group of phagocytes consists of cells that are usually firmly fixed within tissues and are known as the reticuloendothelial system. The cells in this system are designated by a variety of names depending on their location (e.g., Kupffer cells in the liver, macrophages or histiocytes in loose connective tissue). They are particularly abundant in the spleen, liver, lymph nodes, and bone marrow but are also scattered throughout the blood vessels and virtually all the other tissues of the body. If, for example, bacteria do find a portal of entry but the bacterial invasion is not too massive and the organisms are not too virulent, these phagocytic cells are capable of engulfing and destroying them before they can cause injury.

The inflammatory response
      Whenever cells are damaged or destroyed, a series of vascular and cellular events known as the inflammatory (inflammation) response is set in motion. This response is protective of health in that it destroys or walls off injurious influences and paves the way for the restoration of normality. The sequence of events is as follows: in an area of injury (as in a bacterial infection), cells release substances that cause the small blood vessels in the affected area to become dilated (vasodilation) and thus increase the blood flow to the injured area; at the same time, clear fluid leaks out of the vessels into the area; this fluid tends to dilute any harmful substances in the area of injury; next, white cells from the blood flow out of the blood vessels into the damaged area and phagocytize the bacteria and dead cells; the resulting mixture of dead cellular debris and white blood cells is known as pus.

      The major signs of inflammation are redness and increased heat (caused by blood-vessel dilation), swelling (resulting from the accumulation of fluid), and pain. The last of these is one of the cardinal signs of all inflammatory responses. Pain in inflammation is caused by substances released by damaged tissues that render local nerve endings more sensitive to stimulation. Inflammation can be classified as either acute or chronic. Acute inflammation, such as may be seen around a skin cut, lasts for only a few days and is characterized microscopically by the presence of polymorphonuclear leukocytes. Chronic inflammation is of longer duration and is characterized microscopically by the presence of lymphocytes, monocytes, and plasma cells and, in general, is associated with little fluid exudation.

      Because of the pain and swelling, the inflammatory response is often viewed as an unwelcome event following injury. Yet it is important to recognize that it is the first step in the healing process and represents an important protective response in the maintenance of health.

The immune response
      The immune reaction is one of the most important defense mechanisms against biotic invasion and is therefore vital to the preservation of health. The devastating effects of acquired immune deficiency syndrome (AIDS) and other conditions that suppress or destroy the immune system are cases in point (see below The causes of disease: Diseases of immune origin (human disease)).

      The immune response is a relatively recent evolutionary development found only in vertebrates (vertebrate). This complex system has multiple components, which include antigens (antigen), antibodies (antibody), complement, and various types of white blood cells such as B and T lymphocytes (lymphocyte). The interaction of these components collectively results in a reaction that serves to protect the host from the potentially adverse effects of infectious organisms. Antigens are proteins, polysaccharides (complex carbohydrates), or foreign substances that trigger an immune response; they include molecules that are important constituents of bacteria, viruses, and fungi and substances that mark the surfaces of foreign materials such as pollen or transplanted tissue. Antibodies, or immunoglobulins, are proteins raised against specific antigens; they are formed in the lymph nodes and bone marrow by mature B lymphocytes called plasma cells and are released into circulation to bind and neutralize antigens located throughout the body. This type of response, called humoral immunity, is active mainly against toxins and free pathogens (those not ingested by phagocytes) in body fluids. A second type of response, called cell-mediated immunity, does not yield antibodies but instead generates T lymphocytes that are reactive against specific antigens. This defense is exhibited against bacteria and viruses that have been taken up by the host's cell as well as against fungi, transplanted tissue, and cancer cells. In each case the immune response prevents the invaders from causing further damage to the host. The complement system is a group of proteins found in the blood that facilitates the immune response by both attracting phagocytes to the area of invasion and forming a complex that results in lysis of the foreign cell.

      Two remarkable qualities of the immune system are specificity and memory. When an antigen enters the body, it elicits production of either a specific antibody or specific immunologically competent cells; that is, the antibody or the cells will neutralize only the antigen that evokes them. Furthermore, the system exhibits what appears to be memory: once challenged by an antigen, such as the measles virus, the body “remembers” it for years and perhaps for life. The child who has an attack of measles becomes immune for life. If the child is exposed to this specific antigen at a later date, the immune system recognizes it and responds and thereby prevents a reinfection. Indeed, these two characteristics of the immune system, specificity and memory, serve as the basis for preventive immunization. inoculation of infants or children with inactivated or attenuated biotic agents will cause the immune system to be made alert to such an antigen should it appear at a later date. Poliomyelitis, for example, once dreaded as a cause of paralysis and death, has been effectively controlled if not abolished with the polio vaccine.

      What has been said will aid in understanding why certain illnesses (such as measles) seem to affect only children (childhood disease and disorder). While these viral diseases can affect persons of any age, most adults have had previous exposure to the antigens (viruses) and are thus immune. Children with no previous exposure have no specific immunity to these invaders and consequently develop the diseases.

      Thus, the immune system is a vital part of the defense against biotic invasion. However, if it malfunctions, the immune system may also cause disease.

Repair and regeneration
      By replacing damaged or destroyed cells with healthy new cells, the processes of repair and regeneration work to restore an individual's health after injury. Unlike the salamander, which is capable of regenerating a limb if it is lost, human beings cannot regenerate whole organs or limbs. If one kidney is destroyed by disease, it is permanently lost. However, the remaining contralateral kidney, if normal, is capable of limited regeneration to compensate for the decrease in kidney mass. The many cell types of the body have varying capacities for regeneration.

      Regeneration is the production of new cells exactly like those destroyed. Of the three categories of human cells—(1) the labile cells, which multiply throughout life, (2) the stable cells, which do not multiply continuously but can do so when necessary, and (3) the permanent cells, incapable of multiplication in the adult—only the permanent cells are incapable of regeneration. These are the brain cells and the cells of the skeletal and heart muscles.

      Labile cells are those of the bone marrow, the lymphoid tissues, the skin, and the linings of most ducts and hollow organs of the body.

      Stable cells are found in the liver, in many of the glands of the body, such as the pancreas and salivary glands, in the lining of the kidney tubules, and in the connective tissues. Normally these cells do not divide unless some are destroyed by disease or injury and must be replaced.

      If only a small area of the liver (made up of stable cells) is damaged or destroyed, unaffected cells around the area of injury can replace those that were lost. When large areas of the liver are destroyed, however, cellular regeneration cannot occur, and the area of cell loss is replaced by new healthy connective-tissue cells, which produce scars. If a heart attack occurs, a certain number of heart muscle cells (permanent cells) are killed because of loss of blood supply. Because heart muscle cells cannot regenerate, the area of injury is replaced by a scar (if the patient survives). Such repair is by no means perfect, but it nonetheless permits restoration of reasonable heart function with perhaps only a slightly reduced level of health, depending on the number of heart muscle cells that have been lost.

      Cellular regeneration in humans is limited by many other factors, such as the availability of blood supply and a supporting connective tissue. When the blood vessels and supporting cells (connective tissue) are destroyed in the liver along with the liver cells, perfect reconstitution of the liver is not possible. There may be some regrowth of liver cells, but they do not form the normal liver architecture, and the newly regenerated cells cannot function because they do not have an appropriate orientation to the blood vessels and bile ducts.

      A review of the events that occur after a simple cut in the skin provides a good example of the processes of regeneration. At first, the area becomes red, swollen, and painful because of the inflammatory reaction. A scab forms. Beneath the scab, while the inflammatory process is going on, the cells from the adjacent healthy skin begin to regenerate by dividing and growing over the damaged area. If the damage is minor, perfect reconstruction of the skin and its appendages is likely to result. If the damage has extended below the skin surface, deeper connective-tissue cells, notably the fibroblasts (fibroblast), proliferate and fill the area. These cells lay down collagen (connective-tissue protein) composed of tough, durable fibrils (minute fibres), and, eventually, scar formation ensues. Once scarring has occurred, it cannot be reversed, although considerable shrinking of the scar may occur. If scar formation is limited, total function will return. On the other hand, if scar tissue formation is excessive, it often leads to a loss of function of the part.

Hemostasis
      Another mechanism of defense is hemostasis, the prevention of loss of blood from damaged blood vessels by formation of a clot. (This process is covered more at length in the article blood: Bleeding and blood clotting (bleeding and blood clotting).) Simply stated, a break in a blood vessel leads to activation of a complex sequence of events that results in the formation of a solid plug of platelets, red blood cells, and fibrin (a fibrous protein formed from fibrinogen). This plug, or clot, seals the damaged vessel and prevents further loss of blood (coagulation) (hemorrhage). The numerous components of the blood called clotting factors contribute in sequential fashion to the formation of the clot. (The clotting factors are commonly referred to by a roman numeral rather than by name. Fibrinogen, for example, is clotting factor I.) A defect in one of these factors can undermine hemostasis; for example, the absence of clotting factor VIII leads to hemophilia A, a disorder of uncontrolled bleeding.

Interrelationship of defensive mechanisms
 The homeostatic and defensive mechanisms involved in maintaining a constant internal environment are complex and yet wonderfully coordinated. Thus, the normal state of health is not a static condition but exists rather within a narrow range maintained by the coordinated responses of many systems and mechanisms. Health requires the proper function of all these controls. Disease may begin in a single organ or system, but the interdependence and close coordination of the many bodily functions, which cooperate so beautifully in health, may be upset by a chain reaction when one breaks down. A disease of the kidney leading to abnormal retention of sodium, for example, can cause hypertension (high blood pressure). Prolonged hypertension in turn can induce heart failure, and this can result in the abnormal collection of fluid in the lungs. The impairment of respiratory function may then result in a sudden rise in the level of carbon dioxide in the blood, which brings with it further complications. Similarly, if the normal inflammatory response malfunctions, a trivial skin infection (popularly known as a pimple) can enlarge into a boil (a furuncle). The responsible bacterial agents may proliferate in the local site and penetrate small blood vessels to seed the bloodstream, thus causing a generalized infection (septicemia or bacteremia). Such a widespread infection is extremely serious and may cause secondary infections of the heart (endocarditis) or of the coverings of the brain (meningitis) and end in death of the host.

      Thus, health implies the proper functioning of the homeostatic mechanisms that have just been described, including those systems involved in the defense of health. The state of disease basically represents a failure of these mechanisms. Although one tends to think of disease in terms of offending agents, these agents are able to produce disease only by their ability to disrupt normal homeostasis, and it is precisely those disruptions that are the manifestations of disease.

Disease: signs and symptoms
      Disease may be acute, chronic, malignant, or benign. Of these terms, chronic and acute have to do with the duration of a disease, malignant and benign with its potentiality for causing death.

      An acute disease process usually begins abruptly and is over soon. Acute appendicitis, for example, is characterized by the sudden onset of nausea, vomiting, and pain usually localized in the lower right side of the abdomen. It usually requires immediate surgical treatment. The term chronic refers to a process that often begins very gradually and then persists over a long period. For example, ulcerative colitis—an inflammatory condition of unknown cause that is limited to the colon—is a chronic disease. Its peak incidence is early in the second decade of life. The disease is characterized by relapsing attacks of bloody diarrhea that persist for weeks to months. These attacks alternate with asymptomatic periods that can last from weeks to years.

      The terms benign and malignant, most often used to describe tumours, can be used in a more general sense. Benign diseases are generally without complications, and a good prognosis (outcome) is usual. A wart on the skin is a benign tumour caused by a virus; it produces no illness and usually disappears spontaneously if given enough time (often many years). Malignancy implies a process that, if left alone, will result in fatal illness. cancer is the general term for all malignant tumours.

      Diseases usually are indicated by signs and symptoms. A sign is defined as an objective manifestation of disease that can be determined by a physician; a symptom is subjective evidence of disease reported by the patient. Each disease entity has a constellation of signs and symptoms more or less uniquely its own; individual signs such as fever, however, may be found in a great number of diseases. Some of the common manifestations of disease—as they relate to an imbalance of normal homeostasis—are taken up in this section. They are covered more at length in the article diagnosis.

      Fever is an abnormal rise in body temperature. It is most often a sign of infection but can be present whenever there is tissue destruction, as, for example, from a severe burn or when large amounts of tissue have died because of lack of blood supply. Body temperature is controlled by the thermostatic centre in the hypothalamus. Certain protein and polysaccharide substances called pyrogens, released either from bacteria or viruses or from destroyed cells of the body, are capable of raising the thermostat and causing a rise in body temperature. Fever is a highly significant indicator of disease.

      An increase in the number of circulating phagocytic white blood cells (leukocyte) (leukocytosis), mentioned above (see Maintenance of health: Defense against biotic invasion: Phagocytic cells of the body (human disease)), is one of the more common manifestations of disease. The stimulus for such an event may be any inflammatory process in the body, such as is caused by bacteria, viruses, or any process that leads to the destruction of cells. Such leukocytosis is reflected in the white blood cell count, which may be substantially elevated above the normal upper value of 10,000 cells per cubic millimetre of blood.

      The pulse rate is another easily obtainable and important piece of information. The heart rate varies with the level of physical activity: the heart beats faster during exercise and more slowly during rest. An inappropriate heart rate (or pulse) may be indicative of disease. The heart rate increases in the feverish patient. A weak, rapid pulse rate may be a sign of severe blood loss or of disease within the heart itself. Irregularity of the pulse ( arrhythmia) is an important indicator of heart malfunction.

      The respiratory rate (rate of breathing) is modified by disease. Persons with fever have an increased respiratory rate ( hyperventilation), which serves to lower body temperature (this rapid breathing is analogous to the panting of a dog). Hyperventilation is a common response to painful stress. Any condition leading to acidosis (lowering of body pH) similarly drives the respiratory rate upward. Diseases of the lungs—with the accompanying inability to oxygenate the blood adequately—have a similar effect.

      Temperature, pulse, and respiratory rate—called the vital signs—may be important manifestations of disease. A fourth vital sign, blood pressure, is equally significant. Among other things, it indicates the amount of blood in circulation. A decrease in circulating blood volume, as is seen with severe bleeding, lowers the blood pressure and deprives the tissues of adequate blood flow. Reflexes are initiated that compensate for the reduced blood volume and blood pressure. The heart rate increases and compensates to some extent for the sudden reduction in blood volume and pressure; at the same time, peripheral blood vessels in such areas as the abdomen constrict, tending to divert the reduced blood volume to the more vital areas such as the brain and head. Unusual elevation of pressure (hypertension) is a disease by itself.

      Fluid and electrolyte imbalances may be further consequences of homeostatic failure and additional significant manifestations of disease. The causes of these abnormalities are complex. edema, or swelling, results from shifts in fluid distribution within body tissues. Edema may be localized, as when the leg veins are narrowed or obstructed by some disease process. The pressure of the blood in the distended veins rises, and fluid is driven out of the vessels into the tissues, causing swelling of the extremity. Generalized edema is seen in renal (kidney) disease that causes abnormal retention of sodium and water. Heart failure is an additional cause of generalized edema, usually most manifest as swollen feet and ankles. Alterations such as dehydration, hyperventilation, and tissue destruction can all lead to varying fluid and electrolyte derangements. The levels of the serum electrolytes (sodium, potassium, bicarbonate, chloride), determined relatively easily in the laboratory, provide the physician with valuable clues to deranged homeostasis induced by disease.

      Finally, the determination of body pH and a number of blood tests (blood analysis) designed to evaluate adequate (or inadequate) metabolic regulation provide diagnostic clues of homeostatic failure. These tests include determination of the levels of the blood glucose, blood urea nitrogen, and serum protein.

      The disease diabetes mellitus provides an excellent example of failure of the homeostatic mechanisms. Diabetes is a common disease of metabolic-endocrine (ductless gland) origin involving a relative or absolute deficiency of insulin, a hormone that plays a major role in carbohydrate metabolism. Any or all of the homeostatic derangements can be found in this disease. Patients with a severe form of diabetes may at one time be dehydrated because of obligatory excretion of water (osmotic diuresis), be acidotic because of formation of increased amounts of keto acids derived from the oxidation of free fatty acids, be hyperventilating as a result of the acidosis, be comatose because of high levels of blood glucose, have a weak pulse because of severe dehydration, have electrolyte abnormalities, and so on. The signs and symptoms are numerous, all illustrating the interdependence of the homeostatic mechanisms, which, when not functioning properly, provide the manifestations of disease.

      At the most elemental level, disease develops when any disruptive or adverse influence overcomes the homeostatic and defensive controls of the body. As will be seen, there are numerous influences that can tip the scales of health toward disease. Viruses and bacteria are obvious threats to health. There are a great many others, some so subtle as to be poorly understood. The following section focuses on the causes of disease rather than on a detailed description of each entity. It represents one method of classification. There is considerable overlap in categories; certain diseases grouped as metabolic-endocrine in origin could also be classified as diseases of genetic origin. Indeed, the interdependence of the organ systems, the metabolic pathways, and the defense systems renders finite classification in medicine difficult. The human body acts as a unit—an individual—both in health and in disease.

The causes of disease
      The search for the causes (etiologies) of human diseases goes back to antiquity. Hippocrates, a Greek physician of the 4th and 5th centuries BC, is credited with being the first to adopt the concept that disease is not a visitation of the gods but rather is caused by earthly influences. Scientists have since continually searched for the causes of disease and, indeed, have discovered the causes of many.

      In the development of a disease (pathogenesis) more is involved than merely exposure to a causative agent. A room full of people may be exposed to a sufferer from a common cold, but only one or two may later develop a cold. Many host factors determine whether the agent will induce disease or not. Thus, in the pathogenesis of disease, the resistance, immunity, age, and nutritional state of the person exposed, as well as virulence or toxicity of the agent and the level of exposure, all play a role in determining whether disease develops.

      In the following sections the many types of human disease will be divided into categories, and in each only a few examples will be given to establish the nature of the process. These categories are divided on the basis of the presumed etiology of the disease. Many diseases are still of unknown (idiopathic) origin. With others the cause may be suspected but not yet definitively proved. In a few instances the discovery of the etiology of a disease represents the individual achievement of a solitary investigator who may have worked many years on the problem; the story of Louis Pasteur (Pasteur, Louis) and the discovery of the cause of anthrax is a classic example. More often the individual investigator who makes the final breakthrough stands on the shoulders of hundreds of earlier workers who provided bits and pieces of knowledge vital to the final understanding.

Diseases of genetic (genetic disease, human) origin
      Certain human diseases result from mutations in the genetic complement (genome) contained in the deoxyribonucleic acid ( DNA) of chromosomes. A gene is a discrete linear sequence of nucleotide bases (molecular units) of the DNA that codes for, or directs, the synthesis of a protein, and there may be as many as 100,000 genes in the human genome. Proteins, many of which are enzymes (enzyme), carry out all cellular functions. Any alteration of the DNA may result in the defective synthesis and subsequent malfunctioning of one or more proteins. If the mutated protein is a key enzyme in normal metabolism, the error may have serious or fatal consequences. More than 5,000 distinct diseases have been ascribed to mutations (mutation) that result in deficiencies of critical enzymes.

      Mutations are classified on the basis of the extent of the alteration. Large mutations, which include alterations to chromosome structure and number, are relatively rare because most cause such major disruptions to development that the fetus is naturally aborted. However, certain alterations are not so immediately lethal, and the fetus can survive with a characteristic disorder. Down syndrome is one such case. It involves an error in the division of chromosome 21 that results in trisomy (three copies of a chromosome instead of two are inherited), bringing the total number of chromosomes to 47 instead of 46. Many characteristics such as distinctive facial features and mental retardation result from the presence of this extra chromosome. Smaller mutations are more common and include point mutations, in which substitution of a single nucleotide base occurs, and deletion or insertion mutations, which involve several bases. Point, deletion, and insertion mutations may cause an abnormal protein to be synthesized or may prevent the protein from being made at all.

      Mutations that occur in the DNA of somatic (body) cells cannot be inherited, but they can cause congenital malformations and cancers (see below Abnormal growth of cells (human disease)); however, mutations that occur in germ cells—i.e., the gametes (gamete), ova and sperm—are transmitted to offspring and are responsible for inherited diseases. Each gamete contributes one set of chromosomes and therefore one copy (allele) of each gene to the resultant offspring. If a gene bearing a mutation is passed on, it may cause a genetic disorder.

      Genetic diseases caused by a mutation in one gene are inherited in either dominant (dominance) or recessive fashion. In dominantly inherited conditions, only one mutant allele, which codes for a defective protein or does not produce a protein at all, is necessary for the disorder to occur. In recessively (recessiveness) inherited disorders, two copies of a mutant gene are necessary for the disorder to manifest; if only one copy is inherited, the offspring is not affected, but the trait may continue to be passed on to future offspring. In addition to dominant or recessive transmission, genetic disorders may be inherited in an autosomal or X-linked manner. Autosomal genes are those not located on the sex chromosomes, X and Y; X-linked genes are those located on the X chromosomes that have no complementary genes on the Y chromosome. Females have two copies of the X chromosome, but males have an X and a Y chromosome. Because males have only one copy of the X chromosome, any mutation occurring in a gene on this chromosome will be expressed in male offspring regardless of whether its behaviour is recessive or dominant in females. Autosomal dominant disorders include Huntington's chorea (Huntington disease), a degenerative disease of the nervous system that usually does not develop until the carrier is between 30 and 40 years of age. The delayed onset of Huntington's chorea allows this lethal gene to be passed on to offspring. Autosomal recessive diseases are more common and include cystic fibrosis, Tay-Sachs disease, and sickle cell anemia. X-linked dominant disorders are rare, but X-linked recessive diseases are relatively common and include Duchenne's muscular dystrophy and hemophilia A.

      Most genetic disorders can be detected at birth because the child is born with characteristic defects. Thus these abnormalities are congenital (congenital disorder) (existing at birth) genetic disorders. A few genetic defects, such as Huntington's chorea mentioned above, do not become manifest until later in life. Hence it may be said that most but not all genetic diseases are congenital.

      Conversely, some congenital diseases are not genetic in origin; instead they may arise from some direct injury to the developing fetus. If a woman contracts the viral disease German measles ( rubella) during pregnancy, the virus may infect the fetus and alter its normal development, leading to some malformations, principally of the heart. These malformations constitute a congenital disease that is not genetic.

      Further confusion often arises over the terms genetic and familial. A familial disease is hereditary, passed on from one generation to the next. It resides in a genetic mutation that is transmitted by mother or father (or both) through the gametes to their offspring. Not all genetic disorders are familial, however, because the mutation may arise for the first time during the formation of the gametes or during the early development of the fetus. Such an infant will have some genetic abnormality, though the parents themselves do not. Down syndrome is an example of a genetic disease that is not familial.

Factors relating to genetic injury
      The causes of mutations are still poorly understood. Certain factors, however, are thought to be important. Maternal age plays an important role in predisposing toward genetic injury. The frequency of Down syndrome and of congenital malformations increases with the age of the mother. This may be so for a variety of reasons. Unlike men, who produce new sperm continually, women are born with all the eggs (ova (ovum)) they will ever have. Thus the eggs are exposed to the same internal and external agents that the woman comes in contact with. The longer the exposure to such factors (i.e., the older the mother), the greater the chance of genetic injury to the ova. A paternal contribution to the disease also has been discovered—roughly 25 percent of cases may be caused by extra chromosomal material from the father. At present, the nature of the factors responsible for impaired division of chromosomes remains unknown.

       radiation is a well-recognized cause of chromosomal damage. The survivors of the atomic bomb blasts in Japan in 1945 have shown definite chromosomal abnormalities in certain types of their circulating white blood cells. Indeed, a higher incidence of leukemia (a form of cancer of white cells), as well as other cancers, has been reported in this population, suggesting that the chromosomal changes may have played some role in the induction of the disease (see also radiation: Biologic effects of ionizing radiation (radiation)).

      Viruses (virus) have been shown to cause mutations in human cells when the cells are grown in tissue culture, but there is no clear evidence that viral infections can cause genetic injury in humans. Instead, current evidence suggests that the oncogenic viruses implicated in some human cancers facilitate genetic mutations rather than cause them directly.

      The induction of DNA mutations in cells by drugs and chemicals is complex. It involves metabolism of the drug by detoxification enzymes into reactive intermediates that damage DNA. The mutations that remain are those not removed by DNA repair enzymes. In contrast to viruses, drugs and chemicals have been shown to cause mutations not only in human cells in culture but also in a living host.

      Diseases can be spread across a wide spectrum, with predominantly genetic diseases at one extreme of the spectrum and diseases of largely environmental origin at the other. In the genetic part of the spectrum are diseases such as Turner's syndrome; in the environmental part are infectious diseases and chemical poisoning. Between these two extremes lie most human diseases—those with both genetic and environmental causative influences that are significant. Indeed, even at the very extreme ends of the spectrum both factors play some role. The genetic constitution dictates in part the host's response to environmental challenges. Similarly, environmental factors play significant roles in the manifestation of genetically induced disease. sickle cell anemia, for example, an inherited disease characterized by abnormal red blood cells and hemoglobin, is seriously exacerbated by low levels of oxygen in the air.

      Furthermore, there are many disorders in which there is a familial tendency to develop the disease but no formal pattern of inheritance has been delineated. Many forms of cancer, high blood pressure, arthritis, and obesity, for example, seem to have a familial tendency. Although the exact roles of environmental and genetic factors are unknown in all these diseases, it is strongly felt that both factors contribute to the disease process.

Chemical and physical injury
Chemical injury: poisoning (poison)
      A poison is any substance that can cause illness or death when ingested in small quantities. This definition excludes the multitude of substances that cause damage if ingested in large quantities. For example, even oxygen and glucose, so crucial to life, are toxic to cells when administered at high concentrations.

      There are several considerations to keep in mind when one discusses poisoning. The first of these, as already suggested, is the degree of toxicity. A substance with a very high toxicity (such as cyanide) need be taken only in minute amounts to cause serious harm or death.

      A second consideration is the mechanism by which a poison operates. Each poison acts at particular sites in the cell that are critical for the maintenance of homeostasis. These sites include the genome, whose expression dictates cell structure and function, and the cell membrane, which regulates ion transport, energy metabolism, and synthesis of vital proteins. Each poison also has a characteristic ability to cause damage at particular sites within the body, such as the liver, kidneys, or central nervous system.

      A third factor is the body's ability to eliminate (excretion) the substance. Some chemicals, rapidly excreted in the urine, must act quickly while they remain transiently in the body. Others are poorly eliminated, and, because of this, a chronic ingestion of nontoxic amounts leads to a buildup in the body that can reach toxic levels. Lead poisoning is a good example of this phenomenon.

      The route of entry is also important. Many substances are harmless when eaten but become deadly if injected into a vein. There are chemicals and drugs that are highly reactive and interact directly with an important cellular component to cause cell injury or death. Other chemicals or drugs that are not toxic per se become so following their metabolic conversion to toxic intermediates by the host. Similarly, the chemical form of a substance affects its action on the body. Metallic mercury, as found in thermometers, is harmlessly excreted, whereas the chloride salt of the same substance is deadly.

      Finally, the condition of the host, the recipient of the poison, is an important consideration. A dose of aspirin (acetylsalicylic acid) that is harmless to an adult may be poisonous to an infant. Similarly, an elderly person's tolerance of a substance may be much lower than that of a healthy young adult.

      A wide variety of poisons exist, among which a few stand out as being the most commonly encountered in medical practice. Some are of relatively low toxicity but are important because of their widespread use. Many physicians consider aspirin the most dangerous poison because of its commonplace use and abuse and because it is the leading cause of poisoning in children. In the following paragraphs three groups of agents will be presented: (1) organic chemicals, (2) inorganic chemicals, and (3) drugs.

Organic chemicals
      Among the organic chemicals commonly encountered in instances of poisoning are two forms of alcohol, ethyl alcohol (ethanol) and methyl alcohol ( methanol). Ethyl alcohol is the form found in most alcoholic beverages. Methyl alcohol, or wood alcohol, is used for a variety of household purposes.

      Acute ethyl alcohol poisoning is encountered after ingestion of large quantities over a relatively short time. The alcohol is quickly absorbed from the gastrointestinal tract, and high blood levels can be achieved in a remarkably short time. Ethyl alcohol acts principally as a central-nervous-system depressant and, fortunately, stupor usually results before fatal doses can be reached. The difference in blood levels between intoxication and fatal stupor is very slight, however, and death may result with the ingestion of large quantities of alcohol from depression of the respiratory centre in the brain.

      Methyl alcohol is usually ingested either by accident or with suicidal intent. Once inside the body it is metabolized to formic acid, an extremely toxic substance that selects the nerves in the eye as its target. Without treatment, blindness results. Methyl alcohol also can affect the brain tissue itself.

       carbon monoxide is a nonirritating, inert gas without colour, taste, or odour. A poison responsible for a large number of accidental and suicidal deaths, it is one of the chemical products of any combustion of organic material. Inhalation of a 1 percent concentration can be fatal within 10 to 20 minutes. Carbon monoxide acts as an internal asphyxiant (asphyxia) causing oxygen starvation of tissues. It should be noted that exposure to even low concentrations can result in the slow accumulation of this poison over hours, days, or weeks, leading very gradually to toxic or fatal levels.

      The inorganic chemicals most commonly responsible for poisonings in the United States are cyanide (cyanide poisoning), mercury, arsenic, and lead. While the last three often appear in chemical forms that are quite harmless, it is the soluble salts of the substances that are poisons.

      Cyanide is a dangerous substance in any form. It may occur in the form of hydrocyanic gas or as solid compounds such as potassium cyanide. It is one of the most lethal poisons known; an amount of 0.2 gram (0.007 ounce) administered to a 70-kilogram (154-pound) human causes death within minutes. Like carbon monoxide, it acts as a cellular asphyxiant.

      Mercury in the pure metallic form is rather harmless, but the salt of the same substance, notably mercuric chloride, is a deadly poison. As little as 0.1 gram is enough to cause damage to body tissues, and 2 grams can cause death in a 70-kilogram person. This agent causes extensive tissue damage wherever high concentrations of the poison are encountered. When the substance is swallowed, the stomach represents the portal of entry. The mercuric chloride is partially absorbed into the blood, and this portion is excreted through the urine. The remainder affects organs in the digestive tract, principally the stomach and the colon, and the kidneys. Mercuric salts cause death of cells by precipitating the proteins within the cells, a form of cell injury called coagulative necrosis. With careful treatment, affected persons survive with full recovery. Chronic ingestion of smaller amounts of mercuric salts, as is seen in some industrial settings, can result in disease involving the mouth, skin, and nervous system.

      Arsenic (arsenic poisoning) is contained in many items used around the house. Both odourless and tasteless compounds of arsenic are found in some rat poisons, plant sprays, paints, and other household preparations. Many of these household staples are ingested accidentally by children. Principally affected by arsenic are the blood vessels and the central nervous system; vascular collapse and depression of the central nervous system can be followed by coma and death within hours after ingestion.

      The soluble salts of inorganic lead are also strong systemic poisons. They may accumulate within the body over a long period until toxic levels are reached and cell damage ensues. These salts were at one time commonly found in paints, and lead poisoning was frequently seen in children who chewed on their painted cribs or woodwork. Legislation in many countries has outlawed the use of lead-base paints for infants' furniture. Other forms of poisoning are incurred through industrial exposure and ingestion of water from lead pipes. Lead poisoning damages red blood cells and leads to hemolysis (rupturing of red blood cells) with resulting anemia. In the brain, lead accumulation causes the degeneration of nerve cells. This produces such manifestations as mental depression, psychoses, convulsions, and even coma and death. If an early fatality does not occur, the lead is slowly excreted and complete recovery may be anticipated.

      Drugs are another important cause of poisoning. It is a pharmacological principle that, for any therapeutic gain derived from a drug, a price is paid. There are few drugs used today that have no side effects (i.e., effects unintended when the drug is administered). Although these side effects may be harmless and inconsequential, certain drugs have side effects that are potent. Similarly, a drug may be useful in a certain dose range but harmful when larger doses are taken. morphine, for example, is an excellent drug for the control of severe pain, but it can depress respiration, and too much of it can cause death. All drugs are, therefore, potentially harmful.

      Barbiturates (barbiturate) and salicylates are the major drugs commonly found to cause serious illness from overingestion. Barbiturates affect the central nervous system almost exclusively. With toxic levels, the vital centres located within the midbrain are depressed; this leads to profound coma, depression of respiration, oxygen starvation of the tissues, and even shock. The identification of barbiturate poisoning relies almost exclusively on finding the substance in the blood or urine, because there is little anatomic change in tissues. Treatment is directed toward getting the drug out of the system as quickly as possible, either by inducing copious urinary excretion of the drug or by the use of the artificial kidney—a process called hemodialysis.

       aspirin, or acetylsalicylic acid, is a drug that deserves special mention because it is such a common household item and often within the reach of small children. Approximately 10 to 30 grams of aspirin can be fatal in adults, and much smaller amounts can be fatal in children. (A single aspirin tablet of standard size contains approximately one-third gram.) There are many signs and symptoms associated with salicylate poisoning, including headaches, drowsiness, dyspepsia, nausea, vomiting, sweating, and thirst. Salicylate poisoning is an acute medical emergency. Rigorous medical treatment is demanded, and use of the artificial kidney is often required.

Physical injury (wound)
      Physical injuries include those caused by mechanical trauma, heat and cold, electrical discharges, changes in pressure, and radiation. Mechanical trauma is an injury to any portion of the body from a blow, crush, cut, or penetrating wound. The complications of mechanical trauma are usually related to fracture, hemorrhage, and infection. They do not necessarily have to appear immediately after occurrence of the injury. Slow internal bleeding may remain masked for days and lead to an eventual emergency. Similarly, wound infection and even systemic infection are rarely detectable until many days after the damage. All significant mechanical injuries must therefore be kept under observation for days or even weeks.

Injuries from cold or heat
      Among physical injuries are injuries caused by cold or heat. Prolonged exposure of tissue to freezing temperatures causes tissue damage known as frostbite. Several factors predispose to frostbite, such as malnutrition leading to a loss of the fatty layer under the skin, lack of adequate clothing, and any type of insufficiency of the peripheral blood vessels, all of which increase the loss of body heat.

      When the entire body is exposed to low temperatures over a long period, the result can be alarming. At first blood is diverted from the skin to deeper areas of the body, resulting in anoxia (lack of oxygen) and damage to the skin and the tissues under the skin, including the walls of the small vessels. This damage to the small blood vessels leads to swelling of the tissues beneath the skin as fluid seeps out of the vessels. When the exposure is prolonged, it leads eventually to cooling of the blood itself. Once this has occurred, the results are catastrophic. All the vital organs become affected, and death usually ensues.

      Burns (burn) may be divided into three categories depending on severity. A first-degree burn is the least destructive and affects the most superficial layer of skin, the epidermis. sunburn is an example of a first-degree burn. The symptoms are pain and some swelling. A second-degree burn is a deeper and hence more severe injury. It is characterized by blistering and often considerable edema (swelling). A third-degree burn is extremely serious; the entire thickness of the skin is destroyed, along with deeper structures such as muscles. Because the nerve endings are destroyed in such burns, the wound is surprisingly painless in the areas of worst involvement.

      The outlook in burn injuries is dependent on the age of the victim and the percent of total body area affected. Loss of fluid and electrolytes and infection associated with loss of skin provide the major causes of burn mortality.

      The injurious effects of an electrical current (electric current) passing through the body are determined by its voltage, its amperage, and the resistance of the tissues in the pathway of the current. It must be emphasized that exposure to electricity can be harmful only if there is a contact point of entry and a discharge point through which the current leaves the body. If the body is well insulated against such passage, at the point of either entry or discharge, no current flows and no injury results. The voltage of current refers to its electromotive force, the amperage to its intensity. With high-voltage discharges, such as are encountered when an individual is struck by lightning, the major effect is to disrupt nervous impulses; death is usually caused by interruption of the regulatory impulses of the heart. In low-voltage currents, such as are more likely to be encountered in accidental exposure to house or industrial currents, death is more often due to the stimulation of nerve pathways that cause sustained contractions of muscles and may in this way block respiration. If the electrical shock does not produce immediate death, serious illness may result from the damage incurred by organs in the pathway of the electrical current passing through the body.

Pressure-change (pressure) injuries
      Physical injuries from pressure change are of two general types: (1) blast injury and (2) the effects of too-rapid changes in the atmospheric pressure in the environment. Blast injuries may be transmitted through air or water; their effect depends on the area of the body exposed to the blast. If it is an air blast, the entire body is subject to the strong wave of compression, which is followed immediately by a wave of lowered pressure. In effect the body is first violently squeezed and then suddenly overexpanded as the pressure waves move beyond the body. The chest or abdomen may suffer injuries from the compression, but it is the negative pressure following the wave that induces most of the damage, since overexpansion leads to rupture of the lungs and of other internal organs, particularly the intestines. If the blast injury is transmitted through water, the victim is usually floating, and only that part of the body underwater is exposed. An individual floating on the surface of the water may simply be popped out of the water like a cork and totally escape injury.

       decompression sickness is a disease caused by a too-rapid reduction in atmospheric pressure. Underwater divers (scuba diving), pilots of unpressurized aircraft, and persons who work underwater or below the surface of the Earth are subject to this disorder. As the atmospheric pressure lessens, dissolved gases in the tissues come out of solution. If this occurs slowly, the gases diffuse into the bloodstream and are eventually expelled from the body; if this occurs too quickly, bubbles will form in the tissues and blood. The oxygen in these bubbles is rapidly dissolved, but the nitrogen, which is a significant component of air, is less soluble and persists as bubbles of gas that block small blood vessels. Affected individuals suffer excruciating pain, principally in the muscles, which causes them to bend over in agony—hence the term “bends” used to describe this disorder.

      Radiation can result in both beneficial and dangerous biological effects. There are basically two forms of radiation: particulate, composed of very fast-moving particles (alpha and beta particles, neutrons, and deuterons), and electromagnetic radiation such as gamma rays and X rays. From a biological point of view, the most important attribute of radiant energy is its ability to cause ionization—to form positively or negatively charged particles in the body tissues that it encounters, thereby altering and, in some cases, damaging the chemical composition of the cells (cell). DNA is highly susceptible to ionizing radiation. Cells and tissues may therefore die because of damage to enzymes, because of the inability of the cell to survive with a defective complement of DNA, or because cells are unable to divide. The cell is most susceptible to irradiation during the process of division. The severity of radiation injury is dependent on the penetrability of the radiation (radiation therapy), the area of the body exposed to radiation, and the duration of exposure, variables that determine the total amount of radiant energy absorbed.

      When the radiation exposure is confined to a part of the body and is delivered in divided doses, a frequent practice in the treatment of cancer, its effect depends on the vulnerability of the cell types in the body to this form of energy. Some cells, such as those that divide actively, are particularly sensitive to radiation. In this category are the cells of the bone marrow, spleen, lymph nodes, sex glands, and lining of the stomach and intestines. In contrast, permanently nondividing cells of the body such as nerve and muscle cells are resistant to radiation. The goal of radiation therapy of tumours is to deliver a dosage to the tumours that is sufficient to destroy the cancer cells without too severely injuring the normal cells in the pathway of the radiation. Obviously, when an internal cancer is treated, the skin, underlying fat, muscles, and nearby organs are unavoidably exposed to the radiation. The possibility of delivering effective doses of radiation to the unwanted cancer depends on the ability of the normal cells to withstand the radiation. However, as is the case in drug therapy, radiation treatment is a two-edged sword with both positive and negative aspects.

      Finally, there are probable deleterious effects of radiation in producing congenital malformations, certain leukemias, and possibly some genetic disorders (see radiation: Biologic effects of ionizing radiation (radiation)).

Diseases of immune origin
      The immune system protects against infectious disease, but it may also at times cause disease. Disorders of the immune system fall into two broad categories: (1) those that arise when some aspect of the host's immune mechanism fails to prevent infection (immune deficiencies) and (2) those that occur when the immune response is directed at an inappropriate antigen, such as a noninfectious agent in an allergic reaction, the body's own antigens in an autoimmune response, or the cells of a transplanted organ in graft rejection.

Immune deficiencies
      The immune system may fail to function for many reasons. Many immunodeficiency disorders are caused by a genetic defect in some component of the system and thus usually manifest early in life. Some deficiencies, however, are acquired through the action of infectious agents such as viruses, through the action of immunosuppressive agents used to treat various medical conditions, and through the effects of certain disease processes such as cancer. Both inherited and acquired immune deficiencies suppress one or many aspects of the immune response, rendering the affected individual unable to resist infection unless treated by administration of immunoglobulins (antibody) or by bone marrow transplant.

      Inherited immune disorders undermine the immune response in a variety of ways: B lymphocytes may be unable to produce antibodies, phagocytes may be unable to digest microbes, or specific complement components may not be produced. Severe combined immunodeficiency (SCID), a condition that arises from several different genetic defects, disrupts the functioning of both the humoral and cell-mediated immune responses.

      Acquired immune deficiency syndrome ( AIDS) is caused by infection with the human immunodeficiency virus (HIV), which destroys a certain type of T lymphocyte, the helper T cell. An infected individual is susceptible to a variety of infectious organisms, including those called opportunistic pathogens, which may live benignly in the human body and cause disease only when the immune system is suppressed. Certain diseases such as Kaposi's sarcoma and Pneumocystis carinii pneumonia, which until recently were rarely encountered by clinicians, have become prevalent in the AIDS population and are often the cause of mortality.

Immune responses in the absence of infection

Allergies
      The immune system may react to any foreign substance, and consequently it can respond to innocuous materials in the same way that it responds to infectious agents. If the foreign material poses no threat to the individual, an immune response is unnecessary, but it nevertheless may ensue. This misplaced response is called an allergy, or hypersensitivity, and the foreign material is referred to as an allergen. Common allergens include pollen, dust, bee venom, and various foods such as shellfish. What causes one person and not another to develop an allergy is not completely understood.

      An allergic response occurs in the following manner. On first exposure to the allergen, the person becomes sensitized to it—that is, develops antibodies and specific T cells to the allergen. An allergic reaction does not usually accompany this initial event. When reexposure occurs, however, symptoms of the allergic response appear. These symptoms range from the mild response of sneezing and a runny nose to the sometimes life-threatening reaction of anaphylaxis, or anaphylactic shock, symptoms of which include vascular collapse and potentially fatal respiratory distress.

      Allergic reactions exhibit different symptoms depending on which immune mechanisms are responsible. On the basis of this criterion, they can be categorized into four types, the first three of which involve antibodies and occur in a matter of minutes or hours. Type I hypersensitivity (atopy), which occurs immediately after the sensitized person comes in contact again with the allergen, is responsible for most common allergies. The allergen reacts with antibodies attached to the surface of either of two types of cells: mast cells (mast cell), which are scattered throughout the supporting tissues of the body, and basophilic leukocytes (white blood cells that stain readily with basic dyes), which circulate in the blood. The cells release various substances such as histamine, which causes dilation of blood vessels and contraction of smooth muscles in the bronchial airways, characteristic symptoms of asthma and anaphylaxis. In type II, or cytotoxic, reactions, antibodies are not bound to cells, as in the type I reaction, but circulate freely and interact with cell-bound antigens in the same way that antibodies bind to cells containing infectious agents. Complement is usually activated, leading to cell destruction. A special class of type II hypersensitivity involves an immune response to certain “self” proteins (antigens that belong to the host) on the surface of cells, a mechanism that underlies autoimmune disorders such as autoimmune hemolytic anemia (see below Autoimmune disorders (human disease)). Type III, or immune-complex, reactions are directed against soluble antigens. Circulating antibodies combine with antigens, usually not bound to the cell surface, to form an immune complex, which is deposited in tissues or the walls of blood vessels. The complex attracts complement, to which polymorphonuclear leukocytes are drawn. These cells then release powerful enzymes that cause inflammation and vessel damage. Immune complexes also form in autoimmune disorders such as rheumatoid arthritis. Type IV hypersensitivity, unlike the other reactions, does not involve antibodies but instead is mediated by T cells. In these reactions, also called delayed-type because they arise in a matter of days rather than minutes or hours, T cells either activate a local inflammatory reaction, which can cause extensive tissue damage, or they kill tissue cells directly. Chronic inflammation characteristic of many autoimmune disorders, such as chronic thyroiditis, results from this reaction. With the exception of the type I response, all responses are seen in both allergies and autoimmune disorders.

Autoimmune disorders
      Immune responses can be mounted against proteins that belong to the host, giving rise to autoimmune diseases. Although the immune system naturally generates antibodies to its own cells, mechanisms exist to keep this activity in check. Two mechanisms that prevent the immune system from mounting an attack against the host's own tissues have been identified. The first involves the elimination of self-reactive lymphocytes (lymphocyte) during their development and maturation in the thymus, a lymphoid organ in the chest. Self-reactive lymphocytes present in these cell populations are destroyed when they encounter the self-antigen to which they react. Because this protective selection process is not highly efficient, some self-reactive lymphocytes survive, exit the thymus, and enter the blood and tissues. Outside the thymus a second line of defense against immune self-destruction is afforded in which self-reactive lymphocytes lose their ability to react to self-antigens when they are encountered in blood and tissues. This state is referred to as immunologic ignorance. Autoimmune diseases arise when this mechanism fails and self-reactive lymphocytes are activated by self-antigens in the host's own tissues, often with devastating effects. Systemic lupus erythematosus, thyroiditis, insulin-dependent diabetes mellitus, and rheumatoid arthritis are examples of this type of disorder.

Graft rejection
      Transplantation (transplant) of organs and cells from one individual to another has become an important medical treatment. As are other forms of therapy, it is accompanied by certain risks. Each individual's cells have a spectrum of genetically determined cell surface protein antigens, the major histocompatibility complex (MHC) antigens, or human leukocyte antigens as they are referred to in humans. MHC antigens determine a person's tissue type just as red blood cell antigens determine blood type. There are two classes of MHC antigens: class I molecules, encoded by three genes, and class II molecules, encoded by four possible sets of genes. Each of these genes has many alternative forms, and thus the probability of any two individuals—aside from siblings, especially identical twins—having the same form of each gene is extremely small. Even parents will have different tissue antigens from their children.

      These differences in tissue antigens pose an obstacle to transplantation because it is highly likely that foreign donor tissue will introduce antigens in the recipient that will trigger an immune response leading to tissue death and rejection. However, by careful matching of the MHC type of donor and recipient, rejection can be diminished or avoided. Because perfect matching is possible only between identical twins or very close relatives, many transplants occur between less closely matched tissue types, and success is achieved with the administration of powerful immunosuppressive drugs.

Diseases of biotic origin
Factors in infection

      Biotic agents include life-forms that range in size from the smallest virus, measuring approximately 20 nanometres (0.000 000 8 inch) in diameter, to tapeworms that achieve lengths of 10 metres (33 feet). These agents are commonly grouped as viruses, rickettsiae, bacteria, fungi, and parasites. The disease that these organisms cause is only incidental to their struggle for survival. Most of these agents do not require a human host for their life cycles. Many survive readily in soil, water, or lower animal species and are harmless to humans. Other living organisms, which require the temperature range of endothermic (warm-blooded) animals, may flourish on the skin or in the secretions of fluids of the mouth or intestinal tract but do not invade tissue or cause disease under normal conditions. Thus there is a distinction to be made between infection and disease.

      All animals are infected with biotic agents. Those agents that do not cause disease are termed nonpathogenic, or commensal (commensalism). Those that invade and cause disease are termed pathogenic. Streptococcus viridans bacteria, for example, are found in the throats of more than 90 percent of healthy persons. In this area they are not considered pathogenic. The same organism cultured from the bloodstream, however, is highly pathogenic and usually indicates the presence of the disease subacute bacterial endocarditis (chronic bacterial invasion of the valves of the heart). In order for such nonpathogenic agents to achieve pathogenicity, they obviously must overcome the defenses of the host. Most biotic agents require a portal of entry through the intact skin or mucosal linings of the body. They must be present in sufficient number to escape the phagocytes. They must be capable of surviving the inflammatory and immune response. Ultimately, to induce disease, they must have sufficient virulence and invasiveness to cause significant tissue injury.

Invasiveness and virulence
      Invasiveness is the capability of penetrating and spreading throughout tissues. Remarkably, little is known of the factors that condition it. In a few instances enzymes produced by biotic agents have been identified that are capable of breaking down the integrity of the supporting tissues of the body, thereby preparing a pathway for the spread of the organism.

      Only very few bacteria release such enzymes, however, and there are marked differences in invasiveness to be found among the various types of bacteria. The organism that causes diphtheria (Corynebacterium diphtheriae), for example, is capable of invading only the surface cells of the mouth and throat. The disease that results is caused by the production of a powerful exotoxin (a chemical substance produced by the organism and released into the surrounding tissues) that is absorbed into the bloodstream from the local infection within the throat. This exotoxin causes major damage in the heart and the nervous system. The diphtheria bacillus, therefore, is an example of a serious infection in which the organism has low invasiveness. In contrast, the bacterium that causes syphilis (Treponema pallidum) has a high degree of invasiveness. It is one of the rare biotic agents that are capable of penetrating intact skin and mucosal linings of the body.

      The invasiveness of viruses undoubtedly is facilitated by their extremely small size, but, because of this size, the exact mechanism is difficult to study. In the case of fungi (fungus) and parasites (parasitism), the invasiveness is related to the life cycle of the organism. The formation of tiny spores by fungi and the smaller reproductive forms of the parasites provide vehicles by which infection may be drawn into the lungs or may pass through tiny defects in the skin or mucosal linings of the various openings and tracts of the body.

      In general, virulence is the degree of toxicity or the injury-producing potential of a microorganism. The words virulence and pathogenicity are often used interchangeably. The virulence of bacteria usually relates to their capability of producing a powerful exotoxin or endotoxin. Invasiveness also adds to an organism's virulence by permitting it to spread.

Predisposition of the host
      Up to this point, diseases caused by biotic agents have been considered in terms of the role of the invader. Equally important is the role of the host, the individual who contracts the disease. Any infectious disease is a test between the invader and the defender. Virulent organisms may be capable of inducing serious illness even in the most robust. The converse is perhaps more important. The weak host is prey to many forms of biotic infection, even those of low virulence and invasiveness. Some of the more important of the many factors that condition the level of resistance to biotic infection in the individual are age, with infancy and old age being times of maximum vulnerability; poor nutrition; genetic disorders and immunosuppressive agents, such as the human immunodeficiency virus, that compromise the immunologic system; and metabolic disorders such as diabetes that increase vulnerability to infectious agents.

      Therapeutic agents, paradoxically, also have become important factors in predisposing to disease of biotic origin and indeed in altering the incidence patterns of infectious disease. The drugs (drug) that are principally involved include those used to suppress the immune response, as well as the host of antimicrobial and antibiotic agents now employed in the treatment of infectious disease. Immunosuppressive drugs are used to block the immune response in patients about to receive an organ transplant and in the treatment of the autoimmune diseases, but such treatment renders the patient vulnerable to attack by biotic agents. Indeed, these immunologically compromised persons become susceptible to organisms of extremely low virulence.

      Antimicrobial drugs also have drawbacks as well as benefits. A patient suffering from a streptococcal disease, for example, may appropriately be treated with penicillin. Certain strains of staphylococci (staphylococcus), however, are resistant to penicillin. Although the streptococcal organisms, as well as other commensals, may be eradicated by the antibiotic, the resistant staphylococci begin to proliferate, possibly because the competition with other bacteria for nutrients and food supply has been removed. In this noncompetitive situation they may cause disease. More powerful antibiotics may destroy all bacteria, including staphylococci, but permit the unrestrained proliferation of fungi and other agents of low virulence that are nonetheless resistant to the antibiotic. Thus antibiotics have changed the entire frequency pattern of biotic disease. Organisms that have proved to be more resistant to antibiotics have become the more common causes of serious clinical infection. For this reason certain forms of drug-resistant bacteria that include Escherichia coli, Aerobacter aerogenes, Pseudomonas aeruginosa, and strains of Proteus as well as fungi have emerged as the important biotic causes of death.

      Of the many existing viruses (virus), a few are of great importance as causes of human sickness. They are responsible for such diseases as smallpox, poliomyelitis, encephalitis, influenza, yellow fever, measles, and mumps and such minor disorders as warts and the common cold.

      Viruses may survive for some time in the soil, in water, or in milk, but they cannot multiply unless they invade or parasitize living cells. Certain viruses proliferate within the host cells and accumulate in sufficient number to cause rupture and death of the cells. Others multiply within the cell body and compete with the host for nutrition or vital constituents of the cell's metabolism. Both types of viruses are said to be cytotoxic.

      Viral agents, particularly those capable of producing tumours in humans and lower animals, flourish within cells and stimulate the cells to active growth. These viruses are referred to as oncogenic (tumour-producing). The number of oncogenic viruses that cause tumours in lower animals is large. In humans, several DNA viruses and one RNA virus have been implicated strongly in the induction of a variety of tumours (see cancer).

      Most viral infections occur in childhood. This age distribution has been explained on immunologic grounds. Viruses usually induce a firm and enduring immunity. On first exposure to a virus, children (childhood disease and disorder) may or may not contract the disease, depending on their resistance, the size of the infective dose of virus, and many other variables. Those who contract the disease, as well as those who resist the infection, develop a permanent immunity to any further exposure. By either pathway, as children grow older they progressively gather protection against viral infections. Consequently, the incidence of these infections falls in adulthood and later life. The frequency of common colds (common cold) is explained on the grounds that a host of different viral agents all induce similar respiratory infections, and, while a single attack confers immunity against the specific causative agent, it provides no protection against the rest.

      Viral diseases are resistant to antibiotics (antibiotic) and other antimicrobial agents. This point is made because of a distressing tendency among individuals to take penicillin or another antibiotic for a common cold.

      Human rickettsial diseases are caused by microorganisms that fall between viruses and bacteria in size. These minute agents are barely visible under the ordinary light microscope. Like viruses, they multiply only within the cells of susceptible hosts. They are found in nature in a variety of ticks and lice and, when transmitted to humans by the bite of one of these arthropods, usually cause acute febrile (fever-producing) illnesses, most of which are characterized by skin rashes. Rocky Mountain spotted fever, a systemic rickettsial infection, invades and kills the cells lining blood vessels and causes hemorrhage, inflammation, blood clots, and extensive tissue death; if untreated, it is fatal in about 20 to 30 percent of cases.

      The diseases produced by bacteria are the most common of infectious biotic diseases. They range from trivial skin infections to such devastating disorders as bubonic plague and tuberculosis. Various types of pneumonia; infections of the cerebrospinal fluid (meningitis), the liver, and the kidneys; and the sexually transmitted diseases syphilis and gonorrhea are all forms of bacterial infection.

      All bacteria induce disease by one of three methods: (1) the production of an exotoxin, a harmful chemical substance that is secreted or excreted by the bacterium (as in food poisoning caused by Clostridium botulinum), (2) the elaboration of an endotoxin, a harmful chemical substance that is liberated only after disintegration of the micro-organism (as in typhoid (typhoid fever), caused by Salmonella typhi), or (3) the induction of sensitivity within the host to antigenic properties of the bacterial organism (as in tuberculosis, after sensitization to Mycobacterium tuberculosis).

Fungi (fungus) and other parasites (parasitism)
      Diseases caused by fungi and parasites are relatively uncommon in developed countries. Fungal infections, also known as mycotic infections, may affect the skin surfaces or the internal organs of the body. The superficial mycotic infections are generally not serious and include such well-known disorders as athlete's foot (tinea pedis (athlete's foot)), caused by the dermatophyte Trichophyton. Deep mycotic infections such as histoplasmosis and candidiasis are potentially life-threatening.

      Other parasites that attack humans range in size from unicellular organisms such as Entamoeba histolytica to such multicellular forms as tapeworms and roundworms. Most parasitic infestations are encountered in the less-developed areas of the world where sanitation is not optimal. Indeed, parasitic infestations constitute major causes of death in regions of Central and South America, Africa, India, and Asia. (For additional information about diseases of biotic origin, see infection (infectious disease).)

Abnormal growth of cells (cell)
Normal and abnormal cell growth

Cell growth inhibition
      The growth of cells in the body is a closely controlled function, which, together with limited and regulated expression of various genes, gives rise to the many different tissues that constitute the whole organism. For the most part, control of cell growth persists throughout life except for episodic instances such as healing of an injured tissue. In this situation the growth of a localized group of cells is accelerated to reconstitute the tissue to its previous state of normal structure and function, following which tightly regulated growth resumes. Such areas of increased cell growth are referred to as hyperplasias; they consist of expanded numbers of normal-appearing cells and, depending on the duration of growth, can result in an enlargement of tissues and organs. In general, hyperplasias arise to meet special needs of the body and subside once these needs are met. Hyperplasias are the result of the sustained impact over time of stimulatory influences together with a loss of growth-inhibitory factors that are normally found within or around cells. As long as the loss of inhibition of cell growth is temporary, the capacity for enhanced cell proliferation when necessary has obvious advantages. However, if cells permanently lose their ability to respond to growth-inhibitory factors, their growth becomes irrepressible, and cancer may result.

Neoplasms: malignant and benign tumours (tumour)
      Diseases arising from uncontrolled cell growth and behaviour collectively constitute the second most common cause of human death (the most common cause being heart disease). Cancers (cancer), the most important form of abnormal growth and behaviour, were responsible for approximately 538,000 deaths, or almost one-fourth of all deaths, in the United States in 1994. The significance of this incidence is placed in proper perspective by a consideration of the following facts. While cancer arises at all stages of life, its incidence (number of cases) increases with age, reaching a peak between 55 and 74 years. This fact, together with the increasing longevity of the general population and improved diagnostic modalities that enable clinicians to detect cancers with greater frequency, tempers the notion that the incidence of cancer is increasing.

      In addition to cancers—malignant tumours that may eventually kill the host—there are benign tumours that rarely produce serious disease. The two types of tumours are collectively referred to as neoplasms (new growths), and their study is known as oncology. Tumours are referred to as malignant or benign based on the structural and functional properties of their component cells and their biological behaviour. The cells and tissues of malignant tumours differ from the tissues from which they arise. They exhibit more rapid growth and altered structure and function, including stimulation of new blood vessel growth (angiogenesis) and a capacity to invade adjacent normal tissues, enter the blood vascular system, and spread (metastasize) to distant sites. The properties of malignant tumour cells serve to enhance and support their proliferation and extension throughout the body tissues and organs, eventually leading to death of the host. In contrast, the cells and tissues of benign tumours tend to grow more slowly and in general closely resemble their normal tissues of origin. When the structure and function of benign tumour cells are morphologically and functionally indistinguishable from those of normal cells, their growth as a tumour mass is the sole feature indicative of their neoplastic nature. It is hoped that a greater understanding of malignant cell growth and behaviour will lead to the development of novel cancer therapies based on tumour cell biology that will complement or replace the current treatments of surgical extirpation (complete excision), chemotherapy, and radiation.

Characteristics of cancer

      Epidemiological studies of the worldwide incidence of cancers have identified striking differences among countries and population groups. For example, the incidence of and death rates for skin cancer are much higher in Australia and New Zealand than in the Scandinavian countries—presumably because of the marked differences between these two regions in total annual hours of exposure to sunlight. The importance of environmental influences is highlighted by comparing the incidence of and death rates for cancers among populations in different geographic regions. For example, prostate and colon cancer rates in Japanese (Japan) persons living in Japan differ from the rates in Japanese persons who have emigrated to the United States, the rates of their offspring born in California, and the rates of long-term white residents of that state. These rates are much lower among Japanese living in Japan than they are in white Californians. However, the rates for each type of tumour among first-generation Japanese immigrants are intermediate between the rates in Japan and those in California, suggesting that environmental and cultural factors may play a more important role than genetic ones.

The role of genetics
      The irreversibility of the structural and behavioral changes of cancer cells has long been recognized and has favoured the postulate that they are probably due to permanent genetic alterations. This postulate remained speculative until the discovery in 1979 that oncogenes (oncogene) (cancer-causing genes) are derived from proto-oncogenes (normal growth-regulatory cellular genes). When proto-oncogenes become mutated or deregulated, they are converted to oncogenes, which are capable of causing the malignant transformation of cells, including those of humans. Cellular proto-oncogenes code for proteins involved in cell regulation, such as growth factors, their receptors, and transmembrane signal transducers. Thus, changes in the structure of proto-oncogenes and their conversion to oncogenes results in the synthesis of abnormal proteins that are incapable of carrying out their usual growth-regulatory functions. In identifying the genes involved in the development of cancer, researchers discovered a group of cellular genes—tumour-suppressor, or suppressor, genes—whose protein products normally negatively regulate cell growth by suppressing cell proliferation, thus counterbalancing the growth-stimulatory effects of proteins synthesized by proto-oncogenes. Genetic analyses of various animal and human cancers have demonstrated that, in the majority, alterations of oncogenes and suppressor genes were often simultaneously present. These analyses suggest that multiple genetic alterations involving growth-stimulatory and growth-inhibitory genes are required for the induction of malignancy. Such discoveries have ushered in a new era in cancer biology and may well lead to the eventual control, cure, and prevention of malignant diseases.

      The many causes of cancer include intrinsic factors, such as heredity, and extrinsic factors, such as environment and lifestyle. Hereditary causes of cancer are less common and are due to the inheritance of a single mutant gene that greatly increases the risk of developing a malignant tumour. Such cancers include (1) a childhood tumour of the eye, retinoblastoma, and a bone tumour, osteosarcoma, both of which involve the loss of a tumour suppressor gene, and (2) familial adenomatous polyposis, in which all patients develop colon cancer by age 50. The most common types of cancer that occur sporadically, such as cancers of the breast, ovary, colon, and pancreas, also have been documented to occur in familial forms. The children in such families appear to have a two- to threefold increased risk of developing a particular tumour, but the transmission pattern is unclear. A still rarer hereditary cause of cancer is an inherited deficiency in the ability to repair DNA. Patients with this defect (known as xeroderma pigmentosum) are particularly sensitive to sunlight and develop skin cancer during early adolescence because of unrepaired mutations induced by ultraviolet (UV) light.

      Although the environment contains many agents that can cause cancer in humans, the extent to which they contribute to the human disease is often difficult to assess. For example, the link between tobacco smoking and lung cancer is clear; however, little is known about the cause of cancer of the prostate, the most common form of cancer in males, despite the fact that many factors—including age, race, male hormone, increased consumption of dietary fat, and a genetic basis—have been implicated.

      Three categories of carcinogens (chemical or physical agents that mutate DNA) that induce cancer in experimental animals and humans have been identified in the environment: (1) chemicals (chemical compound), (2) radiant energy, and (3) oncogenic viruses.

Chemicals
      Chemicals capable of causing cancer arise from a variety of sources. These include certain synthetic chemicals used in industry, some natural compounds formed during the curing and burning of tobacco, compounds formed during the cooking of meat, and chemicals present in certain plants and molds. Two categories have been identified, those capable of causing DNA damage and mutations directly (genotoxic, or direct-acting, carcinogens) and those that require prior metabolic activation by cells of the host to be converted to mutagens (epigenic, or indirect-acting, carcinogens). In the industrial countries much progress has been made in significantly decreasing and preventing exposure to chemical carcinogens in the workplace. However, exposure to carcinogens as a consequence of cultural practices, such as tobacco smoking and the cooking and consumption of meats, is difficult if not impossible to control or eradicate.

      Sustained exposure to two forms of radiant energy—namely, UV (ultraviolet radiation) light and ionizing radiation—is carcinogenic for humans. Repeated and sustained exposure to UV rays emanating from the Sun causes mutations of DNA that ultimately are capable of inducing three different types of skin (skin disease) cancer. As one would expect, the incidence of UV-induced skin cancer is high among farmers, sailors, and sunbathing enthusiasts. The degree of risk depends on the extent of exposure and the amount of melanin pigment in the skin, which absorbs UV rays. Dark-skinned individuals are protected by the high content of melanin in their skin; in contrast, fair-skinned persons and albinos have very little or no protective melanin pigment in their skin.

      The carcinogenic effects of ionizing radiation first became apparent from the results of inappropriate exposure of early uranium ore miners and of physicians who first used X-ray machines for diagnostic purposes and were unaware of the health hazards. The devastating complications that resulted are rare today because of stricter indications for the use of radiation therapy, careful focusing of radiation beams, and effective shielding of adjacent normal tissues. However, the risks of exposure to ionizing radiation have been reemphasized from time to time by the appearance of neoplastic disease following radiation therapy and following the release of enormous amounts of radiation into the environment, as occurred from atomic bombing of Hiroshima and Nagasaki in Japan and the accident at the Chernobyl nuclear power station in Ukraine.

      Reactive forms of carcinogenic chemicals and, in the case of ionizing radiation, reactive forms of oxygen damage DNA directly. If repair of damaged DNA is slow, error-prone, or not accomplished at all and cell replication occurs, the damage is amplified and becomes a permanent (fixed) mutation.

Viruses (virus)
      In recent years certain DNA viruses have been strongly implicated as causal agents for a variety of cancers in humans. These include human papillomavirus (human papillomavirus) (HPV) as a cause of genital cancers in both sexes worldwide, the Epstein-Barr virus (EBV (Epstein-Barr virus)) for childhood lymphoma in Africa and cancer of the nose and throat in Asia and Africa, and the hepatitis viruses B and C that cause liver cancer worldwide with the highest incidence in Asia and Africa. However, at present only one type of human cancer, the rare adult T-cell leukemia, has been solidly linked to infection with an RNA virus, the human T-cell leukemia virus (HTLV-1). While much experimental and clinical evidence supports the carcinogenic role of the above-mentioned viruses in humans, additional research suggests that other factors also may be required. Observations that support the multifactorial nature of viral carcinogenesis include the continuous but not neoplastic growth of human cells infected in culture with HPV, the restricted geographic distribution of cancers induced by EBV, and the lack of either an oncoprotein (protein product produced by an oncogene) for HBV or evidence of consistent integration of the virus near a proto-oncogene encoding for a growth-regulatory protein. Thus far, oncogenic viruses have not been shown to induce DNA mutations directly in human cells; rather, their contribution seems to lie in promoting and hastening the process of mutation. (For greater detail on how viruses contribute to the induction of cancer, see the articles cancer and virus.)

Diseases of metabolic-endocrine (metabolic disease) origin
      The term metabolism encompasses all the chemical reactions vital to the growth and maintenance of the body. Defects in metabolism are found in almost every disease condition. Most are secondary; i.e., they result from some other basic disorder (infection, kidney disease, or heart disease, for example). In a few primary metabolic disorders, small genetic mutations (mutation) lead to structural alterations of specific proteins that disrupt protein function and are responsible for the disease state. At this point, another group of primary metabolic disorders—those associated with hormonal defects—will be touched on.

      Hormones (hormone) are large organic molecules secreted in small amounts by specific cells in the various endocrine (ductless) glands. These secretions are carried by the blood to distant sites (target organs), where they bind to specific receptors on target cells and act to regulate specific chemical reactions.

      All endocrine (endocrine system, human) disease stems from either an overproduction (hyperfunction) or underproduction (hypofunction) of some hormone-secreting endocrine gland. There are relatively few causes of hormone overproduction. In general, overproduction results from hyperplasia, an increase in the number of cells (in this case, hormone-secreting cells) in a specific endocrine gland. It can also be caused by neoplasia, the growth of a tumour in an endocrine gland. Although most endocrine tumours are benign, the resulting hypersecretion of hormone can have far-reaching effects. For example, the pituitary gland, tucked into the base of the skull, produces many hormones that have far-ranging effects, mostly controlling the function of the other endocrine glands, such as the thyroid, adrenals, ovaries, and testes. acromegaly, characterized by the enlargement of many skeletal parts, is a rare endocrine disease caused by excess secretion of pituitary growth hormone in the adult. An example of hormone overproduction because of hyperplasia is hyperthyroidism, the disease produced by an excess of thyroid hormone. It is characterized by a rapid pulse, increased sweating, weight loss, heat intolerance, and frequent disturbances in the heart rhythm. Cushing's syndrome (Cushing syndrome), an exception to the generalization that hypersecretion of hormones is due to either neoplasia or hyperplasia, results from an overproduction of the adrenal steroid hormones (such as cortisol). Although the disease is occasionally caused by tumours or by hyperplasia of the adrenals, in most instances it is not. It has been suggested that the disease results from excessive adrenocorticotropic hormone (ACTH) from the pituitary; in rare cases when the level of ACTH is not elevated, it is thought that autoantibodies to ACTH receptors cause the hyperplasia.

      Underproduction of hormone is most often the result of destruction of hormone-secreting cells. This destruction may be caused by infection, infarction (tissue death due to loss of blood supply), or obliteration of endocrine glands by cancer. Underproduction of hormone also may result from failure of the gland to undergo normal fetal development, or it may be a feature of an autoimmune disease (as in juvenile diabetes mellitus).

      Treatment of endocrine disease involves either hormone supplementation, in the case of hypofunction, or, in cases of hyperfunction, destruction of endocrine gland tissue by surgery or radiation (see Endocrine Systems (endocrine system, human)).

Diseases of nutrition
      Diseases of nutrition include the effects of undernutrition, prevalent in less-developed areas but present even in affluent societies, and the effects of nutritional excess.

Diseases of nutritional excess
       obesity, perhaps the most important nutritional disease in the United States and Europe, results usually from excessive caloric intake, although emotional, genetic, and endocrine factors may be present.

      Obesity predisposes one toward several serious disorders, including a state of chronic oxygen deficiency called the hypoventilation syndrome; high blood pressure; and atherosclerosis, a degenerative condition of the blood vessels that is discussed further below.

      Excessive intake of certain vitamins (vitamin A), especially vitamins A and D (vitamin D), can also produce disease. Vitamins (vitamin B complex) A and D are both fat-soluble and tend to accumulate to toxic levels in the bodily tissues when taken in excessive quantities. vitamin C and the B vitamins, soluble in water, are more easily metabolized or excreted and, therefore, rarely accumulate to toxic levels.

Diseases of nutritional deficiency
      Nutritional deficiencies may take the form of inadequacies of (1) total caloric intake, (2) protein intake, or (3) certain essential nutrients such as the vitamins and, more rarely, specific amino acids (components of proteins) and fatty acids.

      Protein-calorie malnutrition remains prevalent in certain areas. It has been estimated that about two-thirds of the world's population has less than enough food to eat. Not only is the quantity inadequate but the quality of the food is nutritionally deficient and usually lacks protein. In deprived areas malnutrition has its greatest impact on the young. Deaths from protein-calorie malnutrition result from the failure of the child to thrive, with progressive weight loss and weakness, which in turn can lead to infection and disease, usually some form of gastrointestinal bacterial or parasitic disorder. In other circumstances adequate calories may be available, but a deficiency of protein induces a disorder known as kwashiorkor.

      Vitamin deficiencies, the most important forms of selective malnutrition, may arise in a variety of ways, the most common and the most important being an improper, inadequate diet. When the total caloric intake is inadequate, vitamin deficiencies may also occur, but in these circumstances the more profound lack of calories and proteins masks the lack of vitamins.

      Vitamin deficiencies may also be encountered despite a diet that is apparently adequate nutritionally. One source of such a deficiency, called secondary, is interference with absorption of the vitamin. pernicious anemia is a classic example of this phenomenon. This disorder results from an autoimmune response to intrinsic factor, a substance normally found in the stomach lining with which 2 (vitamin B12) must form a complex to be absorbed. (Vitamin B12 is necessary for red cells to form properly.) The basis of pernicious anemia, then, is a lack of absorption of vitamin B12. The absence of certain digestive enzymes, as is found in pancreatic disease, can lead to the inability to digest and absorb fats and the fat-soluble vitamins (A, D, E, and K). Impaired uptake of vitamins may be encountered in gastrointestinal diseases. Some of these diseases reduce the absorptive function of the bowel. Similarly, diseases associated with severe, prolonged vomiting may interfere with adequate absorption.

      Avitaminosis (vitamin lack) may be encountered when there are increased losses of vitamins such as occur with chronic severe diarrhea or excessive sweating or when there are increased requirements for vitamins during periods of rapid growth, especially during childhood and pregnancy. Fever and the endocrine disorder hyperthyroidism are two additional examples of conditions that require higher than the usual levels of vitamin intake. Unless the diet is adjusted to the increased requirements, deficiencies may develop. Lastly, artificial manipulation of the body and its natural metabolic pathways, as by certain surgical procedures or the administration of various drugs, can lead to avitaminoses. (Diseases involving deficiencies of particular vitamins are discussed in nutrition: Deficiency diseases: Vitamins (nutritional disease).)

Diseases of neuropsychiatric origin
      Diseases of neuropsychiatric origin afflict large segments of the population. For example, a total of about 2.8 million persons in the United States suffer from three major psychiatric diseases—schizophrenia, major depression, and mania—and three major neurological disorders—Alzheimer's disease, Huntington's chorea, and Parkinson's disease. These six conditions will be briefly reviewed here. More in-depth coverage is found in the articles mental disorder and nervous system disease (nervous system).

      The key function of the nervous system is to collect information about the body and its external environment, process the information, and coordinate the body's responses to that information. This complex function depends on each nerve cell ( neuron) receiving signals from other neurons and transmitting this input to still other neurons. This critical input and output of communication (signaling) between neurons is mediated by chemical transmitter molecules (neurotransmitters (neurotransmitter)). Neurotransmitters are synthesized by nerve cells and released from one cell to another across a narrow gap between the two neurons known as the synapse. Eight different major neurotransmitters and a large number of neuropeptide molecules (which serve to modulate the effects of neurotransmitters) have been identified. Different types of nerve cells respond to different neurotransmitters and neuropeptides. Chemical signaling between nerve cells is rapid and precise and can occur over long distances. The precision is due to receptor molecules, which are activated following their recognition and binding of specific neurotransmitters. In some types of nerves the synapses do not possess receptors, in which case interneuronal communication is achieved by electrical transmission. In many neuropsychiatric diseases alterations in the levels of transmitter substances appear to play a major role in pathogenesis.

Psychiatric diseases
      Mental illnesses (mental disorder) affect the very fabric of human nature, robbing it of its various facets of personality, purposeful behaviour, abstract thinking, creativity, emotion, and mood. Those suffering from mental disorders exhibit a spectrum of symptoms depending on the severity of their disease. These diseases include obsessive-compulsive personality disorder, dementia, schizophrenia, major depression, and manic disorders.

      Schizophrenia in its severe form is a catastrophic mental illness that begins in adolescence or early adult life. It is relatively common, occurring in about 1 percent of the general population worldwide. Because the incidence of schizophrenia among parents, children, and siblings of patients with the disease is increased to 15 percent, it is believed that heredity plays an important role in the genesis of the disease. However, other studies suggest that nongenetic factors are also influential. The biochemical basis of the disease may be an excess of the neurotransmitter substance dopamine, as high levels of dopamine and its metabolites, as well as increased dopamine receptors, are found in the brains of persons with schizophrenia. Further evidence for this hypothesis is that the drugs most effective in treating the disease are those that have a high capacity to block dopamine receptors.

      Pathological disturbances of mood, ranging from severe depression to manic behaviour, are common forms of mental illnesses. Severe depression is characterized by despondency, diminished interest in most or all activities, weight fluctuation not due to dieting, disruption in sleep patterns, psychomotor agitation or retardation, feelings of worthlessness, excessive quiet, and recurrent thoughts of death or suicide. Manic (bipolar disorder) behaviour involves a period in which an expansive, elevated, or irritable mood persists abnormally. During this episode symptoms such as increased talkativeness, distractibility, decreased need for sleep, inflated self-esteem, and excessive involvement in pleasurable yet risky activities may be present. Major depression is associated with decreased brain levels of the neurotransmitters norepinephrine and serotonin, and the most effective therapy consists of drugs that inhibit the breakdown of these compounds. The neurochemical alterations in mania are less clearly understood, but it is well established that drugs effective in the treatment of mania are those that antagonize dopamine and serotonin. The mechanism responsible for the therapeutic efficacy of lithium for the treatment of mania is not yet clear. Although mood disorders have a familial background, the evidence for a genetic component is not convincing.

Neurological diseases
      The three neurological diseases considered in this section—Alzheimer's disease, Huntington's chorea, and Parkinson's disease—are age-related (human aging), and to varying degrees they manifest as deterioration of mental function that involves the loss of memory and of acquired intellectual skills. This deterioration is referred to as dementia. Because dementia can result from many causes, other features of each disease must be present before a definitive diagnosis can be made.

Alzheimer's disease (Alzheimer disease)
      Alzheimer's disease is the most common form of dementia, being responsible for about two-thirds of the cases of dementia in patients over 60 years of age. Women are affected twice as often as men. More rarely there are familial forms of the disease that have an early onset affecting individuals in the fourth and fifth decades of life. Alzheimer's disease is insidious in onset. Early manifestations include memory loss, temporary confusion, restlessness, poor judgment, and lethargy. A failure to retain new information and a deterioration of social relationships often ensue. In some patients paranoia and delusions, which worsen during the night, are the first symptoms of the disease. Whatever the onset, the last stages are characterized by intellectual vacuity and loss of control over all body functions.

      The brains of patients with Alzheimer's disease are characterized by the loss of neurons, which, as the disease progresses, becomes severe and leads to decreased brain size and weight. Because nerve cells synthesize the neurotransmitters (neurotransmitter) necessary for interneuronal communication, it is not surprising that Alzheimer's disease is associated with diminished levels of neurotransmitters, including acetylcholine, norepinephrine, and serotonin, as well as modulatory neuropeptide molecules that transmit signals between nerve cells. Two other characteristic tissue lesions found in the cerebral cortex of patients with Alzheimer's disease are neuritic plaques and neurofibrillary tangles. Neuritic plaques are deposits of neuron fragments surrounding a core of amyloid β-protein. Neurofibrillary tangles are twisted fibres of the protein tau found within neurons.

      A variety of genetic factors have been identified in the different forms of Alzheimer's disease. The rare cases of the early familial forms of the disease are linked to three different genetic defects found on three different chromosomes—chromosomes 1, 14, and 21. Another gene on chromosome 19 is believed to play a part in the more common late-onset cases. The gene on chromosome 21 was the first to be identified. (This finding is significant because an abnormality in chromosome 21—an extra copy—is found in patients with Down syndrome, virtually all of whom develop Alzheimer's disease if they live to age 35.) The defective gene on chromosome 21 normally codes for amyloid precursor protein. A defect in this gene is thought to result in abnormal cleavage of the protein that increases the production and deposition of amyloid β-protein. This gene, however, is linked to only 2 to 3 percent of all early familial cases of the disease. The majority of patients with early-onset disease—70 to 80 percent—have the genetic mutation on chromosome 14, and another group of patients have a defective gene on chromosome 1. The gene on chromosome 19 codes for apolipoprotein E, a protein involved in cholesterol transport and metabolism. Three forms, or alleles, of the gene exist. The presence of one form—ApoE4—in an individual's genome seems to increase the deposition of amyloid β-protein in the brain and may also increase the number of neurofibrillary tangles.

      Huntington's chorea occurs at the rate of about 5 per 100,000 individuals. It affects both sexes equally and usually becomes manifest in the fourth decade of life. The disorder is characterized by uncontrolled movements (chorea), dementia, and death within 20 years after onset. The symptoms worsen until the patient becomes totally incapacitated and bedridden. Huntington's chorea is a hereditary disease passed on as an autosomal dominant trait (see above Diseases of genetic origin (human disease)). Because of its highly regular familial inheritance, the disease is often traceable to the original carriers who introduced the defective gene. For example, British immigrants to colonial America in the 17th century are believed to be responsible for almost all cases of Huntington's chorea in the eastern United States, and an English sailor is thought to have introduced the defective gene into Venezuela almost 200 years ago. The recent localization of the Huntington's chorea gene to chromosome 4 and its cloning will allow identification of the gene product, insight into the mechanism responsible for the disease, and perhaps effective treatment. It will also permit the disease to be diagnosed in fetuses as well as in children before the onset of symptoms.

      Parkinson's disease is a motor disorder characterized by the onset of a “pill rolling” rhythmic tremor, muscle rigidity, difficulty and slowness in movement, and stooped posture. As the disease progresses, the face of the patient becomes expressionless, the rate of swallowing is reduced, leading to drooling, and depression and dementia increase. The prevalence of Parkinson's disease is estimated to be about 160 per 100,000 persons in the general population, with about 16 to 19 new cases per 100,000 appearing each year. Men are slightly more affected than women, and there are no apparent racial differences. The disease appears typically in the sixth and seventh decades, although occasionally it can begin as early as the third decade. Parkinson's disease has no known cause. A marked decrease in the level of dopamine, a major neurotransmitter, has been noted in the brains of patients with Parkinson's disease, and this change has been attributed to the loss of so-called dopaminergic neurons that normally synthesize and use dopamine to communicate with other neurons in parts of the brain that regulate motor function. This information has opened a new approach to the treatment of the disease—namely, administration of the metabolic precursor to dopamine (L-dopa) that can be converted by the body to dopamine. Although initially beneficial in causing a significant remission of symptoms, L-dopa frequently is effective for only 5 to 10 years, and serious side effects accompany treatment. Cotreatment with an inhibitor of the enzyme that breaks down L-dopa and thus allows the substance to remain in the brain longer has yielded an effective therapy, which allows many patients to live reasonably normal lives. Nevertheless, although treatment may slow the progress of the disease, it does not alter its course. This suggests that factors other than variation in neurotransmitter levels are responsible for the disease.

Diseases of senescence
      The process of aging (human aging) begins at the time of conception. Throughout life the body undergoes a series of changes that can be considered as manifestations of aging. During the first half of life these changes are generally referred to as maturation, during the last half of life as progressive senescence. Visual acuity, sensitivity of hearing, and muscular vigour begin to deteriorate after the third decade of life. These changes, although they may begin at different ages and progress at differing rates, are universal among all individuals and must therefore be considered as the normal aging process. A critical question remains unanswered concerning the cause of the intrinsic retrogressive changes in cell and organ structure and function that occur throughout the aging process. Are these changes genetically determined, or are they a result of accumulated sublethal injuries that the cell sustains from exposure to noxious environmental factors over time? Or perhaps both elements act in concert to effect the changes that occur as life progresses.

      It is extremely difficult to draw a sharp line between the deleterious effects of normal aging and the deleterious effects of the diseases of aging. The diseases most commonly manifested in the elderly are disorders of the heart, blood vessels, and joints. The heart disease of the elderly is related to the generalized vascular disease known as arteriosclerosis, which frequently attacks the major coronary arteries of the heart. Arteriosclerosis and arthritis will therefore be briefly touched upon here. More extended discussions may be found in cardiovascular disease and in joint disease. These problems and other aspects of aging are also considered in human aging.

      Arteriosclerosis is not a specific disease. The term is applied to all diseases that cause hardening of the arteries. Several minor processes can induce hardening of the arteries, but the overwhelming preponderance of cases of arteriosclerosis are caused by atherosclerosis. This disorder, which eventually affects all individuals to varying degrees, begins relatively early in life in most persons. There are great variations, however, in the severity of this disease among individuals and among racial, national, and ethnic populations. These differences depend on the presence or absence of risk factors such as diet, hypertension, tobacco smoking, diabetes, obesity, family history, and stress.

      Atherosclerosis is characterized by the deposition of fats (cholesterol and other complex lipids) in the linings (intima) of the arteries. It is accompanied by cell injury, cell death, and scarring and sometimes produces total obstruction of an artery. Atherosclerosis has a predilection for the aorta, the major artery of the body, and the arteries of the heart, brain, and legs. Atherosclerosis of the arteries of the heart (the coronaries) causes myocardial infarction, otherwise known as heart attack.

      When atherosclerosis narrows but does not totally block the coronary arteries, the heart also is injured by lack of adequate blood supply and nutrition and becomes progressively smaller and weaker; even though this disease is not as life-threatening as a heart attack, it nonetheless frequently causes heart failure, an inability of the heart to deliver an adequate supply of blood to the tissues. Atherosclerosis of the arteries of the brain is the usual cause of stroke. When the arteries to the legs become affected in this way, gangrene may develop.

       arthritis, probably the second most common and distressing disease among the elderly, is a disease of the joints. It causes considerable pain, discomfort, and lack of mobility and so makes life burdensome. Moreover, arthritic individuals are more subject to other illnesses. Degenerative arthritis ( osteoarthritis) is common to all elderly people to a lesser or greater degree. Osteoarthritis usually begins in the fourth decade of life and slowly progresses with increasing age. Coinciding with the characteristic degeneration of the joints are changes involving the bone (bone disease) itself. The bone of elderly persons is known to be less dense and more brittle; it tends, therefore, to fracture more easily. It also heals with greater difficulty.

      There are many subtle changes that occur with the normal aging process. These may include degenerative changes in the brain, leading to impaired mental ability and even senility. As this damage is usually accompanied by atherosclerosis of the arteries of the brain, it is difficult to know how much of the change is the result of impaired blood flow and how much is related to normal aging. Finally, but of no less significance, is the general decline in the body's ability to defend itself against disease. Thus elderly persons are more susceptible to infections, trauma, and a number of other bodily defects. Simple, uncomplicated pneumonia, which might be easily tolerated by the young, healthy adult, may be fatal for an elderly, weakened person.

Classifications of diseases
      Classifications of diseases become extremely important in the compilation of statistics on causes of illness (morbidity) and causes of death ( mortality). It is obviously important to know what kinds of illness and disease are prevalent in an area and how these prevalence rates vary with time. Classifying diseases made it apparent, for example, that the frequency of lung cancer was entering a period of alarming increase in the mid-20th century. Once a rare form of cancer, it had become the single most important form of cancer in males. With this knowledge a search was instituted for possible causes of this increased prevalence. It was concluded that the occurrence of lung cancer was closely associated with cigarette smoking. Classification of disease had helped to ferret out an important, frequently causal, relationship.

      The most widely used classifications of disease are (1) topographic, by bodily region or system, (2) anatomic, by organ or tissue, (3) physiological, by function or effect, (4) pathological, by the nature of the disease process, (5) etiologic (causal), (6) juristic, by speed of advent of death, (7) epidemiological, and (8) statistical. Any single disease may fall within several of these classifications.

      In the topographic classification, diseases are subdivided into such categories as gastrointestinal disease, vascular disease, abdominal disease, and chest disease. Various specializations within medicine follow such topographic or systemic divisions, so that there are physicians who are essentially vascular surgeons, for example, or clinicians who are specialized in gastrointestinal disease. Similarly, some physicians have become specialized in chest disease and concentrate principally on diseases of the heart and lungs.

      In the anatomic (anatomy) classification, disease is categorized by the specific organ or tissue affected; hence, heart disease, liver disease, and lung disease. Medical specialties such as cardiology are restricted to diseases of a single organ, in this case the heart. Such a classification has its greatest use in identifying the various kinds of disease that affect a particular organ. The heart is a good example to consider. By the segregation of cardiac disease it has been made apparent that heart disease is now the most important cause of death in the United States and in most other industrialized nations. Moreover, it has become apparent that disease caused by atherosclerosis of the coronary arteries is by far the most important form of heart disease. In making a diagnosis of cardiac disease in an elderly patient, the cardiologist must first determine whether this disease of the coronary arteries is responsible for the heart's failure to function normally.

      The physiological (physiology) classification of disease is based on the underlying functional derangement produced by a specific disorder. Included in this classification are such designations as respiratory and metabolic disease. Respiratory diseases are those that interfere with the intake and expulsion of air and the exchange of oxygen for carbon dioxide in the lungs. Metabolic diseases are those in which disturbances of the body's chemical processes are a basic feature. Diabetes and gout are examples.

      The pathological (pathology) classification of disease considers the nature of the disease process. Neoplastic and inflammatory disease are examples. Neoplastic disease includes the whole range of tumours, particularly cancers, and their effect on human beings.

      The etiologic classification of disease is based on the cause, when known. This classification is particularly important and useful in the consideration of biotic disease. On this basis disease might be classified as staphylococcal or rickettsial or fungal, to cite only a few instances. It is important to know, for example, what kinds of disease staphylococci produce in human beings. It is well known that they cause skin infections and pneumonia, but it is also important to note how often they cause meningitis, abscesses in the liver, and kidney infections. The sexually transmitted diseases syphilis and gonorrhea are further examples of diseases classified by etiology.

      The juristic basis of the classification of disease is concerned with the legal circumstances in which death occurs. It is principally involved with sudden death, the cause of which is not clearly evident. Thus, on a juristic basis some deaths and diseases are classified as medical-legal and fall within the jurisdiction of coroners and medical examiners. A person living alone is found dead in bed—dead of natural causes or killed? Had the person who dropped dead on the street been given some poison that took a short time to act? Much less dramatic, but perhaps more common, are disease and death caused by exposure of the individual to some unrecognized danger to health in working or living conditions. Could the illness or disease be attributable to fumes or dusts in a factory? These are examples of the many types of disease and death that fall properly in this classification.

      The epidemiological (epidemiology) classification of disease deals with the incidence, distribution, and control of disorders in a population. To use the example of typhoid (typhoid fever), a disease spread through contaminated food and water, it first becomes important to establish that the disease observed is truly caused by Salmonella typhi, the typhoid organism. Once the diagnosis is established, it is obviously important to know the number of cases, whether the cases were scattered over the course of a year or occurred within a short period, and what the geographic distribution is. It is critically important that the precise address and activities of the patients be established. Two widely separated locations within the same city might be found to have clusters of cases of typhoid all arising virtually simultaneously. It might be found that each of these clusters revolved about a family unit including cousins, grandparents, aunts and uncles, and friends, suggesting that in some way personal relationships might be important. Further investigation might disclose that all the infected persons had dined at one time or at short intervals in a specific home. It might further be found that the person who had prepared the meal had recently visited some rural area and had suffered a mild attack of the disease and was now spreading it to family and friends by unknowing contamination of food. This hypothetical case suggests the importance of the etiologic, as well as the epidemiological, classification of disease.

      Epidemiology is one of the important sciences in the study of nutritional and biotic diseases around the world. The United Nations supports, in part, the World Health Organization, whose chief function is the worldwide investigation of the distribution of disease. In the course of this investigation, many observations have been made that help to explain the cause and provide approaches to the control of many diseases.

      The statistical basis of classification of disease employs analysis of the incidence (the numbers of new cases of a specific disease that occur during a certain period) and the prevalence rate (number of cases of a disease in existence at a certain time) of diseases. If, for example, a disease has an incidence rate of 100 cases per year in a given locale and, on the average, the affected persons live three years with the disease, it is obvious that the prevalence of the disease is 300. Statistical classification is an additional important tool in the study of possible causes of disease. These studies, as well as epidemiological, nutritional, and pathological analyses, have made it clear, for example, that diet is an important consideration in the possible causation of atherosclerosis. The statistical analyses drew attention to the role of high levels of fats and carbohydrates in the diet in the possible causation of atherosclerosis. The analyses further drew attention to the fact that certain populations that do not eat large quantities of animal fats and subsist largely on vegetable oils and fish have a much lower incidence of atherosclerosis. Thus, statistical surveys are of great importance in the study of human disease.

Stanley L. Robbins Jonathan H. Robbins Dante G. Scarpelli

Additional Reading
Lawrie Reznek, The Nature of Disease (1987), written for the general reader, discusses the nature of disease from several perspectives, including medical, legal, political, philosophical, and economic. David O. Slauson, Barry J. Cooper, and Maja M. Suter, Mechanisms of Disease: A Textbook of Comparative General Pathology, 2nd ed. (1990), written for the veterinary student but a great resource for pathologists and biomedical researchers, provides a fundamental overview of the mechanisms of diseases, often at the molecular level. Max Samter (ed.), Immunological Diseases, 4th ed., 2 vol. (1988), covers the collagen diseases. F.M. Burnet, The Natural History of Infectious Disease, 3rd ed. (1962), offers a unique view of infectious disease as an ecological and evolutionary phenomenon. Books for the general reader include June Goodfield, Quest for the Killers (1985), exploring efforts to conquer several epidemic diseases; Andrew Scott, Pirates of the Cell: The Story of Viruses from Molecule to Microbe, rev. ed. (1987); and Peter Radetsky, The Invisible Invaders: The Story of the Emerging Age of Viruses (1991).William Burrows Dante G. Scarpelli Kenneth F. Kiple (ed.), The Cambridge World History of Human Disease (1993), a reference text written for advanced undergraduates and professionals in the biomedical and social sciences, surveys the medical and geographic characteristics of human diseases worldwide throughout history. James B. Wyngaarden, Lloyd H. Smith, Jr., and J. Claude Bennett (eds.), Cecil Textbook of Medicine, 19th ed. (1992), considers all facets of human disease in depth from the modern point of view. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th ed. by Joel G. Hardman and Lee E. Limbird (1996), is a comprehensive text on drugs. T.R. Harrison, Harrison's Principles of Internal Medicine, 13th ed. edited by Kurt J. Isselbacher et al. (1994), discusses in detail the cardinal manifestations of disease under various headings. Theodore Lidz, The Person: His and Her Development Throughout the Life Cycle, rev. ed. (1976, reissued 1983), provides an excellent insight into humans, the psychological organisms. Vinay Kumar, Ramzi S. Cotran, and Stanley L. Robbins, Basic Pathology, 5th ed. (1992), clearly and succinctly presents the causes and pathogenesis of human disease with an emphasis on molecular mechanisms. Margaret W. Thompson, Roderick R. McInnes, and Huntington F. Willard, Thompson & Thompson Genetics in Medicine, 5th ed. (1991), is a well-illustrated and clearly written text on basic genetic principles and their relation to the genesis of human disease. Charles R. Scriver et al. (eds.), The Metabolic Basis of Inherited Disease, 6th ed., 2 vol. (1989), a monumental, highly technical text, provides a comprehensive presentation of the clinical, biochemical, and genetic information concerning those diseases thought to be a consequence of genetic variation. More specific in focus and perhaps less monumental (if not less technical) than the above are Roger N. Rosenberg et al. (eds.), The Molecular and Genetic Basis of Neurological Disease (1993); Aldons J. Lusis, Jerome I. Rotter, and Robert S. Sparkes (eds.), Molecular Genetics of Coronary Artery Disease (1992); and Linda L. Gallo (ed.), Cardiovascular Disease: Molecular and Cellular Mechanisms, Prevention, and Treatment (1987), which address their particular topics on cellular and molecular levels. Robert C. Gallo and Flossie Wong-Staal (eds.), Retrovirus Biology and Human Disease (1990), written for the technically advanced reader, covers various topics in retrovirology, including historical background, epidemiology, clinical features, molecular biology, immunology, and therapeutic approaches. Adrianne Bendich and C.E. Butterworth, Jr. (eds.), Micronutrients in Health and in Disease Prevention (1991), discusses evidence of a correlation between the intake of nonoptimal levels of dietary micronutrients and the development of chronic diseases; although written for the health-care professional, it is also valuable to anyone interested in the relationship between nutrition and health.Stanley L. Robbins Jonathan H. Robbins Dante G. Scarpelli

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