Constancy of the internal environment is maintained by effectors that act to compensate for the change that served as the stimulus for their activation; in short, by negative feedback loops. A thermostat, for example, maintains a constant temperature by increasing heat production when it is cold and decreasing heat production when it is warm. The opposite occurs during positive feedback—in this case, the action of effectors amplifies those changes that stimulated the effectors. A thermostat that works by positive feedback, for example, would increase heat production in response to a rise in temperature.
It is clear that homeostasis must ultimately be maintained by negative rather than by positive feedback mechanisms. The effectiveness of some negative feedback loops, however, is increased by positive feedback mechanisms that amplify the actions of a negative feedback response. Blood clotting, for example, occurs as a result of a sequential activation of clotting factors; the activation of one clotting factor results in activation of many in a positive feedback cascade. In this way, a single change is amplified to produce a blood clot. Formation of the clot, however, can prevent further loss of blood, and thus represents the completion of a negative feedback loop that restores homeostasis.
воскресенье, 10 октября 2010 г.
четверг, 7 октября 2010 г.
Quantitative Measurements
Normal ranges and deviations from the set point must be known quantitatively in order to study physiological mechanisms. For these and other reasons, quantitative measurements are basic to the science of physiology. One example of this, and of the actions of antagonistic mechanisms in maintaining homeostasis. Blood glucose concentrations were measured in five healthy people before and after an injection of insulin, a hormone that acts to lower the blood glucose concentration. A graph of the data reveals that the blood glucose concentration decreased rapidly but was brought back up to normal levels within 80 minutes after the injection. This demonstrates that negative feedback mechanisms acted to restore homeostasis in this experiment. These mechanisms involve the action of hormones whose effects are antagonistic to that of insulin—that is, they promote the secretion of glucose from the liver.
Homeostasis of the blood glucose concentration.
Average blood glucose concentrations of five healthy individuals are graphed before and after a rapid intravenous injection of insulin. The “0” indicates the time of the injection. Notice that, following injection of insulin, the blood glucose is brought back up to the normal range. This occurs as a result of the action of hormones antagonistic to insulin, which cause the liver to secrete glucose into the blood. In this way, homeostasis is maintained.
понедельник, 4 октября 2010 г.
Antagonistic Effectors
Most factors in the internal environment are controlled by several effectors, which often have antagonistic actions. Control by antagonistic effectors is sometimes described as “push-pull,” where the increasing activity of one effector is accompanied by decreasing activity of an antagonistic effector. This affords a finer degree of control than could be achieved by simply switching one effector on and off.
Room temperature can be maintained for example, by simply turning an air conditioner on and off, or by just turning a heater on and off. A much more stable temperature, however, can be achieved if the air conditioner and heater are both controlled by a thermostat. Then the heater is turned on when the air conditioner is turned off, and vice versa. Normal body temperature is maintained about a set point of 37° C by the antagonistic effects of sweating, shivering, and other mechanisms.
The blood concentrations of glucose, calcium, and other substances are regulated by negative feedback loops involving hormones that promote opposite effects. While insulin, for example, lowers blood glucose, other hormones raise the blood glucose concentration. The heart rate, similarly, is controlled by nerve fibers that produce opposite effects: stimulation of one group of nerve fibers increases heart rate; stimulation of another group slows the heart rate.
Room temperature can be maintained for example, by simply turning an air conditioner on and off, or by just turning a heater on and off. A much more stable temperature, however, can be achieved if the air conditioner and heater are both controlled by a thermostat. Then the heater is turned on when the air conditioner is turned off, and vice versa. Normal body temperature is maintained about a set point of 37° C by the antagonistic effects of sweating, shivering, and other mechanisms.
How body temperature is maintained within the normal range.
The body temperature normally has a set point of 37° C. This is maintained, in part, by two antagonistic mechanisms—shivering and sweating. Shivering is induced when the body temperature falls too low, and it gradually subsides as the temperature rises. Sweating occurs when the body temperature is too high, and it diminishes as the temperature falls. Most aspects of the internal environment are regulated by the antagonistic actions of different effector mechanisms.
The blood concentrations of glucose, calcium, and other substances are regulated by negative feedback loops involving hormones that promote opposite effects. While insulin, for example, lowers blood glucose, other hormones raise the blood glucose concentration. The heart rate, similarly, is controlled by nerve fibers that produce opposite effects: stimulation of one group of nerve fibers increases heart rate; stimulation of another group slows the heart rate.
пятница, 1 октября 2010 г.
Negative Feedback Loops
The concept of homeostasis has been of immense value in the study of physiology because it allows diverse regulatory mechanisms to be understood in terms of their “why” as well as their “how.” The concept of homeostasis also provides a major foundation for medical diagnostic procedures. When a particular measurement of the internal environment, such as a blood measurement, deviates significantly from the normal range of values, it can be concluded that homeostasis is not being maintained and that the person is sick. A number of such measurements, combined with clinical observations, may allow the particular defective mechanism to be identified.
In order for internal constancy to be maintained, the body must have sensors that are able to detect deviations from a set point. The set point is analogous to the temperature set on a house thermostat. In a similar manner, there is a set point for body temperature, blood glucose concentration, the tension on a tendon, and so on. When a sensor detects a deviation from a particular set point, it must relay this information to an integrating center, which usually receives information from many different sensors. The integrating center is often a particular region of the brain or spinal cord, but in some cases it can also be a group of cells in an endocrine gland. The relative strengths of different sensory inputs are weighed in the integrating center, which responds by either increasing or decreasing the activity of particular effectors—generally, muscles or glands.
The thermostat of a house can serve as a simple example. Suppose you set the thermostat at a set point of 70° F. If the temperature of the house rises sufficiently above the set point, a sensor within the thermostat will detect the deviation. This will then act, via the thermostat’s equivalent of an integrating center, to activate the effector. The effector in this case may be an air conditioner, which acts to reverse the deviation from the set point.
If the body temperature exceeds the set point of 37° C, sensors in a part of the brain detect this deviation and, acting via an integrating center (also in the brain), stimulate activities of effectors (including sweat glands) that lower the temperature. If, as another example, the blood glucose concentration falls below normal, the effectors act to increase the blood glucose. One can think of the effectors as “defending” the set points against deviations. Since the activity of the effectors is influenced by the effects they produce, and since this regulation is in a negative, or reverse, direction, this type of control system is known as a negative feedback loop.
The nature of the negative feedback loop can be understood by again referring to the analogy of the thermostat and air conditioner. After the air conditioner has been on for some time, the room temperature may fall significantly below the set point of the thermostat. When this occurs, the air conditioner will be turned off. The effector (air conditioner) is turned on by a high temperature and, when activated, produces a negative change (lowering of the temperature) that ultimately causes the effector to be turned off. In this way, constancy is maintained.
It is important to realize that these negative feedback loops are continuous, ongoing processes. Thus, a particular nerve fiber that is part of an effector mechanism may always display some activity, and a particular hormone, which is part of another effector mechanism, may always be present in the blood. The nerve activity and hormone concentration may decrease in response to deviations of the internal environment in one direction, or they may increase in response to deviations in the opposite direction. Changes from the normal range in either direction are thus compensated for by reverse changes in effector activity.
Since negative feedback loops respond after deviations from the set point have stimulated sensors, the internal environment is never absolutely constant. Homeostasis is best conceived as a state of dynamic constancy, in which conditions are stabilized above and below the set point. These conditions can be measured quantitatively, in degrees Celsius for body temperature, for example, or in milligrams per deciliter (one-tenth of a liter) for blood glucose. The set point can be taken as the average value within the normal range of measurements.
In order for internal constancy to be maintained, the body must have sensors that are able to detect deviations from a set point. The set point is analogous to the temperature set on a house thermostat. In a similar manner, there is a set point for body temperature, blood glucose concentration, the tension on a tendon, and so on. When a sensor detects a deviation from a particular set point, it must relay this information to an integrating center, which usually receives information from many different sensors. The integrating center is often a particular region of the brain or spinal cord, but in some cases it can also be a group of cells in an endocrine gland. The relative strengths of different sensory inputs are weighed in the integrating center, which responds by either increasing or decreasing the activity of particular effectors—generally, muscles or glands.
The thermostat of a house can serve as a simple example. Suppose you set the thermostat at a set point of 70° F. If the temperature of the house rises sufficiently above the set point, a sensor within the thermostat will detect the deviation. This will then act, via the thermostat’s equivalent of an integrating center, to activate the effector. The effector in this case may be an air conditioner, which acts to reverse the deviation from the set point.
If the body temperature exceeds the set point of 37° C, sensors in a part of the brain detect this deviation and, acting via an integrating center (also in the brain), stimulate activities of effectors (including sweat glands) that lower the temperature. If, as another example, the blood glucose concentration falls below normal, the effectors act to increase the blood glucose. One can think of the effectors as “defending” the set points against deviations. Since the activity of the effectors is influenced by the effects they produce, and since this regulation is in a negative, or reverse, direction, this type of control system is known as a negative feedback loop.
A rise in some factor of the internal environment (⇑X) is detected by a sensor.
This information is relayed to an integrating center, which causes an effector to produce a change in the opposite direction (⇓X). The initial deviation is thus reversed, completing a negative feedback loop (shown by the dashed arrow and negative sign). The numbers indicate the sequence of changes.
The nature of the negative feedback loop can be understood by again referring to the analogy of the thermostat and air conditioner. After the air conditioner has been on for some time, the room temperature may fall significantly below the set point of the thermostat. When this occurs, the air conditioner will be turned off. The effector (air conditioner) is turned on by a high temperature and, when activated, produces a negative change (lowering of the temperature) that ultimately causes the effector to be turned off. In this way, constancy is maintained.
It is important to realize that these negative feedback loops are continuous, ongoing processes. Thus, a particular nerve fiber that is part of an effector mechanism may always display some activity, and a particular hormone, which is part of another effector mechanism, may always be present in the blood. The nerve activity and hormone concentration may decrease in response to deviations of the internal environment in one direction, or they may increase in response to deviations in the opposite direction. Changes from the normal range in either direction are thus compensated for by reverse changes in effector activity.
Since negative feedback loops respond after deviations from the set point have stimulated sensors, the internal environment is never absolutely constant. Homeostasis is best conceived as a state of dynamic constancy, in which conditions are stabilized above and below the set point. These conditions can be measured quantitatively, in degrees Celsius for body temperature, for example, or in milligrams per deciliter (one-tenth of a liter) for blood glucose. The set point can be taken as the average value within the normal range of measurements.
A fall in some factor of the internal environment (⇓X) is detected by a sensor.
Negative feedback loops maintain a state of dynamic constancy within the internal environment. The completion of the negative feedback loop is indicated by negative signs.
вторник, 28 сентября 2010 г.
History of Physiology
The Greek philosopher Aristotle (384–322 B.C.) speculated on the function of the human body, but another ancient Greek, Erasistratus (304–250? B.C.), is considered the father of physiology because he attempted to apply physical laws to the study of human function. Galen (A.D. 130–201) wrote widely on the subject and was considered the supreme authority until the advent of the Renaissance. Physiology became a fully experimental science with the revolutionary work of the English physician William Harvey (1578–1657), who demonstrated that the heart pumps blood through a closed system of vessels.
However, the father of modern physiology is the French physiologist Claude Bernard (1813–1878), who observed that the milieu interieur (“internal environment”) remains remarkably constant despite changing conditions in the external environment. In a book entitled The Wisdom of the Body, published in 1932, the American physiologist Walter Cannon (1871–1945) coined the term homeostasis to describe this internal constancy. Cannon further suggested that the many mechanisms of physiological regulation have but one purpose—the maintenance of internal constancy.
Most of our present knowledge of human physiology has been gained in the twentieth century. Further, new knowledge is being added at an ever more rapid pace, fueled in more recent decades by the revolutionary growth of molecular genetics and its associated biotechnology, and by the availability of ever more powerful computers and other equipment. A very brief history of twentieth-century physiology, limited by space to only two citations per decade.
However, the father of modern physiology is the French physiologist Claude Bernard (1813–1878), who observed that the milieu interieur (“internal environment”) remains remarkably constant despite changing conditions in the external environment. In a book entitled The Wisdom of the Body, published in 1932, the American physiologist Walter Cannon (1871–1945) coined the term homeostasis to describe this internal constancy. Cannon further suggested that the many mechanisms of physiological regulation have but one purpose—the maintenance of internal constancy.
Most of our present knowledge of human physiology has been gained in the twentieth century. Further, new knowledge is being added at an ever more rapid pace, fueled in more recent decades by the revolutionary growth of molecular genetics and its associated biotechnology, and by the availability of ever more powerful computers and other equipment. A very brief history of twentieth-century physiology, limited by space to only two citations per decade.
суббота, 25 сентября 2010 г.
Development of Pharmaceutical Drugs
The development of new pharmaceutical drugs can serve as an example of how the scientific method is used in physiology and its health applications. The process usually starts with basic physiological research, often at cellular and molecular levels. Perhaps a new family of drugs is developed using cells in tissue culture (in vitro, or outside the body). For example, cell physiologists, studying membrane transport, may discover that a particular family of compounds blocks membrane channels for calcium ions (Ca2+). Because of their knowledge of physiology, other scientists may predict that a drug of this nature might be useful in the treatment of hypertension (high blood pressure). This drug may then be tried in experimental animals.
If a drug is effective at extremely low concentrations in vitro, (in cells cultured outside of the body), there is a chance that it may work in vivo (in the body) at concentrations low enough not to be toxic (poisonous). This possibility must be thoroughly tested utilizing experimental animals, primarily rats and mice. More than 90% of drugs tested in experimental animals are too toxic for further development.
Only in those rare cases when the toxicity is low enough may development progress to human/clinical trials.
Biomedical research is often aided by animal models of particular diseases. These are strains of laboratory rats and mice that are genetically susceptible to particular diseases that resemble human diseases. Research utilizing laboratory animals typically takes several years and always precedes human (clinical) trials of promising drugs. It should be noted that this length of time does not include all of the years of “basic” physiological research (involving laboratory animals) that provided the scientific foundation for the specific medical application.
In phase I clinical trials, the drug is tested on healthy human volunteers. This is done to test its toxicity in humans and to study how the drug is “handled” by the body: how it is metabolized, how rapidly it is removed from the blood by the liver and kidneys, how it can be most effectively administered, and so on. If no toxic effects are observed, the drug can proceed to the next stage. In phase II clinical trials, the drug is tested on the target human population (for example, those with hypertension). Only in those exceptional cases where the drug seems to be effective but has minimal toxicity does testing move to the next phase. Phase III trials occur in many research centers across the country to maximize the number of test participants. At this point, the test population must include a sufficient number of subjects of both sexes, as well as people of different ethnic groups. In addition,
people are tested who have other health problems besides the one that the drug is intended to benefit. For example, those who have diabetes in addition to hypertension would be included in this phase. If the drug passes phase III trials, it goes to the Food and Drug Administration (FDA) for approval. Phase IV trials test other potential uses of the drug.
The percentage of drugs that make it all the way through these trials to eventually become approved and marketed is very low. Notice the crucial role of basic research, using experimental animals, in this process. Virtually every prescription drug on the market owes its existence to such research.
If a drug is effective at extremely low concentrations in vitro, (in cells cultured outside of the body), there is a chance that it may work in vivo (in the body) at concentrations low enough not to be toxic (poisonous). This possibility must be thoroughly tested utilizing experimental animals, primarily rats and mice. More than 90% of drugs tested in experimental animals are too toxic for further development.
Only in those rare cases when the toxicity is low enough may development progress to human/clinical trials.
Biomedical research is often aided by animal models of particular diseases. These are strains of laboratory rats and mice that are genetically susceptible to particular diseases that resemble human diseases. Research utilizing laboratory animals typically takes several years and always precedes human (clinical) trials of promising drugs. It should be noted that this length of time does not include all of the years of “basic” physiological research (involving laboratory animals) that provided the scientific foundation for the specific medical application.
In phase I clinical trials, the drug is tested on healthy human volunteers. This is done to test its toxicity in humans and to study how the drug is “handled” by the body: how it is metabolized, how rapidly it is removed from the blood by the liver and kidneys, how it can be most effectively administered, and so on. If no toxic effects are observed, the drug can proceed to the next stage. In phase II clinical trials, the drug is tested on the target human population (for example, those with hypertension). Only in those exceptional cases where the drug seems to be effective but has minimal toxicity does testing move to the next phase. Phase III trials occur in many research centers across the country to maximize the number of test participants. At this point, the test population must include a sufficient number of subjects of both sexes, as well as people of different ethnic groups. In addition,
people are tested who have other health problems besides the one that the drug is intended to benefit. For example, those who have diabetes in addition to hypertension would be included in this phase. If the drug passes phase III trials, it goes to the Food and Drug Administration (FDA) for approval. Phase IV trials test other potential uses of the drug.
The percentage of drugs that make it all the way through these trials to eventually become approved and marketed is very low. Notice the crucial role of basic research, using experimental animals, in this process. Virtually every prescription drug on the market owes its existence to such research.
среда, 22 сентября 2010 г.
Use of Measurements, Controls, and Statistics
Suppose you wanted to test the hypothesis that a regular exercise program causes people to have a lower resting heart rate. First, you would have to decide on the nature of the exercise program. Then, you would have to decide how the heart rate (or pulse rate) would be measured. This is a typical problem in physiology research, because the testing of most physiological hypotheses requires quantitative measurements.
The group that is subject to the testing condition—in this case, exercise—is called the experimental group. A measurement of the heart rate for this group would only be meaningful if it is compared to that of another group, known as the control group. How shall this control group be chosen? Perhaps the subjects could serve as their own controls—that is, a person’s resting heart rate could be measured before and after the exercise regimen. If this isn’t possible, a control group could be other people who do not follow the exercise program. The choice of control groups is often a controversial aspect of physiology studies. In this example, did the people in the control group really refrain from any exercise? Were they comparable to the people in the experimental group with regard to age, sex, ethnicity, body weight, health status, and so on? You can see how difficult it could be in practice to get a control group that could satisfy any potential criticism.
Another potential criticism could be bias in the way that the scientists perform the measurements. This bias could be completely unintentional; scientists are human, after all, and they may have invested months or years in this project! Thus, the person doing the measurements often does not know if a subject is part of the experimental or the control group. This is known as a blind measurement.
Now suppose the data are in, and it looks like the experimental group indeed has a lower average resting heart rate than the control group. But there is overlap—some people in the control group have measurements that are lower than some people in the experimental group. Now, is the difference in the average measurements of the groups due to a real, physiological difference, or is it due to chance variations in the measurements? Scientists attempt to test the null hypothesis (the hypothesis that the difference is due to chance) by employing the mathematical tools of statistics. If the statistical results so warrant, the null hypothesis can be rejected and the experimental hypothesis can be deemed to be supported by this study.
The statistical test chosen will depend upon the design of the experiment, and it can also be a source of contention among scientists in evaluating the validity of the results. Because of the nature of the scientific method, “proof” in science is always provisional. Some other researchers, employing the scientific method in a different way (with different measuring techniques, experimental procedures, choice of control groups, statistical tests, and so on) may later obtain different results. The scientific method is thus an ongoing enterprise.
The results of the scientific enterprise are written up as research articles, and these must be reviewed by other scientists who work in the same field before they can be published in peer-reviewed journals. More often than not, the reviewers will suggest that certain changes be made in the articles before they can be accepted for publication.
The group that is subject to the testing condition—in this case, exercise—is called the experimental group. A measurement of the heart rate for this group would only be meaningful if it is compared to that of another group, known as the control group. How shall this control group be chosen? Perhaps the subjects could serve as their own controls—that is, a person’s resting heart rate could be measured before and after the exercise regimen. If this isn’t possible, a control group could be other people who do not follow the exercise program. The choice of control groups is often a controversial aspect of physiology studies. In this example, did the people in the control group really refrain from any exercise? Were they comparable to the people in the experimental group with regard to age, sex, ethnicity, body weight, health status, and so on? You can see how difficult it could be in practice to get a control group that could satisfy any potential criticism.
Another potential criticism could be bias in the way that the scientists perform the measurements. This bias could be completely unintentional; scientists are human, after all, and they may have invested months or years in this project! Thus, the person doing the measurements often does not know if a subject is part of the experimental or the control group. This is known as a blind measurement.
Now suppose the data are in, and it looks like the experimental group indeed has a lower average resting heart rate than the control group. But there is overlap—some people in the control group have measurements that are lower than some people in the experimental group. Now, is the difference in the average measurements of the groups due to a real, physiological difference, or is it due to chance variations in the measurements? Scientists attempt to test the null hypothesis (the hypothesis that the difference is due to chance) by employing the mathematical tools of statistics. If the statistical results so warrant, the null hypothesis can be rejected and the experimental hypothesis can be deemed to be supported by this study.
The statistical test chosen will depend upon the design of the experiment, and it can also be a source of contention among scientists in evaluating the validity of the results. Because of the nature of the scientific method, “proof” in science is always provisional. Some other researchers, employing the scientific method in a different way (with different measuring techniques, experimental procedures, choice of control groups, statistical tests, and so on) may later obtain different results. The scientific method is thus an ongoing enterprise.
The results of the scientific enterprise are written up as research articles, and these must be reviewed by other scientists who work in the same field before they can be published in peer-reviewed journals. More often than not, the reviewers will suggest that certain changes be made in the articles before they can be accepted for publication.
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