Propranolol

Eric H. Awtry, MD, FACC

• Boston Medical Center
• Assistant Professor of Medicine
• Boston University School of Medicine
• Director of Education, Division of Cardiology
• Boston, Massachusetts

In limnological studies ischaemic heart disease 60 propranolol 40mg free shipping, water temperatures as a function of depth often are required blood vessels in eye order generic propranolol line. Elevated temperatures resulting from discharges of heated water may have significant ecological impact cardiovascular system yoga order 20mg propranolol with mastercard. Identification of source of water supply capillaries wall structure propranolol 20 mg on-line, such as deep wells blood vessels eye order propranolol 20 mg otc, often is possible by temperature measurements alone heart disease forum cheap 20mg propranolol. Industrial plants often require data on water temperature for process use or heat-transmission calculations. Laboratory and Other Non-Depth Temperature Measurements Normally, temperature measurements may be made with any good mercury-filled Celsius thermometer. The thermometer should have a minimal thermal capacity to permit rapid equilibration. One calibrated for total immersion must be completely immersed to the depth of the etched circle around the stem just below the scale level. Depth Temperature Measurements Depth temperature required for limnological studies may be measured with a reversing thermometer, thermophone, or thermistor. The thermistor is most convenient and accurate; however, higher cost may preclude its use. Make readings with the thermometer or device immersed in water long enough to permit complete equilibration. It often is mounted on the sample collection apparatus so that a water sample may be obtained simultaneously. Correct readings of reversing thermometers for changes due to differences between temperature at reversal and temperature at time of reading. If series observations are made it is convenient to prepare graphs for a thermometer to obtain T from any values of T 1 and t. General Discussion Particles are ubiquitous in natural waters and in water and wastewater treatment streams. Particle counting and size distribution analysis can help to determine the makeup of natural waters, treatment plant influent, process water, and finished water. Similarly, it can aid in designing treatment processes, making decisions about changes in operations, and/or determining process efficiency. Methods for measuring particle size distribution included herein depend on electronic measurement devices because manual methods are likely to be too slow for routine analysis. Principles of various types of instruments capable of producing both size and number concentration information on particulate dispersions are included. In most particle-counting instruments, particles pass though a sensing zone where they are measured individually; the only exception included is the static type of light-scattering instrument. Instruments create an electronic pulse (voltage, current, or resistance) that is proportional to a characteristic size of the particle. The instrument responses (pulse height, width, or area) are classified by magnitude and counted in each class to yield the particle size distribution. Selection of Method Three instrument types are included: electrical sensing zone instruments, light-blockage instruments, and light-scattering instruments. Instruments vary in the particle characteristic being sensed, lower and upper size limits of detection, degree of resolution of the size distribution, particle number concentration range that can be measured accurately, amount of shear to which a sample is subjected before measurement, amount of sample preparation, operator skill required, and the ease with which data can be obtained and manipulated into the desired forms. For instruments usable in both modes, check that no systematic differences in particle size distributions occur between continuous-flow measurements and batch samples taken at or near the intake point for continuous-flow samples. Batch samples: Use extreme care in obtaining, handling, and preparing batch samples to avoid changing total particle count and size distribution. Ensure that particles are not subjected to greater physical forces during collection than in their natural setting. Collect samples from a body of water with submerged vessels to minimize turbulence and bubble entrainment. If sampling from particular depths, use standard samplers designed for that purpose. For flowing systems, make sure that the velocity into the opening of the sampling device is the same as that of the flowing stream (isokinetic sampling) and that the opening diameter is at least 50 times as large as the particles to be measured. For sampling from a tap, let water flow slowly and continuously down the side of the collection vessel. Minimize exposure to air by keeping sample in a closed container and by minimizing time between sampling and analysis. Clean all glassware scrupulously by automatic dishwashing, vigorous hand brushing, and/or ultrasonication. Between samples, rinse any part of the instrument that comes in contact with samples with either clean water or the upcoming sample. To avoid breakup of aggregates of particles or flocs, sample and make dilutions very slowly using wide-bore pipets, needles, or other sampling devices; cut off pipet tips to avoid high velocities at the entrance. Use minimum intensity and duration of mixing adequate to dilute the suspension into the dilution water. Simultaneously gently rotate and partially invert entire sample in a closed bottle. Do not mix during measurement unless absolutely necessary to prevent sedimentation. Most surface and ground waters contain relatively stable particles that aggregate slowly. Particle size distribution in biologically active waters or waters that have been treated with coagulants is more likely to change over short time periods. In highly flocculent systems, maximum holding time should be only a few minutes; for more stable samples, a few hours may be acceptable. Dilution slows flocculation kinetics and, in some cases, makes flocculation less likely. Samples measured at different temperature or pressure than when collected and those with biological activity may develop entrained air bubbles that interfere with measurement accuracy. If any gas bubbles are visible, let sample stand for a short time to degas naturally or use a mild vacuum to speed degassing. Minimize time between sampling and analysis; if at all possible, make measurements immediately after sampling. Continuous-flow: Using a particle counter as a continuous-flow monitor may be desirable. Many more samples can be processed by automated particle counting than by batch sample analysis. All the instruments mentioned in Methods B through D can be used in this mode, although instruments and samples not requiring dilution are easier to set up. For some instruments, this type of operation requires custom hardware; for others there is commercially available hardware. Place entrance to sample line facing the flow, with the velocity at the opening nearly the same as the surrounding flow. Sample preservation within the instrument is difficult because both deposition (or temporary holdup) of particles and floc breakup must be avoided. Minimize length of transmission lines, especially in horizontal components, and preferably have no horizontal lines. For continuous particle size distribution measurements, flow control, not simply flow monitoring, is necessary. Provide a flow control system downstream of the sensor, maintain a constant rate, and do not introduce turbulence or pulsations before or through the sensor. Dilution Water Particle-free water is virtually impossible to obtain, but it is possible to produce water containing very few particles within the size range to be measured. Dilution water preparation systems are available from particle-counter manufacturers. Alternatively, assemble a system similar to that shown in Figure 2560:1 (or any system that produces a water of sufficient quality). In the system shown, a pump draws the water from a bottle and puts it through the in-line filter. Use membrane filters with nominal pore sizes no more than 10% of the smallest particle size expected; alternatively use cartridge filters. The system lets water be passed directly from the product-water bottle to the source-water bottle by opening of the clamps and three-way stopcock. Use glass tubing in the bottles, but use flexible tubing to allow draining product-water bottle into source-water bottle. Dilute samples by drawing water directly from the three-way stopcock into the bottle to be used in sample analysis. A simpler system with one-pass filtration directly into the sample bottle may be adequate for many samples, depending on the particle size range to be measured. Such a system would omit the product-water bottle, the connections between the two bottles and associated stopcock and clamps of Figure 2560:1. Dilution water is produced on demand and the effluent is put directly, without additional handling, into the sample container. Guard against biological growth within filtration systems by frequent disassembly and adequate washing or replacement of components. For many samples, do not use chemical disinfectants because they might change the particle count and size distribution by their oxidizing potential. Calibration As a particle is detected in the sensing zone of any instrument, an electrical response is generated and sorted into a channel of the instrument based on its magnitude. Calibrate by determining the channel number into which particles of known size are sorted by the instrument. Over time, suspensions are likely to undergo some aggregation; use ultrasound to break up flocs before calibration. Calibration particles are nearly monodisperse but do exhibit a small inherent (true) variance. Resolution is a measure of the ability of an instrument to distinguish between particles of similar but different sizes. An instrument with high precision and good resolution will measure monodisperse particles in a very narrow size range; some instruments have sufficient precision and resolution so that calibration particles with extremely narrow size distributions (very small variance) are sorted into a few adjacent channels. In such cases, the true variance of the particle size and the measured variance will be nearly equal. An instrument with low precision but high resolution will yield a wide distribution on the same particles. Use at least three sizes of calibration particles in reasonably similar number concentrations to calibrate a sensor. To analyze different-size particles in a mixture, ensure that the different sizes do not interfere with one another. The calibration curve depends on the characteristic of the particle measured by the instrument (diameter, area, or volume) and whether the pulses are sorted into channels on an arithmetic or logarithmic basis. For example, if an electrical sensing zone instrument (which responds to particle volume) is used in a logarithmic mode, the calibration curve will be the logarithm of particle volume vs. Generally, increments between channels are equal on an arithmetic or logarithmic basis. In most light-blockage and light-scattering instruments, the lower and upper limits for each channel can be set by the user. Because most samples have broad particle size distributions, spanning at least one order of magnitude, and often two or three, preferably use larger increments for larger sizes. This is consistent with equal logarithmic spacing, although other less systematic intervals that preserve the characteristic of larger increments for larger sizes are permissible. At a given set of settings for a given sensor, each channel represents a certain average size and size increment. After measuring the channel number associated with several sizes of calibration particles, use a calibration equation to assign average sizes or, in some cases, the lower limit of size, to all other channels. Knowledge of the average size and both the arithmetic and logarithmic increment of each channel is necessary for reporting. In contrast to calibration particles, environmental particles are rarely spherical. Because most sample particles are nonspherical and different instruments respond to different characteristics of particles, different measured particle size distributions result from different instruments. Some light-scattering instruments calculate particle size from first principles and do not require calibration per se.

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The reptilian response to a stimulus is different from the fright one might experience before giving a lecture cardiovascular system the blood cheap propranolol 40 mg on line. So capillaries near alveoli discount 20 mg propranolol with mastercard, even before you feel the nail coronary heart 7 acupressure generic propranolol 20 mg amex, the information is trans mitted up to the brain cardiovascular disease 2013 buy generic propranolol line. This is the brain that is concerned with feelings and emo tions and is much like that of our pet dogs or cats cardiovascular system wikipedia cheap propranolol online master card. However cardiovascular technologist jobs purchase propranolol australia, pets have absolutely no sense of time, no sense of prioritized thinking, and no ability to dream of the future. Therefore, animals are not really subject to the acculturation processes that humans are. The third brain is the human brain, which is affliated with the limbic system, but controlled by the prefrontal neocortex. The human brain is capable of higher cogni tive processes, of perceiving time, and of pondering the spiritual self. The triune brain is sometimes inaccurately described as simply an evolutionary pro cess culminating in the human brain. However, our brains should more correctly be thought of as a dynamic interaction of the evolutionary trends of the three. As we develop as individuals, we have the daunting task of effectively integrating our so-called three minds. Electrical impulses, carried by neurons, move information to various locations, but they com municate with each other in a chemical language via neurotransmitters. As already mentioned, the neuron is the basic unit of communication or informa tion processing in the nervous system. Dendrites increase the available area for a neuron to receive incoming information. The axon is wrapped in a fatty coating called a myelin sheath, which is like a coat of insulation that preserves electrical impulses. The sympathetic nervous system is myelinated, and the parasympathetic is unmyelinated. Multiple sclerosis, for instance, occurs when the myelin sheath is disturbed or destroyed, preventing the electrical impulses from being transmitted properly. After processing A Review of Classic Physiological Systems 15 this information, if the brain determines that a motor response is needed, it sends the message via the motor neurons, and your body moves. When a neuron is at rest, there is a steady voltage difference across its plasma membrane. This is a get-up-and-go message, caus ing a brief reversal in voltage across the plasma membrane. Action potentials arise and move rapidly along sensory and motor neurons because of the myelin sheath. When the action potential reaches the postsynaptic output zone, it either just stops or it may release a neurotransmitter that passes the message along. They can be either excitatory, causing the receiving neuron to continue passing the electrical impulse, or inhibitory, stopping the chain of electrical frings. The region of communi cation between two neurons is called a synapse, which is illustrated in Figure 1. Presynaptic nerve cell Axon Action potential Synapse Neurotransmitter vesicles Difusion of neurotransmitter Postsynaptic nerve cell figuRe 1. The frst nerve cell is called the preganglionic nerve, and the second nerve to receive the message is called the postganglionic nerve. The neurotransmitter for sympathetic and parasympathetic preganglionic and for the parasympathetic postganglionic neurons is acetylcholine. The postganglionic nerve carries the message along to the outlying effector organs. When I was in medical school, we were taught that humans were born with something like 100 billion neurons, and when any one neuron died, that was the end. Recently, Fred Gage, from the Salk Institute for Biological Studies in La Jolla, California, and his colleagues in Sweden have shown that neurons can be produced in the adult human being, not just the child, which completely blows a major theory. The neurons Gage researched were produced in the dentate gyrus of the hippocampus. The rate of proliferation was not high, about 500 new neurons a day, but they did have the morphologic and phenotypic characteristics of neurons (Eriksson et al. Although the biological signifcance of this neurogenesis is yet to be fully deter mined, it is very interesting to keep in mind for later when we talk about the healing response because, as you will remember, the hippocampus is the center of traumatic memory. Neurotransmitters can bind with receptor proteins on the membrane of a neuron, a muscle (this is called the neuromuscular junction), or a gland, and as we said, they can excite or inhibit them. In medical school, I learned that one neuron was capable of secreting only one neurotransmitter. Neuromodulators can make the postsynaptic neuron more sensitive or less sensi tive to the neurotransmitter that is present. Endorphins, which are naturally occurring substances in our body, are important neuromodulators because they are powerful painkillers. It is also my opinion that cortical activity, which means a thought, produces a series of hormones (neuropeptides) that food into other portions of the brain, frequently the limbic system. A feld of research called psychoendocrinology is concerned with hormones and the behavioral effects attributed to them. Neuropeptides that func tion as hormones produce chemical signals instead of electrical signals. For instance, when we think a particular thought, receptors in the limbic system (the limbic system is rich in receptors) affect numerous functions, including sexual behavior, sleep, temperature regulation, breathing, blood pressure, addiction, habituation, memory, and learning. The core limbic structures, long considered the emotional center of the brain, are infused with recep tors, not only for opioids, such as endorphins and enkephalins, but also for the majority of the neuropeptides. The neuropeptides are secreted when you have a thought process that impinges on this limbic system. If there are receptors in the limbic system for these particular hormones, there will be an alteration of the response. Recent 18 the Scientifc Basis of Integrative Medicine research has shown that there is a whole calcitonin-based system for pain relief that is similar to the endorphins. For example, you go wandering in the desert and it is a hot day, and you forgot your water bottle. We will devote all of Chapter 2 to understanding this and other system integration issues. The important concept to grasp now is that these very cells that we have elaborated are secreting hormones and, consequently, allowing communication across major systems. We ar e o n the Pl a n e T li k e a Wo r k o f ar T There are basically three directions of information transmission to the command center, which is our hypothalamus. Moving via chemical and electrical pathways, our thoughts go to the hypothalamus from the cortex; our emotional reactions go to the hypothalamus from the limbic system; and, as described, our states of awareness go to the hypothalamus from the reticular formation. If some one has been meditating, maybe for 10 years, he or she begins to get a sense of eter nity, a sense of accepting the fact that we are on the planet like a work of art. When we deeply understand this truth, there is a sense of serenity that comes to our lives. This, I think, is going to be the key to future research in consciousness and awareness, and how it interfaces with physiology. I think that research will increas ingly show that when our higher awareness center. And when the reticular forma tion becomes the command center, everything settles down into a state of physi ologic relaxation, healing, and harmony. Another route to experiencing higher states of conscious ness comes by working on quieting our state of mind, using a technique that I call limbic therapy. They appear in different patterns, depending upon how much electrical current is emanating from the nerve cells. States of awareness in which you are fully alert and in which there is intense activity of the nervous system are called beta. The alpha state, from 8 to 12 Hz, includes normal waking hours and when you are in a relaxed state of mind. You are not ruminating over memories of things you have to do, things you may not want to do, or arguments you may have had. Theta, which is 4 to 7 Hz, is a state between wake and sleep that is called hypnagogia. Theta also is involved in some nonrelaxation actions, such as learning, memory, and acquisition of information. Until recently, it was thought that meditation occurs exclusively during alpha and more rarely during theta states. However, as discussed in Chapter 11, at least for meditations that focus on compassion for others and possibly during other types of meditation, it is now known the mind emits gamma waves (25 to 42 Hz). A person demonstrating predominant delta (< 4 Hz) wave activity is in deep sleep, a coma, or has signifcant brain pathology. It is my theory that theta is a state of mind in which the healing of old emotional traumas may occur, which is why I call it limbic therapy. It is a state that allows us to get into the traumatic memories that have been encoded in the hippocampus and either greatly decrease their impact or actually erase them. A Review of Classic Physiological Systems 21 section 2: the endocRine systeM the endocrine system is a system of internal structures that secrete hormones (mostly into the bloodstream) to regulate metabolism and perform myriad other bodily func tions. It turns an elec trical signal into the elaboration of a single hormone or of several hormones, which then travel to various places in the body, communicating and directing physiological activity. The glands of the endocrine system include the pituitary, hypothalamus, thyroid, parathyroid, pancreas, adrenals, gonads (ovaries and testes), thymus, and the pineal gland (see Figure 1. In addition, there are various other organs with hormonal functions that are not technically considered to be endocrine glands, such as the previously discussed enteric system. For a hormone to have an effect, the cell must have a receptor site specifc to that hormone. If the hormone does not exactly ft into the receptor (which is similar to the paradigm of a triangle ftting into a triangle or a circle into a circle), the hormone has absolutely no effect on that cell. Not every cell has a receptor for every hormone, although many cells have receptor sites for more than one hormone. Sometimes the receptors for a given hormone are predominantly localized on one organ, but increasingly, receptors for such hormones are being found in other organs as well as the brain. The body produces its hormones or neurotransmitters, which are referred to as endogenous ligands. However, different pharmaceutical agents and other exogenous substances also ft into a receptor. In some instances, the drug mimics the endogenous ligand; in other instances, it can produce a much stronger or different reaction. When either a drug or an endog enous ligand produces a known effect, it is called an agonist. When a drug or endoge nous ligand exhibits the ability to block a receptor, it is called an antagonist. A reverse or inverse agonist is a drug or endogenous ligand that produces symptoms opposite to those that are known. In Chapter 4, which addresses the relaxation system, you will read about the benzodiazepine receptor that accepts all three types of ligands. Keep in mind that mul tiple receptors also may be activated by the same ligand via a number of mechanisms. Different ligands for the same receptor probably elicit diverse magnitudes of response and use several signaling pathways under varied conditions (Pauwels, 2000). The interaction between the hormone and the receptor activates an enzyme, called adenyl cyclase, within the cell. A Review of Classic Physiological Systems 23 Another type of hormone is the group of eicosanoid hormones. They are transported through the bloodstream like endocrine hormones and act locally. The eicosanoids are derived from arachidonic acid, an essential fatty acid, and have short half-lives. Each locally acting hormone system mainly affects the tissue from which it is produced. We will be discussing a class of arachidonic acid hormones, called the cannabinoids, in Chapter 4, which covers relaxation. Hormonal messages are not always passed via the classic means of release of neurotransmitter and acceptance by receptor. These chemical messengers may also communicate in more localized ways (see Figure 1. For instance, when some mes sengers are diffused into the interstitial fuid, that is, the fuid between two neurons, they latch onto receptors on neighboring cells.

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In other words 4 blocked arteries best propranolol 40 mg, the lymphocyte does not even reveal that it has a receptor for insulin until it is faced with an antigen cardiovascular system blood vessel structure and function purchase cheapest propranolol and propranolol. Some investigators and scientists who write about the immune system are still resistant to incorporating discussion of systems interaction 3 arteries buy discount propranolol 20mg, which is evidenced by the fact that recently written arteries have thicker walls than veins order propranolol without prescription, standard medical textbooks describe the immune system as an autonomous entity cardiovascular disease case study order propranolol, entirely ignoring information about systems integration capillaries blood flow purchase propranolol canada. In 43 44 the Scientifc Basis of Integrative Medicine looking at the history of medicine, there has been a propensity among the medical community to separate and simplify everything in the body. Yet, research has shown that neither cellular functions nor body systems are pristinely discrete units, as previ ously taught. In spite of considerable capacity for self-regulation, the immune system can be modulated by endocrine and neural activity, and it can just as easily infuence endo crine, neural, stress, and other behavioral functions (Ader et al. We will begin by reviewing numerous studies of functional and cellular interactions among the body systems. There are interactions between each of the classic body systems and the stress system as well. However, we will cover these issues in the chapter on stress (Chapter 3) and not here. The implications of systems integration for human disease will then be discussed and sometimes speculated upon. It is important to recognize that we are now faced with terms whose meanings no longer ft their designated defnition. In Chapter 1, we made every effort to defne these terms by their classic or traditional terminology. It is beyond our interest and scope in this book to attempt to create new defnitions (although it is our contention that they are needed), so we have chosen to use these words in their classic descriptive sense as we peruse the frontiers of medicine. First, studies show that various neurons can have recep tors for both hormones and neurotransmitters. Second, investigations have revealed that many clas sic hormones behave like a neurotransmitter, that is, they are not only released from endocrine tissue, but from nerve cells as well. Therefore, hormones can be found in the brain of humans and various other mammals, functioning both as hormonal and electrical transmitters. For example, the functional interactions between a neuropeptide, called galanin, and the classic neu rotransmitter, acetylcholine, appear to be related to memory inhibition, and there is some suggestion that the mitigation of this interaction may beneft those suffering from various types of dementia (Crawley, 1990). Most of these neuropeptides previously were thought to be localized only in discrete areas of one of the three classically defned body systems and not in the brain. The list of neuro peptides is so numerous that there are undoubtedly some that we have left out, and with equal assuredness, there are others that will be discovered in the near future. I reiterate; it is my contention that the brain is capable of secreting any hormone produced by the body, as needed, and that it is only a matter of time before this is determined scientifcally. The implications of the nervous and endocrine systems sharing transmitters are enormous and set the stage for signifcant interactions with the immune and stress systems. The body houses an effcient organization not only for the nervous system to communicate with the hormones of the endocrine system, or vice versa, but also, as we shall review, for the immune and stress systems to infuence and be infuenced by the nervous and endocrine systems. As mentioned in the Introduction of this book, in 1975, Robert Ader and his colleagues published research on the conditioned immune response in a rat population. If you recall, the rats in the experimental group were injected with cyclophosphamide (an immunosuppressive agent) and given drinking water favored with saccharin. Rats later given only the saccharin-favored water nevertheless continued to evidence reduced immune responses. Similarly, over a hundred years ago, Sir William Osler, the notable physi cian from Johns Hopkins, describes a patient having an asthma attack after smelling an artifcial rose. Conditioned immune enhancement, like suppression, has now been illustrated with the use of the same chemical, cyclophosphamide, as well as by a variety of Systems Integration 47 other stimuli, including taste and smell (Bovbjerg et al. However, much of the earlier research on conditioning involved studies of immune suppression. Many of these studies showed that an aversive stimulus can induce glucocorticoid elevation and immune suppression. All of this research suggests that behavior itself is the regulator of immune function (Ader, 1990; Reichlin, 1993). Conversely, accu mulated research shows that any immune function can occur in the brain. Think about how amazing that statement is; our immune system is fully expressed in the home of our thoughts and emotions. The nervous system communicates with the immune system via sympathetic fbers coming from and going to the brain. Neurotransmitters typically must be activated by the immune system before passing on their message. So, how does the brain receive and respond to chemical and electrical information from the immune system The information received involves messages about the general type and level of intensity of the intruder, not information about the specifc antigen. It then lets the central and peripheral nervous systems in on the news, 48 the Scientifc Basis of Integrative Medicine figuRe 2. There is, in fact, an inter actional and functional relationship between the two systems. One of the greatest examples of the interdependency of the nervous and immune systems came out of pioneering work begun in the late 1970s, which was performed by Hugo Besedovsky and his colleagues in Germany. They determined that neu ronal fring rates increased in the hypothalamus during peak antibody response to an immunization, with a corresponding decrease of norepinephrine content in the hypo thalamus. Norepinephrine also showed a time-dependent decrease in the spleens of mice following immunization as well as after antigen challenge (Besedovsky et al. Ten years later, a pattern of increased fring rate cor responding to antibody production was ascertained by another investigator as well (Saphier et al. Any alteration in neuroendocrine factors, whether local or systemic, can mark edly alter the immune activity (Felten et al. Given the mobile nature of immune cells, messages can reach the immune system by nerves in the vicinity of the target immune cells or via the circulation. This systemic change results in immune system adjustments, which we will discuss in detail in the chapter on stress (Chapter 3). Likewise, local synthesis and secretion of neuropeptides by immune cells are important for subtler adjustments in the maintenance of immune homeosta sis. Bear in mind that the body systems are sharing receptors for multiple possible combinations of immune, endocrine, stress, and/or nervous system factors that can be elaborated either within or between one another. Cy T o k i n e s a s im m u n o l o g i C a l me s s e n g e r s Cytokines are nonantibody proteins that function like hormones and can trigger fur ther cytokine and hormonal secretions. In addition, cytokines are the principal mediators of communication between the immune and neuroendocrine systems, which also results in immune system 50 the Scientifc Basis of Integrative Medicine modulation, particularly regarding infammation and infection. However, the immune sys tem can communicate the presence of such stimuli through cytokine immunological messengers (Bulloch, 1985). By and large, the cytokines (and their receptors) that are found in the nervous sys tem are localized to the brain. The effect of hav ing cytokines localized in the brain is that they are capable of infuencing neuroen docrine production. However, now we know that cytokines are responsible for numerous neuroendocrine alterations (see partial list in Table 2. The activated immune system sends both humoral and neural messages to the brain that there is some type of intruder (antigen, virus, or bacteria) pres ent in the body (Besedovsky and del Rey, 2001). Studies show that these brainborne cytokines can infuence peripheral neuroendocrine functions and infuence behavioral effects, particularly those associated with the hypothala mus and hippocampus (Kent et al. These actions prob ably help maintain homeostasis by modulating the interaction of the systems during antigen challenge. These lymphocyte-derived, pituitary-like hormones actually modulate subtle adjustments in pituitary hormone secretions (Schwartz, 2000). In other words, stimulated lympho cytes produce neuropeptides to modulate their own immunity (Smith and Blalock, 1981). We will next briefy review the ways in which some of the neuroendocrine hor mones can affect immune function. Its ability to suppress immune function via glucocorticoid stimulation will be discussed later in this chapter. In 1979, T lympho cytes were shown to have receptors for enkephalins (Wybran et al. Receptors for endorphins were frst located on virus-infected leukocytes (Blalock and Smith, 1980). Generally, endorphin and the enkephalins (to a lesser extent) inhibit antibody production, and and endorphins increase antibody production. Therefore, it is probable that the endogenous opioids complete a circuit, linking 54 the Scientifc Basis of Integrative Medicine the immune with the nervous and endocrine systems as well as acting independently within each system (Smith et al. It is associated with control of food intake, the regulation of skin pigmentation, protection against microbes, and the modulation of infammation. It acts both by modu lating infammatory mediators, such as cytokines, and at peripheral infammatory receptors. We will now take a look at the thymus and pineal glands as organs that have major roles as facilitators of immune and neuroendocrine communication. Th y m u s gl a n d In addition to its role as the master trainer of the immune system, the thymus is also a very active endocrine gland. It is capable of secreting various hormones and is infuenced by neurotransmitter secretions, resulting in actions that both regulate the immune system and impact on other body systems. Incorporated on this gland there is actually an integration of all three classic systems. In addition, numerous hormones produced within the thymus are classically thought of as pituitary hormones. At high concentrations, they induce thymocyte apoptosis, but at lower concentrations, they actually potentiate thymocyte maturation (Vacchio et al. We will come back to this point when we look at the role that glucocorticoids play in stress (see Chapter 3, which covers the stress system). Sympathetic noradrenergic innervation of the thymus is well established both from animal and human studies, and norepinephrine is the primary hormone affecting the thymus (Ackerman et al. There is evidence that norepinephrine regulates lymphocyte entry and exit of immune organs in general and with the thymus in particular (Madden, 2001; Wiedmeier et al. As the thymic cortex progressively alters in composition with 56 the Scientifc Basis of Integrative Medicine age, noradrenergic innervation becomes denser and norepinephrine increases, possibly playing a role in immune regulation (Bellinger et al. An aging thymus contrib utes to decreased effcacy of the immune system because of a reduction in secretion of thymic hormones and fewer T lymphocytes capable of functioning at full competency. It also affects B-cell effcacy, possibly because there are fewer helper T cells to prepare the antigen for the B cells. Pi n e a l gl a n d the pineal gland is eminently important to systems integration; in fact, it is my conten tion that the pineal gland, not the pituitary, is the master gland (see Chapter 10 on the pineal gland). It is the primary neuroendocrine energy trans ducer, which means that its sensory receptors are capable of receiving environmental stimuli and converting them into action potentials capable of communicating with the brain. Pineal innervation is supplied by the sympathetic nervous system as well as by fbers coming directly from the brain. Nerve endings typically are found in proximity to the specialized secretory cells of the pineal gland, called pinealocytes, which are the cells that elaborate melatonin. The primary neurotransmitter is norepinephrine, which acts on adrenergic receptors on the pinealocyte membrane. However, some researchers describe the pineal gland as having numerous types of receptors (Ebadi and Govitrapong, 1986). The neuronal pathways are connected to the hypothalamus and, in particular, its suprachiasmatic nucleus (the home of our biological clock). This ebb and fow of melatonin provides us with the circadian rhythm governing our daily sleep cycles and the seasonal cycles of many animals. Melatonin has been shown to stimulate immune function and reduce the del eterious effects of stress. Notably, the immune-boosting effects of melatonin appear to be mediated by opioid agonists. These opioid agonists arise when melatonin stimu lates T-lymphocyte helper cells that have already been stimulated by an antigen (Maestroni and Conti, 1991).

Diseases

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• Carcinoma, squamous cell of head and neck
• Euhidrotic ectodermal dysplasia
• Coloboma of macula
• Richieri Costa Guion Almeida syndrome
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• Faciocardiomelic dysplasia lethal