Joseph A Carrese, M.D., M.P.H.

• Chair, JHBMC Ethics Committee
• Professor of Medicine

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0013208/joseph-carrese

Therefore symptoms ms purchase generic solian on-line, veins can accommodate large volumes of blood with a relatively small increase in internal pressure medicine expiration dates purchase solian without a prescription. Some exchange of materials occurs between the interstitial fluid and the venules symptoms kidney purchase solian master card, just as in capillaries treatment associates 100 mg solian buy with amex. Indeed symptoms 13dpo buy cheap solian 100 mg on line, permeability to macromolecules is often greater for venules than for capillaries, particularly in damaged areas. The veins are the last set of tubes through which blood flows on its way back to the heart. In the systemic circulation, the force driving this venous return is the pressure difference between the peripheral veins and the right atrium. The pressure in the first portion of the peripheral veins is generally quite low-only 10 to 15 mmHg-because most of the pressure imparted to the blood by the heart is dissipated by resistance as blood flows through the arterioles, capillaries, and venules. Therefore, the total driving pressure for flow from the peripheral veins to the right atrium is only 10 to 15 mmHg on average. Cardiovascular Physiology 403 the walls of the veins contain smooth muscle innervated by sympathetic neurons. Stimulation of these neurons releases norepinephrine, which causes contraction of the venous smooth muscle, decreasing the diameter and compliance of the vessels and increasing the pressure within them. Increased venous pressure then drives more blood out of the veins into the right side of the heart. Note the different effect of venous constriction compared to that of arterioles; when arterioles constrict, the constriction reduces forward flow through the systemic circuit, whereas constriction of veins increases forward flow. Although sympathetic neurons are the most important input, venous smooth muscle, like arteriolar smooth muscle, also responds to hormonal and paracrine vasodilators and vasoconstrictors. Two other mechanisms, in addition to contraction of venous smooth muscle, can increase venous pressure and facilitate venous return. During skeletal muscle contraction, the veins running through the muscle are partially compressed, which reduces their diameter and forces more blood back to the heart. As Chapter 13 describes, at the base of the chest cavity (thorax) is a large muscle called the diaphragm, which separates the thorax from the abdomen. During inspiration of air, the diaphragm descends, pushing on the abdominal contents and increasing abdominal pressure. Simultaneously, the pressure in the thorax decreases, thereby decreasing the pressure in the intrathoracic veins and right atrium. The net effect of the pressure changes in the abdomen and thorax is to increase the pressure difference between the peripheral veins and the heart. Thus, venous return is enhanced during inspiration (expiration would reverse this effect if not for the venous valves), and breathing deeply and frequently, as in exercise, helps blood flow toward the heart. You might get the incorrect impression from these descriptions that venous return and cardiac output are independent entities. Rather, any change in venous return almost immediately causes equivalent changes in cardiac output, largely through the Frank­Starling mechanism. Venous return and cardiac output therefore must be the same except for transient differences over brief periods of time. The effects of increased inspiration on end-diastolic ventricular volume are actually quite complex, but for the sake of simplicity, they are shown here only as increasing venous pressure. During muscle contraction, venous diameter decreases and venous pressure increases. The increase in pressure forces the flow only toward the heart because backward pressure forces the valves in the veins to close. Present in the interstitium of virtually all organs and tissues are numerous lymphatic capillaries that are completely distinct from blood vessel capillaries. Like the latter, they are tubes made of only a single layer of endothelial cells resting on a basement membrane, but they have large water-filled channels that are permeable to all interstitial fluid constituents, including protein. The lymphatic capillaries are the first of the lymphatic vessels, for unlike the blood vessel capillaries, no tubes flow into them. Small amounts of interstitial fluid continuously enter the lymphatic capillaries by bulk flow. This lymph fluid flows from (a) Lymph capillaries (b) the lymphatic capillaries into the next set of lymphatic vessels, which converge to form larger and larger lymphatic vessels. Ultimately, the entire network ends in two large lymphatic ducts that drain into the veins near the junction of the jugular and subclavian veins in the upper chest. Valves at these junctions permit only one-way flow from lymphatic ducts into the veins. Therefore, the lymphatic vessels carry interstitial fluid to the circulatory system. The movement of interstitial fluid from the lymphatics to the circulatory system is very important because, as noted earlier, the amount of fluid filtered out of all the blood vessel capillaries (except those in the kidneys) exceeds that absorbed by approximately 4 L each day. In the process, small amounts of protein that may leak out of blood vessel capillaries into the interstitial fluid are also returned to the circulatory system. The arteries function as low-resistance conduits and as pressure reservoirs for maintaining blood flow to the tissues during ventricular relaxation. The difference between maximal arterial pressure (systolic pressure) and minimal arterial pressure (diastolic pressure) during a cardiac cycle is the pulse pressure. Mean arterial pressure can be estimated as diastolic pressure plus one-third of the pulse pressure. Arterioles are the dominant site of resistance to flow in the vascular system and have major functions in determining mean arterial pressure and in distributing flows to the various organs and tissues. Arteriolar resistance is determined by local factors and by reflex neural and hormonal input. Local factors that change with the degree of metabolic activity cause the arteriolar vasodilation and increased flow of active hyperemia. Flow autoregulation involves local metabolic factors and arteriolar myogenic responses to stretch, and it changes arteriolar resistance to maintain a constant blood flow when arterial blood pressure changes. Sympathetic neurons innervate most arterioles and cause vasoconstriction via a-adrenergic receptors. In certain cases, noncholinergic, nonadrenergic neurons that release nitric oxide or other vasodilators also innervate blood vessels. Epinephrine causes vasoconstriction or vasodilation, depending on the proportion of a-adrenergic and b2-adrenergic receptors in the organ. Some chemical inputs act by stimulating endothelial cells to release vasodilator or vasoconstrictor paracrine agents, which then act on adjacent smooth muscle. These paracrine agents include the vasodilators nitric oxide (endothelium-derived relaxing factor), prostacyclin, and the vasoconstrictor endothelin-1. Under some circumstances, the lymphatic system can become occluded, which allows the accumulation of excessive interstitial fluid. Surgical removal of lymph nodes and vessels during the treatment of breast cancer can similarly allow interstitial fluid to pool in affected tissues. In addition to draining excess interstitial fluid, the lymphatic system provides the pathway by which fat absorbed from the gastrointestinal tract reaches the blood (see Chapter 15). The lymphatics can also be the route by which cancer cells spread from their area of origin to other parts of the body (which is why cancer treatment sometimes includes the removal of lymph nodes). Capillaries are the site at which nutrients and waste products are exchanged between blood and tissues. Blood flows through the capillaries more slowly than through any other part of the vascular system because of the huge crosssectional area of the capillaries. Capillary blood flow is determined by the resistance of the arterioles supplying the capillaries and by the number of open precapillary sphincters. Diffusion is the mechanism that exchanges nutrients and metabolic end products between capillary plasma and interstitial fluid. Lipid-soluble substances can move through the endothelial cells, whereas ions and polar molecules only move through water-filled intercellular clefts or fused-vesicle channels. Plasma proteins do not easily move across capillary walls; specific proteins like certain hormones can be moved by vesicle transport. The diffusion gradient for a substance across capillaries arises as a result of cell utilization or production of the substance. Increased metabolism increases the diffusion gradient and increases the rate of diffusion. Bulk flow of protein-free plasma or interstitial fluid across capillaries determines the distribution of extracellular fluid between these two fluid compartments. Filtration from plasma to interstitial fluid is favored by the hydrostatic pressure difference between the capillary and the Mechanism of Lymph Flow In large part, the lymphatic vessels beyond the lymphatic capillaries propel the lymph within them by their own contractions. The smooth muscle in the wall of the lymphatics exerts a pumplike action by inherent rhythmic contractions. Because the lymphatic vessels have valves similar to those in veins, these contractions produce a oneway flow toward the point at which the lymphatics enter the circulatory system. The lymphatic vessel smooth muscle is responsive to stretch, so when no interstitial fluid accumulates and, therefore, no lymph enters the lymphatics, the smooth muscle is inactive. However, when increased fluid filtration out of capillaries occurs, the increased fluid entering the lymphatics stretches the walls and triggers rhythmic contractions of the smooth muscle. This constitutes a negative feedback mechanism for adjusting the rate of lymph flow to the rate of lymph formation and thereby preventing edema. In addition, the smooth muscle of the lymphatic vessels is innervated by sympathetic neurons, and excitation of these neurons in various physiological states such as exercise may contribute to increased lymph flow. These include the same external forces we described for veins-the skeletal muscle pump and respiratory pump. Absorption from interstitial fluid to plasma is favored by the protein concentration difference between the plasma and the interstitial fluid. Filtration and absorption do not change the concentrations of crystalloids in the plasma and interstitial fluid because these substances move together with water. There is normally a small excess of filtration over absorption, which returns fluids to the bloodstream via lymphatic vessels. Sympathetically mediated vasoconstriction reflexively reduces venous diameter to maintain venous pressure and venous return. The skeletal muscle pump and respiratory pump increase venous pressure and enhance venous return. What is the only solute that has a significant concentration difference across the capillary wall What four variables determine the net filtration pressure across the capillary wall Give representative values for each of them at the arteriolar and venous ends of a systemic capillary. How do changes in local arteriolar resistance influence downstream capillary pressure What is the relationship between cardiac output and venous return in the steady state The lymphatic system provides a one-way route to return interstitial fluid to the circulatory system. Lymph returns the excess fluid filtered from the blood vessel capillaries, as well as the protein that leaks out of the blood vessel capillaries. Lymph flow is driven mainly by contraction of smooth muscle in the lymphatic vessels but also by the skeletal muscle pump and the respiratory pump. Draw the pressure changes along the systemic and pulmonary vascular systems during the cardiac cycle. What are normal values for systolic, diastolic, and mean arterial pressures in young adult males What denotes systolic and diastolic pressure in the measurement of arterial pressure with a sphygmomanometer Write the formula relating flow through an organ to mean arterial pressure and to the resistance to flow that organ offers. Name a mechanism other than chemical factors that contributes to flow autoregulation. Name four hormones that cause vasodilation or vasoconstriction of arterioles, and specify their effects. Describe the role of endothelial paracrine agents in mediating arteriolar vasoconstriction and vasodilation, and give three examples. What are the relative velocities of flow through the various vessel types of the systemic circulation Which mechanism is more important in the exchange of nutrients, oxygen, and metabolic end products across the capillary wall This relationship cannot be emphasized too strongly: All changes in mean arterial pressure must be the result of changes in cardiac output and/or total peripheral resistance. Keep in mind that mean arterial pressure will change only if the arithmetic product of cardiac output and total peripheral resistance changes. For example, if cardiac output doubles and total peripheral resistance decreases by half, mean arterial pressure will not change because the product of cardiac output and total peripheral resistance has not changed. Because cardiac output is the volume of blood pumped into the arteries per unit time, it is intuitive that it should be one of the two determinants of mean arterial volume and pressure. At steady state, fluid also leaves through the outflow tubes at a total rate of 1 L/min. Therefore, the height of the fluid column (P), which is the driving pressure for outflow, remains stable. We then disturb the steady state by dilating outflow tube 1, thereby increasing its radius, reducing its resistance, and increasing its flow. The total outflow for the system immediately becomes greater than 1 L/min, and more fluid leaves the reservoir than enters from the pump. Therefore, the volume and height of the fluid column begin to decrease until a new steady In Chapter 1, we described the fundamental components of homeostatic control systems: (1) a variable in the internal environment maintained in a relatively narrow range, (2) receptors sensitive to changes in this variable, (3) afferent pathways from the receptors, (4) an integrating center that receives and integrates the afferent inputs, (5) efferent pathways from the integrating center, and (6) effectors that act to change the variable when signals arrive along efferent pathways. The control and integration of cardiovascular function will be described in these terms.

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The proper performance of the knee jerk tells the physician that the afferent fibers medications prescribed for migraines 50 mg solian fast delivery, the balance of synaptic input to the motor neurons symptoms 14 days after iui 100 mg solian purchase mastercard, the motor neurons 7mm kidney stone treatment purchase cheap solian online, the neuromuscular junctions symptoms gluten intolerance purchase generic solian from india, and the muscles themselves are functioning normally medications over the counter buy generic solian 100 mg online. Because the afferent nerve fibers in the stretched muscle synapse directly on the motor neurons to that muscle without any interneurons, this type of reflex is called a monosynaptic reflex. All other reflex arcs are polysynaptic; they have at least one interneuron- and usually many-between the afferent and efferent neurons. When activated, these inhibit the motor neurons controlling antagonistic muscles whose contraction would interfere with the reflex response. In the knee jerk, for example, neurons to muscles that flex the knee are inhibited. Afferent information about muscle length continues to reach the central nervous system. In the example of the knee-jerk reflex, this would include other muscles that extend the leg. Therefore, feedback is necessary to inform the motor control systems of the tension actually achieved. Some of this feedback is provided by vision (you can see whether you are lifting or lowering an object) as well as by afferent input from skin, muscle, and joint receptors. An additional receptor type specifically monitors how much tension the contracting motor units are exerting (or is being imposed on the muscle by external forces if the muscle is being stretched). When the muscle is stretched or the attached extrafusal muscle fibers contract, tension is exerted on the tendon. This tension straightens the collagen bundles and distorts the receptor endings, activating them. Therefore, the Golgi tendon organs discharge in response to the tension generated by the contracting muscle and initiate action potentials that are transmitted to the central nervous system. Tapping the patellar tendon stretches the extensor muscle, causing (paths A and C) compensatory contraction of this and other extensor muscles, (path B) relaxation of flexor muscles, and (path D) information about muscle length to go to the brain. Time Time Action potentials in afferent neurons Time Answer can be found at end of chapter. The axon of the afferent neuron continues to the brainstem and synapses there with interneurons that form the next link in the pathway that conveys information about the muscle length to areas of the brain dealing with motor control. This information is especially important during slow, controlled movements such as the performance of an unfamiliar action. Ascending paths also provide information that contributes to the conscious perception of the position of a limb. Compared to when a muscle is contracting, passive stretch of the relaxed muscle produces less stretch of the tendon and fewer action potentials from the Golgi tendon organ. The tension depends on muscle 304 Chapter 10 Which of these conditions would result in the greatest action potential frequency in afferent neurons from muscle-spindle receptors Note that this reciprocal innervation is the opposite of that produced by the muscle-spindle afferents. This difference reflects the different functional roles of the two systems: the muscle spindle provides local homeostatic control of muscle length, and the Golgi tendon organ provides local homeostatic control of muscle tension. In addition, the activity of afferent fibers from these two receptors supplies the higher-level motor control systems with information about muscle length and tension, which can be used to modify an ongoing motor program. During very intense contractions that have the potential to cause injury, Golgi tendon organs are strongly activated. The resulting high-frequency action potentials arriving in the spinal cord stimulate interneurons that inhibit motor neurons to the muscle associated with that tendon, thus reducing the force and protecting the muscle. Neurons ending with: Excitatory neuromuscular junction Excitatory synapse Inhibitory synapse A Afferent nerve fiber from Golgi tendon organ Motor neuron to flexor muscles Motor neuron to extensor muscles Extensor muscle Begin Extensor muscle tendon with Golgi tendon organ Kneecap (bone) Flexor muscle B the Withdrawal Reflex In addition to the afferent information from the spindle stretch receptors and Golgi tendon organs of the activated muscle, other input is transmitted to the local motor control systems. For example, painful stimulation of the skin, as occurs from stepping on a tack, activates the flexor muscles and inhibits the extensor muscles of the ipsilateral leg (on the same side of the body). In this diagram, contraction of the extensor muscles causes tension in the Golgi tendon organ and increases the rate of action potential firing in the afferent nerve fiber. By way of interneurons, this increased activity results in (path A) inhibition of the motor neurons of the extensor muscle and its synergists and (path B) excitation of flexor muscle motor neurons. Control of Body Movement 305 the opposite response in the contralateral leg (on the opposite side of the body from the stimulus); motor neurons to the extensors are activated while the flexor muscle motor neurons are inhibited. Cerebral Cortex the cerebral cortex has a critical function in both the planning and ongoing control of voluntary movements, functioning in both the highest and middle levels of the motor control hierarchy. Although these areas of the cortex are anatomically and functionally distinct, they are heavily interconnected, and individual muscles or movements are represented at multiple sites. Thus, the cortical neurons that control movement form a neural network, meaning that many neurons participate in each individual movement. The neural networks can be distributed across multiple sites in parietal and frontal cortex, including the sites named in the preceding two paragraphs. The interactions of the neurons within the networks are flexible so that the neurons are capable of responding differently under different circumstances. This adaptability enhances the possibility of integrating incoming neural signals from diverse sources and the final coordination of many parts into a smooth, purposeful movement. It probably also accounts for the remarkable variety of ways in which we can approach a goal. For example, you can comb your hair with the right hand or the left, starting at the back of your head or the front. This same adaptability also accounts for some of the learning that occurs in all aspects of motor behavior. We have described the various areas of sensorimotor cortex as giving rise, either directly or indirectly, to pathways descending to the motor neurons. However, additional brain areas are involved in the initiation of intentional movements, such as the areas involved in memory, emotion, and motivation. Association areas of the cerebral cortex also have other functions in motor control. For example, neurons of the parietal-lobe association cortex are important in the visual control of reaching and grasping. The premotor, supplementary motor, primary motor, somatosensory, and parietal-lobe association cortices together make up the sensorimotor cortex. Within the broad areas, no one area exclusively controls the movement of a single body region and there is much overlap and duplication of cortical representation. Relative sizes of body structures are proportional to the number of neurons dedicated to their motor control. Only the right motor cortex, which principally controls muscles on the left side of the body, is shown. Imagine a glass of water sitting in front of you on your desk-you could reach out and pick it up much more smoothly with your eyes tracking your arm and hand movements than you could with your eyes closed. During activation of the cortical areas involved in motor control, subcortical mechanisms also become active. Subcortical and Brainstem Nuclei Numerous highly interconnected structures lie in the brainstem and within the cerebrum beneath the cortex, where they interact with the cortex to control movements. Their influence is transmitted indirectly to the motor neurons both by pathways that ascend to the cerebral cortex and by pathways that descend from some of the brainstem nuclei. It is not known to what extent-if any-these structures are involved in initiating movements, but they definitely are very important in planning and monitoring them. Their role is to establish the programs that determine the specific sequence of movements needed to accomplish a desired action. Subcortical and brainstem nuclei are also important in learning skilled movements. As described in Chapter 6, these structures are often referred to as basal ganglia, but their presence within the central nervous system makes the term nuclei more anatomically correct. This explains why brain damage to subcortical nuclei following a stroke or trauma can result in either hypercontracted muscles or flaccid paralysis-it depends on which specific circuits are damaged. The importance of the basal nuclei is particularly apparent in certain disease states, as we discuss next. For example, a common set of symptoms includes a change in facial expression resulting in a masklike, unemotional appearance, a shuffling gait with loss of arm swing, and a stooped and unstable posture. These neurons normally project to the basal nuclei, where they release dopamine from their axon terminals. In a small fraction of cases, there is evidence that it may have a genetic cause, based on observed changes in the function of genes associated with mitochondrial function, protection from oxidative stress, and removal of cellular proteins that have been targeted for metabolic breakdown. Scientists suspect that exposure to environmental toxins such as manganese, carbon monoxide, and some pesticides may also be a contributing factor to developing the disease. They fall into three main categories: (1) agonists (stimulators) of dopamine receptors, (2) inhibitors of the enzymes that metabolize dopamine at synapses, and (3) precursors of dopamine itself. The most widely prescribed drug is Levodopa (L-dopa), which falls into the third category. L-dopa enters the bloodstream, crosses the blood­brain barrier, and is converted in neurons to dopamine. Side effects sometimes occurring with L-dopa include hallucinations, like those seen in individuals with schizophrenia who have excessive dopamine activity (see Chapter 8), and spontaneous, abnormal motor activity. The latter is accomplished by surgically implanting electrodes in regions of the basal nuclei; the electrodes are connected to an electrical pulse generator similar to a cardiac artificial pacemaker (Chapter 12). Injection of undifferentiated stem cells capable of producing dopamine is also being explored as a possible treatment. The cerebellum receives information from the sensorimotor cortex and also from the vestibular system, eyes, skin, muscles, joints, and tendons- that is, from some of the very receptors that movement affects. One role of the cerebellum in motor functioning is to provide timing signals to the cerebral cortex and spinal cord for precise execution of the different phases of a motor program, in particular, the timing of the agonist/antagonist components of a movement. It also helps coordinate movements that involve several joints and stores the memories of these movements so they are easily achieved the next time they are tried. The cerebellum also participates in planning movements- integrating information about the nature of an intended movement with information about the surrounding space. The cerebellum then provides this as a feedforward (see Chapter 1) signal to the brain areas responsible for refining the motor program. Moreover, during the course of the movement, the cerebellum compares information about what the muscles should be doing with information about what they actually are doing. If a discrepancy develops between the intended movement and the actual one, the cerebellum sends an error signal to the motor cortex and subcortical centers to correct the ongoing program. The importance of the cerebellum in programming movements can best be appreciated when observing its absence in individuals with cerebellar disease. They typically cannot perform limb or eye movements smoothly but move with a tremor- a so-called intention tremor that increases as a movement nears its final destination. People with cerebellar disease also cannot combine the movements of several joints into a single, smooth, coordinated motion. The role of the cerebellum in the precision and timing of movements can be appreciated when you consider the complex tasks it helps us accomplish. For example, a tennis player sees a ball fly over the net, anticipates its flight path, runs along an intersecting path, and swings the racquet through an arc that will intercept the ball with the speed and force required to return it to the other side of the court. People with cerebellar damage cannot achieve this level of coordinated, precise, learned movement. Unstable posture and awkward gait are two other symptoms characteristic of cerebellar disease. For example, people with cerebellar damage walk with their feet wide apart, and they have such difficulty maintaining balance that their gait is similar to that seen in people who are intoxicated by ethanol. Visual input helps compensate for some of the loss of motor coordination-patients can stand on one foot with eyes open but not closed. Individuals with cerebellar disease find it hard to modify movements in response to new situations. Unlike damage to areas of sensorimotor cortex, cerebellar damage is not usually associated with paralysis or weakness. Descending Pathways the influence exerted by the various brain regions on posture and movement occurs via descending pathways to the motor neurons and the interneurons that affect them. The pathways are of two types: the corticospinal pathways, which, as their name implies, originate in the cerebral cortex; and a second group we will refer to as the brainstem pathways, which originate in the brainstem. It influences posture and movement indirectly by means of input to brainstem nuclei and (by 308 Chapter 10 Neurons from both types of descending pathways end at synapses on alpha and gamma motor neurons or on interneurons that affect them. Sometimes these are the same interneurons that function in local reflex arcs, thereby ensuring that the descending signals are fully integrated with local information before the activity of the motor neurons is altered. In other cases, the interneurons are part of neural networks involved in posture or locomotion. The ultimate effect of the descending pathways on the alpha motor neurons may be excitatory or inhibitory. They do this via (1) presynaptic synapses on the terminals of afferent neurons as these fibers enter the central nervous system, or (2) synapses on interneurons in the ascending pathways. The overall effect of this descending input to afferent systems is to regulate their influence on either the local or brain motor control areas, thereby altering the importance of a particular bit of afferent information or sharpening its focus. For example, when performing an exceptionally delicate or complicated task, like a doctor performing surgery, descending inputs might facilitate signaling in afferent pathways carrying proprioceptive inputs monitoring hand and finger movements. This descending (motor) control over ascending (sensory) information provides another example to show that there is no real functional separation between the motor and sensory systems. Corticospinal pathway Sensorimotor cortex Basal nuclei Thalamus Brainstem Crossover of corticospinal pathway Brainstem pathway Cerebellum Spinal cord Spinal cord To skeletal muscle To skeletal muscle Corticospinal Pathway the nerve fibers of the corticospinal pathways have their cell bodies in the sensorimotor cortex and terminate in the spinal cord. The corticospinal pathways are also called the pyramidal tracts or pyramidal system because of their triangular shape as they pass along the ventral surface of the medulla oblongata. The skeletal muscles on the left side of the body are therefore controlled largely by neurons in the right half of the brain, and vice versa. As the corticospinal fibers descend through the brain from the cerebral cortex, they are accompanied by fibers of the corticobulbar pathway (bulbar means "pertaining to the brainstem"), a pathway that begins in the sensorimotor cortex and ends in the brainstem. The corticobulbar fibers control, directly or indirectly via interneurons, the motor neurons that innervate muscles of the eye, face, tongue, and throat. These fibers provide the main source of control for voluntary movement of the muscles of the head and neck, whereas the corticospinal fibers serve this function for the muscles of the rest of the body.

Unlike the relatively slow medicine journal generic solian 100 mg with mastercard, long-lasting signals of the endocrine system that are released into the blood medicine plus solian 100 mg buy otc, the nervous system sends rapid electrical signals that communicate directly from one cell to another medications nursing cheap solian 50 mg on-line. As you read about the structure and function of neurons and the nervous system in this chapter medications 2 purchase solian 50 mg on line, you will encounter numerous examples of the general principles of physiology that were outlined in Chapter 1 medicine 4 you pharma pvt ltd buy solian american express. Section A highlights how the structure of neurons contributes to their specialized functions in mediating the information flow between organs and integration of homeostatic processes. In Section B, controlled exchange of materials (ions) across cellular membranes and the laws of chemistry and physics will be key principles underlying the electrical properties of neurons. Information flow that allows for integration of physiological processes between cells of the nervous system is the theme of Section C. In Section D, you will see how the nervous system illustrates the general principle of physiology that most physiological functions are controlled by multiple regulatory systems, often working in opposition. Knoblike outgrowths called dendritic spines increase the surface area of dendrites still further. Neurons operate by generating electrical signals that move from one part of the cell to another part of the same cell or to neighboring cells. In most neurons, the electrical signal causes the release of chemical messengers- neurotransmitters-to communicate with other cells. Most neurons serve as integrators because their output reflects the balance of inputs they receive from up to hundreds of thousands of other neurons. The other major cell types of the nervous system are nonneuronal cells called glial cells. These cells generally do not participate directly in electrical communication from cell to cell as do neurons, but they are very important in various supportive functions for neurons. The break in the axon indicates that axons may extend for long distances; in fact, they may be 5000 to 10,000 times longer than the cell body is wide. This neuron is a common type, but there is a wide variety of neuronal morphologies, some of which have no axons. Neuronal Signaling and the Structure of the Nervous System 137 the axon, sometimes also called a nerve fiber, is a long process that extends from the cell body and carries outgoing signals to its target cells. The region of the axon that arises from the cell body is known as the initial segment (or axon hillock). The initial segment is the location where, in most neurons, propagated electrical signals are generated. Each branch ends in an axon terminal, which is responsible for releasing neurotransmitters from the axon. These chemical messengers diffuse across an extracellular gap to the cell opposite the terminal. Alternatively, some neurons release their chemical messengers from a series of bulging areas along the axon known as varicosities. In the brain and spinal cord, these myelinforming cells are a type of glial cell called oligodendrocytes. As we will see, the myelin sheath speeds up conduction of the electrical signals along the axon and conserves energy. To maintain the structure and function of the axon, various organelles and other materials must move as far as 1 meter between the cell body and the axon terminals. Kinesin transport mainly occurs from the cell body toward the axon terminals (anterograde) and is important in moving nutrient molecules, enzymes, mitochondria, neurotransmitter-filled vesicles, and other organelles. The receptor region may be a specialized portion of the plasma membrane or a separate cell closely associated with the neuron ending. One branch, the peripheral process, begins where the afferent terminal branches converge from the receptor endings. There are exceptions, however, such as in the enteric nervous system of the gastrointestinal tract described in Chapter 15. Note that nerve fiber is a term sometimes used to refer to a single axon, whereas a nerve is a bundle of axons (fibers) bound together by connective tissue. They account for over 99% of all neurons and have a wide range of physiological properties, shapes, and functions. The number of interneurons interposed between specific afferent and efferent neurons varies according to the complexity of the action they control. The knee-jerk reflex elicited by tapping below the kneecap activates thigh muscles largely without interneurons-most of the afferent neurons interact directly with efferent neurons. In contrast, when you hear a song or smell a certain perfume that evokes memories of someone you know, millions of interneurons may be involved. The anatomically specialized junction between two neurons where one neuron alters the electrical and chemical activity of another is called a synapse. At most synapses, the signal is transmitted from one neuron to another by neurotransmitters, a term that also includes the chemicals efferent neurons use to communicate with effector cells. The neurotransmitters released from one neuron alter the receiving neuron by binding with specific protein receptors on the membrane of the receiving neuron. A neuron that conducts a signal toward a synapse is called a presynaptic neuron, whereas a neuron conducting signals away from a synapse is a postsynaptic neuron. A postsynaptic neuron may have thousands of synaptic junctions on the surface of its dendrites and cell body, so that signals from many presynaptic neurons can affect it. Interconnected in this way, the many millions of neurons in the nervous system exemplify the general principle of physiology that information flow between cells, tissues, and organs is an essential feature of homeostasis and allows for complex integration of physiological processes. Both afferent and efferent components may consist of two neurons, not one as shown here. A nerve is a collection of neuron axons encased in connective tissue and is located in the peripheral nervous system. Glial cells surround the axon and dendrites of neurons, and provide them with physical and metabolic support. Account for > 99% of all neurons 140 Chapter 6 Presynaptic Postsynaptic Axon Synapse Presynaptic Postsynaptic addition, astrocytes have many neuronlike characteristics. For example, they have ion channels, receptors for certain neurotransmitters and the enzymes for processing them, and the capability of generating weak electrical responses. Thus, in addition to their well defined functions, it is speculated that astrocytes may take part in information signaling in the brain. Lastly, ependymal cells line the fluid-filled cavities within the brain and spinal cord and regulate the production and flow of cerebrospinal fluid, which will be described later. As mentioned earlier, Schwann cells produce the myelin sheath of the axons of the peripheral neurons. Postsynaptic Growth and Development of Neurons Development of the nervous system in the embryo begins with a series of divisions of undifferentiated precursor cells (stem cells) that can develop into neurons or glia. After the last cell division, each neuronal daughter cell differentiates, migrates to its final location, and sends out processes that will become its axon and dendrites. A specialized enlargement, the growth cone, forms the tip of each extending axon and is involved in finding the correct route and final target for the process. As the axon grows, it is guided along the surfaces of other cells, most commonly glial cells. Which route the axon follows depends largely on attracting, supporting, deflecting, or inhibiting influences exerted by several types of molecules. Astrocytes also sustain the neurons metabolically- for example, by providing glucose and removing the secreted metabolic waste product ammonia. Neuronal Signaling and the Structure of the Nervous System 141 these molecules, such as cell adhesion molecules, reside on the membranes of the glia and embryonic neurons. Others are soluble neurotrophic factors (growth factors for neural tissue) in the extracellular fluid surrounding the growth cone or its distant target. During these early stages of neural development­ which occur during all trimesters of pregnancy and into infancy­ alcohol and other drugs, radiation, malnutrition, and viruses can exert effects that cause permanent damage to the developing fetal nervous system. A surprising aspect of development of the nervous system occurs after growth and projection of the axons. Exactly why this seemingly wasteful process occurs is unknown, although neuroscientists speculate that this refines or fine-tunes connectivity in the nervous system. Throughout the life span, our brain has an amazing ability to modify its structure and function in response to stimulation or injury, a characteristic known as plasticity. This may involve the generation of new neurons, but particularly involves the remodeling of synaptic connections. These events are stimulated by exercise and by engaging in cognitively challenging activities. For many neural systems, the critical time window for development occurs at a fairly young age. In visual pathways, for example, regions of the brain involved in processing visual stimuli are permanently impaired if no visual stimulation is received during a critical time, which peaks between 1 and 2 years of age. By contrast, the ability to learn a language undergoes a slower and more subtle change in plasticity-humans learn languages relatively easily and quickly until adolescence, but learning becomes slower and more difficult as we proceed from adolescence through adulthood. However, the creation and removal of synaptic contacts begun during fetal development continue throughout life as part of normal growth, learning, and aging. Also, although it was previously thought that production of new neurons ceased around the time of birth, a growing body of evidence now indicates that the ability to produce new neurons is retained in some brain regions throughout life. For example, cognitive stimulation and exercise have both been shown to increase the number of neurons in brain regions associated with learning even in adults. In addition, the effectiveness of some antidepressant medications has been shown to depend upon the production of new neurons in regions involved in emotion and motivation (Chapter 8). Return of function following a peripheral nerve injury is delayed because axon regrowth proceeds at a rate of only about 1 mm per day. So, for example, if afferent neurons from your thumb were damaged by an injury in the area of your shoulder, it might take 2 years for sensation in your thumb to be restored. Spinal injuries typically crush rather than cut the tissue, leaving the axons intact. In this case, a primary problem is selfdestruction (apoptosis) of the nearby oligodendrocytes. When these cells die and their associated axons lose their myelin sheath, the axons cannot transmit information effectively. They are creating tubes to support regrowth of the severed axons, redirecting the axons to regions of the spinal cord that lack growthinhibiting factors, preventing apoptosis of the oligodendrocytes so myelin can be maintained, and supplying neurotrophic factors that support recovery of the damaged tissue. Medical researchers are also attempting to restore function to damaged or diseased spinal cords and brains by implanting undifferentiated stem cells that will develop into new neurons and replace missing neurotransmitters or neurotrophic factors. Initial stem cell research focused on the use of embryonic and fetal stem cells, which, while yielding promising results, raises ethical concerns. Recently, however, researchers have developed promising techniques using stem cells isolated from adults, and using adult cells that have been induced to revert to a stem-cell-like state. The axon (nerve fiber), which may be covered with sections of myelin separated by nodes of Ranvier, transmits information to other neurons or effector cells. Neurotransmitters, which are released by a presynaptic neuron and combine with protein receptors on a postsynaptic neuron, transmit information across a synapse. After such an injury, the axon segment that is separated from the cell body degenerates. The part of the axon still attached to the cell body then gives rise to a growth cone, which grows out to the effector organ so that 142 Chapter 6 Glial Cells I. Neurons develop from stem cells, migrate to their final locations, and send out processes to their target cells. Cell division to form new neurons and the plasticity to remodel after injury markedly decrease between birth and adulthood. After degeneration of a severed axon, damaged peripheral neurons may regrow the axon to their target organ. Describe the direction of information flow through a neuron in response to input from another neuron. What is the relationship between the presynaptic neuron and the postsynaptic neuron Where are afferent neurons, efferent neurons, and interneurons located in the nervous system The total charge that can be separated in most biological systems is very small, so the potential differences are small and are measured in millivolts (1 mV 5 0. The electrical potential between charges tends to make them flow, producing a current. If the charges are opposite, the current brings them toward each other; if the charges are alike, the current increases the separation between them. The amount of charge that moves-in other words, the magnitude of the current-depends on the potential difference between the charges and on the nature of the material or structure through which they are moving. As discussed in Chapter 4, the predominant solutes in the extracellular fluid are sodium and chloride ions. The intracellular fluid contains high concentrations of potassium ions and ionized nonpenetrating molecules, particularly phosphate compounds and proteins with negatively charged side chains. A fundamental physical principle is that charges of the same type repel each other-positive charge repels positive charge, and negative charge repels negative charge. Separated electrical charges of opposite sign have the potential to do work if they are allowed to come together. This potential is called an electrical potential or, because it is determined Materials that have a high electrical resistance reduce current flow and are known as insulators. Materials that have a low resistance allow rapid current flow and are called conductors. As we have seen, the intracellular and extracellular fluids contain many ions and can therefore carry current. Therefore, the lipid layers of the plasma membrane are regions of high electrical resistance separating the intracellular fluid and the extracellular fluid, two low-resistance aqueous compartments. The voltmeter records the difference between the intracellular and extracellular electrodes. By convention, extracellular fluid is designated as the voltage reference point, and the polarity (positive or negative) of the membrane potential is stated in terms of the sign of the excess charge on the inside of the cell by comparison.

The stoppage of bleeding is known as hemostasis (do not confuse this word with homeostasis) medicine q10 cheap 100 mg solian fast delivery. Hemostatic mechanisms are most effective in dealing with injuries in small vessels-arterioles medications with acetaminophen generic solian 100 mg free shipping, capillaries symptoms your having a girl discount solian on line, and venules treatment jellyfish sting order solian overnight delivery, which are the most common sources of bleeding in everyday life medications while pregnant 100 mg solian purchase. In contrast, the body usually cannot control bleeding from a medium or large artery. Venous bleeding leads to less rapid blood loss because veins have low blood pressure. Indeed, the decrease in hydrostatic pressure induced by raising the bleeding part above the level of the heart level may stop hemorrhage from a vein. In addition, if the venous bleeding is internal, the accumulation of blood in the tissues may increase interstitial pressure enough to eliminate the pressure gradient required for continued blood loss. Accumulation of blood in the tissues can occur as a result of bleeding from any vessel type and is known as a hematoma. When a blood vessel is severed or otherwise injured, its immediate inherent response is to constrict. In addition, this constriction presses the opposed endothelial surfaces of the vessel together and this contact induces a stickiness capable of keeping them "glued" together. Permanent closure of the vessel by constriction and contact stickiness occurs only in the very smallest vessels of the microcirculation, however, and the staunching of bleeding ultimately depends upon two other interdependent processes that occur in rapid succession: (1) formation of a platelet plug and (2) blood coagulation (clotting). Injury to a vessel disrupts the endothelium and exposes the underlying connective-tissue collagen fibers. In addition to prostacyclin, the adjacent endothelial cells also release nitric oxide, which is not only a vasodilator (see Section C of this chapter) but also an inhibitor of platelet adhesion, activation, and aggregation. The platelet plug is built up very rapidly and is the primary mechanism used to seal breaks in vessel walls. In the following section, we will see that platelets are also essential for the next, more slowly occurring hemostatic event: blood coagulation. Once started, why does the platelet plug not continuously expand, spreading away from the damaged endothelium along intact endothelium in both directions Thus, whereas platelets possess the enzymes that produce thromboxane A2 from arachidonic acid, normal endothelial cells contain a different enzyme that converts Blood coagulation, or clotting, is the transformation of blood into a solid gel called a clot or thrombus, which consists mainly of a protein polymer known as fibrin. Clotting occurs locally around the original platelet plug and is the dominant hemostatic defense. Its function is to support and reinforce the platelet plug and to solidify blood that remains in the wound channel. These events, like platelet aggregation, are initiated when injury to a vessel disrupts the endothelium and permits the blood to contact the underlying tissue. At each step of the cascade, an inactive plasma protein, or "factor," is converted (activated) to a proteolytic enzyme, which then catalyzes the generation of the next enzyme in the sequence. Each of these activations results from the splitting of a small peptide fragment from the inactive plasma protein precursor, thereby exposing the active site of the enzyme. However, several of the plasma protein factors, following their activation, function not as enzymes but rather as cofactors for enzymes. Thrombin then catalyzes a reaction in which several polypeptides are split from molecules of the large, rod-shaped plasma protein fibrinogen. The fibrin, initially a loose mesh of interlacing strands, is rapidly stabilized and strengthened by the enzymatically mediated formation of covalent cross-linkages. However, thrombin does even more than this-it exerts a profound positive feedback effect on its own formation. It does so by activating several proteins in the cascade and also by activating platelets. Therefore, once thrombin formation has begun, reactions leading to much more thrombin generation are activated by this initial thrombin. We will make use of this crucial fact later when we describe the specifics of the cascade leading to thrombin. Activated platelets are essential because several of the cascade reactions take place on the surface of the platelets. As noted earlier, platelet activation occurs early in the hemostatic response as a result of platelet adhesion to collagen, but in addition, thrombin is an important stimulator of platelet activation. The activation causes the platelets to display specific plasma membrane receptors that bind several of the clotting factors, and this permits the reactions to take place on the surface of the platelets. In addition to protein factors, plasma Ca21 is required at various steps in the clotting cascade. However, Ca21 concentration in the plasma can never decrease enough to cause clotting defects because death would occur from muscle paralysis or cardiac arrhythmias before such low concentrations were reached. Now we present the specifics of the early portions of the clotting cascade-those leading from vessel damage to the 430 Chapter 12 prothrombin­thrombin reaction. These early reactions consist of two seemingly parallel pathways that merge at the step just before the prothrombin­thrombin reaction. Under physiological conditions, however, the two pathways are not parallel but are actually activated sequentially, with thrombin serving as the link between them. It will be clearer, however, if we first discuss the two pathways as though they were separate and then deal with their actual interaction. Rather, clotting is initiated solely by the extrinsic pathway, as described in the text. Contact activation also explains why blood coagulates when it is taken from the body and put in a glass tube. A silicone coating delays clotting by reducing the activating effects of the glass surface. This last factor then activates factor X to factor Xa, which is the enzyme that converts prothrombin to thrombin. This pathway begins with a protein called tissue factor, which is not a plasma protein. It is located instead on the outer plasma membrane of various tissue cells, including fibroblasts and other cells in the walls of blood vessels outside the endothelium. The blood is exposed to these subendothelial cells when vessel damage disrupts the endothelial lining. The two paths merge at factor Xa, which then catalyzes the conversion of prothrombin to thrombin, which catalyzes the formation of fibrin. As stated earlier, under physiological conditions, the two pathways just described actually are activated sequentially. The amount of thrombin is too small, however, to produce adequate, sustained coagulation. This pathway then generates the large amounts of thrombin required for adequate coagulation. Moreover, thrombin not only recruits the intrinsic pathway but facilitates the prothrombin­ thrombin step itself by activating factor V and platelets. First, the liver is the site of production for many of the plasma clotting factors. Second, the liver produces bile salts (Chapter 15), and these are important for normal Begin Synthesizes bile salts intestinal absorption of the lipid-soluble substance vitamin K. The liver requires this vitamin to produce prothrombin and several other clotting factors. Because this aggregation is an essential precursor for clotting, these agents reduce the magnitude and extent of clotting. In addition, however, the body has mechanisms for limiting clot formation itself and for dissolving a clot after it has formed. The presence of mechanisms that both favor and limit blood clotting is a good example of the general principle of physiology that most physiological functions are controlled by multiple regulatory systems, often working in opposition. Factors That Oppose Clot Formation There are at least three different mechanisms that oppose clot formation, thereby helping to limit this process and prevent it from spreading excessively. Defects in any of these natural anticoagulant mechanisms are associated with abnormally high risk of clotting, a condition called hypercoagulability (see Chapter 19 for a case discussion of a patient with this condition). This anticoagulant mechanism is the reason that the extrinsic pathway by itself can generate only small amounts of thrombin. There are many different plasminogen activators and many different pathways for initiating their activity. The fibrinolytic (or thrombolytic) system is the principal effector of clot removal. The fibrinolytic system is proving to be every bit as complicated as the clotting system, with multiple types of plasminogen activators and pathways for generating them, as well as several inhibitors of these plasminogen activators. Fibrin, therefore, is an important initiator of the fibrinolytic process that leads to its own dissolution. One of the most common uses of these drugs is in the prevention and treatment of myocardial infarction (heart attack), which, as described in Section E, is often the result of damage to endothelial cells. For example, atherosclerosis interferes with the ability of endothelial cells to secrete nitric oxide. Tissue plasminogen activator catalyzes the formation of plasmin, which dissolves clots. Because thromboxane A2, produced by the platelets, is important for platelet aggregation, aspirin reduces both platelet aggregation and the ensuing coagulation. Platelets, once formed and released from megakaryocytes, have lost their ability to synthesize proteins. In addition, the administration of aspirin following a heart attack significantly reduces the incidence of sudden death and a recurrent heart attack. A variety of drugs that interfere with platelet function by mechanisms different from those of aspirin also have great promise in the treatment or prevention of heart attacks. In particular, certain drugs block the binding of fibrinogen to platelets and thus interfere with platelet aggregation. One type interferes with the action of vitamin K, which in turn reduces the synthesis of clotting factors by the liver. Another type recently developed includes drugs that specifically inactivate factor Xa. In contrast to aspirin, the fibrinogen blockers, the oral anticoagulants, and heparin, all of which prevent clotting, the fifth type of drug-plasminogen activators-dissolves a clot after it is formed. The platelet plug does not spread along normal endothelium because the latter secretes prostacyclin and nitric oxide, both of which inhibit platelet aggregation. Blood is transformed into a solid gel when, at the site of vessel damage, plasma fibrinogen is converted into fibrin molecules, which then bind to each other to form a mesh. The formation of thrombin from the plasma protein prothrombin is the end result of a cascade of reactions in which an inactive plasma protein is activated and then enzymatically activates the next protein in the series. Thrombin exerts a positive feedback stimulation of the cascade by activating platelets and several clotting factors. Activated platelets, which display platelet factor and binding sites for several activated plasma factors, are essential for the cascade. This complex activates factor X, which then catalyzes the conversion of small amounts of prothrombin to thrombin. The liver requires vitamin K for the normal production of prothrombin and other clotting factors. A plasma proenzyme, plasminogen, is activated by plasminogen activators to plasmin, which digests fibrin. Tissue plasminogen activator is secreted by endothelial cells and is activated by fibrin in a clot. Aspirin inhibits platelet cyclooxygenase activity thereby inhibiting prostaglandin and thromboxane production-this inhibits platelet aggregation. Oral anticoagulants and heparin interfere with clotting factors- they prevent clot formation. The initial response to blood vessel damage is vasoconstriction and the sticking together of the opposed endothelial surfaces. The next events are formation of a platelet plug followed by blood coagulation (clotting). Platelets adhere to exposed collagen in a damaged vessel and release the contents of their secretory vesicles. This process is also enhanced by von Willebrand factor, secreted by the endothelial cells, and by thromboxane A2, produced by the platelets. Describe the sequence of events leading to platelet activation and aggregation and the formation of a platelet plug. His resting respiratory rate was increased at 16 breaths per minute, compared to 13 breaths per minute a year before. A 72-year-old man saw his primary care physician; he was complaining of shortness of breath when doing his 15 min daily walk. However, he did experience a pressure-like chest pain under the sternum (angina pectoris) when walking up several flights of stairs. He had also felt light-headed and as if he were going to faint when walking up the stairs, but both the pain and lightheadedness passed when he sat down and rested. For the past few months, he has had to prop his head up using three pillows to keep from feeling short of breath when lying in bed. This symptom was relieved by sitting upright and letting his legs hang off the side of the bed. His feet got swollen, particularly at the end of the day when he had been standing quite a bit. Auscultation of his chest revealed a prominent systolic murmur (see description of heart sounds in Section 12. Reflect and Review #3 What clinical condition could explain all of the findings in this patient His heart rate was 86 bpm, which was increased compared to a year before when it was 78 bpm. The shortness of breath on walking suggested that the failure of cardiac output to keep up with need caused a backup of blood in the lungs leading to accumulation of fluid that reduced the capacity for air exchange in the lungs. This was not a problem at rest but was with the increase in whole-body oxygen consumption that occured with even mild exercise like walking.

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