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If the membrane potential de- Purkinje system may become the dominant pacemaker polarizes above the threshold for the opening of I buy generic nizagara 100mg on-line, maintaining cardiac rhythm and cardiac output cheap nizagara 50mg fast delivery. The rate of pacemaker discharge within these spe- Myocytes within the sinoatrial node possess the cialized myocytes is influenced by the activity of both most rapid intrinsic rate of automaticity; therefore, the divisions of the autonomic nervous system. Increased sinoatrial node serves as the normal pacemaker of the sympathetic nerve activity to the heart, the release of heart. Specialized cells within the atria, atrioventricular catecholamines from the adrenal medulla, or the exoge- (A-V) node, and His-Purkinje system are capable of nous administration of adrenomimetic amines will spontaneous depolarization, albeit at a slower rate. The cause an increase in the rate of pacemaker activity more rapid rate of depolarization of the sinoatrial nodal through stimulation of -adrenoceptors on the pace- cells normally suppresses all of the other cells with the maker cells (Figure 16. The other cells will become The parasympathetic nervous system, through the pacemakers when their own intrinsic rate of depolariza- vagus nerve, inhibits the spontaneous rate of depolar- tion becomes greater than that of the sinoatrial node or ization of pacemaker cells. The release of acetylcholine when the pacemaker cells within the sinoatrial node are from cholinergic vagal fibers increases potassium con- depressed. When impulses fail to conduct across the ductance (gK ) in pacemaker cells, and this enhanced A-V node to excite the ventricular myocardium (heart outward movement of K results in a more negative po- TP A. The rate of spontaneous discharge is determined by the initial slope of the membrane potential and the time required to reach the threshold potential. There is a decrease in the slope of diastolic depolarization as well as hyperpolarization of the cell. The time to reach the threshold potential is prolonged, with the net effect being a decrease in the rate of spontaneous depolarization. Refractory Period Thus, during vagal stimulation, the threshold potential Depolarized cardiac cells are transiently unresponsive of the sinoatrial node pacemaker cells is achieved more to any activation stimuli. The refractory Cardiac Conduction period is subdivided into three phases, absolute, effec- tive, and relative. The absolute refractory period is the The cardiac impulse begins in the sinoatrial node in the time from the onset of the action potential until a stim- high lateral right atrium near the junction of the supe- ulus is able to evoke a local nonconducted response. Excitation leaves During this period, the cell is completely refractory to the sinoatrial node and spreads throughout the atrium. The effective re- The myocytes (both atrial and ventricular) are long thin fractory period (ERP) begins with the onset of the ac- structures linked electrically via low-resistance pores tion potential, incorporates the absolute refractory pe- known as gap junctions. The gap junctions are hetero- riod, and ends when an excitatory stimulus is able to geneously dispersed throughout the sarcolemmal mem- generate a conducted signal. The ERP is determined as brane, although they are mainly concentrated on the the shortest interval between two stimuli of equal in- ends of the myocytes. This distribution leads to polarity tensity that results in the generation of a propagated re- of the myocyte, with end-to-end conduction occurring sponse. The relative refractory period begins with the at a more rapid rate than side-to-side (anisotropic) con- completion of the ERP and continues through the time duction. The difference in conduction velocity is up to a in which a signal may be conducted slowly, prior to ob- factor of three and may be important in supporting cer- taining normal propagation of the signal. If additional connections tion exert their effects by prolonging the refractory pe- exist between the atrium and ventricle (accessory path- riod of the tissue, thereby prolonging the interval before way), the potential for arrhythmia is present (atrioven- the myocardial cells are capable of responding to a sub- tricular reciprocating tachycardia), such as occurs with sequent stimulus that will propagate in a normal man- the Wolff-Parkinson-White syndrome. As the myocytes repolarize, they enter a relative re- locity slows significantly as the electrical signal enters fractory period during which they again can undergo the AV-node, where cellular depolarization depends on depolarization. The delay in ventricular excitation when cells are stimulated, having fully recovered at the allows the atria to contract and enhances the filling of end of the relative refractory period. After passing through the A-V node, the brane potential at which excitation of the cell occurs de- electrical signal is carried via the right and left bundle termines conduction velocity. The number of sodium channels that are recruited to open by a depolarizing stimulus determines Mechanisms of Arrhythmias the Vmax in atrial and ventricular muscle. Changes in the configuration of the sodium channel in the sarcolemmal Disturbances in the orderly formation and conduction membrane at resting membrane potentials, which are of the cardiac impulse may result in heart rates that are more positive (depolarized) than 75mV, cause the either too fast (tachycardia) or too slow (bradycardia). As a result, there is impulse generation within the sinoatrial node or failure a reduction in the peak sodium current leading to a re- of the excitatory wavefront to conduct from the atrium duction in upstroke velocity, action potential amplitude, to the ventricle through the atrioventricular node. This has important general, bradyarrhythmias are not amenable to long- ramifications for the genesis of arrhythmias. One com- term pharmacological therapy and may require perma- mon clinical cause of depolarization of myocardial tissue nent cardiac pacing. The mechanisms supporting tachycardias may quinidine, and dofetilide, may give rise to after-depolar- be classified broadly into three groups: (1) abnormal au- izations and torsades de pointes tachyarrhythmia in tomaticity, (2) triggered activity, or (3) reentry. Conditions leading to bradycardia also may facilitate development of torsades Enhanced Automaticity de pointes tachyarrhythmia.

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It is known that arte- tration purchase nizagara 100mg online, gastrointestinal disturbances order nizagara 25 mg amex, decreased rial blood concentrations immediately following cig- heart rate, and impaired reaction times. You advise arette smoke inhalation can be as much as 10 times your patient that successful cessation of tobacco use the venous concentration. You decide on a nicotine requires attention to both the positive and negative patch and combine this strategy with counseling (withdrawal) reinforcement properties of nicotine and motivational therapy from a professional and tobacco use. During a second relapse period, you may wish to consider ANSWER: Several options are available for the phar- combining the antidepressant drug bupropion with macological approach, including nicotine replace- the other forms of treatment. Finkel and Humayun Mirza DRUG LIST GENERIC NAME PAGE GENERIC NAME PAGE Amrinone 157 Hydralazine 155 Captopril 158 Losartan 156 Carvedilol 156 Metoprolol 156 Digitoxin 152 Milrinone 157 Dobutamine 157 Spironolactone 155 Digoxin 152 Valsartan 156 Furosemide 155 CHRONIC (CONGESTIVE) HEART gressive deterioration and early mortality in individuals FAILURE who have an EF below 40%. Patients who have a significant loss of cardiac pump It is remarkable that the therapeutic approach to a function develop progressively severe symptoms of fa- decreased EF is the same regardless of the etiology. The tigue, dyspnea (shortness of breath), chest pain, syncope principles that guide the pharmacological management (loss of consciousness), and death. The management of of CHF is the same for patients who had damage from these patients requires an understanding that it is an on- a myocardial infarction (MI), viral infection, valvular going process in which the response to the initial injury disease, alcohol, and so on. The challenge ommended approach to the pharmacological manage- of the clinician is to keep the congestive heart failure ment of systolic dysfunction. An historic perspective (CHF) patient out of the hospital while reducing mor- will be followed to provide an appreciation of the evo- bidity and mortality in this high-risk population. A normal individual expels about heart failure commonly occurs in the elderly with 55 to 65% of the blood from the left ventricle per heart- chronic hypertension and left ventricular hypertrophy. The rationale for choosing the The failure of the left ventricle to relax during diastole 40% EF is based on clinical findings demonstrating pro- (diastolic dysfunction) results in elevated end diastolic 151 152 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM pressures and volumes. The shortness of breath (dysp- trolled by phosphodiesterases and phosphatases that nea), chest pain, and fatigue that result from elevated prevent indefinite phosphorylation and activation of pulmonary venous pressures are similar in both systolic regulatory proteins. Also excluded from discus- in the phospholipase C–mediated breakdown of phos- sion are nondrug therapies for CHF, such as coronary phatidylcholine to inositol triphosphate and diacyl glyc- artery bypass, percutaneous coronary interventions, erol; these second messengers further enhance mobi- electronic pacemakers, and cardiac transplantation. An appreciation of the principles involved in ceptor acutely increases Ca influx through sarcolem- this cell signaling process is crucial to understand cur- mal L-type calcium channels. A brief chronic angiotensin II receptor stimulation include car- overview of myocardial excitation–contraction coupling diac myocyte hypertrophy through enhanced expres- will be provided. The maintenance of a resting membrane potential in cardiac myocytes, as well as all cells, depends on meta- bolic energy (ATP) that is used by the Na –K ATPase MYOCARDIAL to drive the gradients for Na and K between the in- EXCITATION–CONTRACTION COUPLING tracellular and extracellular spaces. Cardiac glycosides The physiological processes that begin with cardiac sar- are known to bind to this protein. Depolarization of the car- CARDIAC GLYCOSIDES diac myocyte sarcolemmal membrane during the action potential results in the intracellular entry of extracellu- Historical Background lar calcium. The major regulators of the transsarcolem- mal entry of calcium include L-type calcium channels In “An Account of the Foxglove” William Withering re- and autonomic receptors (Fig. These membrane- lated his experiences while in private practice more bound proteins all contribute to the influx of a minute than 200 years ago. He traveled between two towns quantity of calcium from outside the cell into the myo- where he took care of the wealthy patients on a fee-for- cyte. The entry of this small quantity of calcium causes service basis in one town and the poor people for free the release of the large reservoir of calcium stored in in the other. He encountered during one of his com- the sarcoplasmic reticulum (SR) through the SR cal- mutes a practitioner of the healing arts who was re- cium release channel (ryanodine receptor). She provided care for people with reservoir of calcium interacts with tropomyosin to allow obvious signs and symptoms of fluid overload who were the actin and myosin filaments to overlap, resulting in diagnosed with dropsy (later called CHF). Diastolic relaxation re- these patients a group of herbs that contained digitalis, sults from the resequestration of this large reservoir of and it was Withering who identified Digitalis purpura as calcium back into the sarcoplasmic reticulum through the active plant in this mixture. Calcium exits the cell through the Na –Ca exchanger Although Withering thought that digitalis worked by in- and sarcolemmal Ca ATPase. This stimulates the enzyme adenylyl cyclase to convert ATP to cyclic Digitalis remains notorious today for its very narrow adenosine monophosphate (cAMP).

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Auditory cause vision disturbance occurs in about 20% of evoked potentials (the electric response evoked in the patients cheap nizagara 100 mg fast delivery. EEG (electroencephalogram buy nizagara 100 mg with amex, a record of electrical 812 GALE ENCYCLOPEDIA OF GENETIC DISORDERS impulses in the brain) may be required for patients with Resources suspected seizures. PERIODICALS There are no available treatments for the disorders “Health Supervision for Children with Neurofibromatosis. Prognosis ORGANIZATIONS Prognosis varies depending on the tumor type which March of Dimes Birth Defects Foundation. Laith Farid Gulli, MD Prevention There is no known way to prevent the approximately 50% of all NF cases that occur due to a spontaneous change in the genes (mutation). A person with NF can be made to understand that each of INiemann-Pick disease his or her offspring has a 50% chance of also having NF when a parent has NF. Special tests can be performed on Definition the fetus (developing baby) during pregnancy to deter- Niemann-Pick disease (NPD) is a disorder of fat mine if the fetus will be born with this disorder. It is named for German pediatricians the amniotic fluid and cushions the developing fetus) or Albert Niemann (1880-1921) and Ludwig Pick (1898- chorionic villus sampling (a procedure involving extrac- 1935). Six types of the disease have been identified (A, tion of a tissue sample from the placenta, the structure B, C, D, E, and F). A sphingomyelin is any group of sphingolipids ilies choose to use this information in order to prepare for (consists of a lipid and a sphingosine) containing phos- the arrival of a child with a serious medical condition. It occurs primarily in the tissue of the nervous Other families may choose not to continue the pregnancy. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 813 Types A and B occur mainly in families of eastern KEY TERMS European Jewish descent (Ashkenazi). Type B is also common in indi- Hepatosplenomegaly—Enlargement of the liver viduals from Tunisia, Morocco, and Algeria. As of 2000, it is believed that over Macula—Abnormal pigmentation in the tissue of 300 people in the United States are affected with type C the eye. Type D occurs Sphingomyelin—A group of sphingolipids con- in French-Canadian descendents from Nova Scotia. As Sphingomyelinase—Enzyme required to break- of 2000, it is not clear as to which populations are down sphingomyelin into ceramide. Signs and symptoms Some characteristics of Niemann-Pick disease may Type A be common for all types. Common symptoms include jaundice, hepatosplenomegaly (enlargement of the liver This is the infantile or acute form of Niemann-Pick and spleen), physical and mental impairment, and feed- disease. Symptoms may progress rapidly Alternate names associated with the NPD disorder and include the following: are lipid histiocytosis, sphingomyelin lipidosis, and sphingomyelinase deficiency. Enlargement of the liver and spleen is due to the low levels of the enzyme sphin- gomyelinase. The decreased levels of this Niemann-Pick disease is caused by an autosomal enzyme cause sphingomyelin content of the liver and recessive genetic trait, therefore the condition will not spleen to be abnormally high. This occurs between the appear unless a person receives the same defective gene ages of six and 12 months. Degenerative muscle carrier and if they are homozygous then they will show weakness and floppiness may occur due to a decline in the trait. This is caused by the disorder will passed onto the child (ren) if both par- increased accumulation of sphingomyelin in the nerv- ents are heterozygous for the trait and a 100% chance if ous system. Pigmentation in the tissue of the eyes may has been located on the short arm (p) of chromosome 11. Formation of cherry-red spots may be seen in The gene for types C and D has been located on chromo- approximately 50% of patients diagnosed with NPD some 18. Type E is similar to type C fever, and gastrointestinal (GI) problems such as vomit- and may be a variant form. Demographics Symptoms progress slowly and begin during infancy or Niemann-Pick disease affects males and females early childhood. Like type A, type B occurs due to a defi- equally and has been identified in all races.

For example cheap 50mg nizagara with visa, imagine a reaching movement where position or velocity (or any other kinematic variable of the arm) does not uniquely describe the forces in the task purchase 25 mg nizagara fast delivery. A very simple case is one where a target is presented at a given direction, but the forces that will be presented during that movement depend on the color of the target. If the cells that take part in learning this task are strongly tuned with respect to position or velocity of the arm and not to the color of the target, then this apparently simple task should be, in fact, extremely difficult to learn. Error in each trial was measured as perpendicular displacement from a straight-line trajectory. Performance remained poor and no field specific after-effects developed in catch trials despite 3 days of training. During presentation of each field, the room was flooded with a specific color of light. Despite hundreds of movements, subjects never learned to use the color as a cue to predict the pattern of forces. We recently simplified this experiment by limiting movements to only one direction. Because the movement was always in the same direction, the pattern of forces on that movement depended exclusively on this cue. We trained subjects (n = 3) extensively on this task, providing them with more than 3000 trials, spread over 3 days. Remarkably, in catch trials we consistently found no evidence of after- effects (Figure 11. However, with longer training44 or with explicit instruction about the nature of the forces,45 it is possible to associate color with force fields. The remarkable difficulty in learning this apparently simple task leads to the prediction that the activity fields of the bases are typically only weakly modulated by the color of the target. To measure generalization, subjects are trained with an input x1 and are then tested with a new input x2. The first problem with this approach is that it requires an experimentally naïve set of participants to be trained in each pairing of x1 and x2. As a result, behavioral experiments are often limited to training and testing with one or two pairs of inputs, and conclusions are in terms of qualitative statements regarding the shape of the bases (wide or narrow). The second problem is that in motor control, we have to consider coordinate systems. Generalization depends not only on the distance between training and test locations, but also on the coordinate system in which that space is measured. For example, a force that is experienced at a given location may be generalized in terms of torques on the joints or forces on the hand. These two coordinates predict different patterns of generalization in terms of the position of the hand. The third problem is that the bases that are inferred from one generalization experiment might not be consistent with those that are inferred in another. In other words, adaptation to one force field might result in a pattern of generalization that is inconsistent with the pattern observed in adaptation to another field. It would indeed be remarkable if behavioral data from a wide variety of force adaptation experiments suggested a consistent shape to the bases. If this were the case, then one could argue that one has estimated the basic motor primitives with which internal models are computed. Finally, even if we are lucky enough to solve all of these problems, we would still have the problem of interpretation: we would hope that the bases that are inferred by this abstract model not only explain behavior, but also are interpretable in terms of the neurophysiology of the motor system. To approach the first two questions — being limited to naïve subjects and needing to consider coordinate systems — we have been developing a new mathematical method to estimate the shape of the bases from the trial-to-trial variations in per- formance. That is, the preferred force vector associated with a basis is likely to change most for those bases that are most active. This means that if error on one movement effects behavior on the next movement in a different direction, then some of the bases must be reasonably active during both of these movements. That is because they must be active in the first movement to be influenced by the error and active in the second movement in order to have an influence on behavior.

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