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By V. Wenzel. Crossroads College. 2018.

The hillock acts as a “sink” where Na afterhyperpolarization is a result of K channels remaining ions enter the cell buy 5 mg kemadrin overnight delivery xerogenic medications. The “source” of these Na ions is the ex- open buy 5mg kemadrin free shipping symptoms of flu, allowing the continued efflux of K ions. The entry of way to think about afterhyperpolarization is that the mem- Na ions into the axon hillock causes the adjacent region brane’s permeability to K is higher than when the neuron of the axon to depolarize as the ions that entered the cell, is at rest. Consequently, the membrane potential is driven during the peak of the action potential, flow away from the even more toward the K equilibrium potential (Fig. This local spread of the current depolarizes the adja- The changes in membrane potential during an action cent region to threshold and causes an action potential in potential result from selective alterations in membrane that region. These membrane conductance of the axon, the action potential propagates or moves along changes reflect the summated activity of individual volt- the length of the axon from point to point, like a traveling age-gated sodium and potassium ion channels. This in- phases to both the decrease in sodium conductance and the crease in ion flow in the cytoplasm causes greater lengths increase in potassium conductance, and afterhyperpolariza- of the axon to be depolarized, decreasing the time needed tion to the sustained increase of potassium conductance. Recall CHAPTER 3 The Action Potential, Synaptic Transmission, and Maintenance of Nerve Function 43 +50 Depolarizing Repolarizing phase phase 0 E (mV) B C m Resting Resting state Afterhyper- state -50 A polarization A D -100 Time Voltage-gated Na+ Channel Voltage-gated K+ Channel Na+ A Resting state Resting state K+ Na+ B Active state Resting state FIGURE 3. A, At the resting membrane potential, both channels are in a closed, resting state. B, Dur- ing the depolarizing phase of the K+ action potential the voltage-gated sodium channels are activated Na+ (open), but the potassium channels C Inactive state Active state open more slowly and, therefore, have not yet responded to the depo- larization. C, During the repolariz- ing phase, sodium channels become inactivated, while the potassium channels become activated (open). D, During the afterhyperpolariza- tion, the sodium channels are both closed and inactivated, and the K+ potassium channels remain in their Na+ active state. Eventually, the potas- Closed and sium channels close and the sodium D Active state inactive state channel inactivation is removed, so that both channels are in their rest- ing state and the membrane poten- tial returns to resting membrane po- tential. Note that the voltage-gated potassium channel does not have an inactivated state. In this case, the local stimulus is the inward cause the internal axoplasmic resistance, Ra, decreases, al- sodium current that accompanies the action potential. The lowing the current to spread farther down the inside of the larger the space constant, the farther along the membrane axon before leaking back across the membrane. Affected individuals generally have no neurons and muscle cells and in synaptic transmission. The defect in membrane repolar- nel properties derived from biophysical studies of isolated ization could be a result of a prolonged inward sodium cells or their membranes. The advent of molecular ap- current or a reduced outward potassium current. In fact, proaches resulted in the cloning of the genes for a variety mutations in potassium channels account for two differ- of channels and the subsequent expression of these genes ent LQT syndromes, and a third derives from a sodium in a large cell, such as the Xenopus oocyte, for further char- channel mutation. Myotonia is a condition characterized by a delayed re- This approach also allowed experimental manipulation laxation of muscle following contraction. There are several of the channels by expressing genes that were altered in types of myotonias, all related to abnormalities in muscle known ways. Some myotonias are associated with a skele- which parts of channel molecules were responsible for tal muscle sodium channel, and others are associated with particular properties, including voltage sensitivity, ion a skeletal muscle chloride channel. This genetic understand- and spinocerebellar ataxias, some forms of epilepsy, and ing of the control of channel properties led to the realiza- familial hemiplegic migraine. Ataxias are a disruption in tion that many unexplained diseases may be caused by al- gait mediated by abnormalities in the cerebellum and terations in the genes for ion channels. One specific ataxia associated with altered ion channel function are now collectively called an abnormal potassium channel is episodic ataxia with channelopathies. In this disease, which is autosomal-dominant, muscle, cardiac muscle, and even nonexcitable cells, such cerebellar neurons have abnormal excitability and motor as kidney tubular cells. This hyperex- One of the best-known sets of channelopathies is a citability causes indiscriminant firing of motor neurons, group of channel mutations that lead to the Long Q-T observed as the twitching of small groups of muscle fibers, (LQT) syndrome in the heart. The QT interval on the elec- akin to worms crawling under the skin (myokymia). It is trocardiogram is the time between the beginning of ven- likely that many other neuronal (and muscle) disorders of tricular depolarization and the end of ventricular repolar- currently unknown pathology will be identified as chan- ization. This in- axon, more of the adjacent region that is depolarized by crease in Rm increases the space constant.

If future decisions are to be made under the guidance of the new test kemadrin 5 mg amex medications errors pictures, patients who are positive on the new test will be treated and those who are negative will not buy generic kemadrin 5 mg on line symptoms webmd. This means that the only patients that will be managed differently are the ones who are test positive on the existing test but negative on the new one, and those who are test negative on the existing test but positive on the new one. As patients with concordant test results ( or ) will receive the same management, it is unnecessary and in some circumstances even unethical to examine the treatment effect in these two subgroups. If a new test (B) is then examined with the goal of substituting the old, possibly more invasive, and/or costly test (A), the design in Figure 4. Subsequently, the treatment effect and the predictive values of the discordant result categories (A B and A B ) can be examined (see Table 4. By transposing these tables it is possible to examine the effect of a clinical pathway based on test A or test B for patients with discordant test results (Tables 4. The difference in poor outcome rate between these two tables, after correcting for the frequency of discordant results, is equal to the absolute risk difference of a clinical pathway based on test A compared to a pathway based on test B. To calculate the relative risk or the total risk of each strategy separately it is necessary to have information on the clinical event rate in each concordant group. An alternative design, using the random disclosure principle, is outlined in Figure 4. Subsequently, patients are randomised between a clinical pathway based on test A without disclosing the results of test B, and a pathway based on test B with non-disclosure of the results of test A. The same measures and tables can be obtained from such a design as discussed for the design in Figure 4. In some situations one might wish to let the point of randomisation coincide with that of the clinical decision to choose either test A or test B and 71 THE EVIDENCE BASE OF CLINICAL DIAGNOSIS Table 4. A recent trial used this design to study two different diagnostic approaches for the management of outpatients with dysphagia. A modified barium swallow test (MBS) and flexible endoscopic evaluation of swallowing with sensory testing (FEESST) are supposed to distinguish patients who can benefit from behavioural and dietary management from those who will need a percutaneous endoscopic gastrostomy (PEG) tube. For the discussion we consider a simplified design as outlined in Figure 4. Outpatients presenting with dysphagia were randomly allocated to either a strategy using MBS or a strategy using FEESST to guide subsequent management. During 1 year of follow up the occurrence of pneumonia was recorded in both trial arms. There were six cases of pneumonia in the 50 (12%) patients allocated to the FEESST strategy and 14 in the 76 (18%) patients allocated to the MBS strategy. The absolute risk difference was not significantly different from zero (risk difference 6%; 95% CI 6% to 19%). As no patient received both tests it is not possible to distinguish the 72 DIAGNOSTIC TESTING AND PROGNOSIS (a) Treatment I Outcome + Disclose A – Treatment II Outcome Patients R A B Treatment I Outcome + Disclose B – Treatment II Outcome (b) PEG Outcome + FEESST – Diet Outcome Patients with R dysphagia PEG Outcome + MBS – Diet Outcome Figure 4. Often a new test is introduced to complement rather than to replace existing tests. One example is where the new test is to be added to the diagnostic pathway before an older test as a triage instrument. Patients with a particular test result (say, negative) on the new test will not be subjected to the existing test. Alternatively, the new test is added after the existing test, making further refinement in diagnosis or treatment decisions possible. If a test is added at the end of a diagnostic work up to further classify disease (postaddition) all the designs presented in Figures 4. For 73 THE EVIDENCE BASE OF CLINICAL DIAGNOSIS example, to evaluate the prognostic impact of a genetic test for the classification of women with breast cancer in two different subgroups, one could use a design similar to the one in Figure 4. Women suspected of breast cancer are evaluated with the conventional diagnostic work up. Depending on the results, they are subsequently randomised between two types of treatment. When the goal of a new test is to limit the number of people undergoing the classic diagnostic work up (triage or preaddition), the designs in Figures 4.

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More commonly 5mg kemadrin mastercard 909 treatment, feedback biological effects characteristic of that hormone are initi- regulation in the endocrine system is complex 5 mg kemadrin otc medicine woman cast, involving ated. Therefore, in the endocrine system, the basis for second- or third-order feedback loops. For example, multi- specificity in cell-to-cell communication rests at the level ple levels of feedback regulation may be involved in regu- of the receptor. Similar concepts apply to autocrine and lating hormone production by various endocrine glands un- paracrine mechanisms of communication. The A certain degree of specificity is ensured by the re- regulation of target gland hormone secretion, such as adre- stricted distribution of some hormones. For example, sev- nal steroids or thyroid hormones, begins with production eral hormones produced by the hypothalamus regulate of a releasing hormone by the hypothalamus. These hor- hormone stimulates production of a trophic hormone by mones are carried via small blood vessels directly from the the anterior pituitary, which, in turn, stimulates the pro- hypothalamus to the anterior pituitary, prior to entering duction of the target gland hormone by the target gland. In addition, the trophic hormone may inhibit the distribution of active hormone is the local transforma- releasing hormone secretion from the hypothalamus, and tion of a hormone within its target tissue from a less active in some cases, the releasing hormone may inhibit its own to a more active form. Dihydrotestos- to provide certain advantages compared with the simpler sys- terone is a much more potent androgen than testosterone. Theoretically, it permits a greater degree of fine-tuning Because the enzyme that catalyzes this conversion is found of hormone secretion, and the multiplicity of regulatory steps only in certain locations, its cell or tissue distribution minimizes changes in hormone secretion in the event that partly localizes the actions of the androgens to these sites. Therefore, while receptor distribution is the primary fac- It is important to bear in mind the normal feedback rela- tor in determining the target tissues for a specific hor- tionships that control the secretion of each individual hor- mone, other factors may also focus the actions of a hor- mone are discussed in the chapters that follow. Endocrine Target cell cell Signal Amplification Is an Important Characteristic of the Endocrine System Another important feature of the endocrine system is signal amplification. Blood concentrations of hormones are ex- 9 12 ceedingly low, generally, 10 to 10 mol/L. Even at the 9 Biological effect higher concentration of 10 mol/L, only one hormone molecule would be present for roughly every 50 billion wa- ter molecules. Therefore, for hormones to be effective reg- B ulators of biological processes, amplification must be part of the overall mechanism of hormone action. Hypothalamus Amplification generally results from the activation of a se- ries of enzymatic steps involved in hormone action. At each Releasing hormone step, many times more signal molecules are generated than were present at the prior step, leading to a cascade of ever- increasing numbers of signal molecules. The self-multiplying nature of the hormone action pathways provides the molec- Anterior ular basis for amplification in the endocrine system. For ex- ample, insulin exhibits pleiotropic effects in skeletal mus- cle, where it stimulates glucose uptake, stimulates glycoly- sis, stimulates glycogenesis, inhibits glycogenolysis, Target gland stimulates amino acid uptake, stimulates protein synthesis, hormone and inhibits protein degradation. In addition, some hormones are known to have different effects in several different target tissues. For example, testos- Biological effect terone, the male sex steroid, promotes normal sperm forma- tion in the testes, stimulates growth of the accessory sex Simple and complex feedback loops in the glands, such as the prostate and seminal vesicles, and pro- FIGURE 31. B, A complex, multilevel feedback loop: the hy- istics, such as beard growth and deepening of the voice. Solid lines indicate stim- Multiplicity of regulation is also common in the en- ulatory effects; dashed lines indicate inhibitory, negative-feed- docrine system. For example, liver glycogen metabolism may be regulated hormone-effector pairs relative to normal feedback rela- or influenced by several different hormones, including in- tionships. For example, in the case of anterior pituitary hor- sulin, glucagon, epinephrine, thyroid hormones, and adre- mones, measuring both the trophic hormone and the target nal glucocorticoids. Furthermore, most dynamic tests of en- docrine function performed clinically are based on our The secretion of any particular hormone is either stimu- knowledge of these feedback relationships. Dynamic tests lated or inhibited by a defined set of chemical substances in 570 PART IX ENDOCRINE PHYSIOLOGY CLINICAL FOCUS BOX 31. In one test, a ter 32, the hormone plays a role in regulating bone growth bolus of arginine, which is known to stimulate growth hor- and energy metabolism in skeletal muscle and adipose tis- mone secretion, is given and a blood sample is taken a sue.

Many cells of the SA node reach threshold and depolar- Na channels that open to cause phase 0 close and are in- active until the membrane repolarizes kemadrin 5mg low price medicine x boston. This leads to depolarization of the neighboring the relatively smaller current brings neighboring cells to right atrial cells and a wave of depolarization begins to threshold more slowly cheap kemadrin 5mg with amex medications for migraines, decreasing the rate at which elec- spread over the right and left atria. Other significant factors are the slow upstroke of the action potential because it depends on 2 slow voltage-gated Ca channels and, possibly, weak elec- The Action Potential Is Propagated by Local trical coupling as a result of relatively few gap junctions. Currents Created During Depolarization Propagation of the action potential through the AV node takes approximately 120 msec. Excitation then proceeds As Na ions enter a cell during phase 0, their positive through the AV bundle (bundle of His), the left and right charge repels intracellular K ions into nearby areas where depolarization has not yet occurred. Inflammation, hypoxia, vagus nerve activity, and cer- The local buildup of K depolarizes adjacent areas until threshold is reached. Excitation proceeds as succeeding cycles of hand, its tendency to conduct slowly is sometimes of ben- local ion current and action potential move out of the SA efit in pathological situations in which atrial depolariza- node and across the atria. This process is called the propa- tions are too frequent and/or uncoordinated, as in atrial gation of the action potential. In these conditions, not all of the elec- trical impulses that reach the AV node are conducted to the ventricles, and the ventricular rate tends to stay below the Excitation Usually Spreads From the SA Node level at which diastolic filling is impaired (see Chapter 14). A fibrous, nonconducting connective tissue ring separates the atria from the ventricles everywhere except at the AV Rapid Conduction Through the Ventricles. For this reason, the transmission of electrical activity system is composed of specialized cardiac muscle cells with from the atria to the ventricles occurs only through the AV large diameters. Action potentials in atrial muscle adjacent to the AV locity up to 2 m/sec) action potentials throughout the suben- node produce local ion currents that invade the node and docardium of both ventricles. Excitation pro- complete excitation of both ventricles takes approximately ceeds throughout the atria at a speed of approximately 1 75 msec. It requires 60 to 90 msec to excite all regions of the assures synchronized contraction of all ventricular muscle atria (Fig. Propagation of the action potential con- cells and maximal effectiveness in ejecting blood. The slower conduction velocity is par- tially explained by the small size of the nodal cells. Less THE ELECTROCARDIOGRAM current is produced by the depolarization of a small nodal The electrocardiogram (ECG) is a continuous record of cardiac electrical activity obtained by placing sensing elec- trodes on the surface of the body and recording the voltage A B differences generated by the heart. The equipment ampli- fies these voltages and causes a pen to deflect proportion- AV bundle SVC ally on a paper moving under it. Positively branch septum charged ions flow toward the negative wire (negative pole) The timing of excitation of various areas of and negatively charged ions simultaneously flow in the op- FIGURE 13. CHAPTER 13 The Electrical Activity of the Heart 225 The combination of two poles that are equal in magnitude and opposite in charge and located close to one another, is called a dipole. The flow of ions (current) is greatest in the region between the two poles, but some current flows at every point surrounding the dipole, reflecting the fact that voltage differences exist everywhere in the solution. Points A and B do because A is closest to the positive pole and B is closest to the negative pole. Positive charges are drawn from the area around point B by the negative end of the dipole, which is relatively near. The positive end of the dipole is relatively distant and, therefore, has little ability to attract negative charges from point B (although it can draw nega- tive charges from point A). As positive charges are drawn away, point B is left with a negative charge (or negative voltage). The opposite happens between the positive end of the dipole and point A, leaving A with a net positive FIGURE 13. In a salt solution, the dipole ence between them because they are equally distant from can be represented as a vector having a length and direction de- termined by the dipole magnitude and position, respectively. In both poles and are, therefore, equally influenced by posi- this example, electrodes for the voltmeter are at points C and D. Any other two points on the cir- When a vector is directed parallel to a line between C and D, the cle, E and F, for example, have a voltage difference between voltage is maximum. If the magnitude of the vector is decreased, them that is less than that between A and B and greater than the voltage decreases. This is also true of other combina- tions of points, such as A and C, B and D, and D and F.

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