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The factor common to most changes in (A) Large cells buy sildalis 120 mg on line erectile dysfunction liver cirrhosis, electrically isolated order sildalis 120 mg with visa erectile dysfunction treatment natural in india, (B) Isometric relaxation occurs at a cardiac muscle contractility is the neurally stimulated shorter length than isometric (A) Amplitude of the action potential (B) Small cells, electrically coupled, contraction (B) Availability of cellular ATP chemically stimulated (C) The muscle relaxes along the same (C) Cytoplasmic calcium (C) Small cells, electrically coupled, combination of lengths and forces that concentration spontaneously active it took during contraction (D) Rate of neural stimulation (D) Small cells, electrically isolated, (D) The complete cycle in cardiac 10. At a given muscle length, the velocity spontaneously active muscle is isotonic of contraction depends on 2. What is the physiological role of the (A) Only the afterload electrical and a mechanical syncytium. The regulation of contraction in preload SUGGESTED READING cardiac muscle is (D) It prevents a contraction from American Heart Association. Website: (A) Most like that of smooth muscle having an isometric phase at shorter http://www. Why does cardiac muscle shorten less Mechanisms of Contraction of the (i. Boston: Lit- (C) Independent of filament-related (A) Higher loads cause a reduction in tle, Brown, 1976. New York: McGraw-Hill, stimulation (B) Higher loads cause rapid fatigue, 1981. Carmel, IN: Biological Sci- (A) The rate of neural stimulation is premature relaxation ences Press-Cooper Group, 2000. Oxford: Oxford University potential lasts into the relaxation phase important limit to force production in Press, 1979. CASE STUDIES FOR PART III • • • CASE STUDY FOR CHAPTER 8 four limbs, but the woman does not complain of muscu- lar soreness. She is somewhat underweight, slightly Polymyositis in an Older Patient short of breath, and speaks in a low voice. Laboratory A 67-year-old woman consulted her physician because of tests show a moderately elevated creatine kinase level. She reported There is no family history of muscle problems, and she is difficulty in rising out of a chair and had intermittent diffi- not currently taking any medication. Physical examination reveals the Because of the symptoms present, no muscle biopsy presence of a light purple rash around her eyes and on or electromyographic study is carried out. Muscle weakness is noted in all agnosis of polymyositis/dermatomyositis was made. The (continued) 188 PART III MUSCLE PHYSIOLOGY woman is placed on high-dose prednisone, and arrange- steroidal drug to manage the pain and inflammation and ments are made for periodic tests for circulating muscle is told to lessen the pain by applying ice packs to the af- enzymes. He is advised to avoid stair climbing as specialist to screen for a possible underlying malig- much as possible during this time, but to begin walking nancy, and physical therapy is strongly recommended. On a fol- In follow-up visits, the woman shows gradual im- low-up visit 2 weeks later, he is experiencing little im- provement in muscle strength, and her rash is much less pairment in walking, although the strength of the leg is apparent. She maintains a still less than normal and stair climbing is still somewhat regimen of physical therapy and is able to have the pred- of a problem. He is advised to return to regular activity, nisone dosage progressively reduced over the course of but to avoid any undue overloading of the affected leg the next year. Could the shortness of breath also have been a result of pose a special risk for injury? Does the pattern of recovery suggest that the diagnosis was this injury? Why was the patient given a limited supply of the pain med- life threatening. Although several things could contribute to shortness of Answers to Case Study Questions for Chapter 9 breath, weakness of the respiratory muscles can lead to hy- 1. The muscle was undergoing an eccentric contraction; that poventilation; this, too, can be life threatening. The response to therapy was what one would expect for a landing, and the body weight extended it while it was ac- person suffering from polymyositis. Such a stretch can produce a force considerably in ex- muscular dystrophy would not have responded as well to cess of the maximal isometric capability of a muscle. Second, because the patient was not accustomed to sidered, like most cases of polymyositis, to be of idiopathic the activity in question, the muscle was not conditioned to origin. Third, the height from References which the patient jumped could potentially generate a force Dalakas MC, ed. The pain was localized in the general area of the myotendi- Maddison PJ, et al.

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Recently it has been demonstrated that such an abrupt decline (akin to drug withdrawal) can cause changes in the properties of GABAA receptors that may underlie the symptoms associated with premenstrual syndrome buy generic sildalis 120mg on line erectile dysfunction causes lower back pain,including increased susceptibility to seizures and insensitivity to benzodiazepine agonists discount sildalis 120 mg overnight delivery zopiclone impotence. Steroids appear to act at a distinct site on the GABA- receptor complex,as flumazenil does not block their action,and the ClÀ currents they evoke directly can be potentiated by barbiturates (and vice versa). The 3b-methyl- substituted synthetic analogue of allopregnanolone,ganaxolone (3a-hydroxy-3b- methyl-5a-pregnan-20-one) is less easily metabolised than its endogenous parent 238 NEUROTRANSMITTERS,DRUGS AND BRAIN FUNCTION compound,allowing activity following oral administration,and is currently under investigation as an anticonvulsant. Anaesthetics Steroids,such as alphaxolone,and barbiturates,such as thiopentone,represent only two classes of the many structurally diverse molecules found to induce general anaesthesia. Although a number of these clearly have actions on a range of targets,including glycine,5- HT3,nicotinic and glutamate receptors,all,with the exception of the dissociative anaesthetic ketamine,have an effect on GABAA receptors at relevant concentrations. For example,the intravenous anaesthetic agents propofol,propanidid and etomidate markedly enhance responses to GABA (apparently by prolonging bursts of ClÀ channel openings) and are capable of directly evoking ClÀ currents. The currents produced by these agents at high doses,as well as those caused by steroids and barbiturates,are blocked by bicuculline,indicating that they are due to activation of the ClÀ channel associated with the GABAA receptor. It is also now clear that volatile anaesthetics such as halothane and isoflurane as well as alcohols (including ethanol),rather than having non-specific membrane-disrupting actions,owe at least some of their properties to a potentiation of GABA responses,through a direct interaction with sites on GABAA receptors. STRUCTURE OF GABAA RECEPTORS Over the past decade or so significant advances have been made in our understanding of the structure of the GABAA receptor,which is now known to be formed by the assembly of multiple subunit proteins. In 1987 two subunits of the receptor,designated a and b, were cloned (Schofield et al. Following on from this work,16 mammalian subunits encoded by distinct genes have now been identified. These genes encode proteins of approximately 450±550 amino acids (depending on the species) which,according to their sequence similarities,have been grouped into seven families Ð a, b, g, d, e, p and y (Barnard et al. The a, b and g families contain multiple isoforms (a1±a6, b1±b3 and g1±g3) and in a number of cases additional complexity is generated by alternative mRNA splicing. The subunits share varying degrees of sequence identity but have a similar predicted tertiary structure. This consists of four membrane-spanning a-helices (M1±M4),a large extracellular N-terminal region,a large intracellular domain between M3 and M4 and a short extracellular C-terminal portion (Fig. The highest degree of conservation is in the transmembrane regions and the greatest variation in the intracellular loop between M3 and M4. The extracellular domain contains potential N-linked glycosylation sites and a b-loop formed by a disulphide bridge between two cysteine residues. The intracellular loops of b and g subunits contain sites for phosphorylation by a variety of protein kinases,including cAMP-dependent protein kinase,cGMP- dependent protein kinase,protein kinase C,Ca2‡/calmodulin-dependent protein kinase and tyrosine kinase,which may be important in the regulation of receptor function. These general features are very similar to those of two other ligand-gated ion channels, the nicotinic acetylcholine receptor and the glycine receptor (see below) and there is a considerable degree of sequence homology among these proteins. By analogy with the nicotinic acetylcholine receptor,it is thought that the GABAA receptor is formed by the assembly of five subunits around a central ion channel,with the M2 region of each subunit forming the lining of the channel (Fig. The suggested stoichiometry of the most widely expressed form of receptor is 2a,2b and 1g. Shown below are the possible subunit combinations of one such benzodiazepine-sensitive receptor together with a benzodiazepine-insensitive receptor in which the g subunit is replaced by a d,and a p-containing receptor with four different subunit types Subunit combinations and receptor function Expression studies in Xenopus oocytes or transfected cell lines originally suggested that functional GABA-activated chloride channels could be formed by receptor subunits of each class in isolation. However,much better expression occurs with two or more subunit types in combination and it is likely that most native receptors contain at least three different subunits. Co-expression of a and b subunits results in the assembly of 240 NEUROTRANSMITTERS,DRUGS AND BRAIN FUNCTION functional receptors that can be activated by GABA and are sensitive to the antagonists bicuculline and picrotoxin and show modulation by barbiturates. But only when a g subunit is expressed in conjunction with an a and a b subunit is benzodiazepine binding and potentiation of GABA seen. As benzodiazepines do not bind to g subunits alone,it is likely that the conformation of the receptor is appropriate for benzodiazepine binding only when all three subunit types are present. The large number of cloned subunit proteins makes it clear that GABAA receptors themselves must be diverse. An illustration of this diversity is provided by the pharmacology of benzodiazepine ligands. Even before the existence of GABAA receptor subunits was recognised,variations in the binding of radiolabelled drugs to native benzodiazepine receptors had led to the suggestion that not all GABA receptors were the same. These had similar affinity for agonists such as diazepam and antagonists such as flumazenil,but BZI receptors showed a higher affinity for triazolopyridazines (e. It is now clear that the molecular basis for these differences resides in the variety of a subunits. Thus,while g subunits are required for benzodiazepine binding,the precise nature of this interaction depends on the type of a subunit present.

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The diagnostic tests comprised the clinical signs that are sought when clinicians suspect appendicitis proven 120mg sildalis erectile dysfunction in the morning, and the reference standard is a combination of pathology 33 THE EVIDENCE BASE OF CLINICAL DIAGNOSIS Table 2 sildalis 120 mg low price erectile dysfunction protocol scam or real. Primary care settings Tertiary care settings Appendicitis Appendicitis Yes No Yes No (%) (%) (%) (%) Right lower quadrant tenderness Present 84 11 81 84 Absent 16 89 19 16 Total 100 100 100 100 Frequency of appendicitis 14% 63% Frequency of positive sign 21% 82% Sensitivity 84% 81% Specificity 89% 16% LR 7. The results for the diagnostic test of right lower quadrant tenderness are shown in Table 2. A comparison of the results in primary and tertiary care shows, as we might expect, an increase in the proportions of patients with appendicitis (from 14% to 63%). But, of course, this increase in prevalence occurred partly because patients with right lower quadrant tenderness (regardless of whether this was a true positive or false positive finding) tended to be referred to the next level of care, whereas patients without this sign tended not to be referred onward; this is confirmed by the rise in the frequency of this sign from 21% of patients in primary care to 82% of patients in tertiary care. Although this sort of increase in a positive diagnostic test result is widely recognised, its effect on the accuracy of the test is not. The forward referral of patients with false positive test results leads to a fall in specificity, in this case a dramatic one from 89% down to 16%. As a result, a diagnostic sign of real value in primary care (LR of 8, LR of 0. First, because clinical signs and other diagnostic tests often lose their value along the referral pathway, tertiary care clinicians might be forgiven for proceeding immediately to applying invasive reference standards. Second, tertiary care teachers should be careful what they teach primary care trainees about the uselessness of clinical signs. Primary care settings Tertiary care settings Appendicitis Appendicitis Yes No Yes No (%) (%) (%) (%) Rigid abdomen Present 40 26 23 6 Absent 60 74 77 94 Total 100 100 100 100 Frequency of 14% 47% appendicitis Frequency of 28% 14% positive sign Sensitivity 40% 24% Specificity 74% 94% LR 1. Overcoming this limitation is another bonus that attends the replication of a promising Phase III study in a second “test” setting attended by patients of the sort that the test is claimed to benefit. Does specificity always fall between primary care and tertiary care settings? Might this be employed to generate a “standardised correction factor” for extrapolating test accuracy between settings? In this case, a clinical sign that is useless in primary care (LR barely above 1 and LR close to 1) is highly useful in tertiary care (LR of 5), and in this case specificity has risen (from 74% to 95%), not fallen, along the referral pathway. The solution to this paradox is revealed in the frequency of the sign in these two settings; it has fallen (from 28% to 14%), not risen, along the pathway from primary to tertiary care. We think that the explanation is that primary care clinicians, who do not want to miss any patient’s appendicitis, are “over-reading” abdominal rigidity compared to their colleagues in tertiary care. At this stage in our knowledge of this phenomenon we do not think the “standard correction factors” noted in the previous paragraph are advisable, and this paradox once again points to the need to replicate promising Phase III study results in “test” settings attended by patients (and clinicians! In this regard we welcome the creation of the CARE consortium of over 800 clinicians from over 70 countries14 for their performance of web- based, large, simple, fast studies of the clinical examination. For clinicians who wish to apply the bayesian properties of diagnostic tests, accurate estimates of the pretest probability of target disorders in their locale and setting are required. These can come from five sources: personal experience, population prevalence statistics, practice databases, the publication that described the test, or one of a growing number of primary studies of pretest probability in different settings. The ultimate value of a diagnostic test is measured in the health outcomes produced by the further diagnostic and therapeutic interventions it precipitates. Sometimes this benefit is self-evident, as in the correct diagnosis of patients with life threatening target disorders who thereby receive life saving treatments. At other times these outcomes can be hinted at in Phase III studies if the reference standard for the absence of the target disorder is a benign clinical course despite the withholding of treatment. More often, however, Phase IV questions are posed about diagnostic tests that achieve the early detection of asymptomatic disease, and can only be answered by the follow up of patients randomised to undergo the diagnostic test of interest or some other (or no) test. Methods for conducting randomised trials are discussed elsewhere,17 and we will confine this discussion to an example of the most powerful sort, a systematic review of several randomised trials of faecal occult blood testing. Number needed to screen to Relative Absolute prevent one Unscreened Screened risk risk more colorectal Outcome group group reduction reduction cancer death Colorectal 0. Because most of them remained cancer free, the sample size requirement was huge and the study architecture is relatively inefficient. It would have been far more efficient (but unacceptable) to randomise the disclosure of positive test results, and this latter strategy was employed in a randomised trial of a developmental screening test in childhood. However, parents of the “labelled” experimental children were more likely to worry about their school performance, and their teachers tended to report more behavioural problems among them. This warning that diagnostic tests can harm as well as help those who undergo them is a suitable stopping point for this chapter.

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According to the Oxford English Dictionary (2nd edition) it is: A substance which is released at the end of a nerve fibre by the arrival of a nerve impulse and by diffusing across the synapse or junction effects the transfer of the impulse to another nerve fibre (or muscle fibre or some receptor) buy discount sildalis 120 mg erectile dysfunction treatment bangkok. Based on this definition a neurotransmitter could be exemplified by actylcholine (ACh) released from motor nerves to excite and contract the fibres of our skeletal muscles generic sildalis 120 mg overnight delivery erectile dysfunction natural. Acetylcholine released rapidly from vesicles in the nerve terminal, on arrival of the nerve impulse, binds quickly with postsynaptic sites (receptors). When activated these open channels for sodium ions which pass through into the muscle fibre to depolarise its membrane and cause contraction. The whole process takes less than one millisecond and the ACh is rapidly removed through metabolism by local cholinesterase so that con- traction does not persist and the way is cleared for fresh ACh to act. Anatomically there is a precise and very close relationship between the nerve ending and the muscle fibre at histologically distinct end-plates, where the receptors to ACh are confined. It is better than having the nerve directly linked to the muscle since the time lost through imposing a chemical at the synapse between nerve and muscle is insignificant and the use of a chemical not only facilitates control over the degree of muscle tone developed, but fortuitously makes it possible for humans to modify such tone chemically. Blocking the destruction of ACh potentiates its effects while blocking the receptors on which it acts produces paralysis (neuromuscular blockade). Indeed it was the curare impregnated into the darts used by native South American hunters, so that they could paralyse and then easily kill their prey, that motivated Claude Bernand to investigate its actions at the end of the nineteenth century and so demonstrate the chemical sensitivity of excitable tissue that led to the concept of chemical transmission. He took a sciatic nerve gastrocnemious muscle preparation from a frog (not the actual quest of the hunters), placed the muscle in one dish of appropriate salt solution and extended the nerve into another. Not surprisingly, simple wire electrodes connected to an activated induction coil induced contractions of the muscle whether placed directly on the muscle or on the nerve to it. When, however, curare was added to the dish containing the muscle, direct stimulation of the muscle still induced a contraction, but activation of the nerve was ineffective. This was not due to any effect of curare on the nerve because when curare was added to the nerve rather than the muscle dish, stimulation of the nerve was still effective. Thus there had to be a chemically sensitive site on the muscle, where it was linked with the nerve, which was affected by the curare. This suggested the release of a NEUROTRANSMITTER SYSTEMS AND FUNCTION: OVERVIEW 5 chemical from the vagus, which was made even clearer by allowing the fluid perfused through one frog heart to drip onto a second one and establishing that when the first heart was slowed by stimulating its vagus the fluid from it also slowed the second heart when that was reached. Loewi did not identify the chemical, which he called vagustoff, but it was later shown to be acetylcholine (ACh), the first identified neurotransmitter (and it was also found to transmit the neural stimulation of skeletal muscle, which had been blocked by curare in the experiments of Bernard). Now this brings us to the first problem with the dictionary definition of a neurotransmitter because in the heart ACh is not transmitting an excitatory impulse between nerve and muscle, it is causing inhibition. Its cardiac effect, change in rate, occurs much more slowly, has nothing to do with the direct opening of any ion channel and is not blocked by curare. Thus the sites on cardiac muscle that are chemically sensitive to ACh, its so-called receptors, are different from those for ACh on skeletal muscle. In fact they are blocked by a different poison, namely atropine (from Atropa belladonna, Deadly Nightshade). First, it is the receptor which ultimately determines the effects of a neurotransmitter and second, since only the excitatory effects of ACh at the neuromuscular junction fulfil the original definition of a neurotransmitter in trans- mitting excitation, either acetylcholine cannot be considered to be a neurotransmitter in the heart, despite its effects, or the definition of a neurotransmitter needs modifying. This is without considering whether you feel content, anxious, or depressed and how that can affect your concentration and ability to read and learn or even turn over the pages. Clearly such processes must involve many different neural pathways and types of neuron producing different effects and presumably requiring a number of different chemicals (neurotransmitters). The importance and variety of such chemicals is also emphasised from a look at drug usage and the study of how they work. There are many drugs that affect the nervous system for good (antidepressants, analgesics, anticonvulsants) and bad (toxins, poisons, drugs of abuse) and although it would be naive to think that any drug has only one effect, i. NEUROTRANSMITTER CLASSIFICATION The following substances, listed alphabetically, have been widely implicated and generally accepted as neurotransmitters in the central nervous system (CNS), although some, such as glutamate, are much more important than others, e. Some 6 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION classification is appropriate and the simplest and most commonly used is that based on chemical structure with the substances grouped as follows: Chemical group Examples A Choline ester Acetylcholine (ACh) B Monoamines Catechol Dopamine (DA), noradrenaline (NA) (adrenaline) Indole 5-Hydroxytryptamine (5-HT, serotonin) Imidazole Histamine (HIST) C Amino acids Acidic Glutamate (GLT) Basic g-Aminobutyric acid (GABA), glycine D Peptides Enkephalins, endorphins, cholecystokinin, substance P (Many others have been implicated) E Purines Adenosine triphosphate (ATP), adenosine In addition to the above it is now clear that the following substances may have an important central action but whether they can be classified as true neurotransmitters is uncertain: F Steroids Pregnenalone, dehydroepiandrosterone G Nitric oxide (A gas but it is always in solution in the brain) H Eicosanoids Prostaglandins A glance at the structure of the classical neurotransmitters (Fig. Although we will see that peptides certainly have some properties different from other NTs, in that they rarely have a primary neurotransmitter function and usually just complement the actions of those NTs in groups A±C, to put them in a class of their own and group all the others together simply on the basis of molecular size is inappropriate and misleading since it elevates the peptides to a status that is neither proven nor warranted.