The generally accepted view is that the stimulatory drive for the ARAS comes from collaterals of the classical ascending sensory pathways sildigra 50 mg without a prescription. Indeed buy sildigra 100 mg on line, this is another way in which sensory stimuli can affect our state of arousal (Fig. The ascending reticular activating system (ARAS) extends from the cephalic medulla through the pons and mid- brain to the thalamus (see Moruzzi and Mayoun 1949). It is activated by impulses in collaterals of the spinothalamic sensory pathway running to specific thalamic nuclei (SpThNc) and in turn activates much of the cortex, partly through the non-specific thalamic nuclei (NspThNc), which also receive inputs from SpThNc and also via the nucleus basalis (NcB). It is probable that reciprocal links between cortical areas and the thalamus, particularly NspThN, lead to slow-wave (8 Hz) cortical EEG synchrony and, in the absence of appropriate sensory input and ARAS activity, a sleep state system ensures that all sensory stimuli, whatever their strength or modality, contribute collectively to cortical arousal. This is possible because part of any sensory input is diverted to the ARAS and so prevents the cortex from reverting to its basic slow-wave oscillating rhythm. Thus, not only will the sensory cortex be more responsive to any primary sensory input it receives, but its activation keeps us alert. In this respect, the ARAS can be considered to contribute to our circadian rhythm by helping to ensure that we have an active cortex and so stay awake when we have adequate stimulation. In addition to the excitatory drive, there are also inhibitory neurons from the anterior hypothalamus which provide one route for suppressing activity in the ARAS. Together, these links could help to ensure smooth progression from one state of arousal to another. Also, during REM sleep, pontine±geniculate±occipital (PGO) waves travel to the cerebral cortex and spinal cord and it is this wave of activity, passing through intermediate brain regions, that is thought to blunt sensory and motor function. It is important to emphasise that a lesion of the reticular system disrupts a number of afferent inputs to the cortex. Particularly important in this respect are the mono- aminergic (especially noradrenaline, 5-HT and histamine) and cholinergic pathways. When the ascending inputs from these neurons are destroyed, sleep is passive and not at all like natural sleep which, as detailed above, has distinct phases and depends on brainstem influences on cortical function. How these different neurotransmitters might influence sleep and arousal will be considered next. Whether this results in full arousal, or merely a temporary disruption of sleep to give REM periods without full awaking, will depend on the balance of inputs and the overall state of cortical activity. Some of these inputs come from cholinergic, histaminergic, noradrenergic and 5-HT neurons. These neurons innervate the cortex more than the thalamus and their possible roles will be considered in the following sections. This material draws on studies designed to show:which neurotransmitters are associated with those brain structures concerned with sleep and waking; how their function may change during the cycle; to what extent pharmacological manipulation of their activity influences the cycle; and how drugs which modify our state of arousal affect neurotransmitters. ACETYLCHOLINE Studies of several animal species, ranging from rats to sheep, have shown that the release of acetylcholine (ACh) into cortical cups (see Chapter 4 and 6) is increased in proportion to cortical (EEG) activity, being maximal during convulsions and lowest under deep anaesthesia. These findings are consistent with evidence that cortical arousal (EEG desynchronisation) is increased by injection of ACh into the carotid artery of animals, or by direct stimulation of the ascending reticular system (ARAS), and that both these actions are blocked by the muscarinic receptor antagonist, atropine. It has even been shown in humans that REM sleep is induced by intravenous infusion of centrally-acting cholinomimetic agents, such as arecoline or physostigmine (an acetylcholinesterase inhibitor), and, again, the effects of these treatments are inhibited by atropine. Yet antimuscarinic drugs do not have any marked sedative effects on behavioural arousal. As outlined previously (Chapter 6), cholinergic neurons are located in two broad groups of nuclei, both of which are linked to the ARAS and thalamus (Fig. One group lies rostrally in the basal forebrain, within the nucleus basalis, medial septum and diagonal band. This system is more active during the waking state than during sleep and blocking its effects could well explain how antimuscarinic drugs inhibit EEG desynchronisation. The nucleus basalis, which sends diffuse projections to the cortex and hippocampus, has also been linked with memory function (Chapter 18). The second cluster of neurons lies more caudally, near the pons, in the pedunculo- pontine (PPT) and laterodorsal tegmental (LDT) nuclei (see Fig. It innervates the non-specific thalamic nuclei as well as some more specific ones like the lateral geniculate nucleus (visual pathway), the pontine reticular formation and occipital cortex. Cholinergic neurons are found primarily either rostral to the ascending reticular activating system (ARAS) in the nucleus basalis (NcB) caudally in the pedunculo pontine tegmentum (PPT) nucleus. The former, which innervate much of the cortex, receive inputs from the ARAS and appear to be partly responsible for maintaining the EEG and behavioural arousal. The latter innervate non-specific (NspThNu) and specific (SpThN) thalamic nuclei, including the lateral geniculate nucleus as well as the pontine reticular formation (PRF) and occipital cortex (OC). The high-voltage pontine±geniculo± occipital (PGO) waves they initiate in all three areas are characteristic of REM sleep, which is reduced by their destruction bursts of high-voltage waves occur in all these three terminal areas during REM sleep, forming the pontine±geniculo±occipital (PGO) waves described above, they could derive from the PPT (see Hobson 1992). First, more than half the neurons in the PPT fire rhythmically only when PGO waves are evident and their firing starts immediately before the PGO waves appear. Second, in cats, REM sleep is augmented by direct injection of either carbachol, or more selective muscarinic agonists, or the anticholinesterase, neostigmine, into the pontine reticular formation (one of the projection sites for PPT). Third, REM sleep is abolished by lesion of the PPT nucleus but, interestingly, not by lesion of the LDT. HISTAMINE Although histamine has mixed excitatory and inhibitory effects on central neurons, those antihistamines (H1-receptor antagonists) that enter the brain produce sedation; this indicates that the predominant overall effect of histamine is excitatory. The preferred explanation for this rests on evidence that histaminergic neurons in the posterior hypothalamus are active in waking and silent in deep SWS and REM sleep. The histamine neurons in the tuberomammillary nucleus, in the posterior hypo- thalamus, project to the cortex and thalamus and receive an afferent input from 488 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION Figure 22. The activity of histamine-releasing neurons increases with arousal and diminishes during sleep.

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The reason (indication) for prescription in this group of patients may be a diagnosed temporary worsening of asthma (increasing severity) that in itself would lead to a higher incidence of exacerbations sildigra 25mg otc. Diagnosing severity of the underlying disease that changes over time may therefore order sildigra 25mg otc, have caused this result: confounded by indication. In order to be able to adjust for confounding during the analysis of observational studies, we would need an accurate indicator of the severity of the disease over time. For diseases such as asthma it is difficult reliably to assess changing severity by using data collected during routine care. In the absence of a reliable severity indicator any interpretation can be flawed by the potential (residual) confounding. In case of inability to assess severity, the only method to counter confounding would be the randomisation of patients to different treatment arms in order to make both arms similar as to the spectrum of severity. Currently, however, this option is not feasible in “naturalistic” circumstances. As electronic medical records are becoming available, researchers use them to change medical practice by providing decision support, and analyse observational databases to study the delivery of care. Thus the experience in developing decision support systems and analysing observational databases feeds back into the requirements for electronic medical records. And as new requirements for the electronic record are formulated, the record itself begins to change. In the area of decision support systems, researchers are combining reminder systems that rely solely on recorded data with systems that request additional information from clinicians. The resulting systems rely on the one hand on data already available in the electronic record to determine eligible patients, and subsequently interact with the clinician to assess, for example, whether the patient should be treated according to a certain protocol. Researchers working on the development of observational databases are beginning to combine retrospective research with prospective research. Trials are translated into software, distributed electronically, and added to an electronic medical record. Based on the data in that record, the system automatically detects patients eligible for a trial. It then informs the clinician that the patient is eligible, and requests permission to include them in the trial. The system subsequently performs the randomisation between treatment arms during patient consultation, and the electronic record supports subsequent data collection. As a result, the boundaries between an electronic record, a decision support system, and systems for clinical trials are beginning to fade. Each patient–doctor encounter, each investigation, each laboratory test, and each treatment in medical practice constitutes, in principle, an experiment. Paper as a medium to record data limits our ability to exploit that potential. Electronic medical records will facilitate research that relies on data recorded in routine medical practice. The potential of ICT, however, lies in its ability to close the loop between clinical practice, research, and education. The Computer-Based Patient Record: An Essential Technology for Health Care (revised edn). Comparison of computer-aided and human review of general practitioners’ management of hypertension. The role of electronic patient records in the development of general practice in the Netherlands. Effects of computer-based decision support systems on clinician performance and patient outcomes: a systematic review. Postmarketing surveillance based on electronic patient records: the IPCI project. In residency training, both practice guidelines and evidence-based medicine are seen as responses to the psychological limitations of unaided clinical judgement. Introduction This chapter reviews the cognitive processes involved in diagnostic reasoning in clinical medicine and sketches our current understanding of these principles. It describes and analyses the psychological processes and mental structures employed in identifying and solving diagnostic problems of varying degrees of complexity, and reviews common errors and pitfalls in diagnostic reasoning. It does not consider a parallel set of issues in selecting a treatment or developing a management plan. For theoretical background we draw upon two approaches that have been particularly influential in research in this field: problem solving1–6 and decision making. Psychological decision research has typically looked at factors affecting diagnosis or treatment choice in well defined, tightly controlled problems. Despite a common theme of limited rationality, the problem-solving paradigm focuses on the wisdom of practice by concentrating on identifying the strategies of experts in a field to help learners acquire them more efficiently. Research in this tradition has aimed at providing students with some guidelines on how to develop their skills in clinical reasoning. Consequently, it has emphasised how experts generally function effectively despite limits on their rational capacities. Behavioural decision research, on the other hand, contrasts human performance with a normative statistical model of reasoning under uncertainty, Bayes’ theorem. This research tradition emphasises positive standards for reasoning about uncertainty, demonstrates that even experts in a domain do not always meet 180 CLINICAL PROBLEM SOLVING AND DIAGNOSTIC DECISION MAKING these standards, and thus raises the case for some type of decision support.

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The epithelial layer contains glands edematous order sildigra 120 mg online, and the spiral arteries become tortuous (see that penetrate the stromal layer purchase 50mg sildigra with visa. Peak secretory activity, edema formation, and secretory columnar epithelium. The pro- to 8 after ovulation in preparation for implantation of the liferative phase coincides with the midfollicular to late fol- blastocyst. Progesterone antagonizes the effect of estrogen licular phase of the menstrual cycle. Under the influence of on the myometrium and reduces spontaneous myometrial the rising plasma estradiol concentration, the stromal and contractions. The endometrial glands elongate and are lined with the declining levels of progesterone and estradiol caused by columnar epithelium. Necrotic changes and ized, and more spiral arteries, a rich blood supply to this re- abundant apoptosis occur in the secretory epithelium as it gion, develop. The arteries constrict, reducing the blood supply progesterone receptors and increases myometrial excitabil- to the superficial endometrium. Leukocytes persist in large numbers coincides with the early to midluteal phase of the menstrual throughout menstruation, providing resistance against in- cycle. The endometrium contains numerous progesterone fection to the denuded endometrial surface. Ovulation Proliferative phase Secretory phase Days 0 4 8 12 16 20 24 28 32 Progesterone Estradiol 99 Basal body temperature 98 97 100 Vaginal cornification and 50 pyknotic index 0 3 Cervical mucus 2 ferning 1 0 Glycogen vacuoles 4 Gland Endometrium Cyclic changes in the uterus, 3 FIGURE 38. It is se- layer of the endometrium occurs during the menstrual creted in significant amounts during the luteal phase of the phase (menses). The reduction in steroids destabilizes cretes progesterone throughout the first trimester, and the lysosomal membranes in endometrial cells, resulting in the placenta continues progesterone production until parturi- liberation of proteolytic enzymes and increased production tion. Small amounts of 17-hydroxyprogesterone are se- of vasoconstrictor prostaglandins (e. Progesterone binds prostaglandins induce vasospasm of the spiral arteries, and equally to albumin and to a plasma protein called corticos- the proteolytic enzymes digest the tissue. Progesterone is me- blood vessels rupture and blood is released, together with tabolized in the liver to pregnanediol and, subsequently, cellular debris. The endometrial tissue is expelled through excreted in the urine as a glucuronide conjugate. The menstrual flow lasts 4 to 5 days and averages 30 to ovaries and adrenals and from peripheral conversion. It does not clot because of the presence drostenedione and dehydroepiandrosterone (DHEA) orig- of fibrinolysin, but the spiral arteries constrict, resulting in inate from the adrenal cortex (see Chapter 34), and ovarian a reduction in bleeding. Peripheral conversion from an- Changes in the properties of the cervical mucus promote drostenedione provides an additional source of testos- the survival and transport of sperm and, thus, can be im- terone. Testosterone can also be converted in peripheral portant for normal fertility. The cervical mucus undergoes tissues to dihydrotestosterone (DHT) by 5 -reductase. During the fol- However, the primary biologically active androgen in licular phase, estrogen increases the quantity, alkalinity, women is testosterone. Androgens bind primarily to SHBG viscosity, and elasticity of the mucus. Androgens are relax, and the epithelium becomes secretory in response to also metabolized to water-soluble forms by oxidation, sul- estrogen. By the time of ovulation, elasticity of the mucus fation, or glucuronidation and excreted in the urine. With progesterone rising either after ovulation, during pregnancy, or with low-dose progestogen administration during the cycle, the quantity PUBERTY and elasticity of the mucus decline; it becomes thicker (low During the prepubertal period, the hypothalamic-pituitary- spinnbarkeit) and does not form a ferning pattern when ovarian axis becomes activated—an event known as go- dried on a microscope slide. With these conditions, the nadarche—and gonadotropins increase in the circulation mucus provides better protection against infections and and stimulate ovarian estrogen secretion. The vaginal epithelium proliferates under the influence Factors stimulating the secretion of GnRH include gluta- of estrogen. Basophilic cells predominate early in the fol- mate, norepinephrine, and neuropeptide Y emanating from licular phase. The columnar epithelium becomes cornified synaptic inputs to GnRH-producing neurons. In addition, a (keratinized) under the influence of estrogen and reaches decrease in -aminobutyric acid (GABA), an inhibitor of its peak in the periovulatory period. It is also known that tory period, progesterone induces the formation of thick the response of the pituitary to GnRH increases at the time mucus, the epithelium becomes infiltrated with leukocytes, of puberty. Collectively, numerous factors control the rise in and cornification decreases (see Fig. Estradiol induces the development of secondary sex ESTROGEN, PROGESTIN, AND ANDROGEN: characteristics, including the breasts and reproductive tract, and increased fat in the hips. Estrogens also regulate TRANSPORT AND METABOLISM the growth spurt at puberty, induce closure of the epi- The principal sex steroids in the female are estrogen, prog- physes, have a positive effect in maintaining bone forma- estin, and androgen. Three estrogens are present in signif- tion, and can antagonize the degrading actions of icant quantities—estradiol, estrone, and estriol. Therefore, estrogens have the most abundant and is 12 and 80 times more potent than a positive effect on bone maintenance, and later in life, ex- estrone and estriol, respectively. Much of estrone is derived ogenous estrogens oppose the osteoporosis often associ- from peripheral conversion of either androstenedione or ated with menopause. During pregnancy, large quantities As mentioned earlier, the first menstruation is called of estriol are produced from dehydroepiandrosterone sul- menarche and occurs around age 12.

For ex- inspiratory muscles resumes during the first part of expira- ample generic sildigra 120mg with mastercard, talking while walking requires that some muscles tion discount 100 mg sildigra fast delivery, slowing the initial rate of expiration. As more ventila- simultaneously attend to the tasks of posturing, walking, tion is required—for example, during exercise—other in- phonation, and breathing. Because it is impossible to spiratory muscles (external intercostals, cervical muscles) 363 364 PART V RESPIRATORY PHYSIOLOGY Diaphragm electromyogram Diaphragm electrical activity per unit time Inspiration Expiration Inspiration Expiration Pleural pressure FIGURE 22. During inspiration, the number of active muscle medulla oblongata and a cross section in the region of the fourth fibers, and the frequency at which each fires, increases progres- ventricle. C1, first cervical nerve; X, vagus nerve; IX, glossopha- sively, leading to a mirror-image fall in pleural pressure as the di- ryngeal nerve. In addition, expiration becomes an active complex, but the exact anatomic and functional description process through the use, most notably, of the muscles of remains uncertain. The neural basis of these breathing pat- does not arise from a single pacemaker or by reciprocal in- terns depends on the generation and subsequent tailoring hibition of two pools of cells, one having inspiratory- and of cyclic changes in the activity of cells primarily located in the other expiratory-related activity. An integrator-based theoretical model, as Oblongata Control the Basic Breathing Rhythm described below, is suitable for a first understanding of res- The central pattern for the basic breathing rhythm has piratory pattern generation. Cells in the medulla oblongata associated Onset of Inspiration with breathing have been identified by noting the correla- tion between their activity and mechanical events of the Many different signals (e. Two different groups of cells have been loskeletal movements, pain, chemosensor activity, and hy- found, and their anatomic locations are shown in Figure pothalamic temperature) provide a background ventilatory 22. Inspiration begins by the abrupt re- dorsal location in the region of the nucleus tractus solitarii, lease from inhibition of a group of cells, central inspiratory predominantly contains cells that are active during inspira- activity (CIA) integrator neurons, located within the tion. The ventral respiratory group (VRG) is a column of medullary reticular formation, that integrate this back- cells in the general region of the nucleus ambiguus that ex- ground drive (see Fig. Integration results in a pro- tends caudally nearly to the bulbospinal border and cra- gressive rise in the output of the integrator neurons, which, nially nearly to the bulbopontine junction. The VRG con- in turn, excites a similar rise in activity of inspiratory pre- tains both inspiration- and expiration-related neurons. The rate of ris- groups contain cells projecting ultimately to the bul- ing activity of inspiratory neurons and, therefore, the rate bospinal motor neuron pools. The DRG and VRG are bi- of inspiration itself, can be influenced by changing the laterally paired, but cross-communication enables them to characteristics of the CIA integrator. Inspiration is ended respond in synchrony; as a consequence, respiratory move- by abruptly switching off the rising excitation of inspira- ments are symmetric. The CIA integrator is reset before the begin- The neural networks forming the central pattern gener- ning of each inspiration, so that activity of the inspiratory ator for breathing are contained within the DRG/VRG neurons begins each breath from a low level. CHAPTER 22 The Control of Ventilation 365 may serve to integrate many different autonomic functions Pontine respiratory in addition to breathing. This effect is greatest early in off-switch Chemoreceptors neurons expiration and recedes as lung volume falls. Inspiratory muscle activity is essentially absent in the second phase of expiration, which includes continued passive recoil during quiet breathing or activation of expiratory muscles if more than quiet breathing is required. The duration of expiration is determined by the inten- CIA integrator sity of inhibition of activity of inspiratory-related cells of the DRG/VRG complex. Inhibition is greatest at the start of expiration and falls progressively until it is insufficient to prevent the onset of inspiration. The progressive fall of inhibition amounts to a decline of threshold for initiating the switch from expiration to inspiration. The rate of de- Pulmonary Pulmonary Inspiratory stretch irritant premotor cline of inhibition and the occurrence of events that trig- receptors receptors neurons ger the onset of inspiration are subject to several influ- ences. The duration of expiration can be controlled not only by neural information arriving during expiration but also in response to the pattern of the preceding inspira- To tion. How the details of the preceding inspiration are spinal cord stored and later recovered is unresolved. Various Control Mechanisms Adjust Breathing to Meet Metabolic Demands The basic pattern of breathing generated in the medulla is Inspiratory Activity Is Switched Off extensively modified by several control mechanisms. Mul- to Initiate Expiration tiple controls provide a greater capability for regulating breathing under a larger number of conditions. Their inter- Two groups of neurons, probably located within the VRG, actions modify each other and provide for backup in case of seem to serve as an inspiratory off-switch (see Fig. The set of strategies for controlling a given variable, Switching occurs abruptly when the sum of excitatory in- such as minute ventilation, typically includes individual puts to the off-switch reaches a threshold. Adjustment of the schemes that differ in several respects, including choices of threshold level is one of the ways in which depth of breath- ing can be varied. Two important excitatory inputs to the sensors and effectors, magnitudes of effects, speeds of ac- off-switch are a progressively increasing activity from the tion, and optimum operating points. CIA integrator’s rising output and an input from lung stretch The use of multiple control mechanisms in breathing receptors, whose afferent activity increases progressively can be illustrated by considering some of the ways breath- with rising lung volume. Perhaps the simplest the medulla to generate a breathing pattern on its own; the strategies are feedforward mechanisms, in which breathing second is one of many reflexes that influence breathing. The CIA One such mechanism would be for the central nervous sys- integrator is thus reset by its own rising activity. Other in- tem (CNS) to vary the activity of the medullary pattern puts, both excitatory and inhibitory, act on the off-switch generator in parallel with, and in proportion to, the excita- and change its threshold. For example, chemical stimuli, tion of the muscles used during exercise. Another prospec- such as hypoxemia and hypercapnia, are inhibitory, raising tive feedforward scheme involves sensing the magnitude of the threshold and causing larger tidal volumes. Experimental evidence supports pons called the pontine respiratory group. Electrical stim- this mechanism, but the identity of the required intrapul- ulation in this region causes variable effects on breathing, monary sensor remains uncertain.

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