Michael A. Gropper, MD, PhD

• Associate Professor, Department of Anesthesia, Director, Critical Care Medicine, University of California, San Francisco, CA

https://profiles.ucsf.edu/michael.gropper

The cause of Down syndrome in 90% of cases is nondisjunction of chromosome 21 during gametogenesis; in 5% or less antiviral cream for genital herpes order albendazole in united states online, a translocation is responsible hiv infection mayo clinic buy albendazole 400mg. An almost uniform complication by age 50 years natural anti viral warts order 400mg albendazole mastercard, Down syndrome leads to an Alzheimer-like dementia with cerebral plaques antiviral and antiretroviral order albendazole 400 mg, tangles hiv infection symptoms nhs trusted 400mg albendazole, and accumulation of amyloid (see Chapter 7) quimioterapia antiviral discount albendazole 400 mg without prescription. One theory holds that because Down syndrome individuals have three copies of the gene for the amyloid precursor protein, which is situated on chromosome 21, they overproduce amyloid. Down syndrome children retain social skills that partly compensate for their intellectual disability. Curiously, severely affected children with no neuroleptic exposure may have orofacial dyskinesias. The incidence of Down syndrome correlates with increasing maternal age (especially after 40 years). Its incidence also increases, but not to the same degree, with increasing paternal age. Even though it is obviously genetic, neurologists do not classify Down syndrome as an inherited cause of intellectual disability because it is not transmitted from generation to generation. This distinction allows neurologists to state that fragile X syndrome is the most common form of inherited intellectual disability. The disorder leads to defects in the elastic qualities of the skin and congenital abnormalities at the root of the aorta, which cause supravalvular aortic stenosis, but they have no gross physical neurologic abnormalities, such as microcephaly, stereotypies, or epilepsy. As adults, Williams syndrome individuals rarely find steady employment and develop memory impairment at a greater rate than controls. Most striking, the disorder paradoxically seems to enhance certain neuropsychologic functions. For example, remarkably and so far inexplicably, Williams individuals frequently possess unusual musical talent, many possessing perfect pitch. Their conversations, although lacking substance and often one-sided, are garrulous, bubbly, and engaging. Neurologists often call their interactions "hypersocial" and describe their "cocktail-party personality. Neurologists and other specialists have also called this constellation of disorders DiGeorge sequence, DiGeorge syndrome, 22q11 deletion syndrome, and Shprintzen syndrome. Hearing the nasality, physicians may further suspect the diagnosis by inspection of the palate at rest and during voluntary retraction. About 70% of boys who inherit the entire or "full" mutation have moderate-to-severe intellectual disability. Fragile X syndrome boys display strikingly abnormal behavior, including stereotypies, particularly flapping or wringing of their hands. A tubular nose with a broad tip and small nasal alae, and deformed ears are also typical. Unlike inheritance in Down syndrome, fragile X syndrome parents regularly and predictably transmit the mutation to one or more of their children. Thus, neurologists often find that the child presenting for fragile X evaluation has a male relative with mild if not overt intellectual disability. Individuals with only 55 to 200 repeats have the premutation, which leads to no major intellectual impairment or physical stigmata. In successive generations, as with other excessive trinucleotide repeat disorders, the fragile X mutation tends to increase in size, its symptoms emerge at an earlier age (anticipation), and its symptoms seem more pronounced. As an example of anticipation, the number of repeats in germ cells may expand from premutation levels to ones greater than 200. Thus, an asymptomatic mother who carries the premutation may have boys with the full syndrome and girls with a muted version of it. Sometimes the premutation may produce manifestations only after an individual has reached 40 years of age. For example, women with the premutation undergo premature ovarian failure and menopause, and men with it may develop a tremor-ataxia syndrome, cognitive impairment, and mood disorders. Rett Syndrome Generally restricted to girls, Rett syndrome symptoms emerge at 6 to 18 months of age after an initial normal birth and development. Over the next several years, Rett syndrome girls lose their language skills, ability to walk, and other learned motor activities. This macro-orchidism occurs in almost all fragile X syndrome boys and represents the single most consistent physical anomaly. Rett syndrome children, for practical purposes, are only girls, have microcephaly, and regress in their motor and language skills. Also, in contrast to children with the common storage diseases, Rett syndrome children have neither organomegaly nor retinal abnormalities. With boys outnumbering girls by 2: 1, these children lose their comprehension of words then phrases and then their ability to express themselves, i. The remaining children have persistent disabilities, but they do not deteriorate further. This illness is transmitted in a recessive sex-linked pattern and therefore appears, with rare exceptions, only in boys. Turner Syndrome (X0) Individuals with Turner syndrome have a mutation in or, more usually, absence of one of their sex chromosomes. In another hallmark of the disease, her head circumference is only 48 cm, which is two standard deviations below the mean for her age (51 cm). Because her head circumference had been normal during her first 2 years, neurologists determined that she had developed acquired microcephaly. She has also progressively lost her language ability and now cannot speak in a meaningful manner. When her symptoms first appeared, her pediatrician understandably suggested the diagnosis of autism. Their stereotypies, which first appear at about 18 months of age, consist of incessant hand movements, particularly hand wringing and hand washing, hair pulling, clapping, or flapping. Most of them also develop stereotypies beyond hand movements, such as bruxism, mouthing, and body twisting. Head growth follows a normal trajectory from birth to about 6 months, but then its growth decelerates while relatively normal body growth continues. The mutation is presumably lethal to a male fetus, but occasionally a male fetus will inherit the mutation and survive with a forme fruste of the disorder. As with several other genetic disorders, her ears are low-set (but hidden by a low hairline), her nose is flat, and its bridge spreads into broad epicanthal folds. Because she characteristically failed to undergo puberty, she lacks breast development and other secondary sexual characteristics. As young men, their unusual height and lack of secondary sexual characteristics may draw medical attention, but physicians often diagnose Klinefelter syndrome only after the boys fail to go through puberty. Sometimes physicians first diagnose the disorder when an infertility evaluation reveals small testes and a lack or near lack of sperm. He has grown into a eunuchoid habitus with gynecomastia, sparse facial hair, and small testicles. Moreover, they are able to father children, and those children usually have a normal chromosome complement. If they commit a crime, it is typically nonviolent; however, because of their developmental delays, they are likely to be apprehended and incarcerated. In pregnant women, it readily crosses the placenta and tends to accumulate in fetal brain tissue. Mercury intoxication in fetuses, children, and adults causes cognitive impairment and other signs of brain damage. However, eating certain fish causes most mercury toxicity in neonates and infants. Large sea fish, such as swordfish, shark, king mackerel, and tuna, and certain fresh-water fish, such as pike and bass, have relatively high mercury concentrations. On the other hand, the mercury in old-style dental fillings dissolves, if at all, at such a slow rate that it carries no significant risk. Even dentists who prepared the fillings on a daily basis had no mercury-related illnesses. Even though vaccine manufacturers stopped adding mercury preservatives during the 1990s, the reported incidence of autism continued to climb. Lead intoxication in infants and children, depending on its intensity, causes intellectual disability, learning disabilities, and other signs of cerebral impairment. This intoxication has usually originated in infants and children ingesting lead-based paint chips and environmental pollution. In addition, adverse socioeconomic circumstances and certain genes constitute risk factors. Severely affected children have microcephaly, dysarthria, epilepsy, and intellectual disability. The fetal alcohol syndrome is probably the most common nongenetic cause of intellectual disability. Not only does in utero alcohol exposure lead to learning and attention impairments and the resultant aversion to school, it is associated with antisocial and criminal behaviors, including substance abuse. A national survey of Rett syndrome: Age, clinical characteristics, current abilities, and health. Neurodevelopmental and cognitive outcomes of classical homocystinuria: Experience from Qatar. Psychiatric disorders and intellectual functioning throughout development in velocardiofacial (22q11. The Neurological Examination of the Child with Minor Neurological Dysfunction (3rd ed. Sturge-Weber syndrome: Clinical spectrum, disease course, and outcome of 30 patients. Parent and teacher perspectives about problem behavior in children with Williams syndrome. Autism spectrum disorders in genetic syndromes: Implications for diagnosis, intervention and understanding the wider autism spectrum disorder population. Prevalence of autism spectrum disorder symptoms in children with neurofibromatosis type 1. Psychiatric features in children with genetic syndromes: Toward functional phenotypes. The continuing challenge of understanding, preventing, and treating neural tube defects. For each of the following disorders, state whether it frequently causes episodic inattention or changes in mood in children (Yes/No): 12. This disorder accounts for small but significant segments of the childhood obesity and intellectual disability populations. It may hold clues to the mechanism of satiety because children with this disorder lack negative feedback (to stop eating) when either their blood sugar rises or their stomach is distended. Valproate leads to weight gain but not of this magnitude and not with the compulsive eating. Hypothalamic tumors may cause obesity classically accompanied by headache, visual impairment, and sleep disorders. A son of college professors, an 8-year-old boy has slowly and incompletely acquired milestones. He eats incessantly and disregards any limits that his parents place on his calorie consumption. During and after their teenage years, Down syndrome individuals are vulnerable to depression, hypothyroidism, acute leukemia, obstructive sleep apnea, and hearing loss. Because Down syndrome individuals harbor three copies of the chromosome 21, which carries the amyloid precursor protein, they tend to develop Alzheimer disease routinely and at a young age. With the maximum available knowledge, parents can more easily accept that some illnesses, such as fragile X, do not respond to treatment and others, such as Rett syndrome, follow a relentlessly downhill course. For illnesses that result from a single gene mutation, parents can learn that future children or grandchildren will have a certain chance of expressing or merely carrying the illness or that children of only one gender are at risk. Only about 30% of Klinefelter syndrome individuals have intellectual disability and, when present, it is usually mild. In fact, Klinefelter syndrome often remains undiagnosed until men undergo an evaluation for infertility. Because he has sickle-cell disease, a 1-year-old boy sustained an occlusion of his left middle cerebral artery. He will probably not develop aphasia because his right hemisphere will emerge as dominant for language and fine motor function. However, he will develop right-sided spastic hemiparesis with a foreshortened arm and leg.

This perspective has advantages because it allows a multifactorial process such as atherosclerosis to be broken down into components of a more completely understood process such as the biology of a skin wound hiv infection and stds buy albendazole 400mg online. For example how long from hiv infection to symptoms order generic albendazole, wound healing of any form begins with the formation of a clot (fibrin- and fibronectin-containing gel) that fills the wound and provides a provisional matrix for inflammatory cells antiviral skin ointment cheap albendazole line, fibroblasts antiviral vitamins for hpv purchase discount albendazole line, and newly formed microvessels antiviral tincture order albendazole 400mg without prescription. As the wound matures and undergoes contracture anti viral oil cheap albendazole 400mg mastercard, these blood vessels regress and fibroblasts disappear. After resorption of microvessels, tissue hypoxia develops and likely plays a role in the completion of the final scarring process. Alternatively, macrophages in the artery wall may act as a rich source of factors that, for example, promote cell proliferation, migration, or the breakdown of local tissue barriers. The process of local tissue degradation may be important for the initiation of acute coronary artery syndromes because loss of arterial wall integrity may lead to plaque fissuring or rupture. The transmigration of leukocytes into the artery wall must occur as a facilitated process. The release of proinflammatory cytokines such as interleukin-1 may promote the expression of leukocyte adhesive molecules. However, the premise that regrowth of healthy endothelium limits neointimal accumulation is inconsistent with the results of several independent lines of investigation. For example, in experimental models, smooth muscle cell proliferation is not increased in arterial regions devoid of an endothelium. Finally, the endothelium is not restricted to the central lumen because the artery wall also has a rich supply of microvessels (ie, vasa vasorum). However, the exact mechanisms by which lipid moieties contribute to the pathogenesis of atherosclerosis remain elusive. Although the simple concept of cholesterol accumulating in artery walls until flow is obstructed may be correct in certain animal models, this theory is not correct for human arteries. Much of the pioneering work in understanding cholesterol metabolism is based on seminal observations by Brown and Goldstein. One of the major consequences of cholesterol accumulation in the artery wall is thought to be impairment of endothelial function. The endothelium is more than a physical barrier between the bloodstream and the artery wall. In the presence of traditional risk factors, particularly dyslipidemias, these protective endothelial functions are reduced or lost. The loss of these endothelium-derived functions may occur in the presence or absence of an underlying atherosclerotic plaque and may simply imply that atherogenesis has begun. Aggressive attempts to normalize atherosclerotic risk factors (eg, diet and lipid-lowering therapies) may markedly attenuate endothelial dysfunction, even in the presence of extensive atherosclerosis. Perhaps the first line of evidence that cell replication occurs in human arteries is from the observation that atherosclerotic plaques contain monoclonal cell populations. Murry and colleagues169 studied the monoclonality of atherosclerotic plaques by using X chromosome inactivation patterns. Using the polymerase chain reaction, these investigators examined the monoclonality of plaques according to the methylation pattern of the human androgen receptor gene, a highly polymorphic locus on the X chromosome for which 90% of women are heterozygous. These investigators noted that diseased and normal arteries contain monoclonal populations (or patches) of cells. They speculated that the monoclonality of plaques could result from expansion of a preexisting monoclonal patch of cells, rather than mutation or selection of individual cells in the artery wall. However, it is known that rapid expansion in neointimal smooth muscle cell mass occurs early in life. Sims and associates170,171 described the accumulation of intimal smooth muscle cells in the left anterior descending coronary artery of neonates. Using electron microscopy, these investigators demonstrated interruptions in the internal elastic lamina in coronary arteries where a neointima had formed. These interruptions in the internal elastic lamina are not present in all human arteries. Indeed, the internal mammary artery, which typically is devoid of atherosclerosis, has an intact internal elastic lamina. Investigators have suggested that medial smooth muscle cells migrate inward through breaks in the internal elastic lamina to expand and form a neointima. The frequency and degree of smooth muscle cell replication in adult coronary arteries were examined by various investigators. Most of these studies demonstrated very low replication rates in tissue from both normal and diseased arteries. Finally, it is recognized that programmed cell death, or apoptosis, occurs in the artery wall. Investigators have suggested, however, that like fibroblasts that migrate into the base of a wound, arterial wall smooth muscle cells migrate inward to expand plaque mass. Smooth muscle cell migration into the intima was studied in various animal models of neointimal formation (eg, rat carotid artery model). Certain growth factors (eg, platelet-derived growth factor) were shown to play an important role in facilitating smooth muscle cell migration in these models. More information is required on the factors that regulate smooth muscle cell migration, as well as why smooth muscle cells differ in their propensity to migrate after injury. Finally, the buildup of atherosclerotic plaque does not always translate into the formation of arterial obstructions. Instead, abluminal expansion of the artery wall may occur until 40% of the area encompassed by the internal elastic lamina is occupied by plaque; no further enlargement may occur thereafter, and luminal narrowing may ensue. The response of arteries to chronic alterations in blood flow is endothelium dependent. However, when the endothelium was removed from these vessels, the response to reduced blood flow was abolished. In atherosclerotic arteries that contain a rich network of endothelial cell-lined microvessels or vasa vasorum, the role of the endothelium in regulating remodeling may be important. Plaque rupture leads to incremental growth of coronary stenoses and can cause coronary events. Plaque rupture occurs at the shoulder of the plaque where inflammatory cells are found. Alternatively, cracks or fissures may develop in the atherosclerotic lesions and result in acute thromboses that cause unstable angina or myocardial infarction. Patients with stable angina typically have lesions with smooth borders on angiography. Only a few coronary lesions are concentric; most have complex geometry varying in shape over their length. Eccentric stenoses, with a remaining pliable, musculoelastic arc of normal wall, can vary in diameter and resistance in response to changes in vasomotor tone or intraluminal pressure. In contrast, patients with unstable angina usually have lesions characterized by overhanging edges, scalloped or irregular borders, or multiple irregularities. These complicated stenoses likely represent ruptured plaque or partially occlusive thrombus, or both. At autopsy, however, the most common pathologic finding is diffuse vessel involvement with superimposed segmental obstruction of greater severity. In such an artery, rating the significance of the obstruction by the percentage of diameter reduction relative to adjacent vessel segments underestimates its physiologic importance. Ambrose and associates203 reviewed the coronary angiograms of 38 patients who had had Q-wave myocardial infarction in the interval between serial studies. On the preinfarct angiograms, the mean percentage of stenosis at the coronary segment that was later responsible for infarction was only 34%. Similarly, Little and colleagues204 reviewed the coronary angiograms of 42 patients who also had this procedure performed at an interval before and after myocardial infarction. Total occlusion of a previously patent artery was observed in 29 patients; yet for 19 of these occluded arteries, the degree of stenosis was less than 50% on the initial angiogram. Therefore, although the revascularization of arteries with critical stenoses in target lesions is appropriately indicated to reduce symptoms and myocardial ischemia, a risk of further cardiac events remains because atherosclerosis is a diffuse process, and mild or modest angiographic stenoses are more likely to result in subsequent myocardial infarction than are severe stenoses. With this background comes the problem of predicting which arterial segments with minimal angiographic disease will later develop new critical stenoses. Clues to the solution emerged from careful pathologic studies of lesions by Davies and Thomas. In the absence of obstructive luminal thrombosis, these intimal injuries do not cause clinical events. However, disruption of the fibrous cap, or plaque rupture, is a more serious event that typically results in the formation of clinically significant arterial thromboses. From autopsy studies it is known that rupture-prone plaques tend to have a thin, friable fibrous cap. Hemodynamics If accurate angiographic assessment of the geometry of a coronary stenosis is made, hydrodynamic principles can be used to estimate the physiologic significance of the obstruction. Equations that (accurately) predict the pressure gradient across a stenosis usually ignore entrance effects. Frictional losses are proportional to blood velocity but are usually not important except in very long stenoses. The separation or turbulence factor is: s= k An - 1 2 As 2 where is blood density, and k is an experimentally determined coefficient. Thus frictional losses are directly proportional to the first power of stenosis length but are inversely proportional to the square of the area (or fourth power of diameter). Separation losses are particularly prominent because they increase with the square of flow. Even at resting flows, more than 75% of energy loss results from this turbulence when blood exits the stenosis. For this reason, exercise, anemia, and arteriolar vasodilator drugs (eg, dipyridamole) are poorly tolerated in the presence of severe stenosis. As the severity of the stenosis increases further, the arteriolar bed can no longer compensate, and flow begins to fall. As stenosis severity increases, distal perfusion pressure falls, arterioles dilate to maintain flow until autoregulation is exhausted (in the subendocardium first), and flow becomes pressure dependent. A coronary artery supplying blood through collaterals to a large mass of myocardium requires high resting flow rates, and even mild stenosis may be flow limiting. The frequently used term critical stenosis is usually defined as coronary constriction sufficient to prevent an increase in flow over resting values in response to increased myocardial oxygen demands. This is evidence that autoregulation has been exhausted in at least the inner layer of myocardium (see "Transmural Blood Flow," earlier). If oxygen demand decreases, some coronary autoregulatory reserve is recovered and the stenosis is no longer critical. The failure to recognize this situation has led to misinterpretation of studies designed to demonstrate coronary steal (see later). Coronary Collaterals Coronary collaterals are anastomotic connections, without an intervening capillary bed, between different coronary arteries or between branches of the same artery. In the normal human heart, these vessels are small and have little or no functional role. Individual differences in the capability of developing a sufficient collateral circulation are determinants of the vulnerability of the myocardium to coronary occlusive disease. In dogs collaterals develop in a narrow subepicardial zone, at the border of the potentially ischemic region, whereas in pigs a dense subendocardial plexus develops in response to coronary occlusion. In the presence of coronary disease, humans exhibit a small number of large epicardial collateral vessels and numerous small subendocardial vessels. In response to coronary occlusion, native coronary collateral vessels (present from birth) do not passively stretch but undergo an active growth process that within 8 weeks in dogs can restore perfusion sufficient to support normal myocardial function even during exercise. The reason may be an embryonal pattern of vascular development in which longitudinal growth of smooth muscle cells occurs at the same time as radial growth. Arteriogenesis refers to the transformation of preexisting collateral arterioles into functional arteries with a thick muscular coat and the acquisition of viscoelastic and vasomotor properties. Increased collateral blood flow results in increased shear stress at the endothelium, which upregulates cell adhesion molecules. Upregulation leads to adherence of monocytes, which transform into macrophages, and the production and release of growth factors such as granulocytemacrophage colony-stimulating factor, monocyte chemoattractant protein-1, and basic fibroblast growth factor. Angiogenesis is not directly related to collateral vessel development but rather refers to the proliferation, migration, and tube formation of capillaries in the central area of ischemic regions. Experimental approaches include mechanical strategies to increase shear stress as well as cell therapies. Collaterals do not constrict in response to -receptor activation but do dilate in response to 1- or 2-agonists. Remarkably, collateral vessels constrict in response to vasopressin to a much greater extent than normal vessels. In vivo studies in dogs indicated that levels of vasopressin present during stress (hemorrhage, cardiopulmonary bypass) diminished flow to collateraldependent myocardium. This finding likely reflects both constriction of collateral vessels and enhanced vasoconstriction of the resistance vessels in the collateral-dependent myocardium. The deleterious effects of coronary arteriolar dilators such as adenosine and dipyridamole are discussed later (see "Coronary Steal"). Investigators have estimated that, in humans, perfusion through collaterals can equal perfusion through a vessel with a 90% diameter obstruction. Perhaps persons with coronary obstructions but excellent collateralization remain asymptomatic and are not studied. Such evidence is extremely difficult to obtain, even in experimental preparations. Determinants of Ratio of Myocardial Oxygen Supply to Demand An increase in myocardial oxygen requirement beyond the capacity of the coronary circulation to deliver oxygen results in myocardial ischemia (Box 7. This is the most common mechanism leading to ischemic episodes in chronic stable angina and during exercise testing. An increase in heart rate can reduce subendocardial perfusion by shortening diastole. No universally accepted gold standard exists for the presence of myocardial ischemia. With the onset of ischemia, perfusion may be further compromised by delayed ventricular relaxation (decreased subendocardial perfusion time) and decreased diastolic compliance (increased left ventricular end-diastolic pressure).

Discount albendazole 400 mg on line. “Woke!”: Global and Local Biosafety/Biosecurity Missions in Light of Cura Personalis.

Statin prophylaxis and inflammatory mediators following cardiopulmonary bypass: a systematic review hiv infection personal stories buy albendazole with a visa. Use of N-acetylcysteine to reduce post-cardiothoracic surgery complications: a meta-analysis stories of hiv infection symptoms buy albendazole with mastercard. Recombinant endotoxin neutralizing protein improves survival from Escherichia coli sepsis in rats antiviral essential oil blend safe albendazole 400 mg. Antiinflammatory effects of reconstituted high-density lipoprotein during human endotoxemia hiv kidney infection order albendazole online from canada. A randomized hiv timeline of infection generic 400mg albendazole with amex, double-blind hiv infection hindi purchase discount albendazole on line, placebo-controlled study assessing the anti-inflammatory effects of ketamine in cardiac surgical patients. Effects of ketamine, halothane, enflurane, and isoflurane on systemic and splanchnic hemodynamics in normovolemic and hypovolemic cirrhotic rats. There is no correlation between gastric mucosal perfusion (tonometer pHi) and arterial hemoglobin concentration during major surgery. No effect of preoperative selective gut decontamination on endotoxemia and cytokine activation during cardiopulmonary bypass: a randomized, placebocontrolled study. Black circles indicate inhibitory actions; small green circles indicate stimulatory actions. The acute effects on myocardial function, electrophysiology, coronary vasoregulation, systemic and pulmonary vasoregulation, and the baroreceptor reflex are described. Different volatile agents are not identical in this regard, and the preponderance of information indicates that halothane and enflurane exert equal but more potent myocardial depression than isoflurane, desflurane, or sevoflurane, in part because of reflex sympathetic activation with the latter agents. In the setting of preexisting myocardial depression, volatile agents have a greater effect than in normal myocardium. Ion channels usually are studied in ex vivo circumstances in which they may be altered by multiple modulating influences. Moreover, the studies frequently used nonhuman tissue, and well-recognized species differences make extrapolation to humans difficult. Mechanisms underlying the inotropic action of halothane on intact rat ventricular myocytes. Mechanisms of force inhibition of halothane and isoflurane in intact rat cardiac muscle. The direct actions on myofilaments result in myocardial depression that is independent of calcium concentration. This likely explains the relative paucity of literature detailing the modulating effects of volatile agents on diastolic function. There is reasonable agreement in the literature that volatile agents prolong isovolumic relaxation in a dose-dependent manner. For example, halothane has been reported to decrease compliance and have no effect on myocardial stiffness. Paradoxically, in the setting of reperfusion injury and Ca2+ overload, the volatile agent sevoflurane improves indices of diastolic relaxation and attenuates myoplasmic Ca2+ overload. For volatile agents, the order of sensitization is halothane > enflurane > sevoflurane > isoflurane = desflurane. The molecular mechanisms underlying the effect of volatile anesthetics are poorly understood. Anesthetic-induced modulation of ion channels is important mechanistically in excitation-contraction coupling (discussed earlier), in preconditioning (discussed later), and in modulating automaticity and arrhythmia generation17 (Table 10. Although the effects of a particular volatile agent on a specific cardiac ion channel may be characterized, the information often cannot be extrapolated for use in clinical situations. This partly reflects issues such as species differences and ex vivo studies, but it also recognizes the impossibility of predicting the arrhythmogenic effect that can ensue after modulation with a particular volatile agent. This is one of the lessons garnered from experience with antiarrhythmic drugs such as encainide and flecainide. Studies investigating the effects of volatile agents on coronary vasoregulation should be interpreted in this context. Animal studies indicate that halothane has little direct effect on the coronary vasculature. Current assessments of the effects of isoflurane have been succinctly detailed by Tanaka and colleagues. The patients had significant coronary stenosis in a vessel serving a region of ischemic myocardium, in which vessels were presumably maximally dilated because of local metabolic autoregulation, and had isofluraneinduced vasodilatation in adjacent vessels in nonischemic zones that reduced flow through collateral vessels, diverting coronary flow away from the ischemic region. Teleologically, it can be predicted that in vital organs, control of blood flow is predominantly local, acting through endothelium-dependent or endotheliumindependent mechanisms. Halothane and isoflurane have been shown to attenuate endothelialdependent tone by receptor-dependent and receptor-dependent plus -independent mechanisms, respectively, in coronary microvessels. Systemic Regional and Pulmonary Vascular Effects Volatile agents can modulate vascular tone. However, these overall effects belie the multiple effects in the various regional vascular beds. Within the systemic noncoronary vasculature, aortic and mesenteric vessels have been the best studied. Reversible inhibition of endothelium-dependent relaxation in aortic and femoral vessels was first demonstrated for halothane and then was demonstrated for enflurane, isoflurane, and sevoflurane in capacitance and resistance vessels. In mesenteric vessels, halothane relaxation is largely mediated by Ca2+ and myosin light-chain desensitizing mechanisms. In addition to issues that also apply to systemic vascular beds (eg, vessel size), the pulmonary vasculature is a low-resistance bed (ie, requires preconstriction to access vasoactive effects), is not rectilinear (ie, changes in flow can change certain parameters used to calculate resistance), is contained within the chest and subject to extravascular pressures (ie, that are not atmospheric and change during the respiratory cycle), and exhibits the unique vascular phenomenon of hypoxia-induced vasoconstriction. Volatile agents modulate the baseline pulmonary vasculature and multiple vasoactive mechanisms that control pulmonary vascular tone. Halothane and isoflurane potentiate the vasodilatory response, but enflurane has no effect. Baroreceptor reflex inhibition by halothane and enflurane is more potent than that observed with isoflurane, desflurane, or sevoflurane, each of which has a similar effect. Inhibition of afferent nerve traffic in part results from baroreceptor sensitization,82,83 whereas attenuation of efferent activity in part results from ganglionic inhibition as manifested by differential preganglionic and postganglionic nerve activity. On resolution of the isoflurane coronary steal controversy, the first description of the salutary effects of volatile agents on the consequences of brief ischemia was published in 1988. Delayed Effects Reversible Myocardial Ischemia Prolonged ischemia results in irreversible myocardial damage and necrosis (Box 10. Reperfusion beyond 3 to 6 hours in this model does not reduce myocardialinfarctsize. Recovery of contractile function of stunned myocardium in chronically instrumented dogs is enhanced by halothane or isoflurane. Consequences of brief ischemia: stunning, preconditioning, and their clinical implications, part I. The first (ie, early or classic) occurs at 1 to 3 hours, and the second (ie, late or delayed) occurs 24 to 96 hours after the preconditioning stimulus. For example, rapid pacing affords protection against arrhythmias but not against infarct evolution. This was a statistically significant difference in line elevation but not in slope. Isoflurane postconditioning prevents opening of the mitochondrial permeability transition pore through inhibition of glycogen synthase kinase 3. Preconditioning and Postconditioning Anesthetic Agents Preconditioning and postconditioning anesthetics is an area of intense investigation, as reflected in two issues of Anesthesiology that were predominantly devoted to the subject. Pharmacologic blockade of these receptors attenuates the positive effects of volatile agents. Depending on the specific moiety, the enzymatic source, and most importantly, the oxidant stress load, it may trigger preconditioning or mediate reperfusion injury. Indirect and direct evidence indicate that volatile agents can increase oxidant stress to levels that trigger preconditioning. Although the mechanisms of mitochondrial activation have been aggressively studied, they remain incompletely understood. A metaanalysis by Landoni and associates121 demonstrated a significant reduction in postoperative myocardial infarction after cardiac surgery and significant advantages with respect to postoperative cardiac troponin release, inotrope requirements, time to extubation, intensive care unit stay, hospital stay, and survival. Another metaanalysis by Bignami and colleagues122 demonstrated that the use of volatile anesthetics was beneficial in terms of mortality rates after cardiac surgery. The duration of the volatile anesthetic exposure seemed to have an impact; the longer the exposure, the greater the effect. Further studies are necessary to delineate the role of the anesthetic regimen on outcomes after cardiac surgery and elucidate the mechanisms behind this protection. Intravenous Induction Agents the drugs discussed in this section are induction agents and hypnotics. These effects have been studied at a cellular, tissue, organ, and whole-animal level. Although a detailed discussion of the molecular mechanisms underlying each agent is beyond the scope of this chapter, a focused appraisal of well-established effects of specific drugs is given. Although sophisticated pharmacologic studies dissecting the signal transduction pathways can provide insights into mechanisms, they cannot fully predict the response of an intact organism. Because propofol is the most common induction agent, literature for this agent is used as the paradigm for discussing mechanisms by which cardiovascular regulation is altered by intravenous agents. A summary of the cardiovascular effects of each induction agent is provided later in the chapter. There is, however, emerging evidence that propofol, the mainstay of induction agents, may enhance antioxidant activity in the heart and may prevent lipid peroxidation after ischemia and reperfusion, offering a potential protection of the heart. Isoflurane postconditioning protects against reperfusion injury by preventing mitochondrial permeability transition by an endothelial nitric oxide synthase-dependent mechanism. The studies of propofol remain controversial about whether there is a direct effect on myocardial contractile function at clinically relevant concentrations. Effects of the agents may be species dependent, further confounding the literature regarding mechanisms. For instance, van Klarenbosch and colleagues125 demonstrated that in contrast with use in rats, propofol directly depresses myocardial contractility in isolated muscle preparations from guinea pigs, probably by decreasing transsarcolemmal Ca2+ influx. Negative inotropic effects may partially explain the cardiovascular depression on induction of anesthesia with thiopental but not with propofol, midazolam, and etomidate. Improvement of hemodynamics after induction of anesthesia with ketamine cannot therefore be explained by intrinsic cardiac stimulation but is a function of sympathoexcitation. Negative inotropic effects are reversible with -adrenergic stimulation, suggesting that propofol does not alter the contractile reserve but may shift the dose responsiveness to adrenergic stimulation. Inotropic effects of propofol, thiopental, midazolam, etomidate, and ketamine on isolated human atrial muscle. Although propofol may decrease contractile response to adrenergic stimulation, there is emerging evidence that it may enhance myofilament sensitivity to Ca2+. Parameters include load-independent measures of contractility (eg, slope of the end-systolic pressure-volume relationship, end-systolic elastance [Ees]) and indices of ventricularvascular coupling (eg, ratio of arterial elastance to ventricular elastance [Ea/Ees]) (see Chapters 6 and 13). In one study, the effects of propofol and pentobarbital on integrated cardiovascular function were assessed in pigs at baseline and after an acute increase in ventricular afterload. However, the responses to ventricular afterload induced by aortic banding were maintained in the pentobarbital-anesthetized animals, whereas the responses were markedly attenuated in the propofol-anesthetized pigs, suggesting attenuation of the baroreflex responses with propofol. A decrease in arterial pressure with propofol is consistent with the drug acting as a vasodilator. There is a question about what represents a clinically relevant dose of intravenous induction agents. Although coronary concentrations of propofol have been the major contributor to myocardial depression, they were a less significant contributor to the hypotension caused by this drug. Compensatory decreases in chamber stiffness contribute to relative maintenance of left atrial reservoir function during the administration of propofol. Oxidative Stress Oxidative stress remains an important pathophysiologic mechanism for cellular injury in critically ill patients and represents an imbalance between the production of free radicals and the enzymatic defense system that removes them (Box 10. This has potential therapeutic implications because these agents are used routinely for sedation in the intensive care unit, in which disease processes associated with increased oxidative stress are treated. Calcium concentration was measured as the 340/380 ratio by dual wave spectrofurometry. Propofol attenuates beta-adrenoreceptormediated signal transduction via a protein kinase C-dependent pathway in cardiomyocytes. Propofol has a chemical structure similar to that of phenol-based free radical scavengers (eg, vitamin E) and may therefore act as a free radical scavenger. Propofol also impairs the activity of neutrophils by inhibiting the oxidative burst and may modulate injury at the critical phase of reperfusion by reducing free radicals, Ca2+ influx, and neutrophil activity. An exhaustive review of the effects of each agent on isolated and integrated vascular function is beyond the scope of the chapter, but an overview of the effects of some commonly used agents on vasoregulation is presented. Despite clear effects of anesthetics on vascular smooth muscle and endothelial function, controversy and diversity regarding mechanisms arise because of the species of animals studied, the vessel bed examined, and the drug dosage used. Propofol increases phosphorylation of troponin I and myosin light chain 2 via protein kinase C activation in cardiomyocytes. Comparison of the effects of propofol and pentobarbital on left ventricular adaptation to an increased afterload. Although the effects of anesthetics on a variety of signal transduction pathways are invariably seen with high concentrations of the agents, their clinical relevance remains unclear.

For example hiv infection gay vs straight order cheap albendazole line, patients who have sustained lateral medullary infarctions and other injuries to the medulla (see Chapter 2) hiv infection ppt buy cheap albendazole 400 mg, which houses the respiratory drive center hiv infection from hospital albendazole 400mg on line, are susceptible to central sleep apnea symptoms hiv infection first week discount albendazole amex. Another antiviral blog cheap 400mg albendazole amex, complementary strategy is to phase-delay the schedule by advising the patient to delay sleep and the time of awakening by 1 to 3 hours each day hiv infection stages and symptoms cheap albendazole amex. In these chronotherapy strategies, patients may need to resort to using coffee, sunlight, strong artificial light, or stimulating activities to awaken themselves in the morning and postpone sleep at night. Patients use bright, artificial lights to awaken themselves in the morning and dim or amber lights to create a soporific mood in the evening. Advanced Sleep Phase Type In advanced sleep phase, the less frequently occurring counterpart of delayed sleep phase, patients fall asleep and awaken at substantially earlier times than the conventional schedule. As with delayed sleep phase patients, advanced sleep phase patients secure the full duration and restfulness of sleep. Individuals following this schedule go to sleep, for example, at 9 pm and awake at 5 am. Some accommodate their propensity to this schedule by seeking work in occupations that require full early morning activity, such as living in California and following the New York Stock Exchange. Many normal older individuals who awake early in the morning have Advanced Sleep Phase. Individuals with bipolar and depressive disorders sometimes follow an advanced sleep phase pattern. Shift-Work Type "Shift work" refers to a schedule of either rotating work or perpetual evening or nighttime work. Almost 20% of American workers have schedules that change on a weekly, monthly, or seasonal basis. Shift work tends to cause sleepiness, poor performance at work, and numerous problems when not working. Shift work problems plague medical house-staff, police officers, factory workers, and other individuals who must work daytime shifts and then rotate to evening or nighttime shifts. For example, medical house officers completing shifts longer than 16 hours report committing many more errors than those working fewer hours. Reports have implicated shift work in major public transportation accidents, such as recent New York City train crashes and interstate trucking accidents. Studies have found that shift work is associated with an increased incidence and increased severity of obesity, diabetes, hypertension, congestive heart failure, depression, and substance abuse. Their variants include schedules in which sleep-time constantly begins later or earlier than usual and, most commonly, where the sleep-time varies week by week (shift-work). Although genetic predisposition may play a role, delayed sleep phase commonly develops in adolescents during a vacation when they remain active until the early morning. Although the pattern may seem benign during a vacation, it may persist after the vacation ends. With the unconventional timing, they cannot attend either to school or work without being tardy, and they are sleepy at school and work. In addition, because they cannot fall asleep at a conventional time, they appear to have sleep-onset insomnia. Uncorrected delayed sleep phase in university students portends daytime dysfunction after graduation. Depression and personality disorders are also associated with delayed sleep phase. Delayed sleep phase resists the usual sleep-altering interventions, such as hypnotics and instruction to go to bed earlier. Fortunately, two complementary, predominantly nonpharmacologic therapies are able to restore a conventional schedule. Both require about 2 weeks and then sometimes supplementary melatonin once the desired schedule is reached. While working a midnight shift, for example, their "daytime sleepiness" tends to occur at 4 am. Workers should remain on a given shift for as long as possible and maintain their work schedule through weekends and short holidays. If workers are sleepy on the job or driving home, they should drink coffee, seek bright light, and postpone potentially dangerous activities. If insomnia is a problem, especially when beginning a new schedule, melatonin may help. For example, travelers from New York to Los Angeles can, with a little effort, postpone their sleep-time by 3 hours, but those traveling in the opposite direction cannot so easily fall asleep 3 hours earlier. When going in either direction, travelers can minimize jet lag by adopting the schedule of their destination several days to a week before their trip. When going from New York to Los Angeles, for example, travelers should remain in sunlight as long as possible in the late afternoon on the West Coast to maintain their alertness. Those arriving in New York from the West Coast, the more taxing trip, should seek a sun-exposed location and drink a strong cup of coffee in the early morning. If they wish to go to sleep at a conventional East Coast time, they should avoid bright lights after sunset. In addition, once they reach their destination on long west-to-east flights, travelers can take a hypnotic to adopt the earlier local sleep time. Also, they will not recall the episode or thought content, if any were present, on awakening the next morning. In most cases, an outside event, such as a household noise, passing fire truck, or an internal sensation, such as thirst or a full bladder, arouses a susceptible person and triggers these parasomnias. Sleep deprivation makes children and adults susceptible because, when "overtired," they tend to fall rapidly into N3 sleep. Thus, these parasomnias frequently develop or increase in frequency when toddlers grow old enough to give up their afternoon nap. The parasomnias presumably occur when an immature, exhausted, or disordered physiology cannot make an orderly transition from deep sleep to wakefulness. Children may have more than one variety of parasomnia and display complex behavior during each of them. They are prime examples of physiologic disturbances causing complex mental or behavioral aberrations. Parents trying to prevent sleepwalking and sleep terrors should encourage predisposed children to increase sleep. Similarly, they should limit children to only a few sips of water at bedtime to avoid awakening to urinate. Medications to interrupt these parasomnias are not feasible because each episode is too brief. Sleep Terrors Sleep terrors, also called "night terrors," consist of episodes in which children suddenly, after a partial arousal from N3 sleep, behave as though they were in great danger. They stare, moan, and sometimes scream incessantly with their eyes fully open and their pupils dilated. Although the sleep terrors seem interminable to distraught parents, the episodes usually last 1 to 10 minutes and end abruptly with a return to deep sleep. Sleepwalking Sleepwalking (somnambulism) usually consists of sitting, standing, or walking, but occasionally more complex activities, including sleep talking, in the midst of sleep. In a typical episode, a child walks slowly, with eyes open and a blank facial expression, along familiar pathways. Although they appear partially awake, their parents cannot completely awaken them or capture their attention. When questioned during their trip, children cannot recall their whereabouts, remember recent events, or even converse sensibly; however, they will follow a lead back to bed. Sleepwalking in adults, unlike sleepwalking in children, often arises during N1 or N2 sleep, rather than N3 sleep. Also in adults, various psychiatric disturbances, a history of violence, sleep apnea, and use of hypnotics, particularly zolpidem, are risk factors for sleepwalking. Although they most often eat food that they have left on their night table, they sometimes prepare an entire meal. Probably because they remain asleep while preparing food, they tend to accidentally cut or burn themselves. Better known among some as "sexsomnia" or "sleepsex," sleep-related sexual behavior consists of any variety of sexual activity during sleep. The partner may be a lover or merely an acquaintance in the same room, or anyone of either sex. Sometimes a bed partner is receptive, but often the partner is unwilling and shocked. After awakening, the sexual aggressor has little or no recollection of the sexual behavior. Unlike other parasomnias, physical contact and alcohol consumption are frequent triggers. Also, unlike other parasomnias, sleep-related sexual behavior begins during adolescence and tapers off during the fifth decade. In contrast to sleep terrors, nightmares are essentially dreams with frightening content and complex imagery ("bad dreams"). Children and adults who experience nightmares typically recall them and re-orient themselves when awakened. Another reasonable alternative to a diagnosis of nightmares is nocturnal focal seizures. One clinical difference is that nightmares differ in content, but seizures tend to create the same imagery. This normal immobility, among other purposes, protects people from acting out their dreams. With the capability of moving and with normal muscle tone, patients show dream enactment behavior during an episode. In their case, however, the dream typically has entailed defending themselves or avoiding an attack. In fact, clonazepam suppresses the episodes so consistently that successful treatment supports the diagnosis. In an absolute requirement for the diagnosis, the urge should arise primarily or exclusively during rest, inactivity, or, particularly, bedtime. The criteria exclude cases in the presence of peripheral vascular disease or other local tissue damage, where patients use cocaine or other illicit drugs, or where patients use dopamine-blocking antipsychotics that cause akathisia (see Chapter 18). Neurologists would add that the movements should occur predominantly when patients rest or try to sleep, but not when they are actually asleep. Correcting iron-deficiency anemia frequently reduces the paresthesias and movements. Most often individuals with this disorder repetitively jerk both feet upward (dorsiflex at the ankle) in brief (0. When the movements are confined to the legs, neurologists call the disorder periodic leg movements. Periodic limb movements occur at regular intervals, only during sleep, and do not arise as a response to either paresthesias or an urge. Alcohol One of the most common sleep-altering substances is alcohol, especially because its consumption is widespread and its chronic overuse is often surreptitious. The first few hours of sleep after imbibing alcohol-containing drinks may be tranquil as alcohol often induces deep sleep. For the remainder of the night, after the body metabolizes the alcohol, sleep is light, fragmented, and filled with dreams. Individuals who deliberately or unknowingly ingest excessive caffeine (250 mg or more daily) frequently develop caffeinism, which consists of insomnia accompanied by combinations of restlessness, nervousness, and excitement with physical signs, such as diuresis, gastrointestinal disturbance, tachycardia, and cardiac arrhythmias. In another word of caution, caffeinated "energy drinks" are especially likely to raise plasma caffeine levels to levels that cause arrhythmias and other problems. These drinks contain high concentrations of caffeine and athletes who are dehydrated may gulp them thirstily. Finally, early morning awakening characterizes the sleep schedule of many depressed individuals; however, because the elderly also phase-advance their sleep schedule, early morning awakening is not always indicative of depression. In addition, depressed individuals have neuroendocrine abnormalities related to their sleep alterations. When depressed people fall asleep, they seem to skip into the middle of a normal sleep and neuroendocrine cycle. On the other hand, Parkinson disease and medicines that treat it cause daytime sleepiness with unintentional napping and fragmented nighttime sleep. Also, Parkinson disease medicines, particularly dopamine agonists, may cause episodes of irresistible sleep (sleep attacks) that interrupt activities, preclude driving, and prompt vivid, frightening dreams. In general, sleep disorders affect most Parkinson patients who have moderate to advanced disease. Of the many symptoms of the disease, sleep disturbances are the ones that most often force caregivers to place Parkinson disease patients in nursing homes. To alleviate some of the sleep problems, neurologists reduce the number and dosage of medications and administer the last doses early in the evening. Although antipsychotic agents may reduce nighttime hallucinations and agitation, they generally worsen rigidity and bradykinesia.