By Q. Hamid. Rice University.

Cytokines elicit their activity by binding to high-affinity cell surface receptors on target cells thereby initiating an intracellular signal transduction pathway generic solian 100mg with amex. Cytokine receptors have been grouped into several families which include the following: 1 discount solian online. This family of receptors is characterized by four conserved cysteine residues and a conserved Trp-Ser-X-Trp-Ser sequence in the extracellular domain buy generic solian 100mg on line. These receptors generally have two subunits buy generic solian 100mg line, an - subunit for cytokine binding and a -subunit for signal transduction. This family of receptors is characterized by four con- served cysteine residues but does not have a conserved Trp-Ser-X-Trp-Ser sequence in the extracellular domain. This family of receptors is characterized by seven transmembrane domains and the interaction with G- proteins. Chemokines are chemotactic cytokines that promote chemotaxis (mi- gration) of leukocytes to inflammatory sites. These chemokines have their first two cys- teine residues separated by one amino acid. This family of receptors is characterized by four conserved cysteine residues and a conserved Trp-Ser-X-Trp-Ser sequence in the extracellular domain. Clonal selection is the most widely accepted theory that explains the immune system and contains four major points as follows: A. B cells and T cells of all antigen specificities develop before exposure to antigen. Each B cell carries an immunoglobulin on its surface for only a single antigen; each T cell carries a T-cell receptor on its surface for only a single antigen. B cells and T cells can be stimulated by antigen to give rise to progeny cells with iden- tical antigen specificity, that is, clones. B cells and T cells that are reactive with “self” antigens are eliminated (perhaps through apoptosis) or somehow inactivated so that an autoimmune reaction does not occur. An immunoglobulin consists of four protein subunits: two heavy chains and two light chains that are arranged in a Y-shaped pattern. The chain gene segments are located on chromosome 2 and include 200 variable segments (V ), 5 joining segments (J ), and 1 con- stant segment (C ). The V , J , and C gene segments undergo gene re- arrangement to contribute to immunoglobulin diversity. The chain gene segments are located on chromosome 22 and include 100 variable segments (V ), 6 joining segments (J ), and 6 con- stant segments (C ). The V , J , and C gene segments undergo gene re- arrangement to contribute to immunoglobulin diversity. The location of heavy chain and light chain gene segments on chromosomes 14, 2, and 22 are indicated. The heavy and light chain gene segments are organized into various V, D, J, and C gene segments which undergo gene rearrangement, transcription, splicing, and transla- tion to form an immunoglobulin protein. An immunoglobulin protein consists of either two light chains or two light chains (never a mixture of one light chain and one light chain). For years, the fundamental mystery of the immune system was immunoglobulin diversity: How could B cells (i. If each immunoglobulin was encoded by its own gene, then the human genome would consist almost exclusively of genes dedicated to immunoglobulin synthesis. The answer to this fundamental mys- tery lies in a number of processes which include the following: 1. The process of gene rearrangement where V, D, J, and C gene segments of the heavy and light chains are randomly rearranged in a mil- lion combinations that code for a million different immunoglobulins. Insertional diversity whereby a short se- quence of nucleotides in inserted during gene rearrangement that leads to amino acid changes. Somatic cell mutations whereby V gene segments mutate during the life of a B cell. The IgM monomer is synthesized by B cells and retained on the cell membrane of B cells as a B-cell receptor which is specific for a single antigen. Later in the immune response, the IgM pentamer is synthesized and secreted by plasma cells. The IgM pentamer is designated as ( 2 2)5 or ( 2 2)5 whereby five monomeric IgMs are held together by the J chain. The IgM pentamer is the earliest immunoglobulin to appear after antigenic stimulus; activates complement avidly; and does not cross the placenta. IgD is synthesized by B cells and retained on the cell membrane of B cells as a B-cell receptor which is specific for a single antigen. IgD is a B-cell receptor for antigen and an early immunoglobulin to appear af- ter antigenic stimulus; does not activate complement; and does not cross the placenta. IgE binds to IgE antibody receptors on eosinophils, basophils, and mast cells and thereby participates in parasitic infections and Type I hypersensitivity ana- phylactic reactions; does not activate complement; and does not cross the pla- centa. IgA exists as a monomer, dimer, or dimer with a secretory piece (called se- cretory IgA). The IgA monomer is synthesized by plasma cells and is found in the serum (little is known about the function of IgA in the serum). The IgA dimer is synthesized by plasma cells and is found in the intestinal mucosa. The IgA dimer is designated as ( 2 2)2 or ( 2 2)2 whereby two monomeric IgAs are held together by the J chain. The IgA dimer with secretory piece is an IgA dimer with a secretory piece (which is a portion of the poly-Ig receptor complex found on intestinal ep- ithelial cells) attached to it. The IgA dimer synthesized by plasma cells within the lamina propria of the intestinal tract binds to the poly-Ig receptor on the basal surface of the enterocytes to form an IgA dimer poly-Ig receptor complex. The IgA dimer poly-Ig receptor complex is endocytosed and transported across the enterocyte to the apical or luminal surface. At the apical surface, the complex is cleaved such that IgA dimer is released into the intestinal lumen joined with the secretory piece of the poly-Ig re- ceptor (called secretory IgA). The IgA dimer is found in high concentrations in external secretions like saliva, mucus, tears, sweat, gastric fluid, and colostrum/milk (provides the neonate with a major source of intestinal protection against pathogens) and works by blocking bacteria, viruses, and toxins from binding to host cells; does not activate complement; and does not cross the placenta. If all the production of IgA from various sources is taken into account, IgA is the major immunoglobulin in terms of quantity. Clearly, the production of immunoglobulins is an important aspect of the immune system. However, the question as to what are the gen- eral functions of immunoglobulins that make them so vital needs to be fully under- stood. Agglutination is a process whereby immunoglobulins bind to free antigens to form aggregates that undergo phagocytosis and also reduce the amount of free antigen. Opsonization is a process whereby immunoglobulins bind to anti- gens on the surface of bacteria (for example) which stimulates phagocytosis by neutrophils and macrophages. Neutralization is a process whereby immunoglobulins bind to antigen on viruses or bacteria which blocks their adhesion to host cells and inacti- vates toxins. Complement activation is a process whereby im- munoglobulins bind to antigen on the surface of bacteria (for example) which then binds the proenzyme C 1 of the complement system. The chain gene segments are located on chromosome 14 and include 100 variable segments (V ), 100 joining segments (J ), and 1 constant segment (C ), resembling the im- munoglobulin light chains. The V ,J ,C gene segments undergo gene rearrange- ● Figure 13-3 T Cell Receptor Structure. The chain gene segments are located on chromosome 7 and in- clude 100 variable segments (V ), 2 diversity segments (D ), 15 joining seg- ments (J ), and 2 constant segments (C ), resembling the immunoglobulin heavy chains. The chain gene segments are located on chromosome 7 and include variable segments (V ), joining segments (J ), or constant segments (C ), resem- bling the immunoglobulin light chains. The chain gene segments are located on chromosome 14 and in- clude 4 variable segments (V ), 2 diversity segments (D ), 100 joining seg- ments (J ), and 1 constant segment (C ), resembling the immunoglobulin heavy chains. The location of the chain, chain, chain, and chain gene segments on chromosomes 7 and 14 are indicated. The un-rearranged chain gene segments consisting of 100 V segments, 2 D seg- ments, 15 J segments, and 2 C segments undergo gene rearrangement whereby ● Figure 13-4 T Cell Receptor Diversity.

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The middle cerebellar peduncle buy solian toronto, or brachium The molecular layer contains chiefy the mas- pontis order generic solian line, is the largest peduncle and connects the sive dendritic trees of the Purkinje neurons basilar part of the pons to the cerebellum purchase 100mg solian visa. The stellate neurons are chium conjunctivum cheap solian 100 mg online, connects the cerebellum found in the superfcial part of the molecular layer to the midbrain. In addition number of input fbers, its most abundant and to myriad granule cells in the internal cortical most important components are output fbers. Hence, the cerebellum has numerous afferent connections; in fact, it is Histology said to have 40 times as many afferent fbers as The cytoarchitecture of the cerebellar cortex is efferent. Cerebellar nuclei Cerebellar Fastigial peduncles Vermis Globose Interposed Superior Emboliform Inferior Dentate Middle Fourth Ventricle Inferior cerebellar peduncle Vestibular nerve Olive Restiform body Pyramidal Juxtarestiform body tract Medial longitudinal fasciculus Figure 9-4 Relation of cerebellar peduncles in transverse section at pontomedullary junction. Parallel fiber Basket neuron Stellate neuron Molecular layer Purkinje layer Granule layer Purkinje neuron Granule neuron Golgi neuron Glomerulus Cerebellar Inhibitory synapse nucleus Excitatory synapse Mossy fiber Climbing fiber Figure 9-5 Functional histology of cerebellar cortex in a folium sectioned in the transverse and longitudinal planes. Its hemispheres possess ipsilateral represen- tation of the body parts, whereas the motor areas of the cerebral hemispheres possess con- tralateral representation. Simple spike Complex spike Circuitry of the Cerebellar Cortex Figure 9-6 Simple spike evoked in a Purkinje cell after mossy fber activation of granule cells There are two major types of input fbers to and resultant parallel fber excitation of the neu- the cerebellar cortex: climbing and mossy. Complex spike recorded in Purkinje neurons climbing fbers arise from the olivocerebellar in response to activation of olivocerebellar climb- afferents from the inferior olivary nucleus. As a parallel fber courses orthogonally The massive olivocerebellar projections pass through the Purkinje cell dendritic trees, it will medially, decussate, sweep through the opposite synapse only once on each Purkinje cell. Many inferior olivary nucleus and medullary tegmen- parallel fbers fring synchronously are necessary tum, and enter the cerebellum through the infe- to activate a Purkinje cell and evoke a typical rior cerebellar peduncle. The stellate Purkinje cell layers, and a single olivocerebellar and basket neurons inhibit the Purkinje neurons, axon will climb onto the larger dendritic branches and the Golgi neurons inhibit the granule cells. Climbing of the cerebellar cortex, inhibit the neurons in fber activation of Purkinje cells is so powerful the cerebellar nuclei, which give rise to the out- that when an olivocerebellar axon fres, it always put fbers of the cerebellum. Because the neurons evokes in the Purkinje cell an atypical action of the cerebellar nuclei are excited by collateral potential called a complex spike (Fig. This branches of the climbing and mossy fbers, the complex spike is characterized by an initial spike output of the cerebellar nuclei is regulated and followed by a voltage-gated calcium conduc- fne-tuned by cortical inhibitory impulses from tance, resulting in a prolonged depolarization on the Purkinje neurons. Neuronal Activity in the Cerebellar Unlike the climbing fbers, mossy fbers branch Cortex repeatedly in the cerebellar white matter and even after entering the granule cell layer. Each Purkinje cells are the only output neurons in mossy fber has as many as 50 terminals called the cortex, and their complex and simple spike rosettes, which are large and lobulated, synapse activities have been recorded during movements with dendrites of about 20 granule cells, and are (Fig. In contrast, the low fring frequency of spines on the Purkinje cell dendrites, as well as climbing fbers/complex spikes cannot transmit Chapter 9 The Cerebellum: Ataxia 109 signifcant information about sensory stimuli of the fourth ventricle, are, from medial to lateral, or movements. Olivocerebellar-evoked com- the fastigial, interposed (composed of globose and plex spikes can affect Purkinje cell simple spike emboliform parts), and dentate (Fig. The inferior olive in each nucleus receive excitatory impulses from and olivocerebellar afferents appear to signal collateral branches of the mossy and climbing errors in movements, and complex spikes may be fbers and inhibitory impulses from Purkinje cells instructional to Purkinje cells needed for learn- in topographically defned parts of the cerebellar ing a new motor task. Purkinje neurons in the vermis and foc- shown that the acquisition of a new movement culonodular lobe project to the fastigial nuclei is correlated with an increase of complex spike (Fig. As the movement becomes coordinated, com- Those in the lateral parts of the hemispheres proj- plex spike activity returns to normal, but simple ect to the dentate nuclei. This change have descending and ascending efferent projec- in synaptic effcacy of some parallel fber inputs tions that excite motor centers in the brainstem is called long-term depression and involves and thalamus. Generally, the midline vermis and a decrease in Purkinje cell responsiveness to fastigial nuclei control head, trunk, and proximal those parallel fbers that were selectively active limb movements bilaterally, whereas the hemi- 100 to 200 ms after the climbing fber–evoked sphere and interposed and dentate nuclei con- complex spike. Neuronal activity in the vermis and fastigial nuclei is correlated with posture, gait, and eye Clinical movements. Activity in the hemisphere and inter- Connection posed and dentate nuclei is mainly correlated with multijoint movements of the limbs. Unitary activ- Although the precise function ity in the paravermis and interposed nuclei is tem- of the inferior olivary complex is porally correlated with somatosensory feedback unknown, unilateral lesions of this structure during a movement and especially during the fring in experimental animals result in abnormali- of antagonist muscles and therefore is involved ties similar to destruction of the contralateral with correcting ongoing movements. In humans, olivary the lateral hemispheres and particularly the den- lesions virtually always include the adjacent tate nuclei precedes by about 100 ms activity in pyramid whose injury overshadows the cer- the motor cortex and the onset of movement. In addition to the gait ataxia and chiefy concerned with the learning and storage of intention tremor, dysarthria may develop. The major input to the lateral parts of the affect the patient’s ability to learn new motor cerebellar hemispheres originates in the associa- tasks. As has been described pre- The cerebellum infuences motor centers at various viously, activity in this part of the cerebellum and levels almost exclusively through the cerebellar in its nucleus, the dentate, precedes the activity nuclei. These paired neuronal masses, embed- in the motor cortex that ultimately commands a ded in the medullary white matter near the roof particular movement. The cortical area anatomically related to each nucleus is the principal source of Purkinje neuron input to the nucleus. Dentatofugal fbers pass to the contralat- eral ventral lateral nucleus of the thalamus, from The posterior lobe, by far the largest of the cer- whence there is a thalamocortical projection to ebellar lobes, has massive reciprocal connections the motor cortex. This far the largest group of cerebellar mossy fber affer- prominent bundle arises mainly from the dentate ents, the corticopontocerebellar projections. Most nucleus, although it also contains a considerable of the corticopontine fbers arise from the senso- number of fbers from the interposed nucleus and rimotor, premotor, and posterior parietal parts of a small contribution from the fastigial nucleus. The pontine nuclei give rise of the inferior colliculus, it decussates before to the transverse pontine fbers that, after crossing continuing rostrally through the red nucleus and and proceeding through the contralateral basilar the prerubral feld in the dorsomedial part of the pons, form the massive middle cerebellar pedun- subthalamus. Chapter 9 The Cerebellum: Ataxia 111 Posterior Lobe Syndrome affected limbs, thereby revealing the underlying basis for the ataxic movements. Normal, rapid The neocerebellar or posterior lobe syndrome, single-joint movements are characterized by an commonly resulting from cerebrovascular acci- initial accelerated movement by contraction dents, tumors, trauma, or degenerative diseases, of the agonist muscle, decelerated by an appro- is manifested by a loss of coordination of volun- priately timed contraction of the antagonist tary movements (ataxia) and decreased muscle muscle, and then fnally completed by a second tone, the latter being most prominent in acute small burst of activity in the agonist (reciprocal lesions. After damage to the lateral cer- the limb to a target without its progression ebellum, dentate nucleus, or its efferent projec- being interrupted by a swaying to and fro that tions, contraction of the agonist is not followed is perpendicular to the direction of the move- by timely reciprocal contraction of the antago- ment (Fig. This is referred to as intention nist muscle, resulting in the delayed slowing of tremor because it occurs only when a volitional the movement and overshooting the target. In movement is being performed; it is not present a simple single-joint movement, the inability to at rest. An unexpected release of the Various degrees of intention forearm results in patients striking themselves. These desynchronized contrac- tions result in abnormalities in controlling the range of movements (hypometric undershoot- Other manifestations of posterior lobe lesions, ing or hypermetric overshooting of the target) as described in the case at the beginning of this (Fig. Intention tremor is a manifestation chapter, are dysmetria, the inability to control of the altered agonist-antagonist contractions. The vermal and paravermal parts of the ante- rior lobe chiefy maintain coordination of limb movements while the movements are being exe- Pathophysiology of Limb Ataxia cuted, and, hence, the anterior lobe has strong Ataxia is characterized by abnormalities in the connections with the spinal cord (Fig. Chapter 9 The Cerebellum: Ataxia 113 Ventral lateral nucleus Dentatothalamic fibers in Intnernal capsule thalamic fasciculus posterior limb Dentatothalamic fibers in Mamillary body prerubral field of subthalamus Thalamus Superior colliculus Dentatothalamic fibers in red nucleus and its capsule Oculomotor nucleus Red nucleus Parieto-temporo-occipitopontine tract Pyramidal tract Cerebral crus Frontopontine tract Rostral midbrain Inferior colliculus Decussation of superior cerebellar Parieto-temporo-occipitopontine tract peduncle Cerebral crus Frontopontine tract Caudal midbrain Trochlear nerve Sup. Connections of the Anterior Lobe of this information is from muscular, joint, and cutaneous mechanoreceptors that project Through the spinal cord and, to a cer- monosynaptically via the spinocerebellar, cuneo- tain extent, the brainstem, the cerebellum cerebellar, and trigeminocerebellar tracts to the receives voluminous information from general vermal and paravermal parts of the anterior lobe sensory receptors throughout the body. Normal Hypermetria Hypometria Agonist Antagonist Figure 9-11 Rectifed electromyographic records illustrating the temporal pattern of agonist and antag- onist activation during movement in a normal patient and a patient with a posterior lobe syndrome. Chapter 9 The Cerebellum: Ataxia 115 Discrete proprioceptive information, chiefy 3. Enters the cerebellum through the superior from muscle spindles and tendon organs of indi- cerebellar peduncle and decussates to its origi- vidual lower limb muscles, and exteroceptive nal (ipsilateral) side information from small cutaneous receptive felds The medical importance of the ventral spi- reach the cerebellum through the dorsal spino- nocerebellar tract rivals that of the rostral spino- cerebellar tract. Neurons in the dorsal nucleus receive either pro- Trigeminocerebellar fbers carry information prioceptive or exteroceptive input directly from from the temporomandibular joint, masticatory collateral branches of primary afferent axons and external ocular muscles, and so forth. Sensory ascending in the lumbosacral parts of the gracile information also reaches the cerebellum via the tract. The axons of the dorsal nucleus of Clarke reticular formation, which receives input from ascend ipsilaterally as the dorsal spinocerebellar the spinal cord and brainstem. Through these connections, the anterior as well as in lateral medullary or inferior cer- lobe receives information about the impending ebellar peduncle lesions. When the tract is infuence of the corticospinal fbers on an ongo- damaged, cerebellar input from the ipsilateral ing movement. As a result, ipsilateral Axons from Purkinje neurons in the anterior lower limb ataxia occurs. Through the Equivalent types of information from the fastigial nucleus and its connections with the upper limb ascend in the cuneate tract to the vestibular nuclei and reticular formation, which accessory cuneate nucleus. Its neurons, which occur via the juxtarestiform part of the inferior resemble those of the Clarke column, give rise to cerebellar peduncle, the vermis of the anterior the cuneocerebellar tract that also enters the cer- lobe has a strong, bilateral infuence on head, ebellum through the inferior cerebellar peduncle. Through the the descending motor pathways on the spinal interposed nucleus and its connections with the gray matter and convergent proprioceptive and contralateral red nucleus and reticular formation, exteroceptive information from the entire lower which occur via the superior cerebellar peduncle limb reach the cerebellum through the ventral and its decussation (Fig.

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Similar but shorter runs of atrial fibrillation/flutter can be induced in the absence of vagal stimulation generic solian 100 mg visa. Modulation of electrophysiological properties of canine heart by tonic parasympathetic stimulation 100 mg solian fast delivery. Electrophysiology of the Maturing Atrioventricular Conduction System As we have emphasized discount solian 100 mg otc, a delay in conduction between the atrium and ventricle can be observed already in the early chamber-forming chicken heart purchase 50mg solian with mastercard. Contacts between individual cardiomyocytes are made by the so-called gap junctions, which are highly specialized protein channels that connect adjacent myocytes and allow the passive passage of electrical current, or the flow of charged ions, via a low-resistance pathway from one cell to the next (116). The connexons making up the gap junction may consist of different types of connexins, which vary in their conductivity. Expression of different connexin isoforms results in gap junctions with differing conduction properties. During later fetal stages, concomitant with the fibrous insulation of the bundle of His from the myocardium of the ventricular septum, cardiomyocytes making up the bundle upregulate the expression of connexin 40, changing it to a rapidly conducting structure. Note that left posterior extension (Lt) does not change, whereas right one elongates considerably. Morphology of the human atrioventricular node is age dependent: a feature of potential clinical significance. It has been shown that the “mature” apex-to-base activation pattern of the ventricles is present in the embryonic rabbit heart prior to the completion of ventricular septation (128). As already discussed, there is preferential conduction through the ventricular trabecular myocardium due to the high expression of the fast- conducting connexins. The morphology and gene expression patterns of the developing ventricular chambers are very similar in the rabbit, mouse, chicken, and human, suggesting conservation of the electrical activation pattern between these species. The critical role of connexins during development for normal conduction is demonstrated by the abnormal, often lethal, disturbances of cardiac conduction observed in transgenic mice with deficiencies of these specific connexin isoforms (129,130). In the developing chicken and rat heart, cellular electrophysiologic changes in myocyte action potential characteristics of working myocardium promote an increase in conduction velocity with maturation. Increases in the upstroke velocity and amplitude of the action potential in the ventricular cardiomyocytes, and therefore ventricular conduction velocities, have been noted in both species during embryonic development (131,132). These changes may be the result of the switch from so- called “slow” to “fast” sodium ion channels, responsible for the rapid upstroke phase (133), and the increase of the resting membrane potential, which also contributes to a higher action potential upstroke velocity. The developmental aspects of the maturing Purkinje fiber network mainly have been described in fetal and young postnatal canine hearts. Age-dependent increases in action potential upstroke velocity, amplitude, resting membrane potential, and duration have been described. In addition, changes in the ultrastructure of the developing canine Purkinje myocytes, including changes in cell shape, increases in cross-sectional area, and the development of P. Unfortunately, there are no data on the functional maturation of the Purkinje network in the human beside morphologic analyses in the midgestation fetal hearts (137). A to C demonstrate the patterns of the electrical activity at epicardial ventricular surfaces of the isolated developing chicken hearts studied by high-resolution optical mapping of the color changes of a voltage- sensitive fluorescent dye. The color scale depicts different intervals between atrial excitation and first electrical activity at ventricular surface, while lines between different colors (isochrones) border the groups of signals registered at the same time. At stage 18 looping heart the activation pattern is from ventricular base to apex to outflow tract (oft), while after initiation of chamber forming at stage 26 the earliest ventricular activation shifts toward apical region and spreads equally to both ventricles. Transitions in ventricular activation revealed by two-dimensional optical mapping. The excitation wave reaches first the epicardial surface in the apical region, while the latest activated area is the posterobasal region of both ventricles. Epicardial excitation pattern as observed in the isolated revived and perfused fetal human heart. Developmental changes in action potential duration, refractoriness, and conduction in the canine ventricular conducting system. There are thus two levels of synapses, first between outflow neuron with the ganglion, and second between the postganglionic neuron with the cell of the target organ. Anatomically and functionally, the sympathetic and parasympathetic systems are organized profoundly differently. At the level of synapses with the cardiomyocytes, sympathetic neurons release norepinephrine to stimulate β-adrenergic receptors, while parasympathetic neurons act largely via acetylcholine and muscarinic receptors. Development of the Autonomic Nervous System As stated previously, part of the cells derived from the cardiac neural crest differentiate into the autonomic nerves. At the early stages of embryonic development, some neuroectodermal cells delaminate from the neural tube and initiate migration to virtually every part of the embryo (see Chapter 1). In the case of the sympathetic neurons, the neural crest-derived cells do not migrate to the heart, but accumulate along the developing spinal cord and form bilateral paravertebral sympathetic chains of sympathetic ganglia. In the case of parasympathetic neurons, the neural crest-derived cells migrate all the way to the heart forming thus the efferent pathway of the vagal nerve and the cardiac ganglia (see Fig. An understanding is emerging of the genetic and molecular signals involved in the regulation of autonomic progenitor cell migration and neuronal differentiation (139,140). With respect to neural crest cells destined to form sympathetic neurons, expression of specific somite genes, including EphrinB1, restrict the early migration of neural crest cells to the rostral aspect of the somites, as progenitor sympathetic neurons migrate along their ventral route. Unlike sympathetic precursor neurons, neural crest cells destined to form the parasympathetic ganglia are not restricted to a rostral migratory course with respect to each somite and may pass through and alongside the “cardiac” somites en route to their final destinations on the epicardial surface of the heart, forming cardiac ganglia. Differentiation of sympathetic neurons is dependent upon expression of Gata3, essential for the expression of tyrosine hydroxylase, and Hand2, which promotes the catecholamine phenotype of the cells (148,149). A host of neurotrophic factors, both of vascular and neuronal origin, contribute to neuronal maturation during development. Neural crest-derived cells destined to form the parasympathetic nervous system (blue) are derived from the caudal region of the cranial neural crest, the cardiac neural crest and the vagal neural crest. Cells destined to form the sympathetic nervous system (red) arise from the trunk neural crest. Sensory innervation occurs last with sensory neurons arising in part from the neural crest and in part from the nodose placode (green). Sympathetic preganglionic fibers synapse with postganglionic fibers in the paravertebral sympathetic ganglia. Parasympathetic preganglionic fibers (vagal nerve) synapse with postganglionic fibers in the cardiac plexus and in the cardiac ganglia. With development, cholinergic innervation becomes dense in the regions of the sinus node, atrioventricular node, and throughout the atria. In the human neonate, cholinesterase activity is confined mostly to the sinus node and atrioventricular nodal regions. Postnatal maturation of innervation of the bundle branches then occurs and peaks in childhood (152,153,154). Functional assessments of cardiovagal autonomic function in the human suggest that maturation actually occurs well into adolescence (155). The primary actions of acetylcholine are mediated via a pertussis toxin-sensitive inhibitory protein (G ), and ai toxin-insensitive protein (G ). In the nodal tissues, the increases in outward potassium currents results in hyperpolarization of the cells. This, in conjunction with inhibition on the inward calcium current and to some extent inhibition of “funny” current ( If), accounts for slowing of the sinus pacemaker rate. Shifts in pacemaker site within the sinus node are also observed with parasympathetic stimulation. In the atrioventricular node, inhibition of the inward calcium current results in marked reduction in the amplitude and rate of rise of the action potential and thus accounts for a slowing of conduction and increase in refractoriness. Variable effects of parasympathetic stimulation are observed in ventricular myocardium, with a slight but significant increase in ventricular refractoriness being most commonly reported. The increase in refractoriness may represent a direct effect of acetylcholine (159). A “domination” of parasympathetic modulation over sympathetic one has been described, termed “accentuated antagonism. Maturation of parasympathetic control of cardiac electrophysiology is evident from studies of heart rate variability in preterm humans, and from studies of changes in fetal heart rate in response to muscarinic blockade in utero. In various mammalian species, functional changes in the “cardiac” parasympathetic system are evident by distinct changes in heart rate secondary to vagal nerve P.

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In lower doses (<2 mcg/kg/min) buy online solian, nitroglycerin mainly produced venodilation solian 100 mg low price, as evidenced by an increased requirement of volume to maintain a constant right and left atrial pressure order solian with visa. Frequently generic solian 50 mg online, nitroprusside is incorrectly referred to as a “direct, preferential arterial vasodilator. In patients with diminished myocardial function, cardiac output is increased from an increased stroke volume as a result of decreased aortic impedance. The drop in blood pressure is more dramatic in patients with pre-existing hypovolemia or obstructive cardiac lesions. One of the dangers associated with the use of nitroprusside use is toxicity from the formation of cyanide. This reaction is catalyzed by the enzyme rhodanese; patients with liver failure are more susceptible to cyanide toxicity. The higher doses pose greater risk for toxicity, so doses exceeding 3 mcg/kg/min should not be administered for longer than several hours. Sodium thiosulfate can be added to the infusion to eliminate cyanide; but alternative methods of hypertension treatment should be instituted instead. In the2 2 vascular tissues they are predominantly generated and subsequently released by the endothelium to bind to specific receptors on the underlying smooth muscle cells. It has been demonstrated to maintain ductal patency for as long as 2 months (127) and to reopen a recently closed ductus. These are usually reversible upon lowering the dose or discontinuation of the drug. This is most typically used in patients with severe, end-stage disease, including those awaiting lung transplantation, though it has been used as short-term therapy early after cardiac surgery (131). Sildenafil Sildenafil is a phosphodiesterase-5 inhibitor, which in its intravenous form, appears to be a selective and highly effective pulmonary vasodilator in a piglet model of meconium aspiration with severe pulmonary hypertension (136). Sildenafil has been shown in case reports to ameliorate the effects of nitric oxide withdrawal in a patient after cardiac surgery with persistent pulmonary hypertension (137). The nonresponders are usually those who have long standing pulmonary hypertension and extensive remodeling of the pulmonary vasculature. Inhaled nitric oxide can be administered using a face mask or via nasal cannulae in a spontaneously ventilating patient, or added to the inspiratory limb of the breathing circuit in a mechanically ventilated patient. Side effects of inhaled nitric oxide at these doses are minimal, even with prolonged therapy. The first of these is rebound pulmonary hypertension resulting from abrupt withdrawal of nitric oxide or rapid reductions in drug dosage. This phenomenon can be prevented with a careful weaning protocol that incorporates a single dose of the phosphodiesterase-5 inhibitor, sildenafil prior to discontinuation (152). Therefore, methemoglobin levels should be routinely monitored, especially with prolonged therapy. Finally, nitrogen dioxide which can exacerbate or worsen lung injury, is a byproduct of nitric oxide administration, and its levels should be continuously monitored and maintained below 5 ppm (141). Fenoldopam Fenoldopam is a selective dopamine-1 receptor agonist with moderate affinity for α2-receptors. Despite its binding to α2-receptors, fenoldopam has no significant sedative effect. Fenoldopam administration produces dramatic vasodilation of the peripheral vasculature including renal, mesenteric, coronary, and skeletal muscle. The main indication for the use of fenoldopam is in the treatment of hypertensive emergencies and postoperative hypertension (154,155,156). The theoretical advantage of use of fenoldopam is that it maintains renal perfusion while decreasing blood pressure. During prolonged infusion of fenoldopam there is development of tolerance with a half-life (predicted loss of 50% effectiveness of the drug) of 60 hours, without a prolonged pharmacodynamic effect or rebound hypertension upon discontinuation of fenoldopam. In a retrospective study of 25 postoperative cardiac neonates with inadequate urine output despite conventional diuretic therapy, fenoldopam increased urine output by 50% and had minimal effect on hemodynamics (157). Its negative inotropic effects are minimal, and compensatory tachycardia is less than for other direct vasodilators, that is, nitroprusside. Nicardipine has been used successfully for postcoarctectomy hypertension after repair via thoracotomy in children, with significant decreases in mean arterial pressure, and minimal increase in heart rate (159). Despite its lack of negative inotropic effect, this agent should not be used in patients with decreased systemic ventricular function, and should be used with caution in young infants. Several studies have demonstrated downregulation of beta-adrenoceptors in chronic heart failure as a result of elevated sympathetic tone (162,163). Responsiveness to catecholamines may be preserved in these patients during the perioperative period as a result of beta-blocker therapy. Also, a decrease in heart rate allows a longer diastolic filling time and improved preload. Esmolol in doses of 100 to 700 mcg/kg/min has also been successfully used to control postoperative hypertension after repair of aortic coarctation in children (125,168). A brief description of some of these newer agents is as follows: Levosimendan Levosimendan is an inodilator. Most other positive inotropes work through stimulation of adrenergic receptors and increase intracellular calcium that may be already elevated in the failing heart. Unlike these drugs, levosimendan works by causing conformational changes in the myofilaments making them more sensitive to intracellular calcium. Although drug is not approved for routine clinical use in the United States, there are extensive clinical studies involving large number of patients with end-stage cardiac failure demonstrating that levosimendan is both safe and effective in providing symptomatic relief. Levosimendan was also more effective in decreasing pulmonary artery wedge pressure and increasing cardiac output (169). The hypotension was responsive to volume administration and did not require vasoconstrictors. In 15 children with acute heart failure, levosimendan improved ejection fraction in all while allowing a reduction in the dobutamine dose, in levosimendan doses of 6 to 12 mcg/kg load and 0. Despite exhibiting the expected hemodynamic effects, the drug has shown little or no effect on survival in adult patients with heart failure, and thus the drug has not been further developed for use in the United States. A recent review of 11 published studies of levosimendan use post pediatric cardiac surgery included three randomized controlled trials in 145 patients receiving levosimendan or milrinone after cardiac surgery (172). Currently, the primary use of nesiritide is in the treatment of acute decompensated heart failure. In addition, vasodilation occurs without a change in heart rate and is associated with increases in stroke volume and cardiac output. In a randomized controlled trial involving 489 subjects, nesiritide when given as a bolus dose of 2 mcg/kg and followed by an infusion at 0. Mild diuretic effect of nesiritide therapy has been reported in a few clinical trials (176,177). In a limited pediatric experience of 17 patients after cardiac surgery, a loading dose of 1 mcg/kg was administered on bypass, and then an infusion of 0. Use of this agent has been limited in the pediatric population, likely because multiple controlled adult trials have not demonstrated any survival benefit with this agent. Mechanical support is ideally instituted proactively, rather than after a cardiac arrest or onset of multiorgan failure. However, arrhythmias are a constant threat, and the intensivist must be ever vigilant to this problem when hemodynamic status is not optimal. Other common arrhythmias include supraventricular tachycardia: atrial tachycardias and atrioventricular reentrant nodal tachycardias. Right bundle branch block is common after right ventricular surgery; left bundle branch block is rare but may be seen in some patients after left ventricular outflow tract surgery. Sinus tachycardia may be seen with hyperthermia, excessive circulating catecholamines from exogenous (inotropes) or endogenous (inadequate analgesia or uncompensated heart failure) sources, and may significantly impair ventricular filling and ejection time. Myocardial disease, whether from acute myocarditis, or cardiomyopathy from ischemic or a variety of other causes, may cause any of the arrhythmias noted above. Multilead display allows 8 leads to be displayed simultaneously on the bedside monitor for rapid diagnosis during hemodynamic compromise. Atrial electrograms, obtained with right and left arm leads connected to the temporary atrial pacing wires, is a very important tool in diagnosing tachycardias.

Although bypass time continues to emerge regularly as a risk factor it is perfectly reasonable for the surgeon to delegate deci- for morbidity and mortality after many operations purchase solian 100 mg otc. For these is simple and safe will likely have optimal outcomes for decisions purchase generic solian pills, a team approach between perfusionist solian 100mg fast delivery, surgeon their patients 50mg solian amex. In part this is a refection of the much less The fundamental goal of bypass is often overlooked. Stated complex role that bypass plays in cardiac surgery for adults simply, the goal is to supply adequate substrate for the meta- with acquired heart disease. The challenge procedures must be conducted at normothermia, that fow for the surgeon, perfusionist and anesthesiologist is to be rate must always be the same irrespective of temperature 100% sure that these goals are being met with a reasonable and the patient’s metabolic needs, or that circulatory arrest margin of safety, while allowing the surgical team adequate is never appropriate no matter how small the neonate and exposure in the face of the widely differing venous and arte- how complex the venous anatomy. Unfortunately, failure to rial anatomy presented by the child with congenital heart understand principles of bypass in the child with complex disease. The challenge is exacerbated by the fundamental congenital heart disease increases the risk of brain injury, inadequacy of methods for monitoring the patient during the cognitive decline or even death. In fact, vasoconstriction is highly undesirable in the early phase of Heart rate is extremely helpful in monitoring neonates, bypass when the goal is to cool the body uniformly to reduce infants and young children who are not on cardiopulmonary metabolic demands, thereby increasing the safety margin for bypass. The congenital team therefore uses are critically important in monitoring adults after heart sur- ® vasodilators, such as phentolamine (Regitine ) and phenoxy- gery, they are not important for most congenital cardiac pro- benzamine rather than vasoconstrictors and accepts very low cedures. But when the reduced fow rate, which will be used once the body has the patient is on bypass, even a mild degree of hypothermia been cooled, even lower levels are acceptable. Extremely will slow the heart rate, as does manipulation near the sinus low perfusion pressure during full-fow bypass may indicate node. In addition, during the cross-clamp period, there will dangerous run-off through an unrecognized steal, such as an be no heart rate. Thus, the most important vital sign for the untied shunt or ductus or profuse collateral development. It young patient is rendered useless during cardiopulmonary might also indicate a pressure monitoring problem. A tiny premature neonate may be adequately perfused with a The fundamental premise is that if the oxygen saturation systolic blood pressure of 45 mm, while this would be inad- of blood in the venous tubing (not the individual cannulas) equate for the 5 year old. This is regrettably woefully inadequate and yet a size and degree of vasodilation of the patient. The limita- diopulmonary bypass complicates the interpretation of blood tions are as follows: pressure to the point where it assumes minimal importance. Loss of pulsatility when the heart ceases to eject, either Leftward Shift of Oxyhemoglobin Dissociation because of complete drainage of the right heart or application Cooling of the blood results in a leftward shift of the oxyhemo- of the cross-clamp, means that there is no longer a systolic globin dissociation curve (Fig. In fact, the term “perfusion pressure” is usually used to indicate the difference from pulsatile blood 100 pressure. This is achieved with vasocon- ® gen saturation may be inappropriately elevated during hypothermic strictors, most commonly phenylephrine (Neo-Synephrine bypass. However, this approach is not advised in children being incurred because of inadequate fow. Conduct of Cardiopulmonary Bypass 183 more tightly bound to hemoglobin so that a greater degree steal from the patient’s circulation, e. At the onset of bypass, the brain and assumption is that the blood that is stolen by collaterals or a other rapidly metabolizing organs and tissues are still warm ductus does not infuence the venous oxygen saturation in the and have the same metabolic needs as for any normothermic venous line. Nevertheless, the venous oxygen satura- are likely to have millions of tiny collateral vessels that steal tion can be seen to rise quite rapidly as soon as bypass begins blood from the chest wall and mediastinum to the pulmonary suggesting that oxygen delivery has decreased more rapidly circulation. From there, it passes to the pulmonary veins, to than metabolic needs are decreasing. Although the metabolic needs of the patient are admixture of systemic venous return and left heart return. The general and that 50% will return to the venous line with almost no practice is to continue to consider that a venous saturation of oxygen extraction by the lungs. Differential Saturation between Superior The pH of blood shifts in an alkaline direction with hypo- and Inferior Vena Cava Cannulas thermia. Collaterals from fewer free hydrogen ions and therefore a higher, more alka- the descending aorta or a shunt from the innominate artery line pH. Thus, the pH of unsatisfactory cannula placement can reduce fow to the strategy selected, whether the more alkaline alpha stat strat- brain or lower body resulting in lower venous saturation in egy or the more acidotic pH stat strategy, will infuence oxy- that cannula. However, this is logistically complicated and is blood that is added to the pump prime for neonates and rarely if ever practiced in day-to-day surgery. Therefore, it is infants will exacerbate the leftward shift induced by cooling essential that the surgeon develop the habit of constantly moni- and alkalinity. Thus, this factor also potentially raises venous toring the color of the venous return in both cannulas. It is also oxygen saturation even though there has been no change in possible by looking at the Y junction of the two cannulas to the metabolic needs of the patient until hypothermia has estimate the relative fow in each cannula. How much to adjust the minimal acceptable also be alert to notifcation by the perfusion team that there is level of venous saturation according to the volume of bank a problem with volume loss from the circuit suggesting that blood used in the prime is entirely empirical. This should always lead to an inspection of both cannulas for signs of lower Left Heart Return, Collateral Steal or higher venous saturation with subsequent repositioning. A second dangerous assumption is Because heart rate, perfusion pressure and venous saturation that only macroscopic connections between the systemic all have serious limitations as methods for monitoring the arterial and pulmonary circulations result in a signifcant adequacy of perfusion, it is critically important that accurate 184 Comprehensive Surgical Management of Congenital Heart Disease, Second Edition information is available regarding the fow rate of blood anesthetized patient who is not on bypass, it is of very little actually entering the patient’s arterial circulation through the use during bypass. In addition, hypothermia can result in using modern equipment is able to continuously monitor all vasoconstriction of peripheral vessels resulting in inadequate patient variables, including heart rate and blood pressure on signal. Baseline calibration drift The steal from internal circuits, such as flters and hemocon- and wedging against the venous wall further complicate rou- centrators, adds even greater inaccuracy to calculated rather tine use. The interaction of these perfusion variables must be The principal limitation of these devices that can measure understood by the perfusion, anesthesia and surgical team changes from baseline fow in the middle cerebral artery is and is discussed in detail later in this chapter. Slight movement of the head, for example to operation, there are multiple disadvantages to this approach suction the endotracheal tube will alter the angle and the which supplies far more substrate than is required by the reading. Disadvantages include need for a higher volume to be The minimal acceptable fow relative to baseline that will maintained in the circuit and therefore either a greater use avoid cerebral injury is unknown. They are not recom- A progressive lactic acidosis during bypass is a serious indi- mended for neonates and infants who have reduced synap- cator of a perfusion problem. Fortunately, lactate levels can tic development and where greater degrees of hypothermia now be obtained much more easily than in the past. Hypothermia per se reduces elec- it is still not a real-time monitor and may not be noted until trical activity. Near-infrared tion of circulatory arrest that is safe, the reality is that the light penetrates the skull and allows assessment of changes safe duration of circulatory arrest changes according to from baseline of the oxyhemoglobin and deoxyhemoglo- conditions, particularly brain temperature, pH and hemato- crit. Approximately 70% of the signal is from venous blood so both functional and structural endpoints, i. Although there was initial brain during circulatory arrest because of ongoing metabo- hope that the technique would allow assessment of intracel- lism (Fig. A more acidotic pH and lower temperature lular oxygenation through measurement of changes in cyto- decrease the rate of HbO2 decay, while a higher hematocrit chrome aa3 redox state, studies using cyanide suggested that raises the baseline from which the decay begins, i. It instrument is a useful real-time monitor for determining the is longest with a lower temperature, more acidotic pH and safety of a reduced fow rate under specifc bypass condi- higher hematocrit (Table 10. The duration of arrest beyond the nadir time (oxyhemoglobin nadir time) is a useful predictor of behavioral and histological injury after circulatory arrest. Prediction of safe duration of hypothermic circulatory arrest by near infrared spectroscopy. No injury is seen under 25 minutes so that if it takes 30 minutes for the signal to fat-line, 55 minutes of circulatory arrest is “safe. In the world of cardiopulmonary bypass for adults, there was considerable enthusiasm for normothermic bypass in the mid-1990s. The usual practice minutes were free of behavioral and histologic evidence of today is to use “tepid” bypass, meaning that active warming brain injury. Analogies are frequently drawn between the airline indus- try and cardiac surgery, particularly in the domain of safety. In the absence of information from instru- Decreased Infammatory Response ments, a pilot must maintain safety margins: adequate speed of Cardiopulmonary Bypass greater than stall speed and adequate altitude greater than any Among the most obvious sequelae of bypass in the neonate or possible ground elevation in the fight path. Unfortunately, young infant are whole body edema, fuid retention, pleural cardiac surgeons have limited monitoring information as effusions and ascites. Conduct of Cardiopulmonary Bypass 187 What Is the Infammatory Response to Cardiopulmonary 100 Bypass? The systemic infammatory response to bypass 90 consists of activation of multiple humoral cascades, as well 80 as activation of cellular components of blood and endothelial 70 cells throughout the body. There are multiple humoral 40 cascades which are activated during bypass includ- 30 ing the coagulation cascade, the fbrinolytic cascade, 20 the complement system and the kallikrein/bradyki- 29,30 31 10 nin cascade. Previously in 32 (a) 1981, Chenoweth and colleagues, also from the University of Alabama, Birmingham, had demon- 100 strated that there was a progressive rise in plasma 90 C3a during cardiopulmonary bypass.

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In addition to physiologic changes that occur during development buy solian without a prescription, the concomitant presence of certain disease states (e buy solian 100 mg mastercard. A summary of important factors that can influence drug absorption in neonates cheap 50 mg solian fast delivery, infants buy solian 50mg mastercard, and children is provided in Table 82. Oral Absorption As is the case in adults, the majority of therapeutic drugs administered in the outpatient setting are given by the oral route. During development, maturational changes of gastric, intestinal, and biliary tract function (Fig. Given that most orally administered drugs have the physicochemical property of being either a weak acid or weak base, pH within the gastrointestinal tract can influence the amount of potentially absorbable drug (i. Gastric pH changes significantly throughout development with the highest values occurring during the neonatal period. In the fully mature neonate, the gastric pH ranges from 6 to 8 at birth and drops to 2 to 3 within a few hours of birth. However, after the first 24 hours of postnatal life, the gastric pH increases due to the immaturity of the parietal cells and gradually reaches expected adult values (e. As a result of these developmental differences, the bioavailability of acid-labile drugs (e. During development, one of the most important physiologic changes capable of altering the rate of drug absorption resides with gastrointestinal motility. By 6 to 8 months of age, gastrointestinal transit times may be shorter than those observed for older children and adults; a situation which can significantly influence both the rate and extent of bioavailability of drugs with limited water solubility (e. Finally, immature biliary function in neonates and young infants in the first few months of life has the potential for reducing the extent of oral bioavailability of lipophilic drugs which are dependent upon bile acids for their solubility in the small intestine (e. Developmental differences in the activity of intestinal drug-metabolizing enzymes (e. The clinical consequence of this observation of diminished expression in neonates and infants would be reduced presystemic clearance of substrates for these drug- metabolizing enzymes and higher circulating concentrations of the active compound in plasma (e. Conversely, if the medication is administered as a prodrug which is activated by these enzymes, we would expect reduced concentrations of the active compound in the plasma (e. While the patterns of ontogeny for these enzymes and transporters are not concordant, the majority appear to have adult expression within the first 6 to 12 months of postnatal life at which time, the influence of development on their activity as a determinant of bioavailability would be expected to be minimal (9,10). Extravascular Drug Absorption As is the case with oral drug absorption, development can influence the bioavailability of drugs administered by other extravascular routes (e. In the neonate, muscular blood flow is reduced in the first few days of life, as is the relative efficiency of muscular contractions. Furthermore, neonates and young infants have greatly reduced muscle mass (compared to older infants and children) an increased percentage of water per unit of muscle mass. Collectively, these developmental changes can produce variable and delayed rates of absorption of drugs given by the intramuscular route. In contrast, mucosal (rectal and buccal) and dermal permeability in the neonate and young infant is increased and thus, may result in enhanced absorption by these routes. In the case of transdermal drug absorption, a more highly perfused and hydrated stratum corneum (Fig. In addition, the ratio of body surface area to body weight is greater in infants and children as compared to adults. Collectively, these developmental differences may predispose infants and young children in the first 8 to 12 months of life to increased exposure and risk for toxicity for drugs/chemicals placed on the skin (e. Normal developmental differences in drug absorption from most all extravascular routes of administration can influence the dose–plasma concentration relationship in a manner sufficient to alter pharmacodynamics. Disease states that affect the integrity of the physiologic barriers that drugs given by extravascular routes must traverse prior to their translocation to the vascular space must be considered, as they can influence both the rate and extent of drug absorption. Finally, with regard to extravascular drug administration, it must be recognized that the onset of drug effect is directly dependent upon the route of administration. For example, the onset of effect for most drugs given intravenously in most cases, virtually instantaneous. This is contrasted with drugs given by inhalation (onset ∼ 2 to 3 minutes), sublingual administration (onset ∼ 3 to 5 minutes), intramuscular injection (onset ∼ 10 to 20 minutes), subcutaneous injection (onset ∼ 15 to 30 minutes), rectal (onset ∼ 30 minutes), oral (onset ∼ 30 to 90 minutes), and transdermal (onset ∼ minutes to hours) routes. Drug Distribution Drug distribution is influenced by a variety of factors which include drug-specific physiochemical properties, tissue composition (e. To a great degree, changes in drug distribution during development are associated with changes in body composition and the quantity of plasma proteins capable of drug binding. The reduction in relative total body water occurs rapidly during the first year of life and by 12 years, adult values (i. In contrast, the percentage of intracellular water as a function of body mass remains stable from the first months of life through adulthood. For drugs that are primarily distributed to a space which approximates the extracellular fluid pool and are not highly bound to plasma proteins (e. The body fat percentage tends to increase up to about 10 years of age and then changes composition with respect to puberty and sex. In normal children and adolescents with age-appropriate body habitus, changes in body composition beyond the first 3 months of life do not appear to produce profound developmental differences in drug disposition. This does not appear to be the case for obese children where increased body fat appears to require adjustment in the normal age-appropriate dosing regimen for several drugs (e. Of the circulating proteins in plasma, albumin (which preferentially binds weak acids) and α1-acid glycoprotein (which preferentially binds weak bases) are quantitatively the most important for drug binding. A similar pattern of maturation is observed with α1-acid glycoprotein where neonatal plasma concentrations are approximately three times lower than in maternal plasma and attain adult values by approximately 1 year of age. Binding affinity for acidic drugs is also reduced in the neonate as a consequence of the higher concentrations of fetal albumin (which has a lower binding capacity) and endogenous substances (e. For example, circulating fetal albumin in the neonate has significantly reduced binding affinity for acid drugs such as phenytoin which is extensively (∼94% to 98%) bound to albumin in adults as compared to 80% to 85% in the neonate. Transporter proteins are distributed throughout the body and contribute to the uptake and efflux of substrates to and from tissues. These drug transporters can markedly influence the extent to which drugs cross membranes in the body and whether drugs can penetrate or are secreted from the target sites. While there are limited data on the ontogeny of drug transport proteins, available information demonstrates their presence in enterocytes and hepatocytes as early as 18 weeks of gestation and low levels in the neonatal period which increase to adult values at varying ages during childhood (10,14,15). There remains a significant paucity of data regarding individual transporter function and transporter protein expression during childhood, and these knowledge gaps that directly influence drug disposition in the growing child, require further elucidation. Drug Metabolism Metabolism reflects the biotransformation of an endogenous or exogenous molecule by one or more enzymes to moieties which generally are more polar (hydrophilic) and thereby, more easily P. While in many cases, drug metabolism results in pharmacologic inactivation of a drug, there are instances where it can either contribute to or be a determinant of drug action. The former situation is illustrated by drugs which have pharmacologically active metabolites (e. It should be noted that metabolic activation for some drugs has been identified as a mechanism underlying toxicity (e. Quantitatively, the most important organ responsible for drug biotransformation is the liver. Drug metabolism has historically been conceptualized as occurring via two general classes of enzymatic processes: phase I, or nonsynthetic reactions (e. At birth, the concentration of drug- oxidizing enzymes in fetal liver (corrected for liver weight) appears similar to that in adult liver. However, the activity of these oxidizing enzyme systems is reduced, which results in slow clearance (and prolonged elimination) of many drugs. The impact of ontogeny on the activity of human drug-metabolizing enzymes has been the topic of several reviews (16,17,18). As illustrated by data for human glucuronosyltransferases (19), the impact of ontogeny on drug-metabolizing enzyme activity can be isoform specific. Many drug-metabolizing enzymes represent the products of genes that in some instances, are polymorphically expressed, with the variant alleles often conveying reduced and/or absent activity. Similarly, polymorphic expression of genes responsible for regulation of specific drug transporter proteins also exists. Together with drug-metabolizing enzymes, their activities are often the rate-limiting event for metabolic clearance of a drug from the body and in some instances, for drug action. Thus, genetic polymorphisms can influence both the pharmacokinetics and pharmacodynamics of drugs.

Association of serum digoxin concentration and outcomes in patients with heart failure solian 50mg otc. Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: a retrospective analysis discount solian line. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial order genuine solian on line. Outpatient continuous inotrope infusion as an adjunct to heart failure therapy in Duchenne muscular dystrophy order solian 50mg with visa. Outpatient continuous parenteral inotropic therapy as bridge to transplantation in children with advanced heart failure. Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics. Serelaxin: a novel therapy for acute heart failure with a range of hemodynamic and non- hemodynamic actions. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. A randomized study of the prevention of sudden death in patients with coronary artery disease. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. Incidence of and risk factors for sudden cardiac death in children with dilated cardiomyopathy: a report from the Pediatric Cardiomyopathy Registry. Results of a multicenter retrospective implantable cardioverter-defibrillator registry of pediatric and congenital heart disease patients. Implantable cardioverter-defibrillator lead failure in children and young adults: a matter of lead diameter or lead design? Prevention of sudden cardiac death with implantable cardioverter-defibrillators in children and adolescents with hypertrophic cardiomyopathy. New approach to implantable cardioverter-defibrillators in small pediatric patients: dorsal positioning of superior vena cava shock lead in a 3-year-old. Clinical experience of subcutaneous and transvenous implantable cardioverter defibrillators in children and teenagers. Subxiphoid approach to epicardial implantation of implantable cardioverter defibrillators in children. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. The effect of cardiac resynchronization on morbidity and mortality in heart failure. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. Cardiac resynchronization therapy for pediatric patients with heart failure and congenital heart disease: a reappraisal of results. Cardiac resynchronization therapy (and multisite pacing) in pediatrics and congenital heart disease: five years experience in a single institution. Cardiac resynchronisation therapy in paediatric and congenital heart disease: differential effects in various anatomical and functional substrates. Classic-pattern dyssynchrony and electrical activation delays in pediatric dilated cardiomyopathy. Evaluation of mechanical dyssynchrony in children with idiopathic dilated cardiomyopathy and associated clinical outcomes. Advanced heart failure treated with continuous-flow left ventricular assist device. Left ventricular assist device in Duchenne cardiomyopathy: Can we change the natural history of cardiac disease? The registry of the International Society for Heart and Lung Transplantation: seventeenth official pediatric heart transplantation report–2014; focus theme: retransplantation. Indications for heart transplantation in pediatric heart disease: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young; the Councils on Clinical Cardiology, Cardiovascular Nursing, and Cardiovascular Surgery and Anesthesia; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Waiting list mortality among children listed for heart transplantation in the United States. Long-term outcomes of dilated cardiomyopathy diagnosed during childhood: results from a national population-based study of childhood cardiomyopathy. Recovery of echocardiographic function in children with idiopathic dilated cardiomyopathy: results from the pediatric cardiomyopathy registry. Competing risks for death and cardiac transplantation in children with dilated cardiomyopathy: results from the pediatric cardiomyopathy registry. The impact of changing medical therapy on transplantation-free survival in pediatric dilated cardiomyopathy. New mechanistic and therapeutic targets for pediatric heart failure: report from a National Heart, Lung, and Blood Institute working group. Newburger The survival of children with congenital heart disease has improved dramatically over the past four decades. As a result, the number of adults with congenital heart disease is now believed to exceed the number of children (1,2,3,4). As mortality has declined, neurologic and developmental morbidities in survivors have come increasingly into focus. Poor school performance and the resultant need for educational support across the developmental span from kindergarten through 12th grade may have considerable personal and societal costs. Furthermore, the increasing number of adults with congenital heart disease has highlighted the consequences of neurodevelopmental impairments for employability and mental health (5). Neurodevelopmental disabilities can derive from innate or genetic factors, from aberrant fetal circulation, from the physiology and sequelae of congenital heart disease itself (e. Particularly in congenital heart disease, it can be difficult to separate developmental outcomes for a particular diagnosis and its genetic underpinnings from consequences of surgical and transcatheter procedures used in its management. It is likely that central nervous system effects of congenital heart disease are cumulative and affected by the complex interaction of genetic, preoperative, intraoperative, and postoperative factors (6,7). In this chapter, we review variables that contribute to neurodevelopmental outcomes in children after heart surgery and summarize findings related to long-term neurodevelopmental outcomes for more common, complex congenital heart malformations. Genetic Abnormalities Genetic abnormalities may cause both congenital heart defects and abnormalities of central nervous system structure and function. Children with genetic syndromes have much worse neurodevelopmental outcome than those without recognizable syndromes (8,9). Furthermore, it is suspected that genetic factors may independently underlie delayed development, either through a primary effect on the central nervous system or by affecting host susceptibility and resiliency, even in some patients without a recognizable constellation of congenital abnormalities. Specific types of congenital heart defects may be associated with different chromosomal abnormalities with varying molecular pathways that impact central nervous system structure and function. Mutations causing congenital heart defects may be associated with specific neurodevelopmental profiles. For example, although the clinical phenotype associated with 22q11 microdeletion is variable (18), a reasonably consistent neurodevelopmental profile has emerged. In adults with velocardiofacial syndrome, specific deficits have been reported in visual– spatial ability, problem solving and planning (executive functions), abstract social thinking, and attentiveness (23,25,26). Finally, some genetic mutations that cause structural heart defects are associated with psychiatric illness, including, the 22q11 microdeletion (19,23,28,29,30,31,32). In adults with 22q11 microdeletion, the prevalence of late-onset psychosis, most commonly schizophrenia and schizo-affective disorders, is 10% to 20% (21,33,34). With advances in research on genetic causes of congenital heart disease, it is likely that an increasing number of genetic and epigenetic abnormalities will be linked to neurologic and developmental outcomes in congenital heart disease patients. Brain Anatomy, Pathology, and Neuroimaging Cerebral dysgenesis has been reported in autopsy series to occur in 10% to 29% of children with congenital heart disease and may include such features as microdysgenesis, incomplete operculization, microcephaly, and agenesis of the corpus callosum (7,35,36,37,38). The cause of cerebral dysgenesis may be related to genetic factors or to abnormalities of fetal cerebrovascular hemodynamics caused by the particular congenital heart defect. Fetuses with congenital heart disease and with low cerebral-to-placental resistance ratios (<1) have smaller head circumferences than normal (41). Multiple studies have demonstrated an association of smaller brains and congenital heart disease (41,43,44,45).

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