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By B. Angar. Bienville University.

The teeth are narrower than a DeBakey style clamp leaving more length of the duct for oversewing allopurinol 300mg on-line. Publications enthusiastic about robotic congenital cardiac surgery are becoming rare buy 100 mg allopurinol with amex. Other robotic systems allow manipulation of more sophisti- rEsults oF surgEry cated instrumentation with complex multidirectional ‘wrist’ Traditional Surgery movements generic 300mg allopurinol. Much of the instrumentation There have been very few reports in the last decade or so is disposable and expensive. Development of instrumenta- describing the results of traditional surgical management of patent ductus arteriosus. However, it Children’s Memorial Hospital in Chicago35 described the remains unclear at this point as to what advantages robotic results of traditional surgical management for 1108 patients assistance will allow for the relatively simple procedure of who underwent surgery between 1947 and 1993. A total of ductal ligation, particularly in an era when device closure is 98% of the patients had interruption of the ductus by liga- increasingly popular. The recurrence rate to allow technically complex manipulations to be performed was 0. In recent years, the transfusion rate was less than 5% free of tremor with excellent visualization. The authors suggest ogy also allows preprogramming of complex stereotactic that these are the standard against which alternative methods measurements derived from noninvasive imaging, which is such as video-assisted ligation and catheter occlusion meth- particularly helpful for example in neurosurgery. These results are in many ways sim- since the ductus is readily visualized and complex techni- ilar to the results from the very large report by Panagopoulos cal manipulations are not required for its closure, it remains et al. Five patients required Evolving Catheter Methods intraoperative repositioning of the clip to eliminate a resid- ual shunt leaving only one long-term small residual shunt. The mean operating time was 20 min- utes and hospital stay averaged 48 hours for patients who been applied for assessment of these very different meth- were more than 6 months of age. Patients were discharged either on the frst or second which rose to 95% at 1 year. Residual ductal fow was assessed in optimal outcome occurred including coil embolization, the operating room both by intraoperative transesophageal abandonment of the procedure, persistent hemolysis, resid- echocardiography which suggested zero residual shunts, ual leak requiring a further procedure, fow impairment in as well as by Doppler echo at discharge which suggested a adjacent structures and duct recanalization. Three procedures were converted to thora- cotomy in adult patients with a dilated ductus. Two patients Cost of Catheter Methods versus Surgery had transient recurrent laryngeal nerve dysfunction. Although some ery, and pleural fuid drainage times were signifcantly reports have found that catheter methods are less expensive than surgery, for example reports by Prieto et al. They described 34 preterm infants with a mean weight at surgery In the past therefore, it was not uncommonly misdiag- of 930 g. Two patients died before dis- Embryology charge, one on postoperative day 2 from an intracranial hem- orrhage and one on postoperative day 88 because of multiple An aortopulmonary window results from incomplete devel- system organ failure. At the more severe end of centers have reverted to a traditional open surgical approach the spectrum, the anomaly merges with truncus arteriosus, 276 Comprehensive Surgical Management of Congenital Heart Disease, Second Edition while at the less severe end of the spectrum, the anomaly is closure in the catheterization laboratory either by coils or by associated with isolated origin of the right pulmonary artery device. Unlike patent ductus arteriosus, it is exceedingly rare pulmonary windows as types 1, 2, and 3. A type 2 aortopulmonary window is located on diagnosis has been delayed to the point that pulmonary vas- the posterior wall of the ascending aorta at the origin of the cular disease has occurred, a careful assessment must be right pulmonary artery. The contraindications arises from the right side of the ascending aorta and there is for surgery are similar to those described for Eisenmenger’s complete absence of the aortopulmonary septum. The Society of Thoracic Surgeons database includes a fourth intermediate category. Gross performed non-bypass Most series suggest that at least 50% of cases of aortopul- surgical ligation in his initial report. The tive cases of aortopulmonary windows described by Hew et 56 introduction of cardiopulmonary bypass allowed safer and al. One complex association that has been identifed in the 57–59 more reliable open techniques to be used. These methods literature and that we have seen involves a large, confu- include external division and oversewing and various inter- ent aortopulmonary window with separate origin of the right nal exposures (e. In 1978, Johansson aorta combined with an interrupted aortic arch and patent et al. Interrupted aortic arch, almost exclu- wall of the aortopulmonary window itself, which provides sively type A, is a common associated lesion in most large 60–62 excellent internal exposure of both the aorta and pulmonary series. The hemodynamic consequences are The approach is through a median sternotomy with subto- essentially identical to those of a large patent ductus arterio- tal resection of the thymus. The ausculatory fndings are also similar so that it can be is harvested and treated with 6% glutaraldehyde for 20–30 extremely diffcult on clinical grounds alone to distinguish minutes. The aortopulmonary window is inspected exter- an aortopulmonary window from a large patent ductus arte- nally to confrm the diagnosis. Today echocardiography with color Doppler mapping be apparent and the positions of the coronary artery origins should allow for accurate diagnosis. Extensive external dissection of the great vessels adds arteriosus, catheterization or other studies are only indicated little information concerning the morphologic details of the when there is concern that pulmonary vascular disease might defect and should be avoided. The procedure can usually The medical therapy for an aortopulmonary window is the be performed using continuous cardiopulmonary bypass same as for a large patent ductus arteriosus. As soon as exposure within the aorta has dioplegia solution is infused into the root of the aorta. At been obtained, the locations of the coronary ostia should be this point the tourniquets may be removed from the branch confrmed. The ductus is controlled with Aortopulmonary Window (18 Cases) a clamp on its pulmonary artery end. The distal divided Lesion n descending aorta is controlled with a C-clamp while it is Secundum atrial septal defect 5 anastomosed to a longitudinal arteriotomy on the undersur- Patent ductus arteriosusa 4 face of the aortic arch (Fig. During this time, a clamp Ventricular septal defect 4 is applied across the proximal aortic arch and perfusion of Interrupted aortic arch 3 the brain continues through the innominate artery. It is rec- Double-outlet right ventricle 3 ommended that the patient be cooled to deep hypothermia Tetralogy of Fallot 2 before placing the aortic arch clamp and that fow be reduced Tetralogy of Fallot with pulmonary atresia 2 to 20 mL/kg/min during the arch anastomosis. When the Hypoplastic right ventricle 2 anastomosis has been completed, the clamps can be released Right aortic arch 2 from the descending aorta and the aortic arch. The ascend- Peripheral pulmonary stenosis 2 ing aorta is clamped inferior to the arterial cannula so Partial anomalous pulmonary venous return 1 that the whole body, other than the heart, is now perfused. Coarctation of the aorta 1 Cardioplegia solution is infused into the root of the aorta. Anomalous right subclavian artery 1 Following administration of cardioplegia, the tourniquets a Patent ductus arteriosus occurred only with inter- around the right and left pulmonary artery can be removed. The ascending aorta is opened with a transverse incision at the level of the right pulmonary artery. A pericardial baffe is placed within the aorta to direct blood from the main pulmo- defect is closed with a small patch of autologous pericardium nary artery to the right pulmonary artery across the posterior using continuous 6/0 prolene in the neonate or small infant wall of the ascending aorta (Fig.

Diffuse sweating may result in long-duration potentials that initially appear as generalized or regional slow activity (Figs order 100 mg allopurinol free shipping. Very slow potentials may occur because of changes caused by alterations in surface electrolyte compositions—these potentials are similar to the galvanic skin response cheap allopurinol 300mg otc. Movement of the head against the bed due to respirations or other body movements may produce sharp and/or slow potentials arising from that particular electrode (Figs buy genuine allopurinol. Pulse also may cause a recorded artifact by production of movement in a region adjacent to an electrode site. This is owing to a mechanical, or ballistic, movement induced by the instrument—a cause of artifact from these devices different from electrical interference described earlier. Other body movements also may alter the patient-electrode interface and result in artifacts. These include limb movements that may be random, purposeful, or associated with clinical seizures and other limb or body movements (Figs. Movements created to comfort the infant, such as rocking and patting the infant, may be particularly troublesome. Digital recordings may have problems relating to malfunction of the operating system. The edema may be the result of transit through the birth canal, more significant birth or other trauma, placement of intravenous lines with or without extravasation of fluid, the placement of a ventriculoperitoneal shunt, or the presence of a surgical wound. Diffuse edema may lead to a pattern of background activity that is low in amplitude in all regions. Regional or asymmetric edema may lead to a pattern of focal depression, suggesting a focal lesion if the edema is not noted. Conductive properties may be altered because of the absence of underlying skull, typically (although rarely) in the case of cranial surgery. Respirations also may appear as artifacts, whether they are spontaneous or driven by a ventilator. These artifacts may be unilateral or bilateral, depending on body and head position. These movements include oral-buccal-lingual movements, such as sucking and tongue thrusting (i. Periodic electrical interference due to mechanical device Alternations of Electrode Impedance Fig. Sustained, high-amplitude, long-duration potentials due to sweat Induced by Movements Fig. Moderately high-amplitude, short-duration, repetitive potentials due to head movement associated with sobbing Fig. High-amplitude generalized spike-like artifact associated with generalized myoclonic movement Fig. Rhythmic sharp wave activity induced by patting Endogenous Noncerebral Potentials Fig. Electrical interference is present in all leads when an infusion pump for intravenous fluids is activated at the bedside. Electrical artifact is present in channels involving the C3 electrode, which has relatively high impedance compared with others. The Pz electrode in this recording has become unstable, resulting in irregular, sustained, low-voltage, relatively fast activity. The high- voltage, long-duration waveforms are predominantly in frontal and central regions and are sustained. The electrocardiogram also is reflected in leads from the left central region and there is electromyographic activity in the anterior leads. Moderately high-amplitude, short- duration, repetitive potentials due to head movement associated with sobbing. This infant experienced a brief sobbing episode characterized by shuddering that involved respiration and truncal muscles as well as head, which was turned to the right. The simultaneous body movements are indicated by waveforms in the electromyogram channel. High-amplitude generalized spike-like artifact associated with generalized myoclonic movement. High-voltage rhythmic theta activity is present with variable localization and is preceded and followed by high-voltage, very slow activity. This movement is marked by the generalized high-amplitude slow activity in the middle of this segment. Although associated with sucking, this activity is not produced by endogenous potentials, but rather by movement of the head that occurs in conjunction with the vigorous sucking movements. A brief run of slow activity in the right frontal region aligns with the activity recorded in the electroculogram channel. Rhythmic, slow, sharp waves are present in the frontal regions bilaterally, higher in amplitude on the left, aligned with the recorded electrooculogram and occurring in association with clinically observed nystagmus. High-voltage, slow activity is present in the frontal regions bilaterally associated with rhythmic eye opening and closure. Visual analysis and interpretation require determination of the degree of continuity of background activity (Fig. They also require recognition of specific wave forms and patterns that occur with increasing age (Fig. Temporal alpha bursts replace 4- to 5-Hz bursts (33 wk) 34-35 C D C +++ + +++ No 1. Continuous bioccipital R delta activity with superimposed 12- to 15- Hz activity during active sleep 2. The voltage of the fast activity varies throughout each burst but rarely exceeds 75 μV. Various names have been given to these complexes: “spindle-delta bursts,” “brushes,” “spindle-like fast waves,” and “ripples of prematurity. An important feature of beta-delta complexes is that they typically occur asynchronously in derivations from homologous areas and show a variable voltage asymmetry on the two sides. During the next 5 to 6 weeks, they become progressively more persistent, and the voltage of the fast component usually increases. Temporal Theta and Alpha Bursts A useful developmental marker is the appearance of rhythmic 4 to 6-Hz waves occurring in short bursts of rarely more than 2 seconds, arising independently in the left and right midtemporal areas. Individual waves may often have a sharp configuration (Hughes, 1987; Werner et al. It is replaced by temporal alpha bursts that otherwise have characteristics of amplitude, burst duration, and spatial distribution as temporal theta bursts (Figs. Frontal Sharp Waves Frontal sharp waves are isolated sharp waves of blunt configuration, usually with an initial surface-negative phase followed by a surface- positive phase, and have been referred to as encouche frontales (Dreyfus-Brisac, 1962; Kellaway and Crawley, 1964). These frontal sharp transients are bilaterally synchronous and symmetrical from the time of their first appearance.

Vitamin A: Not Too Little buy allopurinol 100mg without a prescription, Not Too Much Vitamin A is an essential vitamin buy 300mg allopurinol with amex, widely available in over-the-counter supplements buy 300mg allopurinol amex. Vitamin A is an important molecule in the synthetic pathway of retinoic acid, a potent transcription factor and established cardiac teratogen, and for this reason it has been assessed in several epidemiologic studies of birth defects. In all studies that have looked at it, beta-carotene (a provitamin A) has not been associated with increased risks for congenital heart defects (270,271). Retinol, on the other hand, is preformed vitamin A, and has been associated in some studies with an increased risk for congenital heart defects. Another study, which evaluated the use but not the dose of vitamin A, reported a weaker association (272). Nevertheless, it appears reasonable to recommend avoiding high-dose retinol supplements in the periconceptional period and, if vitamin A is indicated, favor supplements containing beta-carotene. Folic Acid and Multivitamins Because of its established protective effect on neural tube defects, the use of folic acid for all women of childbearing age or those who do not actively exclude a pregnancy is recommended by medical organizations, public health agencies, and lay organizations in many countries. Thus, assessing whether or not folic acid should be recommended to prevent congenital heart defects could seem a useless exercise. Identifying a protective effect on heart defects, if indeed one exists, would be beneficial in several ways. It would add to the potential benefits of folic acids, and the associated “return on investment” that could be achieved with more expansive supplementation and fortification programs worldwide. Identifying a protective effect may require approaches and methods that are different from those used to examine neural tube defects. For example, one might need to evaluate higher doses of folic acid or multivitamins rather than folic acid alone, as there is no guarantee that all folic acid-responsive birth defects are as sensitive to folic acid as are neural tube defects. If preventing congenital heart defects requires high doses of folic acid or multivitamins, then the current fortification programs, which typically use small amounts of folic acid alone, may achieve no or partial results. Also, identifying a role for folic acid or molecules in the broader context of folic acid–related biochemical networks could help understand aspects of the etiology of congenital heart defects, including gene–environment interactions, and ideally open further avenues for prevention. Clinical trials comparing folic acid with placebo, now that folic acid is known to protect against serious nervous system defects, would be unethical. Other options would be available, such as evaluating high dose versus standard dose of folic acid/multivitamins, or including in a vitamin trial a cohort of women who refused to take folic acid, but all these options are imperfect and challenging. Evidence from Clinical and Epidemiologic Studies The main epidemiologic and clinical studies, conducted in the absence of fortification, include one randomized clinical trial from Hungary (277), and four case-control studies from the United States (108,278,279) and the Netherlands (280). Participants were randomized to receive a multivitamin with folic acid or a placebo-like pill containing trace elements. Secondary endpoints included fetal deaths and other structural malformations, including heart defects. The case-control studies evaluated retrospectively the frequency of use of multivitamin supplements, known or presumed to contain folic acid, in case-mothers and control-mothers. Two of the studies evaluated a broad range of heart defects (108,280), whereas the remaining three (278,279,281) were restricted to conotruncal defects (and in one study, also ventricular septal defects). In the randomized clinical trial (277), fewer women taking the multivitamin with folic acid had a child with a congenital heart defect compared to the reference cohort, for an statistically significant risk reduction of 58%. This finding was driven mainly by the lower rate of conotruncal and septal defects (277,282). However, the available sample size limited the precision of the risk estimates for the subtypes of heart defect. For example, the two case-control data that assessed heart defects in the aggregate also found an overall reduced risk (108,280), though the magnitude of the apparent protective effect was lower than in the randomized clinical trial (25% vs. Two case-control studies did not show evidence of risk reduction for conotruncal defects (279,281) whereas three others did (108,278,280). For (ventricular) septal defects, one case-control study did not show evidence of risk reduction (281), whereas two others did (108,280). Why the studies are not entirely consistent is unclear, but methodologic differences as well as varying degrees of bias and confounding could have played a role. In summary, at this time the preponderance of clinical and epidemiologic data, including findings from a randomized clinical trial, seems to indicate a moderate risk reduction for congenital heart defects in the aggregate with periconceptional use of a multivitamin supplement containing folic acid. Ideally a new, well-designed clinical trial or a large, carefully implemented prospective case-control study, preferably with biologic markers, could provide conclusive data on this important issue. Rates after Fortification Several countries in North and South America and Middle East, as well as Australia (but no countries in Europe yet) have introduced folic acid fortification, that is, have added variable amounts of folic acid to the food supply, typically in cereal grain products that make their way into common staples such as breads and pasta. The main goal was to reduce the occurrence of neural tube defects by increasing folic acid consumption in the population as a whole. Fortification has also allowed the opportunity to examine changes in the rates of major congenital heart defects in response to overall changes in folic acid consumption. In the United States, a study using birth defect surveillance data from 23 state programs compared rates of selected congenital heart defects in 1999 to 2000 versus 1994 to 1996 (283). For heart defects, the study reported a modest (12%) but significant decline in d-transposition of the great arteries (12% reduction, rate ratio 0. In Canada, studies from two provinces also reported a modest decline in some heart defects after fortification. In Alberta, researchers using data from a well-established population-based birth defect registry reported a 20% decline in secundum atrial septal defects (rate ratio 0. In Quebec, researchers using linked administrative databases evaluated trends of a group of severe heart defects, including conotruncal defects (60% of the case group), single ventricle, and atrioventricular septal defects (285). They reported a significant decline of these defects, 6% for every year after fortification (yearly rate ratio 0. Limited additional information is available from Latin America, where several countries, including Chile, Argentina, and Brazil introduced fortification at different times and levels. For heart defects, they reported a statistically significant reduction of septal defects. In a similar pattern, a moderate nonsignificant decline in an aggregate group of severe heart defects (conotruncal defects, single ventricle, atrioventricular septal defects) was observed in Argentina (rate ratio, 0. By contrast, the decline for neural tube defects was marked and consistent across the three countries (286). Prevalence rate ratios over 1 indicate increased rates after fortification, prevalence rate ratios below 1 indicate decreased rates. Changes in the birth prevalence of selected birth defects after grain fortification with folic acid in the United States: findings from a multi-state population-based study. Changes in frequencies of select congenital anomalies since the onset of folic acid fortification in a Canadian birth defect registry. Prevalence of severe congenital heart disease after folic acid fortification of grain products: time trend analysis in Quebec, Canada. Some statistically significant reductions have been observed but so far these have not been consistent across phenotypes and geographic areas, even within the same country. Contributing factors could include variations in the effectiveness of fortification (as documented by blood folate levels) and in study methodology (inclusion criteria and classification scheme). In addition, without a concurrent control group, it is difficult to assess the influence of structural changes in reporting and ascertainment, including the influence of elective terminations of pregnancy. Maternal fever, multivitamin use, and selected birth defects: evidence of interaction? However, this seems to be true even for neural tube defects, for which the protective effect of folic acid is well established: with fortification, the reduction in occurrence is less and take longer compared to what is seen in observational studies and clinical trials.

A mouse model of human congenital heart disease: high incidence of diverse cardiac anomalies and ventricular noncompaction produced by heterozygous Nkx2–5 homeodomain missense mutation order allopurinol mastercard. Temporal variability in birth prevalence of congenital heart defects as recorded by a general birth defects registry buy allopurinol 100 mg fast delivery. Total is more than the sum of the parts: phenotyping the heart in cardiovascular genetics clinics buy allopurinol 100 mg low cost. A population-based study of extra-cardiac anomalies in children with congenital cardiac malformations. Goodwin Introduction The structure and function of the myocardium undergoes dramatic changes during fetal life and in postnatal maturation to adulthood. The postnatal period is marked by extensive physiologic and metabolic remodeling with dynamic changes as the fetal heart adapts to birth and converts to adult function (1). These processes are regulated by a number of hormones, neurotransmitters, growth factors, and mechanical forces. The coronary circulation is tightly coordinated with myocardial growth to ensure an adequate supply of oxygen and metabolic substrates. A complete understanding of the physiologic processes that regulate myocardial structure and function is a necessary prerequisite to understand the pathogenesis of congenital and acquired heart disease. While Chapter 1 in this volume provides a comprehensive discussion of the molecular and genetic determinants of heart development, this chapter describes the developmental and postnatal changes in cardiac structure, metabolic regulation, excitation– contraction (E-C) coupling, and growth/regeneration. Postnatal changes in hemodynamic load, autonomic innervation, and hormonal status are summarized. The effects of these changes on myocardial systolic and diastolic dysfunction are also discussed. The majority of studies on developmental changes in myocardial structure and function has been performed in zebrafish, chick embryos, and rodents, with some additional data taken from higher mammals and humans. While the process of E-C coupling is very similar, there is significant spatiotemporal variability in structural development among the different model species. Unless otherwise noted, the majority of the developmental changes described in this chapter will focus on data from rodent models and humans. Myocardial Structure The heart begins functioning as a simple tube composed of only cardiac myocytes and endocardial cells. However, it quickly becomes a complex organ comprising multiple cell types that can be grouped into conducting, supporting, and functional cells (Fig. The cellular constituents of the heart include cardiac myocytes, cardiac fibroblasts, endothelial cells, and vascular smooth muscle cells. The sinoatrial nodes are specialized myocytes responsible for action potential generation. The conducting cells, also derived from cardiac myocytes are mainly Purkinje fibers. While cardiac myocytes are responsible for the mechanical function of the heart, they comprise only ∼30% of the total number of cells. Cardiac fibroblasts predominate in conferring structural integrity to the heart (5). Cardiac Fibroblasts and the Extracellular Matrix The cardiac fibroblast is the most abundant cell type present within the postnatal mature heart. Cardiac fibroblasts are derived from different cell lineages at different developmental stages. Fibroblasts also arise from the differentiation of bone marrow–derived circulating fibrocytes (6). In the neonatal and adult heart, cardiac fibroblasts arise from resident cells via epithelial–mesenchymal transformation and from bone marrow–derived cells (7). Thus, cardiac fibroblasts from the neonatal period are distinct from those in the adult myocardium and are also different from the ones that populate the heart following acute injury or chronic hemodynamic overload (8). During development, fibroblasts secrete a number of growth factors that promote cardiac myocyte proliferation. Matrix deposition during this period establishes a functionally competent ventricle, which provides structural stability necessary for transitioning from fetal to postnatal life (9). Elastic fibers are present in close association to collagen and are responsible for maintaining normal elasticity of the cellular framework. The endothelial cell layers line the surface of the endocardium (top) and is supported by a layer of dense extracellular matrix (collagens, elastins, fibronectin, proteoglycans) secreted by interstitial cardiac fibroblasts (pink). The Purkinje fibers (green) are specialized cardiac muscle fibers located within this matrix that are responsible for electrical impulse propagation from the atrioventricular node to the ventricular myocardium. Cardiac myocytes are organized in myofibers and are electromechanically coupled by intercalated discs. Small blood vessels and capillaries are located adjacent to myofibers to provide nutrients, deliver oxygenated blood, and remove metabolic by-products. Cardiac fibroblasts become enmeshed in this network, which allows them to contract the endomysial collagen, exerting mechanical force on the myocytes. In the adult myocardium, this network includes the epimysium that surrounds large groups of muscle fibers, the perimysium arising from the epimysium that surrounds smaller groups of muscle fibers and the endomysium, which tethers individual fibers to each other and the adjacent vasculature (Fig. In addition to acting as scaffolding for cells and vessels, the collagen network also coordinates the transmission of force generated by myocytes, serving as a viscoelastic medium facilitating compression and recoil properties of the tissue (12). Cardiac fibroblasts are regulated by mechanical and molecular signals during cardiac development. Basement Membrane A specialized area of the matrix termed the basement membrane or basal lamina surrounds all cells in the myocardium except cardiac fibroblasts. An intact basement membrane is necessary for normal cardiac growth and maturation and plays an important role in postnatal cardiac myocyte sarcomerogenesis via activation of integrin-mediated signaling (14). Perlecan is expressed at high levels throughout embryogenesis in the heart and required to ensure mechanical stability until cell–cell contacts have formed and matured (16). Cardiac Myocytes Cardiac myocytes are derived from two waves of anterior splanchnic mesoderm known as the primary heart field, which forms the primary heart tube. Cardiac myocytes have two major mechanistic functions: Force generation by myofibrils in response to E-C coupling and force transmission across cell bundles mediated by the integration of electromechanical signals at the intercalated disc. Plasma Membrane The plasma membrane (or sarcolemma) is the region of the cell that contains ion pumps, channels, and exchangers that contribute to action potential propagation, as well as maintenance of proper ionic and chemical gradients. The flow of ions controlled by these proteins is essential for proper myocyte function and directly regulates cellular contraction and relaxation. Numerous G-protein–coupled receptors, cytokine receptors, and growth factor receptors are located on the plasma membrane and are responsible for transducing changes in the local neurohormonal milieu into intracellular signals that regulate cell growth and function. In the rodent heart, the low digitalis affinity α1 isoform predominates through all phases of development, while there is a postnatal transition from the neonatal α3 isoform to the adult α2 isoform that occurs within the second week of postnatal life (19). B: The interstitial connective tissue consisting of perimysial and endomysial components presents a honeycomb shape. The perimysium (thick arrow) surrounds groups of cardiomyocytes, and the endomysium (thin arrow) surrounds each cardiomyocyte. C: The endomysium (arrow) supports and connects individual cardiomyocyte fascicles.

Among these features purchase allopurinol 300 mg visa, solid consistency has a highest sensitivity (86%) discount allopurinol 100mg overnight delivery, while micro- calcifications and shape taller than width has a specificity of 90% generic allopurinol 300 mg with visa. The differential diagnoses of a midline neck swelling include disorders of thyroid gland like thyroglossal cyst, thyroid nodule (benign or malignant), or thyroid abscess and non-thyroidal disorders like pretracheal lymphadenopa- thy, epidermal cyst, sebaceous cyst, branchial cyst, dermoid cyst, cystic hygroma, lymphangioma, and lipoma. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. He had proptosis (24 mm) of both eyes with marked chemosis and swelling of eyelids with a clinical activity score of 6/7 and severity score moderate to severe. He was diagnosed to have Graves’ disease with active and moderate to severe thyroid-associated orbitopathy. He was advised artificial teardrops, sun- glasses with side cover and elevation of head end of bed while sleeping. He was initiated on carbimazole 30 mg once a day and propranolol 40 mg thrice daily along with pulse methylprednisolone therapy. A week later, he had improvement in clini- cal activity score (4/7) and symptoms of toxicosis. Dose of carbimazole was decreased to 20 mg per day, and β-blockers were discontinued. He was continued on carbimazole for 2 years with close monitoring of thyroid function tests. Later, he was subjected to decompressive eye surgery for severe proptosis after 6 months of consistently inac- tive disease. Disease was moderate to severe as proptosis was >20 mm, and there was severe 11 Extra-thyroidal Manifestations of Autoimmune Thyroid Disease 251 soft tissue involvement. He had marked restriction of eyeball movements (frozen globe) without any cranial nerve involvement. Thyroid function test confirmed the diagnosis of thyrotoxicosis, and he was started on carbimazole and propranolol. Presence of active eye disease suggests ongoing inflammation and merits glucocorticoid treatment. Surgery is indicated only in patients with dysthyroid optic neuropathy, corneal breakdown, and globe subluxation who do not respond to glucocorticoids within 1–2 weeks. Further, absence of smoking in the index case appears to be complimentary for the long-term outcome. It is impor- tant to monitor liver function test as pulse methylprednisolone therapy can rarely induce fatal hepatic failure. Rehabilitative surgeries are undertaken once the eye disease is consistently inactive for 6 months; therefore, the patient was subjected to decompressive eye surgery after 6 months of persistently inactive eye disease. The extra-thyroidal manifestations of autoimmune thyroid disease include thy- roid-associated orbitopathy, infiltrative dermopathy, and thyroid acropachy. The term thyroid-associated orbitopathy denotes orbitopathy associated with autoimmune thyroid disease, either Graves’ or Hashimoto’s thyroiditis, while Graves’ orbitopathy is a specific term for orbitopathy associated with Graves’ disease. Although the terms Graves’ ophthalmopathy and Graves’ orbitopathy are used interchangeably, they are not synonymous. The ocular manifestation in patients with thyroid disorder is due to involvement of retro-orbital tissue and ocular muscles. Therefore, the term “Graves’ ophthalmopathy” is a misnomer as it does not address orbital involvement in the disease process. Clinically evident orbitopathy is seen in nearly one-third of patients with Graves’ disease, although imaging may show evidence of orbitopathy in almost all. It is usually bilateral, but may be asymmetrical in 10–15% and is rarely unilateral. Natural history of Graves’ orbitopathy in a treatment-naive patient is character- ized by an initial active phase of 6–12 months, followed by a plateau for 1–3 months and eventually an inactive phase lasting 1–2 years. The clinical activity of disease progressively declines over time; however, parameters of severity like exophthalmos, diplopia, and lid retraction may not remit com- pletely. A score of ≥3/7 is considered to be clinically active and requires immunosuppressive therapy. Clinical activity score represents acute inflammation in the orbit with extension into anterior region of eye. Clinical activity is the result of cytokine-mediated injury to retro-ocular and ocular tis- sues, and venous outflow obstruction. Severity score represents anatomical/ func- tional aberrations and is due to retro-orbital fibroblast and adipocyte proliferation and thickening of extraocular muscles along with glycosaminoglycan deposition in a closed retro-orbital space and thereby compressing neighboring tissues including optic nerve. If disease is active and severe, immunosuppressive therapy should be started first, and surgery should be contemplated later if indicated, and as with improvement in clinical activity, severity score may also improve. The non-endocrine causes of proptosis include cavernous sinus thrombosis, carotid–cavernous fistula, orbital myositis, orbital tumors and granulomatous infiltration of orbit. In addition, systemic disorders like chronic obstructive air- way disease, chronic liver disease, and chronic kidney disease can also be asso- ciated with proptosis. The degree of protrusion of eye- ball depends on age, sex, ethnicity, extent of myopia, and method used to measure it. Normally it does not exceed 17 mm in Asian adults, and >20 mm is considered as moderate–severe proptosis. It commonly occurs due to ocular cranial nerve 11 Extra-thyroidal Manifestations of Autoimmune Thyroid Disease 255 involvement. However, in patients with Graves’ disease, “frozen globe” can occur due to involvement of extraocular muscles per se without any cranial nerve palsy. Ptosis is uncommon in patients with Graves’ disease, and if present, the patient should be evaluated for myasthenia gravis. Other causes include superior orbital fissure syndrome, orbital apex syndrome, and rarely mechanical failure of leva- tor palpebrae superioris due to long-standing severe proptosis. Ptosis can occur either due to involvement of the Muller’s muscle or levator palpebrae superi- oris, innervated by sympathetic nerve fibers and 3rd cranial nerve, respectively. Ptosis is usually mild with sympathetic nerve involvement, whereas it is severe with oculomotor nerve palsy. Superior orbital fissure is a passage for oculomotor, trochlear, and abducens nerves, ophthalmic branch of trigeminal nerve, inferior and superior ophthal- mic veins, and sympathetic fibers. What are the causes of vision loss in patients with thyroid-associated orbitopathy? Causes of vision loss in patients with thyroid-associated orbitopathy are expo- sure keratitis with severe corneal involvement and dysthyroid optic neuropathy either due to optic nerve compression or stretching of optic nerve. Optic neuropathy is caused by com- pression of optic nerve due to crowding of retro-orbital tissue and thickened extraocular muscles at the apex (orbital apex syndrome) and/or stretching of optic nerve either due to severe proptosis or subluxation of the globe. If there is no improvement in optic nerve function after 1–2 weeks of glucocorticoid therapy, orbital decompression is recommended. In addition, increased production of interleukin-1 in smokers has been shown to induce orbital adipogenesis and may worsen orbitopathy. Therefore, complete cessation of smoking is recommended in all patients with Graves’ disease. What are the indications of orbital imaging in a patient with thyroid- associated orbitopathy? In addition, patients who are planned for rehabilitative surgery need imaging for anatomical details of the orbit.

Further growth of the internal to external discount 100 mg allopurinol free shipping, the spinal meninges are called vertebral column results in the inferior or caudal the pia mater 300 mg allopurinol with visa, arachnoid cheap allopurinol 100mg with amex, and dura mater (Fig. The approximate The pia mater completely surrounds and adheres relation between spinal levels and vertebral lev- to the spinal cord. Its contents include loose connective tissue, the dura by the denticulate ligaments and by the fat, and the internal vertebral venous plexus. The denticulate ligaments are 21 pairs of fbrous sheaths located at the sides of the spi- Clinical nal cord. Medially, the ligaments form a continuous Connection longitudinal attachment to the pia mater. Laterally, they form triangular, toothlike processes that attach The internal vertebral venous to the dura. Because of their pial attachments mid- plexus forms a valveless com- way between the posterior and anterior surfaces of munication between the cranial dural sinuses, the spinal cord, the denticulate ligaments can be which collect blood from the veins of the brain, used as landmarks for surgical procedures. The spi- and the veins of the thoracic, abdominal, and nal cord is also anchored by the roots of the spinal pelvic cavities. It, therefore, provides a direct nerves, which are ensheathed by a cuff of dura where path for the spread of infections, emboli, or they perforate it near the intervertebral foramina. Dura Mater Inferior or caudal to the spinal cord, the dura The spinal dura mater loosely surrounds the spinal mater forms thedural sac(Fig. The area between the spinal dura and the inferiorly to the middle third of the second sacral periosteum lining the vertebral canal is the epidural vertebra. Chapter 2 Spinal Cord: Topography and Functional Levels 21 flum terminale, the threadlike extension of the descending course within the subarachnoid space pia mater, and descends to the back of the coccyx (Fig. Therefore, the dural sac nerves, which then exit from the intervertebral contains (1) the flum terminale; (2) the cauda foramina and immediately begin to branch. A hypodermic needle may be introduced nent of these is the anterior median fssure, occu- into the subarachnoid space (Fig. On the opposite side the spinal cord, thereby causing irreparable dam- is a far less conspicuous groove, the posterior age, because regeneration or repair to neurons and median sulcus. The anterior and posterior root- axons in the spinal cord (or brain) does not occur. A large number of the fbers are puncture is contraindicated in patients with myelinated, thus accounting for the white color elevated intracranial pressure due to trauma, in the fresh or unstained state. White Matter Thus, each segment gives rise to four separate roots, one posterior and one anterior on each The white matter is divided into three areas, called side. According to their positions, these are to the spinal cord by a series of rootlets. The the posterior funiculus, the lateral funiculus, and posterior and anterior roots take a lateral and the anterior funiculus (Fig. Most of their neu- A well-defned separation between these two tracts rons play roles in voluntary movement, and many is not always evident. This is generally true of most of them give rise to axons that emerge in the of the tracts in the spinal cord; hence, the locations anterior roots. Hence, the anterior horns are pri- of the various tracts in the spinal white matter are marily the “motor” parts of the spinal gray matter. The intermedi- ate zones are composed mainly of association or The gray matter is divided into four main parts: interneurons for segmental and intersegmental 1. The anterior or ventral horns intermediate zones are the “association” parts of 3. The lateral horns ing from their neurons remain in the spinal cord; some, however, do project to the brain. For descriptive purposes, an imaginary hori- The lateral horn is a small triangular exten- zontal line passing from side to side through sion of the intermediate zone into the lateral the deepest part of each posterior funiculus and funiculus of the thoracic and the upper two lum- extending laterally through the gray matter bar segments. It contains cell bodies of pregangli- defnes the anterior boundary of the posterior onic neurons of the sympathetic nervous system. The posterior horns contain groups of neurons that are infuenced mainly Nuclei or Cell Columns by impulses entering the spinal cord via the posterior roots. Hence, the posterior horns are The neurons of the spinal gray matter are primarily the “sensory” parts of the spinal gray arranged in longitudinal groups of functionally matter, and many of their neurons give rise to similar cells referred to as columns or nuclei Chapter 2 Spinal Cord: Topography and Functional Levels 23 (Fig. For example, Myelin-stained transverse sections of the four the substantia gelatinosa and the proper sensory major regions of the spinal cord can be distin- nucleus, which are related to pain impulses from guished from each other most readily by the size all spinal nerves, extend throughout the length and shape of the respective gray matter (Figs. Because of the large size of the lower dorsal nucleus and the intermediolateral nucleus, limbs, the lumbar and sacral segments have mas- which are related to the cerebellar and auto- sive posterior and anterior horns. In lumbar seg- nomic systems, respectively, exist only in certain ments, the anterior horn has a distinct medial spinal cord segments. In addition, the Laminae rim of white matter surrounding the sacral gray The spinal gray matter can also be divided into matter is much thinner than that in the lumbar laminae or layers based on layerings of morpho- spinal cord. Laminae The posterior horn in both thoracic and cervi- provide a more precise identifcation of areas cal segments is narrow compared with lumbar and within the spinal gray matter and are very use- sacral segments. However, owing to the muscular ful in describing the locations of the origins or volume of the upper limbs, the cervical anterior terminations of the functional paths. Ten lami- horn is much larger than the thoracic, which nae make up the spinal gray matter, and, in mainly supplies the relatively small intercostal general, they are numbered from posterior to and subcostal muscles. Nevertheless, Lamina X is in the commissural area surrounding because the white matter contains axons trans- the central canal. Posterior median sulcus Posterior funiculus Posterior horn Substantia Intermediate gelatinosa zone Central canal Lateral horn Lateral funiculus Anterior horn Anterior funiculus Anterior median fissure Figure 2-7 Transverse section of thoracic spinal cord. Note the slim anterior and posterior horns and lateral horn indenting the lateral funiculus. Chapter 2 Spinal Cord: Topography and Functional Levels 25 Gracile tract Posterior median sulcus Posterior funiculus Cuneate tract Posterior intermediate sulcus Posterior horn Substantia gelatinosa Intermediate zone Lateral funiculus Anterior horn Anterior funiculus Anterior median fissure Figure 2-8 Transverse section of cervical enlargement. Note the slim posterior horn, the large anterior horn, and the division of the huge posterior funiculus. This is the anatomi- Injury to the spinal cord can be two fundamen- cal basis underlying sacral sparing (See Fig. Acute spi- nal cord injury can result from trauma or stroke, while chronic injury can result from infections, Chapter Review infammation, tumors, genetic disorders, and com- pression. Traumatic injury with momentary or Questions prolonged compression of the spinal cord has an immediate onset of clinical signs that vary depend- 2-1. What are the contents of the spinal ing upon the specifc tracts and neurons/nuclei epidural space? At what three intervertebral articulations are bination of trauma and vascular interruption comes dislocations most likely to occur and what with contusions to the spinal cord. What are the distinguishing characteristics white matter is more resistant to hypoxia than the of transverse spinal cord sections at sacral, gray matter. Each of the following concerning the cauda anatomical landmarks for: equina is true except one: a. The disparity between spinal cord levels spinal cord and vertebral levels in adults is due to b. Differential growth or elongation of the of the cord spinal cord compared to the vertebral c. The diminished size of the caudal spinal eral white matter may remain functional cord compared to rostral levels.

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