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Looping will invert the orientation of the template with respect to the enzyme but not the direction of actual synthesis on a lagging strand order on line plavix arrhythmia genetic. After the synthesis of approximately 1000–2000 base pairs plavix 75 mg for sale prehypertension at 24, the monomer of the enzyme on a lagging strand encounters a completed Okazaki fragment discount plavix hypertension causes and treatment, at which point it releases the lagging strand. In eukaryotic cells, genome replication must be coordinated with the cell cycle so that two copies of the entire genome are available when the cell divides. The cell cycle is a four-stage process that is based upon microscopic observations of dividing cells (Figure 1. These observations showed that dividing cells pass through repeated cycles of metaphase, when nuclear and cell division occurs, and interphase, where few changes can be detected using a microscope. The eukaryotic cell cycle is split into cell division (mitosis) and the period between divisions (interphase). These are termed checkpoint controls • G2-phase (Gap 2) – the second interval period. A human cell in culture takes about 20 hours to progress through one complete cell cycle. Of this, over 9 h will be spent in G1, while S-phase takes about 8 h to complete, and G2 lasts about 2 h. Clearly, it is important that the S- and M-phases are coordinated so that the genome is completely replicated once, but only once, before cell division occurs. The periods immediately before entry into S- and M-phases are the key cell-cycle checkpoints. Lee Hartwell, Paul Nurse and Tim Hunt were awarded the 2001 Nobel Prize in Physiology or Medicine for their discoveries of key regulators of the eukaryotic cell cycle. It is constantly changing, and one mechanism by which this change is brought about is recombination. Cells containing a diploid set of chromosomes have plenty of opportunities to find a homologous partner for recombination to occur. Recombination in a bacterial system was first demonstrated independently by Alfred Hershey and Max Delbru¨ ckin1947. Several mechanisms have been proposed to explain the molecular basis of these events. The key to understanding the molecular processes involved in recombination was first articulated in 1964 by Robin Holliday (Holliday, 1964). The formation of the Holliday junction and its resolution, together with some of the E. The same process outlined above also takes place in eukary- otes, using similar kinds of enzymatic activity. Recently, the high-resolution structure of the Holliday junction stabilized by the RuvA protein has been solved (Hargreaves et al. This site-specific recombination still requires the base pairing of a short homologous region (the attP with the attB sites), but does not involve any of the proteins of the homologous recombination pathways. The complement of proteins within a particular cell type is distinctive – a hair follicle will produce keratin and a pancreatic β-cell will produce insulin – but the protein content of a cell can also change dramatically depending upon, for example, the availability of nutrients. This means that in certain cell types, certain genes will be expressed and others will not, and the cell must have the ability to activate certain genes in response to external signals. How is the cell able to discern within its genome what is a gene and what is not, and how is the cell able to turn a particular gene on while at the same time not affecting the expression of other genes? In its broadest terms a gene may be considered as a unit of heredity composed of nucleic acid. In classical genetics, a gene is described as a discrete part of a chromosome that determines a particular characteristic. Thus a gene is not just the coding sequence itself, but contains the information required for the expression of that coding sequence. The sequence in between will either directly code for the protein (prokaryotes) or be split into a series of exons and introns (eukaryotes). When combined, the coding portions of the gene and these promoter and terminator sequences form the functional gene, sometimes referred to as a ‘transcriptional unit’. How many genes are present within a genome, how many genes are essential to the cell and how many are expressed at one time? The advent of completely sequenced genomes (Chapter 9) has allowed us to address, at least in part, some of these questions. The yeast Saccharomyces cerevisiae, a single-cell eukaryote, has a larger genome size (13. Humans, on the other hand have a genome that is almost 250-fold larger that of yeast (at 3300 Mb) but may have as few as 30 000 genes – representing an increase of only fivefold. To determine whether a gene is essential for the organism, the function of the gene must be impaired in some way. This is usually achieved by gene knockouts,wherethegene is removed from the genome and its effects on cell viability determined. Many apparently non-essential genes may play specialist roles under conditions not examined in this type of experiment (nutrient starvation for example). The apparently low percentage of essential genes, however, may reflect a functional degeneracy among certain sets of genes. Some of the genes expressed in a liver cell must be different to those expressed in a skin cell. Genome-wide analysis of the expression of all genes within fully sequenced organisms such as yeast suggests that about 90% of genes are expressed at any one time, but 80% of these are expressed with very low abundance levels – in the order of 0. Highly abundant proteins are produced from highly expressed genes, whilst other proteins that may be present at a much lower level (e. There are fundamental differences in the ways in which genes are transcribed in prokaryotes and eukaryotes. Many of the experiments we will look at in later chapters involve the use of eukaryotic cells, but the bacterium E. Initiation of transcription usually occurs to the 3 side of the promoter, and termination occurs at specific sites downstream of the coding sequence of the gene. At first glance, the overall architecture of a typical prokaryotic gene and a typical eukaryotic gene may appear to be similar (Figure 1. However, the controlling region for eukaryotic genes will not function in a prokaryotic cell, and vice versa. Therefore, eukaryotic genes are transcriptionally inactive in the absence of other factors. In both prokaryotes and eukaryotes, transcrip- tion is a highly regulated process. Proper timing and levels of gene expression are essential to almost all cellular processes. When the bacterium is in an environment that contains lactose as the sugar source it expresses the following structural genes. Inorderto metabolize lactose, the structural genes must be expressed and the protein products produced.
Posteriorly 75mg plavix with amex pulse pressure greater than 40, the inferior colliculi are separated by the periaqueductal gray matter surrounding the cerebral aqueduct (Fig purchase plavix 75 mg with mastercard arteria intestinalis. Anteriorly is Middle Part of Pons located the cerebral peduncle discount plavix online amex blood pressure chart pregnant, which, from pos- This section is at the midpontine level where the terior to anterior, consists of the tegmentum, trigeminal nerve attaches (Fig. The large its size and shape may vary, the basilar part of the interpeduncular fossa is between the cerebral pons appears similar at all pontine levels. The supe- Posteriorly, the superior colliculi are partially rior cerebellar peduncles are in the roof of the separated by the periaqueductal gray matter and fourth ventricle. Anteriorly, the cere- bral peduncle is composed of the tegmentum, Rostral Part of Pons substantia nigra, and cerebral crus. Cerebral aqueduct Inferior colliculus Tectum Periaqueductal gray matter Reticular Formation Tegmentum Cerebral peduncle Substantia nigra Cerebral crus Interpeduncular fossa Figure 3-12 Transverse section at the level of the caudal midbrain. Chapter 3 Brainstem: Topography and Functional Levels 37 Superior colliculus Cerebral aqueduct Tectum Reticular Formation Periaqueductal gray matter Oculomotor nucleus Cerebral Tegmentum peduncle Substantia nigra Cerebral crus Interpeduncular fossa Figure 3-13 Transverse section at the level of the rostral midbrain. Motor and sensory structures in the foor of the dorsal surface of the (a) closed of the fourth ventricle are separated medulla, (b) open medulla, (c) pons, and by the: (d) midbrain? Immediately posterior to the inferior innervates skeletal muscle on the opposite cerebellar peduncle as it arches dorsally side of the body is the: into the cerebellum is the: a. Forebrain lesions may also affect sensory perception and voluntary movements as well as memory, judgment, and speech. The most common vascular lesions in the entire nervous system are “capsular strokes” that occur deep within the forebrain. The forebrain or prosencephalon consists of the It is oriented almost perpendicularly to the brain- telencephalon, the paired cerebral hemispheres, stem and spinal cord (Figs. The diencephalon con- change in direction occurs at the junction between tains functional centers for the integration of all the midbrain and forebrain, and at this junction, information passing from the brainstem and spi- there is a change in directional terms. In descrip- nal cord to the cerebral hemispheres as well as the tions of the spinal cord and brainstem, the terms integration of motor and visceral activities. The anterior or ventral indicate toward the front of the two cerebral hemispheres integrate the highest body, and the terms posterior or dorsal mean toward mental functions such as the awareness of sensa- the back. Moreover, superior or rostral indicates tions and emotions, learning and memory, intel- higher or toward the top or above, and inferior or ligence and creativity, and language. The diencephalon contains Anterior—toward the front of the skull the third ventricle, and the cerebral hemispheres Posterior—toward the back of the skull contain the lateral ventricles, which are sepa- Ventral or inferior—toward the base of the skull rated from each other in part by the septum pel- Dorsal or superior—toward the top of the skull lucidum (Figs. The midbrain, hindbrain, and spinal cord (stipples) are oriented almost vertically, whereas the forebrain is oriented horizontally. Because of this change in orientation at the midbrain-forebrain junction, the terms dorsal and ventral have different connotations rostral and caudal to this junction. The hypothalamic sulcus traverses the from the medial part of the thalamus to the lateral wall of the third ventricle from the inter- base of the brain; the subthalamus, ventral to ventricular foramen to the cerebral aqueduct and the lateral part of the thalamus and lateral to separates the thalamus, above, from the hypo- the hypothalamus, but not reaching the surface thalamus, below. Chapter 4 Forebrain: Topography and Functional Levels 41 Anterior tubercle Interthalamic adhesion Corpus Callosum (trunk) Septum Posterior (genu) Anterior pelludicum (splenium) Medullary stria (rostrum) of thalamus Habenula Interventricular foramen Pineal Epithalamus Anterior commissure gland Hypothalamic sulcus Pulvinar Lamina terminalis C T M Superior Colliculi Inferior Hypothalamus Cerebral C-Chiasmatic peduncle Cerebral T-Tuberal Regions aqueduct M-Mamillary Optic nerve Cerebellum Optic chiasm Fourth Mamillary ventricle Infundibulum body Oculomotor nerve Medulla Figure 4-2 Median view of right diencephalon and adjacent parts of the brainstem and cerebral hemisphere. Hypothalamus Thalamus The only subdivision of the diencephalon on The thalami are two egg-shaped masses bor- the ventral surface of the brain is the hypothala- dering the third ventricle, dorsal to the hypo- mus (Fig. The hypothalamus is sub- the third ventricle by the interthalamic adhe- divided into three main areas in the antero- sion or massa intermedia. Positioned posteriorly is the lar foramen is a swelling, the anterior tubercle, mamillary region, which is related to the mamil- and on the dorsomedial surface of the thala- lary bodies, paired spherical masses about the mus is a bundle of fbers, the medullary stria. Between the mamillary and the chias- Thalamic Nuclei matic regions is the tuber cinereum after which the tuberal region is named. The anterior part of The thalamus consists of a large number of nuclei the tuberal region contains the infundibulum that form eight nuclear masses named according or stalk of the pituitary gland and is sometimes to their anatomic locations (Fig. The anterior subdivision is located at the area ventral to the thalamus and lateral to the anterior tubercle of the thalamus and consists of hypothalamus. The medial subdivision most prominent of which is the subthalamic chiefy includes a large medial dorsal nucleus nucleus. On the undersurface The right and left cerebral hemispheres consist of the pulvinar are the metathalamic nuclei, the of cortical, medullary, and nuclear parts. Embedded deeply medullary lamina is the reticular (R) nucleus, a in the white matter are the telencephalic nuclei, thin nucleus forming the most lateral part of the the most prominent of which are the caudate thalamus. Chapter 4 Forebrain: Topography and Functional Levels 43 Lateral Surface of a boxing glove, and its most anterior part is called the temporal pole. The occipital lobe is demarcated most uniform and prominent cleft on the lateral from the parietal and temporal lobes by an imagi- surface of the hemisphere is the lateral sulcus or nary line between the parieto-occipital sulcus and fssure of Sylvius, which begins at the base of the preoccipital notch. The occipital pole is the the brain, extends to the lateral surface of the most posterior part of the cerebral hemisphere. It separates the frontal and parietal lobes (superiorly) from the temporal lobe (infe- Medial Surface riorly). The next most uniform and prominent cleft is the central sulcus or fssure of Rolando, The medial surfaces of the hemispheres (Fig. The ante- losal and cingulate, and the vertically oriented rior and posterior walls of the central sulcus are parieto-occipital sulcus. The callosal sulcus is formed by the precentral and postcentral gyri, dorsal to the corpus callosum, the huge mass of respectively. The frontal lobe extends anteriorly from the The cingulate sulcus encircles the cingulate gyrus, central sulcus to the anterior tip of the hemi- which is dorsal to the callosal sulcus. The parietal lobe occipital sulcus, located a short distance posterior is superior to the lateral fssure and behind the to the corpus callosum, separates the parietal and central sulcus. It is shaped like the thumb medial surface of the hemisphere in the posterior Central sulcus Frontal lobe Parieto-occipital sulcus Frontal pole Occipital pole Occipital Lateral fissure lobe Temporal lobe Temporal pole Preoccipital notch Figure 4-4 Lateral view of left hemisphere. Between the para- nucleus, which is lateral to the external medul- central lobule and the parieto-occipital sulcus is lary lamina. In the mid- and the underlying rostral part of the cerebral line, from ventral to dorsal, are the hypotha- peduncle (Fig. The level also includes parts lamic area between the mamillary bodies, the of the cerebral hemisphere: the corpus callosum, third ventricle, the interthalamic adhesion, lateral ventricles, and the caudate and lentiform and the corpus callosum. The caudate and lentiform nuclei are tel- ventricle are formed by the hypothalamus ven- encephalic nuclei. The thalamus As found in the midbrain sections, the mid- extends laterally to the internal capsule, a huge brain here also comprises, from anterior to pos- mass of hemispheric white matter or nerve terior, the cerebral crus, substantia nigra, and fbers. The most prominent thalamic nuclei are the hypothalamus medially, the thalamus dorsally, round, centrally located centromedian nucleus in the internal capsule laterally, and the cerebral the internal medullary lamina and the ventral crus ventrally is the subthalamus. The caudate nucleus the medial dorsal, lateral posterior, and reticular is found in the lateral wall of the lateral ventricle. More ventrally, lateral to the internal capsule, is the lentiform nucleus, which comprises two more Chapter Review medial segments, the globus pallidus, and a lateral Questions segment—the putamen. Which cranial nerves attach to the The tuberal level is at the anterior part of the forebrain, which to the midbrain, and thalamus and the surrounding cerebral hemi- which to the hindbrain?
Perioperative monitoring in high-risk infants after stage 1 palliation of univentricular congenital heart disease buy plavix cheap online blood pressure symptoms. This was performed in a group of patients that were listed for cardiac transplantation order plavix 75 mg without a prescription blood pressure chart diabetes. Cardiac catheterization after stage 1 palliation and prior to stage 2 palliation may be indicated for shunt stenosis discount plavix 75 mg without a prescription blood pressure guidelines chart, atrial septal defect enlargement or recurrent arch obstruction. Information obtained at catheterization would include the measurement of pulmonary artery pressure, pulmonary capillary wedge pressure, right ventricular systolic and diastolic pressures, and pressures in the ascending and descending aorta. The operators should be prepared to perform interventions as needed on the pulmonary arteries, atrial septum, and arch. In selected patients in whom clinical or anatomic concerns are absent by history, physical examination, and echocardiography, cardiac catheterization may not be necessary prior to stage 2 palliation (381). Indications may include excessive cyanosis that may be due to venovenous collateral or stenotic cavopulmonary connections or branch pulmonary artery stenoses. Catheter intervention for aortic arch narrowing occasionally may also be necessary after stage 2 palliation (249,360). Catheterization is routinely performed prior to the completion Fontan operation in many institutions. Important measurements to determine suitability of Fontan palliation include; pulmonary artery pressure, pulmonary capillary wedge pressure, and ventricular end-diastolic pressure. Cardiac catheterization following the Fontan operation may be necessary if there are anatomic or physiologic concerns not easily elucidated by noninvasive imaging techniques. Some centers routinely perform cardiac catheterization 6 to 12 months after the Fontan procedure with consideration for fenestration closure following hemodynamic assessment. In a report of five patients who underwent the Fontan operation with this technique, all returned home in 24 hours, however several patients required subsequent intervention for baffle leak (245). Late Fontan Concerns Staged palliation for single-ventricle physiology has undergone a series of surgical revisions that have reduced early postoperative Fontan mortality from 20% to less than 2% (391,392). Despite the significant morbidities associated with the Fontan operation, overall late mortality (range 4 months to 18 years) continues to decrease from 25% in the early experience to 5% in the recent era (392,393). Indications for successful Fontan have been modified from the initial “Ten Commandments” described by Choussat and Fontan. This list does specify physiologic risk factors for a failing Fontan that prevail and relate to ventricular performance, atrioventricular and aortic valve function, and pulmonary circulation (395). In addition, more complex anatomy that requires main pulmonary artery to ascending aorta anastomoses or ventricular septal defect enlargement, both indicators of ventricular outflow obstruction, has been identified as a risk factor for late morbidity. Ventricular Dysfunction Volume unloading provided by staged palliation results in reduction in ventricular size and wall thickness that, in turn, increases contractility and ventricular performance. Regardless of the early success with staged palliation, late ventricular dysfunction after the Fontan operation may ensue due to morphologic/structural features of the single right systemic ventricle, residual obstructive lesions, and/or atrioventricular valve insufficiency. The failing systemic ventricle after staged palliation can be attributed to systolic dysfunction, diastolic dysfunction, or both (396,398,399,400). Systolic dysfunction is characterized by reduced contractility and an ejection fraction of less than 50%. Diastolic dysfunction is more difficult to define, but is evident by increased ventricular end-diastolic pressure and the rate of ventricular relaxation (401,402). As a result, late ventricular dysfunction and subsequent failure of Fontan circulation become clinically evident with symptoms of lower functional class, exercise intolerance, dyspnea, fatigue, and syncope (403,404). Hypoxemia Slight hypoxemia with SaO in the low 90s is common after Fontan completion even when residual atrial-level2 shunts (fenestrations) are absent (380,395). This desaturation is thought to result from coronary sinus blood return to the pulmonary venous atrium, and/or ventilation/perfusion imbalances within the lung. Desaturation also commonly occurs in patients with residual anatomic shunts such as a persistent atrial-level shunt (fenestration) or acquired collateral circulation within the lung. Venovenous collaterals which drain directly into the left atrium or pulmonary venous circulation can also serve as a source of arterial desaturation after Fontan palliation. The collateral circulation that forms after Fontan palliation plays no role in gas exchange, produces right-to-left intrapulmonary shunts and might contribute to progressive ventricular dysfunction as a source of chronic volume overload (405). Hence, the impact intrapulmonary collateral circulation on oxygen saturation is variable but is often most pronounced in the presence of progressive ventricular dysfunction. This elevation in abdominal venous pressures presumably leads to intestinal congestion, lymphatic obstruction, and enteric protein loss (409). Diastolic dysfunction, as mentioned previously, that results in low cardiac output in the face of elevated venous pressures, or even with venous pressures considered normal for Fontan physiology (<15 mm Hg), predisposes the patient to mesenteric ischemia and subsequent intestinal mucosal injury leading to the onset of enteric protein losses (395,409). If the above therapies prove unsuccessful, cardiac transplantation can be offered. They suggested that budesonide resulted in an improvement of serum albumin within 6 months and that low-dose therapy must be continued in order to result in a sustained effect. They credit improved survival to a systematic multipronged approach including medical-, surgical-, interventional catheter–based and noncardiac disease management (415). Thromboembolism Patients with Fontan circulation have a life-long risk of thromboembolic complications, particularly stroke and pulmonary embolism. In a large series by Coon, the reported prevalence of thrombus formation as detected by transthoracic echocardiography was 8. In smaller series, the diagnosis of thrombus formation was more common with transesophageal echo with a reported prevalence of 17% to 30% (418). The high rate of thrombus formation is postulated to be predominately secondary to venous stasis and impaired cardiac output that is inherent to single-ventricle circulation. No difference has been observed in patients who received a lateral tunnel or atriopulmonary Fontan (417). Several studies report the presence of arrhythmias at the time of thrombus detection (417,418,419,420). Finally, liver dysfunction and coagulation factor deficiency, particularly protein C deficiency, have been identified in patients thought to have good outcomes after the Fontan operation, however appear to be time-related phenomena that resolve over time (421,422). The optimal anticoagulation regimen for the patient after the Fontan operation is still unclear and is the subject of current ongoing investigation. Arrhythmias Late atrial arrhythmias have a reported incidence of 10% to 45% in patients with Fontan physiology (393,395,402,403,423). Sinus node dysfunction, the presence of atrial suture lines, and increased atrial pressure have all been implicated in the etiology of late arrhythmias. In recent years, the surgical approach for the Fontan has been modified from the lateral tunnel to the extracardiac Fontan with the goal of reducing the incidence of atrial arrhythmias. The extracardiac Fontan has theoretic advantages in achieving this objective as this approach minimizes atrial suture lines and lessens the atrial hypertension that is expected with the lateral tunnel Fontan. Several series have reported this outcome with a decrease incidence of atrial tachyarrhythmias or pacemaker insertion for sinus node dysfunction in patients who underwent the extracardiac Fontan when compared to those patients subjected to the lateral tunnel Fontan (371,424,425). Conversely, Cohen reported no early benefit with either approach early after the Fontan operation (373). Actuarial survival of patients who underwent transplant at 1 month, 1, 5, and 7 years was 91%, 84%, 76%, and 70%, respectively. This actuarial survival did not take into account the group of patients that died prior to an available donor heart.
Carvedilol for children and adolescents with heart failure: a randomized controlled trial discount plavix online visa hypertension 24. Use of extracorporeal life support as a bridge to pediatric cardiac transplantation 75mg plavix with mastercard hypertension numbers. Outcomes of children bridged to heart transplantation with ventricular assist devices: a multi-institutional study effective plavix 75 mg blood pressure 40. Long-term follow-up of pediatric cardiac patients requiring mechanical circulatory support. Use of extracorporeal membrane oxygenation in pediatric thoracic organ transplantation. Circulatory support with pneumatic paracorporeal ventricular assist device in infants and children. Biventricular assist devices as a bridge to heart transplantation in small children. Pneumatic paracorporeal ventricular assist device in infants and children: initial Stanford experience. 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The use of advanced-age donor hearts adversely affects survival in pediatric heart transplantation. Outcomes of heart transplantation using donor hearts from infants with sudden infant death syndrome. Potential suitability for transplantation of hearts from human non-heart-beating donors: data review from the Gift of Life Donor Program. Elective extracorporeal membrane oxygenation bridge to recovery in otherwise “unusable” donor hearts for children: preliminary outcomes. Does duration of donor brain injury affect outcome after orthotopic pediatric heart transplantation? Successful outcome with extended allograft ischemic time in pediatric heart transplantation. Report from a consensus conference on primary graft dysfunction after cardiac transplantation. Risk factors for primary graft failure after pediatric cardiac transplantation: importance of recipient and donor characteristics. Pediatric heart transplantation in human leukocyte antigen sensitized patients: evolving management and assessment of intermediate-term outcomes in a high- risk population. Report from a consensus conference on the sensitized patient awaiting heart transplantation. The long-term outcome of treated sensitized patients who undergo heart transplantation. Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease. Pre- and posttransplantation allosensitization in heart allograft recipients: major impact of de novo alloantibody production on allograft survival. Trends and outcomes in transplantation for complex congenital heart disease: 1984 to 2004. Cardiac transplantation in pediatric patients: fifteen-year experience of a single center. Heart transplantation to a physiologic single lung in patients with congenital heart disease. Evidence of pulmonary vascular disease after heart transplantation for Fontan circulation failure. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. Perioperative management in pediatric heart transplantation from 1988 to 2001: anesthetic experience in a single center. Renal insufficiency and end-stage renal disease in the heart transplant population. Donor-recipient size matching in pediatric heart transplantation: a word of caution about small grafts. Sinus node dysfunction after orthotopic cardiac transplantation: postoperative incidence and long-term implications. Anti-T-cell-antibody prophylaxis in children: success with a novel combination strategy of mycophenolate mofetil and antithymocyte serum. Infection and malignancy after pediatric heart transplantation: the role of induction therapy. Calcineurin inhibitor minimization using sirolimus leads to improved renal function in pediatric heart transplant recipients. Empiric switch from calcineurin inhibitor to sirolimus-based immunosuppression in pediatric heart transplantation recipients. Decline in rejection in the first year after pediatric cardiac transplantation: a multi-institutional study. The current state of, and future prospects for, cardiac transplantation in children. Infection after pediatric heart transplantation: results of a multiinstitutional study. Trends in invasive disease due to Candida species following heart and lung transplantation. Noninvasive markers for acute heart transplant rejection in children with the use of automatic border detection. Prospective evaluation of echocardiography for primary rejection surveillance after infant heart transplantation: comparison with endomyocardial biopsy. Diastolic performance assessed by tissue Doppler after pediatric heart transplantation.
