Inferior Outcomes on the Waiting List in Low-Volume Pediatric Heart Transplant Centers.

Low case volume has been associated with poor outcomes in a wide spectrum of procedures. Our objective was to study the association of low case volume and worse outcomes in pediatric heart transplant centers, taking the novel approach of including waitlist outcomes in the analysis. We studied a cohort of 6482 candidates listed in the Organ Procurement and Transplantation Network for pediatric heart transplantation between 2002 and 2014; 4665 (72%) of the candidates underwent transplantation. Candidates were divided into groups according to the average annual transplantation volume of the listing center during the study period: more than 10, six to 10, three to five, or fewer than three transplantations. We used multivariate Cox regression analysis to identify independent risk factors for waitlist and posttransplantation mortality. Of the 6482 candidates, 24% were listed in low-volume centers (fewer than three annual transplantations). Of these listed candidates in low-volume centers, only 36% received a transplant versus 89% in high-volume centers (more than 10 annual transplantations) (p < 0.001). Listing at a low-volume center was the most significant risk factor for waitlist death (hazard ratio [HR] 4.5, 95% confidence interval [CI] 3.5-5.7 in multivariate Cox regression and HR 5.6, CI 4.4-7.3 in multivariate competing risk regression) and was significant for posttransplantation death (HR 1.27, 95% CI 1.0-1.6 in multivariate Cox regression). During the study period, one-fourth of pediatric transplant candidates were listed in low-volume transplant centers. These children had a limited transplantation rate and a much greater risk of dying while on the waitlist.

Neogenin, an avian cell surface protein expressed during terminal neuronal differentiation, is closely related to the human tumor suppressor molecule deleted in colorectal cancer.

Using a monoclonal antibody, we have identified and characterized a previously unknown cell surface protein in chicken that we call neogenin and have determined its primary sequence. The deduced amino acid sequence and structure of neogenin characterize it as a member of the immunoglobulin (Ig) superfamily. Based on amino acid sequence similarities, neogenin is closely related to the human tumor suppressor molecule DCC (deleted in colorectal cancer). Neogenin and DCC define a subgroup of Ig superfamily proteins structurally distinct from other Ig molecules such as N-CAM, Ng-CAM, and Bravo/Nr-CAM. As revealed by antibody staining of tissue sections and Western blots, neogenin expression correlates with the onset of neuronal differentiation. Neogenin is also found on cells in the lower gastrointestinal tract of embryonic chickens. DCC has been observed in human neural tissues and has been shown to be essential for terminal differentiation of specific cell types in the adult human colon. These parallels suggest that neogenin, like DCC, is functionally involved in the transition from cell proliferation to terminal differentiation of specific cell types. Since neogenin is expressed on growing neurites and downregulated at termination of neurite growth, it may also play an important role in many of the complex functional aspects of neurite extension and intercellular signaling.

New immunolatex spheres: visual markers of antigens on lymphocytes for scanning electron microscopy.

New immunochemical reagents consisting of antibodies bound to small latex spheres were used as visual markers for the detection and localization of cell surface antigens by scanning electron microscopy. Cross-linked latex spheres of various sizes from 300 to 3,4000 A in diameter were synthesized by aqueous emulsion copolymerization of methacrylate derivatives containing hydroxyl and carboxyl functional groups. Proteins and other molecules containing primary amino groups were covalently bonded to the acrylic spheres under a variety of mild conditions by the aqueous carbodiimide, cyanogen bromide, and glutaraldehyde methods. For use in the indirect immunochemical-labeling technique, goat antibodies directed against rabbit immunoglobulins were bonded to the spheres. These immunolatex reagents were shown to bind only to cells (red blood and lymphocytes) which had previously been sensitized with rabbit antibodies against cell surface antigens. Mouse spleen lymphocytes with exposed immunoglobulins on their surface (B cells) were labeled with these spheres and distinguished from unlabeled or T lymphocytes by scanning electron microscopy. The distribution of Ig receptors on lymphocytes was also studied using the spheres as visual markers. When lymphocytes were fixed with glutaraldehyde and subsequently labeled with the immunolatex reagents, a random distribution was observed by scanning electron microscopy; a patchy distribution was observed when unfixed lymphocytes were used. These results are consistent with studies using ferritin-labeled antibodies (S. De Petris and M. Raff. 1973. Nature [Lond.]. 241:257.) and support the view that Ig receptors on lymphocytes undergo translational diffusion. In addition to serving as visual markers for scanning electron microscopy, these latex spheres tagged with fluorescent or radioactive molecules have applications as highly sensitive markers for fluorescent microscopy and as reagents for quantitative studies of cell surface antigens and other receptors.

Bravo/Nr-CAM is closely related to the cell adhesion molecules L1 and Ng-CAM and has a similar heterodimer structure.

Diverse cell-surface molecules of the nervous system play an important role in specifying cell interactions during development. Using a method designed to generate mAbs against neural surface molecules of defined molecular weight, we have previously reported on the surface protein, Bravo, found in the developing avian retinotectal system. Bravo is immunologically detected on developing optic fibers in the retina, but absent from distal regions of the same fibers in the tectum. We have isolated cDNA clones encompassing the entire coding region of Bravo, including clones containing five alternative sequences of cDNA. These putative alternatively spliced sequences encode stretches of polypeptide ranging in length from 10-93 amino acids and are predicted to be both extra- and intracellular. The deduced primary structure of Bravo reveals that, like the cell adhesion molecules (CAMs) chicken Ng-CAM and mouse L1, Bravo is composed of six Ig-like domains, five fibronectin type III repeats, a transmembrane domain, and a short cytoplasmic region. Recently, the cDNA sequence of a related molecule, Nr-CAM, was reported and its possible identity with Bravo discussed (Grumet, M., V. Mauro, M. P. Burgoon, G. E. Edelman, and B. A. Cunningham. 1991. J. Cell Biol. 113:1399-1412). Here we confirm this identity and moreover show that Bravo is found on Müller glial processes and end-feet in the developing retina. In contrast to the single polypeptide chain structure of Nr-CAM reported previously, we show that Bravo has a heterodimer structure composed of an alpha chain of M(r) 140/130 and a beta chain of 60-80 kD. As with L1 and Ng-CAM, the two chains of Bravo are generated from an intact polypeptide by cleavage at identical locations and conserved sites within all three molecules (Ser-Arg/Lys-Arg). The similar domain composition and heterodimer structure, as well as the 40% amino acid sequence identity of these molecules, defines them as an evolutionarily related subgroup of CAMs. The relationship of Bravo to molecules known to be involved in cell adhesion and process outgrowth, combined with its pattern of expression and numerous potential isoforms, suggests a complex role for this molecule in cell interactions during neural development.

Topologically restricted appearance in the developing chick retinotectal system of Bravo, a neural surface protein: experimental modulation by environmental cues.

A novel neural surface protein, Bravo, shows a pattern of topological restriction in the embryonic chick retinotectal system. Bravo is present on the developing optic fibers in the retina; however, retinal axons in the tectum do not display Bravo. The appearance of Bravo in vitro is modulated by environmental cues. Axons growing out from retinal explants on retinal basal lamina, their natural substrate, express Bravo, whereas such axons growing on collagen do not. Retinal explants provide a valuable system to characterize the mechanism of Bravo restriction, as well as the cellular signals controlling it. Bravo was identified with monoclonal antibodies from a collection generated against exposed molecules isolated by using a selective cell surface biotinylation procedure. The NH2-terminal sequence of Bravo shows similarity with L1, a neural surface molecule which is a member of the immunoglobulin superfamily. This possible relationship to L1, together with its restricted appearance, suggests an involvement of Bravo in axonal growth and guidance.

Binding between the neural cell adhesion molecules axonin-1 and Nr-CAM/Bravo is involved in neuron-glia interaction.

Neural cell adhesion molecules of the immunoglobulin superfamily mediate cellular interactions via homophilic binding to identical molecules and heterophilic binding to other family members or structurally unrelated cell-surface glycoproteins. Here we report on an interaction between axonin-1 and Nr-CAM/Bravo. In search for novel ligands of axonin-1, fluorescent polystyrene microspheres conjugated with axonin-1 were found to bind to peripheral glial cells from dorsal root ganglia. By antibody blockage experiments an axonin-1 receptor on the glial cells was identified as Nr-CAM. The specificity of the interaction was confirmed with binding studies using purified axonin-1 and Nr-CAM. In cultures of dissociated dorsal root ganglia antibodies against axonin-1 and Nr-CAM perturbed the formation of contacts between neurites and peripheral glial cells. Together, these results implicate a binding between axonin-1 of the neuritic and Nr-CAM of the glial cell membrane in the early phase of axon ensheathment in the peripheral nervous system.

A direct interaction of axonin-1 with NgCAM-related cell adhesion molecule (NrCAM) results in guidance, but not growth of commissural axons.

An interaction of growth cone axonin-1 with the floor-plate NgCAM-related cell adhesion molecule (NrCAM) was shown to play a crucial role in commissural axon guidance across the midline of the spinal cord. We now provide evidence that axonin-1 mediates a guidance signal without promoting axon elongation. In an in vitro assay, commissural axons grew preferentially on stripes coated with a mixture of NrCAM and NgCAM. This preference was abolished in the presence of anti-axonin-1 antibodies without a decrease in neurite length. Consistent with these findings, commissural axons in vivo only fail to extend along the longitudinal axis when both NrCAM and NgCAM interactions, but not when axonin-1 and NrCAM or axonin-1 and NgCAM interactions, are perturbed. Thus, we conclude that axonin-1 is involved in guidance of commissural axons without promoting their growth.

Immunomicrospheres: reagents for cell labeling and separation.

Immunomicrospheres are specially designed microscopic particles that have antibodies or similar molecules chemically bound to their surfaces. The antibody-coated microspheres react in a highly specific way with target cells, viruses, or other antigenic agents. Immunomicropheres may be synthesized so that they incorporate compounds that are highly radioactive, intensely fluorescent, magnetic, electron opaque, highly colored, or pharmacologically active. These various types of microspheres may be coated with pure, highly specific monoclonal antibodies obtained by the new hybridoma cell cloning techniques or with conventional antibody preparations. Some of the many present and potential applications for these new reagents are (i) new types of radioimmune or immunofluorescent assays, (ii) improved fluorescence microscopy, (iii) separation of cells on the basis of the fluorescent, electrophoretic, or magnetic properties of bound immunomicrospheres, (iv) markers for use in several types of electron or standard light microscopy, and (v) delivery of lethal compounds to specific undesirable living cells. The combination of the various new types of synthetic microspheres and the newly available homogeneous antibodies offers new opportunities in research, diagnosis, and therapy.

Mechanism of Antibody Synthesis: Size Differences between Mouse Kappa Chains.

In the report "Mechanism of antibody synthesis: size differences between mouse kappa chains" by W. R. Gray et al. (27 Jan., p. 465), the headings of the final two columns of Table 1 should be reversed to read "Transversions" and "Transitions."

Mechanism of antibody synthesis: size differences between mouse kappa chains.

Structural analysis of immunoglobulin light chains has been carried out in an attempt to elucidate the genetic mechanisms involved in antibody synthesis. Analysis of two mouse kappa-chain proteins is almost complete. The differences are localized in one-half of the molecules, and do not reflect the operation of any one mutational mechanism. The peculiar character of the differences is discussed with reference to various theories of antibody formation. The finding that the two proteins differ in size is incompatible with certain proposed theories.

Neutrophil adherence to isolated adult canine myocytes. Evidence for a CD18-dependent mechanism.

Cardiac myocytes were isolated from adult dogs and incubated with isolated canine neutrophils (PMN). Intercellular adhesion was low and unchanged by stimulation of the PMN with zymosan activated serum or platelet activating factor (PAF) at concentrations that significantly enhance PMN adhesion to protein-coated glass and canine endothelial cell monolayers. Intercellular adhesion was significantly increased only when both myocytes and PMN were stimulated (e.g., myocytes incubated with IL-1, tumor necrosis factor, or phorbol myristate acetate, and PMN were chemotactically stimulated). Inhibitors of protein synthesis diminished the IL-1 beta-induced effect by greater than 80%. The IL-1 beta, PAF-stimulated PMN-myocyte adhesion was associated with substantial H2O2 production. Under conditions with low PMN-myocyte adhesion (i.e., IL-1 beta alone, PAF alone, or no stimulus) H2O2 production was generally less than 5% of that occurring with high adhesion. An anti-CD18 monoclonal antibody (R15.7) inhibited stimulated PMN-myocyte adhesion by greater than 95% and reduced H2O2 production by greater than 90%. Control isotype-matched, binding, and nonbinding antibodies were without effect on adherence or H2O2 production. The results indicate that cytokine stimulation of adult myocytes induces expression of a ligand involved in CD18-dependent adherence of canine neutrophils.

Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome.

BACKGROUND: Mutations in the gene G4.5 result in a wide spectrum of severe infantile cardiomyopathic phenotypes, including isolated left ventricular noncompaction (LVNC), as well as Barth syndrome (BTHS) with dilated cardiomyopathy (DCM). The purpose of this study was to investigate patients with LVNC or BTHS for mutations in G4.5 or other novel genes. METHODS AND RESULTS: DNA was isolated from 2 families and 3 individuals with isolated LVNC or LVNC with congenital heart disease (CHD), as well as 4 families with BTHS associated with LVNC or DCM, and screened for mutations by single-strand DNA conformation polymorphism analysis and DNA sequencing. In 1 family with LVNC and CHD, a C-->T mutation was identified at nucleotide 362 of alpha-dystrobrevin, changing a proline to leucine (P121L). Mutations in G4.5 were identified in 2 families with isolated LVNC: a missense mutation in exon 4 (C118R) in 1 and a splice donor mutation (IVS10+2T-->A) in intron 10 in the other. In a family with cardiomyopathies ranging from BTHS or fatal infantile cardiomyopathy to asymptomatic DCM, a splice acceptor mutation in exon 2 of G4.5 (398-2 A-->G) was identified, and a 1-bp deletion in exon 2 of G4.5, resulting in a stop codon after amino acid 41, was identified in a sporadic case of BTHS. CONCLUSIONS: These data demonstrate genetic heterogeneity in LVNC, with mutation of a novel gene, alpha-dystrobrevin, identified in LVNC associated with CHD. In addition, these results confirm that mutations in G4.5 result in a wide phenotypic spectrum of cardiomyopathies.

Rapid ventricular pacing in dogs with right ventricular outflow tract obstruction: insights into a mechanism of sudden death in postoperative tetralogy of Fallot.

OBJECTIVES: We explored the hypothesis that residual outflow tract obstruction and ventricular hypertrophy associated with rapid ventricular rhythm contribute to sudden death, in part because they result in humoral or hemodynamic changes that predispose to ventricular fibrillation, such as increased catecholamine release or decreased coronary flow, or both. BACKGROUND: Ventricular arrhythmia after surgical repair of tetralogy of Fallot has been associated with sudden death, particularly in patients with residual right ventricular hypertension. However, the mechanisms by which sudden death occurs remain unclear. METHODS: Seven awake, unanesthetized mature beagles with chronically elevated right ventricular pressure (high pressure group: right ventricular/left ventricular systolic pressure ratio > 0.5) were compared with six beagles with low right ventricular pressure at rest and at the end of 5 min of ventricular pacing at 240 beats/min (low pressure group). RESULTS: In the high pressure group, cardiac output decreased during ventricular pacing (compared with sinus rhythm) from 304 +/- 21 to 218 +/- 21 ml/min per kg (p < 0.01) and plasma norepinephrine increased substantially from 673 +/- 64 to 1,047 +/- 92 pg/ml (p < 0.01). Comparable changes were not observed in the low pressure group. Plasma epinephrine levels were similar in both groups at rest and did not change with pacing. Postpacing norepinephrine levels from both groups correlated positively with both right ventricular systolic and diastolic pressure at rest and correlated negatively with the change in cardiac output from rest to pacing. Regional right ventricular myocardial blood flow increased with pacing in the low pressure group, whereas in the high pressure group it was increased at rest and did not increase further with pacing. CONCLUSION: During ventricular pacing, dogs with right ventricular outflow tract obstruction and high right ventricular pressure had a decrease in cardiac output and an increase in plasma norepinephrine, coupled with a loss of right ventricular myocardial blood flow reserve. Similar changes may occur in postoperative patients with similar hemodynamics and tachyarrhythmia and could contribute to the occurrence of ventricular fibrillation and sudden death.

Neutrophil activation and adhesion molecule expression in a canine model of open heart surgery with cardiopulmonary bypass.

OBJECTIVE: The aim was to determine whether, in a canine model, changes in surface expression of the neutrophil adhesion molecules CD11b/CD18 and L-selectin during and after open heart surgery with cardiopulmonary bypass can be used to identify subjects at risk for postoperative pulmonary dysfunction. METHODS: Adult mixed breed dogs underwent cardiopulmonary bypass and were compared to "sham bypass" controls. Flow cytometry was performed on blood from the two groups of dogs and changes in CD11b/CD18 adhesion molecules and L-selectin were investigated. RESULTS: Flow cytometry on blood from bypass dogs showed increased CD18 expression during and after cardiopulmonary bypass and a reciprocal decrease in L-selectin expression. Sham animals showed no significant change. In the bypass animals, changes in adhesion molecule expression were not evenly distributed across the population of circulating neutrophils; however, they were indicative of a percentage of activated cells. There was a significant negative linear relationship between the percentage of activated cells and arterial oxygenation 3 h after bypass (r = -0.80, P < 0.001). From this analysis, 11 animals were identified as "high" responders and seven as "low" responders, with different patterns of cellular activation and oxygenation during and after bypass. High responders had an average of 40(SEM 5)% activated cells during bypass with a persistently raised percentage of activated cells [38(3)%] 3 h later, whereas low responders had only 22(6)% activated cells during bypass and 11(2)% activated cells 3 h after bypass. High responder animals had a marked and continued deterioration in PO2 after bypass [to 25(6)% of baseline 3 h after bypass] whereas low responder animals showed recovery of oxygenation after the first hour postbypass and improved to 80(8)% of baseline at 3 h. CONCLUSIONS: Changes in adhesion molecule expression serve as a marker of neutrophil activation during cardiopulmonary bypass. The percentage of activated neutrophils in the circulation within 3 h after cardiopulmonary bypass may be predictive of an ongoing inflammatory process that is linked to pulmonary dysfunction.

Interleukin 6 induction in the canine myocardium after cardiopulmonary bypass.

OBJECTIVE: Interleukin 6 is a proinflammatory cytokine with a plasma concentration that has been noted to increase in response to cardiopulmonary bypass. The source of interleukin 6 after cardiopulmonary bypass is unknown. This study examined the myocardium as a potential source of interleukin 6 in this context. METHODS: Dogs underwent 90 minutes of hypothermic cardiopulmonary bypass with 60 minutes of cardioplegic arrest. After rewarming, they were reperfused with the chest open for either 3 (n = 4) or 6 (n = 4) hours, at the end of which myocardial samples were obtained. Four additional animals undergoing open thoracotomy without bypass served as time-matched controls. Northern blot analysis, reverse transcriptase-polymerase chain reaction, and in situ hybridization were used to examine the myocardium for the induction of interleukin 6 and intercellular adhesion molecule-1. RESULTS: Northern blot analysis and reverse transcriptase-polymerase chain reaction demonstrated a marked increase in myocardial interleukin 6 messenger RNA in 3 of 4 dogs at 3 hours after bypass and 3 of 4 dogs at 6 hours after bypass, which was not present in sham-bypass control animals. Northern blots at 3 hours after cardiopulmonary bypass also demonstrated myocardial intercellular adhesion molecule-1 induction. In situ hybridization studies confirmed that cardiac myocytes were a principal source of interleukin 6 messenger RNA early after cardiopulmonary bypass. Northern blots of messenger RNA extracted from isolated neutrophils and mononuclear leukocytes obtained from blood samples before bypass, at the end of bypass, and 3 hours after bypass failed to demonstrate interleukin 6 induction. CONCLUSION: Despite protection with cold cardioplegic arrest, the myocardium was a significant source of interleukin 6 synthesis after cardiopulmonary bypass. Local production of interleukin 6 may play a pivotal role in postoperative myocardial function.

Intercellular adhesion molecule-1 regulation in the canine lung after cardiopulmonary bypass.

OBJECTIVE(S): Neutrophil sequestration in the lung after cardiopulmonary bypass has been shown to be dependent on the adhesion molecule CD18. Thus we sought to determine whether endothelial expression of intercellular adhesion molecule-1 (a ligand for CD18) in pulmonary capillaries mediates neutrophil adhesion in this setting. METHODS: Seven adult mongrel dogs underwent 90 minutes of hypothermic cardiopulmonary bypass with 60 minutes of cardioplegic arrest. After warming, dogs were reperfused for up to 9 hours and lung biopsy specimens were obtained. Lung tissue was examined by Northern and Western blot analysis and by immunohistologic methods. Three sham-operated dogs served as time-matched controls. RESULTS: Northern blots demonstrated increased expression of intercellular adhesion molecule-1 messenger ribonucleic acid within 5 minutes of cessation of bypass (or approximately 30 minutes after aortic crossclamp release), which persisted at 9 hours of recovery and was not present in controls. Western blots showed intercellular adhesion molecule-1 protein expression before bypass but a measurable increase in intercellular adhesion molecule-1 protein in four of seven dogs in the bypass group by the ninth hour of recovery. Pulmonary neutrophil accumulation 9 hours after cardiopulmonary bypass was greater in those dogs with an increased intercellular adhesion molecule-1 protein expression. Immunoelectron microscopy demonstrated the pulmonary capillary endothelium capable of increased intercellular adhesion molecule-1 protein expression at the 9-hour time point. CONCLUSIONS: Cardiopulmonary bypass resulted in intercellular adhesion molecule-1 induction in the canine lung during recovery. An increased expression of intercellular adhesion molecule-1 protein in the lung was associated with an increased accumulation of neutrophils in affected animals. Thus intercellular adhesion molecule-1 expression may serve as a mechanism that predisposes the lungs to inflammatory cell-mediated injury postoperatively.

Long-term follow-up of arrhythmias in pediatric orthotopic heart transplant recipients: incidence and correlation with rejection.

BACKGROUND: Arrhythmias in adult orthotopic heart transplant (OHT) recipients are common and have been used as predictors of rejection. Because of the paucity of information in pediatric OHT recipients, the purpose of this study was to determine the incidence and correlation of arrhythmias with rejection or with coronary artery disease (CAD) in children. METHODS: We retrospectively reviewed the records, electrocardiograms (ECGs), and 24-hour ambulatory ECGs of patients who underwent OHT from January 1984 to December 1999. We excluded arrhythmias occurring in the first 2 weeks after OHT. RESULTS: Sixty-nine patients underwent OHT, received triple-immunosuppression therapy, were discharged home, and have been followed for a mean of 4.7 years (0.3-13 years). Each patient had an average of 10 ECGs and three 24-hour ECGs. Twenty-six patients had 33 arrhythmias: sinus bradycardia (n = 9), atrial tachycardia (n = 9), ventricular tachycardia (n = 3), and Wenckebach periodicity (n = 6). Sinus bradycardia was treated with theophylline in 8 patients, and 2 required pacemakers. Atrial tachycardias (atrial flutter in 4 patients and atrial ectopic tachycardia in 5) were treated with digoxin, propranolol, or procainamide. Ventricular tachycardia was treated with mexiletine, lidocaine, and amiodarone. There were 65 episodes of rejection, 20 of which were moderate/severe (> or =3B). Only Wenckebach was associated with the presence of either rejection or CAD (p < 0.05). CONCLUSIONS: We noted clinically significant arrhythmias in 38% of the pediatric OHT recipients. Sinus bradycardia, atrial tachyarrhythmias, and ventricular tachycardia occurred with the same frequency. Only new-onset Wenckebach periodicity was noted in the presence of either CAD or rejection. No arrhythmia was of negative predictive value for rejection or CAD. From this data, we suggest that new-onset Wenckebach prompt evaluation for rejection or CAD.

Immunology and embryogenesis: the chromosomal editing hypothesis.

We have elaborated the chromosomal editing hypothesis of development. This hypothesis, based on evolutionary arguments, states that the immune system must have evolved from pre-existent cell receptor systems on other tissues. Therefore we feel that what we know about development in the immune system can serve as a provisional model for studying development in other organ systems. The model predicts that specifically programmed somatic-genetic events occur as lineages develop. These DNA cutting and splicing events, similar to those which generate antibody molecules, generate a wide diversity of specific cell receptors which allow the cell to properly orient itself in the developing organism. In addition, the chromosomal editing events occur sequentially and generate a temporal organization so that developmental events occur in an orderly fashion as lineages develop. At any point in development, epigenetic factors play a crucial role in triggering cells to undergo specific differentiative events. We believe that this hypothesis explains the apparent contradiction between rigid mosaic development and regulative development by proposing that the same general types of somatic-genetic and epigenetic events occur in both. In mosaic development, however, the organism does not have the residual and redundant stem cells which allow for the cell replacement, repair and regeneration seen in regulative development. We feel that by drawing analogies as we have from the development of the immune system one may gain insights into the genetic and epigenetic factors which govern the development of other tissues and formulate specific experiments to test the resulting hypothesis.

The rare association of tetralogy of Fallot with hypertrophic cardiomyopathy. Report of 2 neonatal patients.

Although tetralogy of Fallot is commonly associated with other congenital heart defects, it is rarely found in conjunction with hypertrophic cardiomyopathy. We describe the cases of 2 neonates with this rare condition, both of whom required surgical intervention during infancy. Because hypertrophic cardiomyopathy is frequently familial, and tetralogy of Fallot is commonly found in patients diagnosed with chromosomal anomalies, we speculate about a possible genetic cause for this association.