Showing papers by "Johns Hopkins University School of Medicine published in 1993"
TL;DR: A gene is identified, named WAF1, whose induction was associated with wild-type but not mutant p53 gene expression in a human brain tumor cell line and that could be an important mediator of p53-dependent tumor growth suppression.
8,339 citations
TL;DR: In primary cultures of olfactory neurons, zinc protoporphyrin-9, a potent selective inhibitor of heme oxygenase, depletes endogenous guanosine 3',5'-monophosphate (cGMP), suggesting that carbon monoxide may be a physiologic regulator of cGMP.
Abstract: Carbon monoxide, an activator of guanylyl cyclase, is formed by the action of the enzyme heme oxygenase. By in situ hybridization in brain slices, discrete neuronal localization of messenger RNA for the constitutive form of heme oxygenase throughout the brain has been demonstrated. This localization is essentially the same as that for soluble guanylyl cyclase messenger RNA. In primary cultures of olfactory neurons, zinc protoporphyrin-9, a potent selective inhibitor of heme oxygenase, depletes endogenous guanosine 3',5'-monophosphate (cGMP). Thus, carbon monoxide, like nitric oxide, may be a physiologic regulator of cGMP. These findings, together with the neuronal localizations of heme oxygenase, suggest that carbon monoxide may function as a neurotransmitter.
1,509 citations
TL;DR: It is shown that, when expressed in Saccharomyces cerevisiae, human MDM2 inhibits human p53's ability to stimulate transcription by binding to a region that nearly coincides with the p53 acidic activation domain.
Abstract: THE tumour-suppressor gene p53 is inactivated in most human malignancies1 either by missense mutations1 or by binding to oncogenic proteins2–4. In human soft tissue sarcomas, inactivation apparently results from MDM2 gene amplification4. MDM2 is an oncogene product5,6 that may function by binding to p53 and inhibiting its ability to activate transcription3. Here we show that, when expressed in Saccharomyces cerevisiae, human MDM2 inhibits human p53's ability to stimulate transcription by binding to a region that nearly coincides with the p53 acidic activation domain. The isolated p53 activation domain fused to another DNA-binding protein is also inactivated by MDM2, confirming that MDM2 can inhibit p53 function by concealing the activation domain of p53 from the cellular transcription machinery.
1,502 citations
TL;DR: It is demonstrated that Hif-1 DNA binding activity is also induced by hypoxia in a variety of mammalian cell lines in which the EPO gene is not transcribed, providing evidence that HIF-1 and its recognition sequence are common components of a general mammalian cellular response to Hypoxia.
Abstract: Transcription of the human erythropoietin (EPO) gene is activated in Hep3B cells exposed to hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a nuclear factor whose DNA binding activity is induced by hypoxia in Hep3B cells, and HIF-1 binds at a site in the EPO gene enhancer that is required for hypoxic activation of transcription. In this paper, we demonstrate that HIF-1 DNA binding activity is also induced by hypoxia in a variety of mammalian cell lines in which the EPO gene is not transcribed. The composition of the HIF-1 DNA binding complex and its isolated DNA binding subunit and the mechanism of HIF-1 activation appear to be similar or identical in EPO-producing and non-EPO-producing cells. Transcription of reporter genes containing the EPO gene enhancer is induced by hypoxia in non-EPO-producing cells and mutations that eliminate HIF-1 binding eliminate inducibility. These results provide evidence that HIF-1 and its recognition sequence are common components of a general mammalian cellular response to hypoxia.
1,405 citations
TL;DR: The most evident effect of disrupting the neuronal NOS gene is the development of grossly enlarged stomachs, with hypertrophy of the pyloric sphincter and the circular muscle layer.
1,304 citations
TL;DR: Results suggest an important link between tumor initiation and cell adhesion and two cellular proteins that associate with APC were identified as the E-cadherin-associated proteins alpha- and beta-catenin.
Abstract: Mutations of APC appear to initiate sporadic and inherited forms of human colorectal cancer. Although these mutations have been well characterized, little is known about the function of the APC gene product. Two cellular proteins that associate with APC were identified by nucleotide sequence analysis and peptide mapping as the E-cadherin-associated proteins alpha- and beta-catenin. A 27-residue fragment of APC containing a 15-amino acid repeat was sufficient for the interaction with the catenins. These results suggest an important link between tumor initiation and cell adhesion.
1,255 citations
TL;DR: From these analyses probability plots and nomograms have been constructed to assist urologists in the preoperative prediction of final pathological stage for patients with clinically localized prostate cancer.
1,232 citations
TL;DR: The studies indicate that COX-2 expression may be important in regulating prostaglandin signaling in brain, and the marked inducibility in neurons by synaptic stimuli suggests a role in activity-dependent plasticity.
1,220 citations
TL;DR: Delineation of these two cooperative regions explains at the level of transcription how IFN-gamma and LPS act in concert to induce maximally the mac-NOS gene and, furthermore, howIFN-Gamma augments the inflammatory response to LPS.
Abstract: The promoter region of the mouse gene for macrophage-inducible nitric oxide synthase (mac-NOS; EC 1.14.13.39) has been characterized. A putative TATA box is 30 base pairs upstream of the transcription start site. Computer analysis reveals numerous potential binding sites for transcription factors, many of them associated with stimuli that induce mac-NOS expression. To localize functionally important portions of the regulatory region, we constructed deletion mutants of the mac-NOS 5' flanking region and placed them upstream of a luciferase reporter gene. The macrophage cell line RAW 264.7, when transfected with a minimal promoter construct, expresses little luciferase activity when stimulated by lipopolysaccharide (LPS), interferon gamma (IFN-gamma), or both. Maximal expression depends on two discrete regulatory regions upstream of the putative TATA box. Region I (position -48 to -209) increases luciferase activity approximately 75-fold over the minimal promoter construct. Region I contains LPS-related responsive elements, including a binding site for nuclear factor interleukin 6 (NF-IL6) and the kappa B binding site for NF-kappa B, suggesting that this region regulates LPS-induced expression of the mac-NOS gene. Region II (position -913 to -1029) alone does not increase luciferase expression, but together with region I it causes an additional 10-fold increase in expression. Together the two regions increase expression 750-fold over activity obtained from a minimal promoter construct. Region II contains motifs for binding IFN-related transcription factors and thus probably is responsible for IFN-mediated regulation of LPS-induced mac-NOS. Delineation of these two cooperative regions explains at the level of transcription how IFN-gamma and LPS act in concert to induce maximally the mac-NOS gene and, furthermore, how IFN-gamma augments the inflammatory response to LPS.
1,083 citations
TL;DR: The initial observation of an expanded and unstable trinucleotide repeat in the Huntington's disease gene has now been confirmed and extended in 150 independent Huntington’s disease families and the analysis of the length and instability of individual repeats in members of these families has profound implications for presymptomatic diagnosis.
Abstract: The initial observation of an expanded and unstable trinucleotide repeat in the Huntington's disease gene has now been confirmed and extended in 150 independent Huntington's disease families. HD chromosomes contained 37-86 repeat units, whereas normal chromosomes displayed 11-34 repeats. The HD repeat length was inversely correlated with the age of onset of the disorder. The HD repeat was unstable in more than 80% of meiotic transmissions showing both increases and decreases in size with the largest increases occurring in paternal transmissions. The targeting of spermatogenesis as a particular source of repeat instability is reflected in the repeat distribution of HD sperm DNA. The analysis of the length and instability of individual repeats in members of these families has profound implications for presymptomatic diagnosis.
1,058 citations
TL;DR: This report describes a gene, MCL1, that is isolated from the ML-1 human myeloid leukemia cell line during phorbol ester-induced differentiation along the monocyte/macrophage pathway and shows that it has sequence similarity to BCL2, a gene involved in normal lymphoid development and in lymphomas with the t(14;18) chromosome translocation.
Abstract: During their lifespan, immature cells normally pass through sequential transitions to a differentiated state and eventually undergo cell death. This progression is aberrant in cancer, although the transition to differentiation can be reestablished in inducible leukemia cell lines. This report describes a gene, MCL1, that we isolated from the ML-1 human myeloid leukemia cell line during phorbol ester-induced differentiation along the monocyte/macrophage pathway. Our results demonstrate that expression of MCL1 increases early in the induction, or "programming," of differentiation in ML-1 (at 1-3 hr), before the appearance of differentiation markers and mature morphology (at 1-3 days). They further show that MCL1 has sequence similarity to BCL2, a gene involved in normal lymphoid development and in lymphomas with the t(14;18) chromosome translocation. MCL1 and BCL2 do not fall into previously known gene families. BCL2 differs from many oncogenes in that it inhibits programmed cell death, promoting viability rather than proliferation; this parallels the association of MCL1 with the programming of differentiation and concomitant maintenance of viability but not proliferation. Thus, in contrast to proliferation-associated genes, expression of MCL1 and BCL2 relates to the programming of differentiation and cell viability/death. The discovery of MCL1 broadens our perspective on an emerging MCL1/BCL2 gene family and will allow further comparison with oncogene families.
TL;DR: It may be justifiable initially to limit use of GH to certain elderly patients such as those suffering from catabolic illnesses, malnourishment, burns, cachexia, etc, but a great deal more research will be necessary to determine whether normalization of GH and IGF-I levels in healthy older persons will lead to improvements in their physical and psychological functional capacity and quality of life.
Abstract: In humans, both aging and GH deficiency are associated with reduced protein synthesis, decreased lean body and bone mass, and increased percent body fat. In healthy individuals, spontaneous and stimulated GH secretion, as well as circulating IGF-I and IGFBP-3 levels, are significantly decreased with advancing age. The extent to which these age-related changes in GH and IGF-I contribute to alterations in body composition and function remains to be elucidated. GH treatment of GH-deficient adults or old men with reduced IGF-I levels with exogenous GH increases plasma IGF-I, nitrogen retention, and lean body mass, decreases percent body fat, and exerts little effect on bone mineral density. Short-term adverse effects of GH therapy have been minimized by using low-dose regimens, but it is still uncertain whether long-term GH supplementation in adult life increases the risk of metabolic abnormalities or malignancy. Administration of GHRH, which has been shown to maintain the pattern of pulsatile GH secretion in old men, may represent another possible physiological approach to therapy. It may be justifiable initially to limit use of GH to certain elderly patients such as those suffering from catabolic illnesses, malnourishment, burns, cachexia, etc. A great deal more research will be necessary to determine whether normalization of GH and IGF-I levels in healthy older persons will lead to improvements in their physical and psychological functional capacity and quality of life.
TL;DR: It is demonstrated that induction of both Hif-1 and erythropoietin RNA is inhibited by the protein kinase inhibitor 2-aminopurine, consistent with the proposed function of HIF-1 as a physiologic regulator of gene expression that responds to changes in cellular oxygen tension.
TL;DR: Evidence is presented to support a model based on the possibility of recombination between homologous sequences located in intron 22 and upstream of the factor VIII gene that leads to an inversion of all intervening DNA and a disruption of the gene.
Abstract: Mutations in the factor VIII gene have been discovered for barely more than half of the examined cases of severe haemophilia A. To account for the unidentified mutations, we propose a model based on the possibility of recombination between homologous sequences located in intron 22 and upstream of the factor VIII gene. Such a recombination would lead to an inversion of all intervening DNA and a disruption of the gene. We present evidence to support this model and describe a Southern blot assay that detects the inversion. These findings should be valuable for genetic prediction of haemophilia A in approximately 45% of families with severe disease.
TL;DR: Treatment of Hep3B cells with desferrioxamine (DFX) induced HIF-1 activity and EPO RNA expression with kinetics similar to the induction of Hif-1 by hypoxia or cobalt chloride, suggesting the existence of a common Hypoxia signal-transduction pathway leading to HIF -1 induction in different cell types.
TL;DR: Recognition of CHIP has provided molecular insight into the biological phenomenon of osmotic water movement, and it is hoped that pharmacological modulation ofCHIP function may provide novel treatments of renal failure and other clinical problems.
Abstract: Despite longstanding interest by nephrologists and physiologists, the molecular identities of membrane water channels remained elusive until recognition of CHIP, a 28-kDa channel-forming integral membrane protein from human red blood cells originally referred to as "CHIP28." CHIP functions as an osmotically driven, water-selective pore; 1) expression of CHIP conferred Xenopus oocytes with markedly increased osmotic water permeability but did not allow transmembrane passage of ions or other small molecules; 2) reconstitution of highly purified CHIP into proteoliposomes permitted determination of the unit water permeability, i.e., 3.9 x 10(9) water molecules.channel subunit-1 x s-1. Although CHIP exists as a homotetramer in the native red blood cell membrane, site-directed mutagenesis studies suggested that each subunit contains an individually functional pore that may be reversibly occluded by mercurial inhibitors reacting with cysteine-189. CHIP is a major component of both apical and basolateral membranes of water-permeable segments of the nephron, where it facilitates transcellular water flow during reabsorption of glomerular filtrate. CHIP is also abundant in certain other absorptive or secretory epithelia, including choroid plexus, ciliary body of the eye, hepatobiliary ductules, gall bladder, and capillary endothelia. Distinct patterns of CHIP expression occur at these sites during fetal development and maturity. Similar proteins from other mammalian tissues and plants were later shown to transport water, and the group is now referred to as the "aquaporins." Recognition of CHIP has provided molecular insight into the biological phenomenon of osmotic water movement, and it is hoped that pharmacological modulation of CHIP function may provide novel treatments of renal failure and other clinical problems.
TL;DR: It is established that this is a distinctive syndrome, distinguishable from poliomyelitis and demyelinating Guillain‐Barré syndrome, which is marked by rapidly progressive ascending tetraparesis, often with respiratory failure, but without fever, systemic illness, or sensory involvement.
Abstract: In northern China, annual epidemics of acute-onset flaccid paralysis diagnosed clinically as Guillain-Barre syndrome have been recognized for at least 20 years. On the basis of an historical analysis of more than 3,200 patients, distinctive features include most cases occurring during the summer months among children and young adults, most of whom reside in rural areas. Of 90 patients with acute flaccid paralysis, 88 had a distinctive pattern that shares clinical and cerebrospinal fluid findings with demyelinating Guillain-Barre syndrome, but that differs from Guillain-Barre syndrome physiologically and pathologically. The clinical course is marked by rapidly progressive ascending tetraparesis, often with respiratory failure, but without fever, systemic illness, or sensory involvement. Cerebrospinal fluid is acellular, and elevations of protein content occur in the second or third week of illness. Electrodiagnostic studies show normal motor distal latencies and limb conduction velocities, but reduced compound muscle action potential amplitudes. Sensory nerve action potentials and, when elicitable, F waves are within the range of normal. Recovery is usually good. Autopsy studies have shown Wallerian-like degeneration of motor fibers. These studies establish that this is a distinctive syndrome, distinguishable from poliomyelitis and demyelinating Guillain-Barre syndrome.
TL;DR: It is suggested that specific neurons and glial cells selectively express glutamate receptors composed of different subunit combinations and the co-expression of all AMPA receptor subunits within individual cells may not be obligatory for the functions of this glutamate receptor in vivo.
TL;DR: These studies demonstrated: (i) CHIP28 water channel activity is retained despite substitution of individual cysteines with serine; (ii) cysteine 189 is the Hg(2+)-sensitive residue; (iii) the subunits of theCHIP28 complex are individually active water pores; and (iv) residue 189 is critical to proper processing of the CHip28 protein.
TL;DR: The long-term value of serum PSA as a measure of progression after anatomic radical prostatectomy is demonstrated and suggests that radiation therapy is not effective in sterilizing occult local residual tumor in many men.
TL;DR: In a stably transfected human kidney 293 cell line overexpressing the gene encoding nitric oxide synthase, FK506 inhibits the calcium ionophore A23187, stimulated increases in nitrite, and potentiates phorbol ester-mediated inhibition of nitrite formation, establishing nitricoxide synthase as a calcineurin substrate.
Abstract: Immunosuppressants FK506 and cyclosporin A inhibit neurotoxicity of N-methyl-D-aspartate in primary cortical cultures, while having no effect on quisqualate- and kainate-mediated neurotoxicity. Rapamycin completely reverses the neuroprotective effect of FK506. Both FK506 and cyclosporin A inhibit NMDA-elicited/nitric oxide-mediated increases in cGMP levels in cortical cultures. FK506 has no effect on sodium nitroprusside-induced increases in cGMP. In a stably transfected human kidney 293 cell line overexpressing the gene encoding nitric oxide synthase [L-arginine, NADPH:oxygen oxidoreductase (nitric oxide-forming), EC 1.14.13.39], FK506 inhibits the calcium ionophore A23187, stimulated increases in nitrite (a breakdown product of nitric oxide), and potentiates phorbol ester-mediated inhibition of nitrite formation. FK506-mediated inhibition of nitric oxide formation is completely reversed by rapamycin. Calcineurin dephosphorylates protein kinase C-mediated phosphorylation of nitric oxide synthase. FK506 prevents the calcineurin-mediated dephosphorylation of nitric oxide synthase and thereby diminishes the enzyme's catalytic activity. These data establish nitric oxide synthase as a calcineurin substrate. Nitric oxide synthase catalytic activity is regulated by the phosphorylation state of the enzyme. Enhanced phosphorylation of nitric oxide synthase diminishes catalytic activity, and dephosphorylation (through activation of calcineurin) enhances catalytic activity. The neuroprotective effect of FK506 and cyclosporin A presumably involves the inhibition of calcineurin, preventing the dephosphorylation of nitric oxide synthase and its subsequent activation.
TL;DR: AAV vectors do efficiently promote in vivo gene transfer to the airway epithelium which is stable over several months and indicates that AAV-CFTR vectors could potentially be very useful for gene therapy.
Abstract: Adeno-associated virus (AAV) vectors expressing the normal cystic fibrosis transmembrane conductance regulator (CFTR) cDNA complement the cystic fibrosis (CF) defect in vitro. Unlike other DNA virus vectors, AAV is a stably integrating virus, which could make possible long-term in vivo complementation of the CF defect in the airway epithelium. We report AAV-CFTR gene transfer and expression after infection of primary CF nasal polyp cells and after in vivo delivery of AAV-CFTR vector to one lobe of the rabbit lung through a fiberoptic bronchoscope. In the rabbit, vector DNA could be detected in the infected lobe up to 6 months after administration. A 26-amino acid polypeptide sequence unique to the recombinant AAV-CFTR protein was used to generate both oligonucleotide probes and a polyclonal antibody which allowed the unambiguous identification of vector RNA and CFTR protein expression. With these reagents, CFTR RNA and protein were detected in the airway epithelium of the infected lobe for up to 6 months after vector administration. AAV vectors do, therefore, efficiently promote in vivo gene transfer to the airway epithelium which is stable over several months. These findings indicate that AAV-CFTR vectors could potentially be very useful for gene therapy.
TL;DR: Transgenic mice that accumulate NF-L to approximately 4-fold the normal level in the sciatic nerve indicate that extensive accumulation of neurofilaments in motor neurons can trigger the neurodegenerative process.
TL;DR: The present study demonstrates that BDNF rescues motor neurons from degeneration and may also play a role in the normal physiology of these cells and raise the possibility that some neurotrophins may be useful in treating patients with motor neuropathies and amyotrophic lateral sclerosis.
TL;DR: Data from a subsample indicate that compared to those who were ineligible or who refused, enrolled participants were younger, more highly educated, more likely to be married, and less likely to report limitations in activity.
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TL;DR: This review concentrates on primary open-angle glaucoma, the most prevalent form of the disorder in Western countries, and the present standard for determining visual loss.
Abstract: Our understanding of glaucoma has undergone dramatic changes in the past decade. The ferment has derived from new epidemiologic information, improved diagnostic methods, and developments in surgical and drug therapy. This review concentrates on primary open-angle glaucoma, the most prevalent form of the disorder in Western countries. Definition Primary open-angle glaucoma usually affects both eyes and combines a particular abnormal appearance of the optic disk (optic-nerve head) with a slowly progressive loss of visual sensitivity (Figure 1). The characteristic appearance of the glaucomatous optic disk is visible by ophthalmoscopy (Figure 2). The present standard for determining visual loss in glaucoma . . .
Journal Article•
TL;DR: The hypothesis that p53 and MDM2 genetic alterations are alternative mechanisms for inactivating the same regulatory pathway for suppressing cell growth is supported.
Abstract: The p53 and MDM2 genes were analyzed in 24 human soft tissue sarcomas (11 malignant fibrous histiocytomas and 13 liposarcomas). Alterations of p53, consisting of point mutations, deletions, or overexpression, were detected in one-third (8 of 24) of the sarcomas. MDM2 gene amplification was detected in another 8 tumors, but no tumor contained an alteration of both genes. Monoclonal antibodies reactive with the human MDM2 gene product were developed, and immunohistochemical analysis revealed nuclear localization and overexpression of MDM2 in those tumors with amplified MDM2 genes. These data support the hypothesis that p53 and MDM2 genetic alterations are alternative mechanisms for inactivating the same regulatory pathway for suppressing cell growth.
TL;DR: The environmental (behavioral) factors that brought about the decline in postcranial robusticity in Homo are ultimately linked to increases in brain size and cultural-technological advances, although changes in robusticity lag behind changes in cognitive capabilities.
Abstract: Temporal trends in postcranial robusticity within the genus Homo are explored by comparing cross-sectional diaphyseal and articular properties of the femur, and to a more limited extent, the humerus, in samples of Recent and earlier Homo. Using both theoretical mechanical models and empirical observations within Recent humans, scaling relationships between structural properties and bone length are developed. The influence of body shape on these relationships is considered. These scaling factors are then used to standardize structural properties for comparisons with pre-Recent Homo (Homo sp. and H. erectus, archaic H. sapiens, and early modern H. sapiens). Results of the comparisons lead to the following conclusions: 1) There has been a consistent, exponentially increasing decline in diaphyseal robusticity within Homo that has continued from the early Pleistocene through living humans. Early modern H. sapiens are closer in shaft robusticity to archaic H. sapiens than they are to Recent humans. The increase in diaphyseal robusticity in earlier Homo is a result of both medullary contraction and periosteal expansion relative to Recent humans. 2) There has been no similar temporal decline in articular robusticity within Homo--relative femoral head size is similar in all groups and time periods. Thus, articular to shaft proportions are different in pre-Recent and Recent Homo. 3) These findings are most consistent with a mechanical explanation (declining mechanical loading of the postcranium), that acted primarily through developmental rather than genetic means. The environmental (behavioral) factors that brought about the decline in postcranial robusticity in Homo are ultimately linked to increases in brain size and cultural-technological advances, although changes in robusticity lag behind changes in cognitive capabilities.
TL;DR: Findings indicate a strong association between the serum cholesterol level measured early in adult life in men and cardiovascular disease in midlife.
Abstract: Background The increased risk of cardiovascular disease associated with higher serum cholesterol levels in middle-aged persons has been clearly established, but there have been few opportunities to examine a potential link between serum cholesterol levels measured in young men and clinically evident premature cardiovascular disease later in life. Methods We performed a prospective study of 1017 young men (mean age, 22 years) followed for 27 to 42 years to quantify the risk of cardiovascular disease and total mortality associated with serum cholesterol levels during early adult life. The mean serum cholesterol level at entry was 192 mg per deciliter (5.0 mmol per liter). Results During a median follow-up of 30.5 years, there were 125 cardiovascular-disease events, 97 of which were due to coronary heart disease. The serum cholesterol level at base line was strongly associated with the incidence of events related to coronary heart disease and cardiovascular disease, as well as to total mortality and mortalit...
Journal Article•
TL;DR: The majority of patients fared well, however, there was a higher-than-normal prevalence of serious arrhythmia and sudden death, including those with small VSDs, and admission severity was the best predictor of survival.
Abstract: Background From 1958 to 1969, 1,280 patients (mostly children) with ventricular septal defects (VSDs) were admitted to the First Natural History Study of Congenital Heart Defects (NHS-1) after cardiac catheterization. Most with small defects and Eisenmenger's syndrome were managed medically; most with large VSDs were managed surgically. Of those with moderate-size defects, some were managed medically, and some were managed surgically. Most had a second catheterization at the conclusion of NHS-1. More than 15 years have elapsed since NHS-1, and most of the cohort are adults. This report (Second Natural History Study) addresses the long-term results of medical and surgical management. Methods and results Of an original cohort of 1,280 patients, 1,099 were alive at completion of NHS-1. New data were obtained on 976 (76.3%) of the original cohort. Probability of 25-year survival was 87%, and admission severity was the best predictor of survival. Of the 860 patients managed medically during NHS-1, 245 subsequently required surgical closure of the VSD. Only 5.5% of patients who had surgical closure required a second operation. On follow-up, there was a higher-than-normal prevalence of serious arrhythmias. Bacterial endocarditis occurred rarely. Of patients with small VSDs, 94.1% were in New York Heart Association functional class I. With the exception of those with Eisenmenger's syndrome, most patients had a final clinical status that was excellent or good. Conclusions The majority of patients fared well. However, there was a higher-than-normal prevalence of serious arrhythmia and sudden death, including those with small VSDs.