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Deadly defects. Managing the pediatric patient with a congenital heart defect.

CHD-specific emergencies may be managed quite effectively in the prehospital environment. The key to successful prehospital management of CHDs is identifying the cardiac anomaly, obtaining an effective history and physical assessment, and providing supportive care. When obtaining a history, it is important to remember that parents know their children and their children's diseases very well. An EMS provider who ignores information from a parent is doomed to failure. Realizing that most EMS providers are not well-versed in the various CHDs and are not likely to have a great deal of experience in working with CHD patients, conferring with medical control prior to initiation of any treatments is strongly encouraged. Finally, remember that patients with CHDs are sick and have traditionally been sick for quite a while. Because of the chronic illness, it is easy to focus on the congenital defect when called to the scene for an ill child and neglect the potential for a noncardiac-related pathology. Although the most commonly seen congenital heart defects have been reviewed here, there are others that have not been addressed. Garnering an understanding of each individual defect is not nearly as important as understanding the difference between cyanotic and acyanotic defects. Prehospital care for the CHD patient is primarily supportive, but, in certain cases, may require substantial intervention. EMS providers should not be concerned with diagnosing specific defects, but should be aware of the global effects that various defects have on normal perfusion. EMS providers' comprehension of the pathophysiology of CHDs and prompt actions will play a vital role in the outcome of the acutely ill CHD patient.

Child↗

Transcatheter closure of secundum atrial septal defect with atrial septal defect occlusion system (ASDOS): initial experience and short-term follow-up.

Transcatheter closure of secundum atrial septal defect is a well known alternative to surgery. It was attempted in seven patients (age range 7-34 years, mean 20.1 +/- 6.5 years) with the double umbrella nitinol device (ASDOS, Dr. Ing Osypka, Germany). The interatrial septal anatomy and blood flow were examined by transthoracic and multiplane transoesophageal echocardiography. The size of atrial septal defect varied from 1.25-2.4 cm (mean 1.75 +/- 0.3 cm), minimal septal rim 0.5-1.0 cm (mean 0.75 +/- 0.20 cm), and Qp/Qs 1.6-3.2:1 (mean 2.4 +/- 0.6). One patient had an atrial septal defect following surgery for left atrial myxoma. The procedure which involved the use of monorail system for deployment of device under transoesophageal echocardiography guidance, was successful in six (86%) of the seven patients. The size of the implanted device ranged from 30-45 mm. In two patients, the right atrial umbrella had to be oversized in comparison to the left atrial umbrella for stability and adequate occlusion of the defect. The patient in whom the procedure failed had a defect size of 1.7 cm, with minimal septal rim (anterosuperior) of 5 mm; however, the device could be easily retrieved. Immediately after and at follow-up of one year, transoesophageal echocardiography-guided colour flow mapping revealed complete abolition of left-to-right shunt in five (83%) of the six patients. One patient had a small residual flow at the posterior rim of the defect; none had atrioventricular valve regurgitation. Although the procedure is complex, it is safe with the advantage of excellent control on the monorail system for proper positioning, repositioning and, if required, retrieval of the device.

Adolescent↗

Transcatheter treatment of perimembranous ventricular septal defect, secundum atrial septal defect and patent ductus arteriosus in a child.

A 4-year-old child with patent ductus arteriosus, perimembranous ventricular septal defect and ostium secundum atrial septal defect was successfully treated with the use of a simultaneous transcatheter for all of the anomalies present. The patent ductus arteriosus was closed first by using a coil, then the perimembranous ventricular septal defect was closed by using a 10-mm Amplatzer eccentric device. Finally, a 10-mm Amplatzer atrial septal defect device was implanted to treat the atrial septal defect.

Abnormalities, Multiple↗

Immunodeficiency of alymphoplasia mice (aly/aly) in vivo: structural defect of secondary lymphoid organs and functional B cell defect.

Alymphoplasia mice (aly/aly) have been shown to be deficient for a nuclear factor-kappaB-inducing kinase involved in signal transduction of lymphotoxin beta receptor (LT-betaR) and of CD40, resulting in structural defects of secondary lymphoid organs and highly increased susceptibility to viral infections. We analyzed the anti-viral immune response of bone marrow chimeras (BMC) between aly/aly mice and (C57BL/6 x DBA2)F1 mice (B6D2F1) to evaluate in vivo whether the structural defects of secondary lymphoid organs or intrinsic B or T cell defects led to immunodeficiency in aly/aly mice. Transfer of aly/aly bone marrow into B6D2F1 mice (aly/aly-->B6D2F1) led to excellent T but poor B cell reconstitution of recipients. Antiviral cytotoxic T cell (CTL) responses of aly/aly-->B6D2F1 BMC were clearly improved compared to aly/aly mice whereas virus-neutralizing IgG reponses were virtually absent. Therefore, the inefficient CTL response was predominantly caused by the structural defect of secondary lymphoid organs and not by an intrinsic T cell defect. In contrast, B cells of aly/aly origin were unable to undergo isotype switch after viral infections, indicating an intrinsic B cell defect in vivo. Overall, aly/aly mice show the combined immunodeficient phenotype of mice deficient for LT-3R with B cells functionally deficient for CD40.

Agammaglobulinemia↗

TGF-beta 1 induces bone closure of skull defects: temporal dynamics of bone formation in defects exposed to rhTGF-beta 1.

The temporal dynamics of bone repair in a skull defect in rabbits was examined to characterize the in vivo cellular events occurring following a single local application of recombinant human TGF-beta 1 (rhTGF-beta 1). Rabbits received vehicle or 0.4, 1, 2, or 5 micrograms rhTGF-beta 1 applied to 12 mm defects at the time of surgery. The defect sites were subsequently evaluated by radiography and qualitative and quantitative histology at time points ranging from 1 to 180 days. Based on radiographic assessment, the defect area decreased rapidly in a dose-dependent manner through 35 days after surgery in the rhTGF-beta 1-treated groups. Minimal closure occurred in sites administered vehicle control at all time points examined. Sites treated with rhTGF-beta 1 were characterized histologically by an increase in parameters of active bone formation through 49 days, including percentage osteoid surface, percentage osteoblast/total surface, and an increase in the trabecular bone volume. Bone resorption parameters were increased at 16 and 49 days with histologic evidence of remodeling from woven to lamellar bone. By 70 days, no differences were observed among the groups for parameters of either bone formation or resorption. Bone formation rate was not altered with rhTGF-beta 1 treatment at any time point. These results indicate that exogenously applied rhTGF-beta 1 stimulated the recruitment and proliferation of osteoblasts at the defect site, resulting in a rapid deposition of bony matrix, with normal remodeling processes occurring thereafter. This study supports the hypothesis that TGF-beta 1 is a potent osteoinductive growth factor in vivo and may have potential application as a therapeutic aid to nonhealing bony defects.

Animals↗

Escherichia coli mutants defective in the gamma subunit of proton-translocating ATPase: intracistronic mapping of the defective site and the biochemical properties of the mutants.

Various hybrid plasmids carrying a portion of the gene for the gamma subunit of the H+-ATPase of Escherichia coli complemented five mutants defective in the enzyme in a genetic test, indicating that the mutants are defective in the gamma subunit. Since the nucleotide sequence of genomic DNA carried on the plasmids is known, the defective site(s) of the mutants could be located within the gene for the gamma subunit as follows: KF10 and NR70, KF1, and KF12 and KF13 have a mutation causing a defect(s) in amino acid residues 1 to 82, 83 to 167, and 168 to 287, respectively, of the gamma subunit. The biochemical properties of all these mutants except NR70 were analyzed in terms of proton permeability of the membranes and assembly of F1. Results suggested that KF1 and KF10 have defective F1 without at least the alpha and beta subunits on their membranes, whereas KF12 and KF13 have F1's of rather similar structure to that of the wild type. Attempts were made to purify F1 oF KF12 as a single complex. Although the F1 complex dissociated during purification, active alpha and beta subunits of KF12 were partially purified. On the basis of these biochemical and genetic results, it is suggested that structural alterations in the primary sequence of the gamma subunit corresponding to residues 1 to 167 cause more extensive defects in the assembly of F1 than alteration in the sequence of residues 168 to 287.

Adenosine Triphosphatases↗

Defective phagocytosis by synovial fluid and blood polymorphonuclear leucocytes in patients with rheumatoid arthritis. I. The nature of the defect.

In a series of thirty-seven patients with rheumatoid arthritis (RA), 50% showed a defect of phagocytosis of Candida albicans by synovial fluid polymorphonuclear leucocytes (SF-PMN) and 40% yielded a defect in peripheral blood (PB-PMN). There was a positive correlation between the defective phagocytosis of SF-PMN and PB-PMN suggesting that defective PB-PMN migrate into the synovial fluid. The defect was associated with the lack of a functional C3b receptor on SF-PMN in 64% of patients and on PB-PMN in 40% of patients. SF-PMN or PB-PMN contained intracellular IgG, IgM and C3 in some patients but the presence of these factors could not be correlated with defective phagocytosis of either cell population. There was no correlation between phagocytosis and the differential agglutination test (DAT) ratio of either serum or synovial fluid. The killing of Candida by SF-PMN and BP-PMN was normal. The results could explain the increased susceptibility to joint infection of patients with RA.

Adult↗

Identification of defective binding of low density lipoprotein by the U937 proliferation assay in German patients with familial defective apolipoprotein B-100.

Familial defective apolipoprotein B-100 (FDB) is a dominantly inherited disorder characterized by decreased binding of low density lipoprotein (LDL) to the LDL receptor due to a substitution of glutamine for arginine in residue 3500 of apolipoprotein B-100. We present the results of the U937 cell proliferation assay for the detection of familial defective apo B100 in 13 German FDB patients. Due to a defect in the pathway of cholesterol synthesis the human myelomonocytic tumour cell line U937 lacks the ability to synthesize cholesterol which makes proliferation of these cells dependent on the presence of exogenous LDL-cholesterol. U937 cells were incubated with LDL from 13 FDB-patients, 10 healthy normocholesterolaemic individuals (NC) and 26 patients with familial hypercholesterolaemia due to a defective LDL-receptor (FH). At LDL-cholesterol concentrations below 1 microgram ml-1 no proliferation occurred. In the presence of LDL from FDB patients at concentrations between 2.5 micrograms ml-1 and 15.0 micrograms ml-1, the proliferation was significantly reduced compared to LDL from FH-patients and normocholesterolaemic controls. At 5 micrograms ml-1 the reduction was 31-80% regardless of age, sex, apo E genotype, Lp(a)- and lipid levels. At concentrations above 25.0 micrograms ml-1 no further differences were observed. The present results indicate that the U937 proliferation assay is a reliable test for the detection of defective LDL-binding due to the 3500 mutation in FDB patients. It may be useful for the detection of defective binding of LDL due to other mutations in the apo B-100 gene.

Adult↗

Persistent thallium-201 defect: can clinical, electrocardiographic and exercise hemodynamic variables predict defect normalization with reinjection?

This study was designed to assess the contribution of clinical, electrocardiographic and exercise hemodynamic variables to the prediction of normalization on resting reinjection scintigraphy of persistent thallium-201 (201Tl) myocardial perfusion defects seen with exercise and 2- to 4-hour delayed (redistribution) imaging. To evaluate this contribution, we studied 159 consecutive patients with persistent 201Tl myocardial perfusion defects on routine exercise and 2- to 4-hour-delayed scintigrams at the University of Rochester Medical Center who were classified as having moderate or greater ischemic normalization (group 1, n = 76) or minimal to no ischemic normalization (group 2, n = 83) by reinjection scintigraphy. Multiple logistic regression analysis with backward elimination was used to model the effects of clinical, electrocardiographic and exercise hemodynamic data on the odds ratio of a normalized defect. No difference was observed in the two groups with regard to gender, angina on exertion, rate-pressure product, exercise duration, resting or exertional ischemic ST changes on electrocardiogram, presence of Q waves or left ventricular hypertrophy on baseline electrocardiogram, or total number of stress thallium defects (2.8 +/- 1.5 segments). No single variable or combination of variables discriminated between groups 1 and 2 by logistic regression analysis. We conclude that defect normalization seen on resting 201Tl myocardial perfusion scintigraphy is prevalent in patients with persistent defects on routine exercise and delayed myocardial perfusion scintigraphy, and was not predictable from available clinical, electrocardiographic and exercise hemodynamic variables.

Aged↗

Defective Vav expression and impaired F-actin reorganization in a subset of patients with common variable immunodeficiency characterized by T-cell defects.

Common variable immunodeficiency (CVID) is a primary immune disorder characterized by impaired antibody production, which is in many instances secondary to defective T-cell function (T-CVID). We have previously identified a subset of patients with T-CVID characterized by defective T-cell receptor (TCR)-dependent protein tyrosine phosphorylation. In these patients, ZAP-70 fails to be recruited to the TCR as the result of impaired CD3zeta phosphorylation, which is, however, not dependent on defective Lck expression or activity. Here we show that neither Fyn nor CD45 is affected in these patients. On the other hand, T-CVID T cells show dramatic defects in the Vav/Rac pathway controlling F-actin dynamics. A significant deficiency in Vav protein was indeed observed; in 3 of 4 patients with T-CVID, it was associated with reduced VAV1 mRNA levels. The impairment in Vav expression correlated with defective F-actin reorganization in response to TCR/CD28 co-engagement. Furthermore, TCR/CD28-dependent up-regulation of lipid rafts at the cell surface, which requires F-actin dynamics, was impaired in these patients. The actin cytoskeleton defect could be reversed by reconstitution of Vav1 expression in the patients' T cells. Results demonstrate an essential role of Vav in human T cells and strongly suggest Vav insufficiency in T-CVID.

Actins↗

One Lewis rat with homozygous defect of the serine proteinase inhibitor 2 (Spi-2) gene and two Lewis rats with heterozygous Spi-2 gene defect.

One LEW/Sea (Lewis) strain rat, Rat P-1, had a homozygous defect of the serine proteinase inhibitor 2 (Spi-2) gene coding for serpin contrapsin. A sibling, Rat P-2, and a rat of the same strain, Rat P-3, had a heterozygous Spi-2 gene defect. The homozygous Spi-2 gene defect of Rat P-1 was diagnosed by the polymerase chain reaction (PCR). The presence of an alpha 1-proteinase inhibitor (PI) gene was confirmed by PCR in all 3 rats. Rat P-1 and the sibling Rat P-2 were sacrificed at 7 days of age because of the severe weakness of Rat P-1, although Rat P-2 appeared healthy. Rat P-3 was sacrificed at 40 days of age because of the severe weakness. Rat P-1's hepatocytes with the homozygous Spi-2 gene defect showed massive accumulation of polymerized alpha 1-antitrypsin (AT) in the rough endoplasmic reticulum (RER). Large, defined accumulations of alpha 1-AT were not found in the heterozygous rats with the Spi-2 gene defects. Nephrogenesis was retarded in all 3 rats, especially in Rat P-1. Extramedullary hematopoiesis was absent in the liver of Rat P-1 and suppressed in the spleen of Rat P-3, where activated alpha 1-AT synthesis was found. Atelectasis mixed with hyperinflated lung regions and thymic apoptosis were observed in the 2 weak rats. As Spi-2 gene defect had some similar clinical points to platelet-derived growth factor (PDGF) deficiency, it was suggested that increased vasoconstrictor peptide hormones competed with PDGF for binding to the PDGF-receptors.

Animals↗

Evidence for defects in accessory and T cell subsets in mice expressing the xid defect.

Mice expressing the X-linked recessive CBA/N genetic defect xid lack a subpopulation of B cells which appears late in normal B cell ontogeny and is characterized by expression of the cell surface antigens Lyb3, Lyb5, and Lyb7. In adult mice with the xid defect, responses to Type 2 antigens such as TNP-ficoll are entirely absent and responses to Type 1 antigens such as TNP-LPS are somewhat reduced. Primary in vitro responses to the T dependent antigen sheep red blood cells (SRBC) are defective but secondary responses are normal. These and other findings have led to the hypothesis that one effect of the xid defect is the inability of a subset of B cells to respond to nonspecific signals from T cells or accessory cells. The cellular basis of the xid defect is not well understood. The simplest explanation is that it reflects a primary lesion in the development of a subpopulation of B cells responsible for the types of immune responses described above. An alternative notion is that the xid defect is expressed primarily in a non-B cell population (e.g., T cells or accessory cells) which are necessary for the development and/or function of this B cell subset. A direct approach to this problem depends on the availability of homogeneous populations of B cells, T cells, or accessory cells. Recently we have described a cloned dendritic cell, Den-1, which is a potent stimulator of some B and T cell responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Defective interleukin 2 production in patients after bone marrow transplantation and in vitro restoration of defective T lymphocyte proliferation by highly purified interleukin 2.

Using OKT3 monoclonal antibody as a mitogen, we have studied interleukin 2 (IL2) production and proliferation in peripheral blood mononuclear cells (PBMC) of 23 patients receiving bone marrow transplants. Twenty patients were recipients of allogeneic bone marrow for treatment of hematologic malignancies, aplastic anemias (AA), or severe combined immunodeficiencies (SCID). Three patients with Hodgkin's disease or neuroblastoma received autologous bone marrow. Endogenous IL2 production was not detectable (less than 0.2 U/mL) in PBMC of 18 patients and was very low in PBMC from five patients (0.5 to 1.5 U/mL), as compared to normal controls (median 3.5 U/mL) or pretransplant patients (median 1.5 U/mL). The low IL2 production was associated with defective OKT3-induced proliferation of PBMC in 19 of 23 patients studied. In the first 6 months after BMT, 14 of 15 patients (93%) showed defective proliferation of PBMC as compared to five of eight patients (63%) tested between 7 and 18 months after BMT (P less than .1). In all but three patients, addition of highly purified human lymphocyte IL2 (hpIL2) restored OKT3-induced proliferation of PBMC to within the normal range. This study demonstrates that PBMC in patients after BMT have a defect of IL2 production but are able to express IL2 receptors in response to OKT3 antibody and to proliferate normally upon addition of hpIL2. PBMC of all patients showed similar functional defects, whether or not they received additional therapy, including various conditioning regimens prior to BMT and immunosuppressive therapy after BMT. These observations suggest that T cell defects after BMT are most likely secondary to quantitative or qualitative defects of transplanted T lymphocytes or their precursors.

Anemia, Aplastic↗

Prevalence, relation to spontaneous closure, and association of muscular ventricular septal defects with other cardiac defects.

Previous studies on muscular ventricular septal defect (VSD) have not taken into account the specific defect location in the septum. We retrospectively reviewed all patients with a muscular VSD, with and without associated malformations, diagnosed over 32 months to determine the prevalence and rate of spontaneous closure of single defects in relation to location in the muscular septum. Defects were classified into 4 groups: midmuscular, apical, anterior, and posterior. Two hundred seven patients were identified, of whom 125 had a single defect. The relative prevalence of single muscular VSD was: midmuscular 55 (44%), apical 31 (25%), anterior 33 (26%), and posterior 6 (5%). Thirty patients had signs of spontaneous closure and only 1 underwent surgery. There was no difference in rate of closure with respect to anatomic locations. Patients with multiple muscular VSD were either referred for surgery in the first year of life or had a course similar to patients with a single VSD. Muscular VSD associated with other cardiac malformations was more often encountered in patients with conoventricular VSD and coarctation of the aorta. The distribution of anatomic groups of muscular VSD in association with malformations was similar to the single VSD.

Child, Preschool↗

Electrocardiogram of secumdum type atrial septal defect simulating endocardial cushion defect.

Three groups of patients are identified in the series of secumdum atrial septal defect with left axis deviation in an analysis of 910 patients of secundum atrial septal defect with or without other accompanying anomalies: 1) 12 patients with isolated ostium secumdum defect; 2) 5 patients with associated prolapse of posterior leaflet of the mitral valve; 3) 4 patients with associated hypertrophic cardiomyopathy and/or single (left) coronary artery. The findings of these 21 patients with proved secumdum atrial septal defect are analysed. The combination of such anomalies should be considered in the differential diagnosis of primum endocardial cushion defect from the electrocardiographic viewpoints.

Adolescent↗