The influence of a restrictive atrial septal defect on pulmonary vascular morphology in patients with hypoplastic left heart syndrome.

Hypoplastic left heart syndrome (HLHS) with a restrictive atrial septal defect (ASD) is a form of congenital heart disease with considerable morbidity and mortality. This morphologic analysis assesses the pulmonary vasculature in this patient population. Pulmonary arteries, the persistence of high-resistance fetal arterioles, pulmonary veins, and lymphatics from multiple lung sections from each of five patients with HLHS and a restrictive ASD were compared to those of five patients with HLHS and nonrestrictive ASD. Lung sections from each patient were qualitatively graded in severity of pathology from 0 to 3 for each of the structures described previously, with the pathologist blinded to the status of the ASD. Patients with a restrictive ASD exhibited more significant pulmonary venous thickening and lymphatic dilatation (p = 0.02), with a tendency toward persistence of high-resistance fetal vessels (p = 0.2), compared to patients with a nonrestrictive ASD. These findings imply that patients with HLHS and a restrictive ASD possess pulmonary vascular abnormalities that place them at higher risk for the current surgical interventions available compared to patients with a nonrestrictive ASD.

Bcl-2 and M-Myc coexpression increases IGF-IR and features of malignant growth in neuroblastoma cell lines.

The bcl-2 and c-myc oncogenes cooperate to transform multiple cell types. In the pediatric malignancy NB(2), Bcl-2 is highly expressed. In tumors with a poor prognosis, N-Myc, a protein homologous to c-Myc, is overexpressed as a result of gene amplification. The present study was designed to determine whether Bcl-2 cooperates with N-Myc to bestow a tumorigenic phenotype to neuroblastoma (NB) cells. NB cell lines that at baseline express neither Bcl-2 nor N-Myc were stably transfected to express these gene products. In this model, we found Bcl-2 rescues N-Myc-expressing cells from apoptosis induced by serum withdrawal. Coexpression of Bcl-2 and N-Myc supports growth in low serum conditions and anchorage-independent growth in soft agar. Similarly, in vivo tumorigenic and angiogenic activity was dependent on coexpression. Our data further suggests that the mechanism underlying these changes involves the receptor for insulin growth factor type I (IGF-IR).

Historical changes in the postoperative treatment of appendicitis in children: impact on medical outcome.

BACKGROUND/PURPOSE: The introduction of managed care in the 1980s caused increased pressure to reduce costs for hospitalized patients. The authors hypothesized that these market forces have resulted in a decreased hospital stay and utilization of sophisticated diagnostic testing in children treated for appendicitis. If true, the impact of this paradigm shift on patient outcome is unknown. METHODS: Hospital records for 913 pediatric patients treated for appendicitis from 1974 to 1998 were reviewed retrospectively. Patients were stratified into those with perforated appendicitis (PA) and nonperforated appendicitis (NPA). Demographics, perioperative hospital course, diagnostic testing, complications, and long-term outcomes were analyzed after stratification into time intervals. RESULTS: Over time, children with NPA were treated with shorter antibiotic courses (P<.05) and were placed on a regular diet earlier (P<.05). These changes in treatment resulted in an earlier discharge (P<.05). The amount of time to become afebrile with a normal white blood cell count (WBC) did not change over time. Children with PA exhibited similar results with shorter antibiotic courses (P<.05), earlier dietary intake (P<.05) and earlier hospital discharge (P<.05) over time. In all children with appendicitis there was no significant difference in the rate of wound infections, abscesses requiring drains, readmission, or reoperations overtime. The utilization of abdominal radiographs (83%) and ultrasonography (USN; 40%) was high and remained unchanged over time. Utilization of computed tomography (CT scan) was low (4.3%) in the early decades and was not used as a preoperative test from 1991 to 1994. Given the high diagnostic accuracy of a pediatric surgeon for this disease, Bayesian analysis indicates that USN utilization rates should be 15%. CONCLUSIONS: The market pressures of managed care have resulted in a new treatment paradigm with an earlier discharge of all children with appendicitis. There has been no concomitant increase in the complication rate in either group as a result of this paradigm shift. Bayesian analysis indicates that USN and abdominal radiographs are overutilized in our institution.

The dimensions of the triangle of Koch in children.

We measured the dimensions of Koch's triangle in children with normal intracardiac anatomy to determine the relation between the size of the triangle of Koch and patient age, weight, height, and body surface area. We found that the dimensions of Koch's triangle varies significantly and directly with patient age and body habitus in this pediatric population.

Renal tubular dysgenesis in twins.

In a fetal autopsy series, we have explored the occurrence of renal tubular dysgenesis in twins. Renal tubular dysgenesis was found exclusively among those monozygotic twins with evidence of twin transfusion syndrome, particularly in those donor twins with oligohydramnios and growth restriction. We infer that hypotension in the donor twin of the twin transfusion syndrome pair is responsible for the failure of proximal convoluted tubule differentiation, and the disturbance of renal function is manifested as oligohydramnios prenatally, and either oliguria or tubular dysfunction postnatally.

Stent redilation in canine models of congenital heart disease: pulmonary artery stenosis and coarctation of the aorta.

In a canine puppy model, pulmonary artery stenosis was created by banding the left pulmonary artery to 30-40% of its original diameter. Animals underwent right heart catheterization and angiography 1-2 mo later, and Palmaz P308 stents were implanted. Stent redilation was performed 3-5 mo later. One mo postredilation, the animals were restudied and sacrificed. Coarctations of the aorta were created by transverse aortic incision and longitudinal repair. P308 stent implantation was performed 2-3 mo later. Stent redilation was performed after 6-10 mo, and the animals were restudied and sacrificed 1-2 mo later. Stent implantation was performed in 6 puppies with pulmonary artery stenosis, as 2 animals developed postoperative pulmonary arterial hypoplasia, precluding stenting. The stenosis diameter increased from 4.8 +/- 0.5 mm to 7.4 +/- 0.6 mm (mean +/- SE) following stenting (P = 0.005), and increased further to 9.2 +/- 0.7 mm following redilation (P < 0.001). There were no significant vessel tears or ruptures. Coarctation stenting was performed in 8 animals. The coarctation was dilated from 5.8 +/- 0.9 mm to 9.8 +/- 0.6 mm (P < 0.001), and to 13.5 +/- 0.5 mm at redilation (P = 0.002). Redilation could not be performed in 1 animal. Aortic rupture and death occurred in 2 of 7 animals at redilation. Stent implantation and redilation in experimental pulmonary artery stenosis appears safe and effective. Though stent implantation for coarctation of the aorta appears safe, there was a 28% aortic rupture rate at stent redilation in this model.

Collagen content in normal, pressure, and pressure-volume overloaded developing human hearts.

Increased myocardial collagen accompanies pressure overload of the adult left ventricle. This phenomenon is poorly understood in infants. This study compares the myocardial volume fraction of collagen in infants who did not have primary heart disease with infants with isolated pressure overload of the right ventricle (tetralogy of Fallot [ToF]), and with infants with combined volume and pressure overload (aortic valve atresia [AVA]). The distribution of collagen in the neonatal myocardium was also determined. We measured the volume fraction of collagen from right ventricular biopsy specimens of cadaver hearts in normal infants (1 to 9 months old; n = 7), infants with ToF (1 day to 9 months old; n = 9), newborns with AVA (AVA-NB) (1 to 4 days old; n = 5), and older patients with AVA (AVA-I) (5 to 8 months old; n = 5). Myocardium from 3 patients undergoing repair of ToF (6 to 8 months old) was also analyzed. Specimens were stained with Masson's trichrome and myocardial volume fraction of collagen determined by point counting. Myocardial volume fraction of collagen was significantly higher (p = 0.02) in AVA-I patients (8.0 +/- 3.5%) versus normal (3.3 +/- 2.7%), ToF (3.2 +/- 1.8%), and AVA-NB (3.5 +/- 2.3%) patients. There was a tendency for increased collagen in the subendocardium, especially in AVA-I patients (p > 0.05). We conclude that patients with AVA-I have increased collagen relative to normal subjects, patients with ToF, and patients with AVA-NB, and that this increase is greatest in the subendocardium.

Craniomicromelic syndrome: a newly recognized lethal condition with craniosynostosis, distinct facial anomalies, short limbs, and intrauterine growth retardation.

We report on two sisters with an unusual form of craniosynostosis, protruding nasal spine, micrognathia, short limbs, lung hypoplasia, absent or hypoplastic gallbladder, short intestine with ileal distention, hypoplastic uterus, and intrauterine growth retardation. This combination of defects appears to be a newly recognized and probably autosomal recessive disorder.

Enterocolitis associated with Hirschsprung's disease: a clinical histopathological correlative study.

Enterocolitis associated with Hirschsprung's disease (HEC) remains a major source of morbidity and even mortality, both before and after definitive surgical treatment. This study was undertaken to investigate whether histopathologic mucosal changes, in the absence of clinical manifestations of HEC, could predict the subsequent development of this complication. The clinical data and histopathology of 25 patients who eventually developed clinical HEC were compared with a control group of 25 age- and sex-matched patients with Hirschsprung's disease (HD) but with no clinical HEC either preoperatively or postoperatively. The histopathologic findings of tissue obtained by rectal biopsy or during laparotomy were graded from 0 to V according to severity and compared with the eventual clinical course. This study showed that (1) histopathologic findings of HEC appear to predict the clinical development, but not the severity, of future episodes of clinical HEC; (2) a histological grade of > or = II (> or = 2 crypt abscesses per high power field) should raise suspicion for subsequent occurrence of HEC, whereas a grade of > or = III (multiple crypt abscesses) places a child at high risk for development of clinical HEC; and (3) contrary to what is generally thought, histopathologic changes of HEC occur in both ganglionic and aganglionic segments. Based on these findings, it is recommended that histopathologic documentation of HEC and its grade should be an integral part of the tissue diagnosis of HD.

Molecular and phenotypic variability in the congenital alveolar proteinosis syndrome associated with inherited surfactant protein B deficiency.

Congenital alveolar proteinosis (CAP) is an often fatal cause of respiratory failure in term newborn infants, which has been associated with a genetic deficiency of surfactant protein B (SP-B) as a result of a frameshift mutation (121ins2) in a family with three affected siblings. In the index cases the deficiency of SP-B was associated with qualitative and quantitative abnormalities of the surfactant proteins A and C. Immunostaining for lung surfactant proteins and a search for the 121ins2 mutation by restriction enzyme analysis of DNA extracted from paraffin-embedded lung tissue was performed for 7 additional affected infants from 6 families, bringing to 10 the total number of patients with CAP who have been studied. In six infants, the surfactant protein immunostaining pattern was similar to that of the index cases. Of these, three patients were homozygous for the 121ins2 mutation; one was a compound heterozygote with the 121ins2 in one allele and a different mutation in the other; and three patients lacked the mutation in both alleles. One infant had an abundance of SP-B, suggesting phenotypic heterogeneity in CAP. Lung ultrastructural abnormalities, such as a reduced number of lamellar bodies, absent tubular myelin, and basal secretion of surfactant lipids and proteins, suggest a significant derangement of surfactant metabolism. The phenotypic heterogeneity in infants with CAP raises the possibility that variable degrees of SP-B deficiency may be more common than previously suspected.

Aneurysmal bone cysts in young children.

We reviewed seven young children (< or = 10 years) with aneurysmal bone cysts. There were four girls and three boys. Six had involvement of the long bones and one had involvement of the clavicle. The average age was 5.5 years (range 2.9-10.6 years). Initial treatment was curettage and bone grafting. There were recurrences in five of the seven children (71%). This represented 100% of children with radiographically aggressive or active lesions. The recurrences appeared rapidly, at an average of 8 months from the first procedure. The mitotic index of the initial lesion did not correlate with that of the recurrent lesion. Surgical management of the recurrences must be handled individually, but repeat curettage and grafting is only recommended when surgical resection is not possible. This high rate of recurrence in radiographically aggressive or active aneurysmal bone cysts in young children should be considered when planning treatment, and in the preoperative counseling of parents.

Expression of the apoptosis-suppressing protein bcl-2, in neuroblastoma is associated with unfavorable histology and N-myc amplification.

Survival rate in neuroblastoma, a tumor of post-ganglionic sympathetic neuroblasts, correlates with disease stage, tumor histology, and N-myc gene amplification. N-myc amplification is associated with rapid tumor progression and poor survival, but is not present in all cases of poor prognosis neuroblastoma. Moreover, overexpression of N-myc is not sufficient to cause cellular transformation. These data suggest that other genetic factors are important for neuroblastoma development. We investigated the expression of the, bcl-2 proto-oncogene in untreated cases of neuroblastoma. bcl-2 is a novel proto-oncogene that promotes cell growth by inhibiting programmed cell death (apoptosis), a form of cellular demise common during normal neurogenesis. Immunocytochemical localization using a monoclonal anti-bcl-2 antibody revealed that 16 of 40 patient specimens stained positive for bcl-2. bcl-2 was strongly associated with unfavorable histology (P = 0.002) and N-myc gene amplification (P = 0.002) and marginally associated with poor stage disease (P = 0.06). A logistic regression model evaluating the simultaneous association of stage, histology, and N-myc revealed that bcl-2 was most associated with unfavorable histology and N-myc gene amplification. These results support the notion that bcl-2 may play an important role in the genesis or progression of malignant neuroblastoma.

Congenital mesoblastic nephroma metastatic to the brain.

BACKGROUND: Congenital mesoblastic nephroma (CMN) is generally considered to be a benign neoplasm requiring only total excision. Rare local recurrences have usually been related to incomplete removal, and distant metastases to the lung have been reported three times. METHODS: The authors reported the first case of CMN metastatic to the brain, illustrating a comparison of the histopathology of the primary and secondary lesions. RESULTS: The gross appearance of the renal tumor was that of a benign CMN. On histopathologic examination, there was a single nodule of more cellular tissue with focal necrosis. This area was diagnosed as within the designation "cellular" mesoblastic nephroma. The appearance of the brain metastasis corresponded to that of the cellular nodule. CONCLUSIONS: This report expands the spectrum of metastatic potential of CMN. Though a rare event, this case underscores the need for close follow-up of infants with CMN.

Balloon-expandable stent treatment of experimental coarctation of the aorta: early hemodynamic and pathological evaluation.

The present study was intended to evaluate the acute and short-term hemodynamic, angiographic, and pathological response to balloon-expandable stent treatment of experimental coarctation of the aorta. A discrete thoracic coarctation was surgically created in six mongrel dogs (two adults, four puppies). Two months postoperatively all six dogs (8.9-30 kg) underwent left heart catheterization and coarctation stenting performed through a femoral artery cutdown. A Palmaz PS-30 stent was advanced to the coarctation through a 10 French sheath, and expanded with an angioplasty balloon chosen to equal the diameter of the proximal aorta (9-12 mm). Stent implantation was successful in each dog. The systolic pressure gradient decreased from 26.3 +/- 9.1 mmHg (mean +/- SE) to 0.5 +/- 0.5 mmHg (P = 0.04), and the coarctation diameter improved from 50 +/- 6% to 82 +/- 6% of the diameter of the proximal descending aorta (P less than 0.01). Follow-up catheterization 4-7 weeks after stenting documented no stent migration, early restenosis, thrombosis, obstruction of arterial side branches, or aneurysm formation. Pathological evaluation of the explanted segments of stented aorta documented that by 6-7 weeks the stents are covered by a neointima composed of intimal proliferation and fibrosis with an endothelial cell surface. These data suggest that balloon-expandable stainless steel stents provide excellent acute and short-term relief of coarctation in this experimental model. Larger and longer-term studies are needed to better assess the incidence of restenosis or aneurysm formation following stenting of coarctation of the aorta.

Osteoid osteoma and osteoblastoma of the spine.

Eleven patients with spinal osteoid osteoma and six patients with spinal osteoblastoma treated between 1975 and 1990 were reviewed to characterize the tumors as they affect the spine and to define the important differences between the two tumors. All patients with cervical osteoid osteoma presented with pain, limited range of motion of the neck, and torticollis. Four osteoblastomas had soft-tissue components in the epidural space, necessitating dissection of the tumor from the dura. No soft-tissue component was found in any of the osteoid osteomas. Our results were similar to a metaanalysis of the clinical, radiographic, and surgical findings of all published cases of spinal osteoid osteoma and osteoblastoma. Important features that have not been emphasized in the literature are the high incidence of torticollis with cervical lesions and the frequent association of epidural invasion with osteoblastoma. Surgeons treating osteoblastoma of the spine should be prepared to dissect tumor from the dura.

Surgical repair is safe and effective after unsuccessful balloon angioplasty of native coarctation of the aorta.

Since 1985 balloon angioplasty, followed by surgical repair if angioplasty is unsuccessful, has been used as a treatment strategy for eligible children with discrete native coarctation of the aorta. Although balloon angioplasty has been successful in most patients, this strategy is appropriate only if surgery is safe and effective in children in whom angioplasty does not succeed. To address this issue, the surgical procedure and clinical outcome in 11 children who underwent surgery after unsuccessful balloon angioplasty (defined as a residual systolic gradient greater than 20 mm Hg in 10 and a saccular aneurysm in 1) were evaluated. Data for subjects were compared with data for a control group of seven children who had surgical repair of a discrete coarctation without prior angioplasty during the same time period. In the study group, balloon angioplasty was performed at 4.3 +/- 1.2 years of age, resulting in a balloon/isthmus ratio of 0.98 +/- 0.05 and decreasing mean peak systolic gradient from 54 +/- 3 to 27 +/- 2 mm Hg (p less than 0.001). Follow-up angiography (n = 7) or nuclear magnetic resonance imaging (n = 4) documented a discrete residual stenosis in 10 patients and a small saccular aneurysm in 1. Collateral circulation decreased in three patients. The subsequent surgical procedure and its outcome were similar in the study and control groups. Chylothorax was the only complication, occurring in one child from each group. No paraplegia or mortality occurred. Pathologic examination revealed irregular intimal surfaces with small flaps of intima in 5 of 10 resected specimens from the study group and in 2 of 6 from the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Echocardiographic indexes of allograft rejection in pediatric cardiac transplant recipients.

To determine the usefulness of echocardiographic indexes of left ventricular (LV) function as possible predictors of cardiac rejection, 12 transplant recipients (ages 3 to 17 years) underwent a total of 52 serial echocardiographic examinations and cardiac biopsies. The results were compared to those of 12 normal children (ages 2 to 17 years). Biopsies were graded as no rejection (n = 23), mild rejection (cellular infiltrate, n = 13), and moderate rejection (myocyte necrosis, n = 16). LV dimensions, percent shortening fraction, indexed LV mass, and ejection fraction were measured from M-mode and two-dimensional echocardiography. From the mitral valve Doppler tracing, the following measurements were made: isovolumic relaxation time, peak E and peak A velocities, and the fraction of filling under the E and A waves as well as in the first third of diastole. Compared with normal subjects, transplant recipients with no rejection had higher heart rates (95 +/- 15 vs 80 +/- 17 beats/min), longer isovolumic relaxation time (68.8 +/- 11.2 vs 51.5 +/- 13.6 msec), decreased first third area fraction (0.48 +/- 0.10 vs 0.57 +/- 0.10), and similar shortening fraction, LV mass, and peak E and A velocities (p less than 0.03). Compared with transplant recipients with no rejection, patients in whom mild rejection developed also had decreased shortening fraction (31% +/- 10% vs 37% +/- 8%) and decreased peak E velocity (0.68 +/- 0.19 vs 0.88 +/- 0.15 m/s) (p less than 0.03). From mild to moderate rejection, no further changes were noted in any echocardiographic indexes measured.(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged extracorporeal life support of pediatric and adolescent cardiac transplant patients.

Options for mechanical support of pediatric patients with severe heart failure who are awaiting transplantation or have undergone transplantation are limited. This report examines 3 patients placed on extracorporeal life support (ECLS) while awaiting transplantation and 3 patients who underwent transplantation and suffered subsequent heart failure due to rejection or postoperative myocardial dysfunction. The overall survival rate was 2 of 6. The 2 surviving patients had a failing transplanted heart. There were no survivors among the patients placed on ECLS as a bridge to transplantation. In each case a contraindication to transplantation developed before a donor heart could be obtained. The mean time of ECLS support was 147.5 hours (range, 70 to 370 hours). The ECLS circuit did not affect cyclosporin levels or antirejection therapy. Extracorporeal life support can be used to support pediatric cardiac transplant patients with biventricular failure due to acute rejection or postoperative dysfunction. Although the results have been discouraging, ECLS may still have a role as a bridge to transplantation. However, complications can develop during ECLS that may preclude transplantation.

Hepatic fibrosis with the use of methotrexate for juvenile rheumatoid arthritis.

Methotrexate (MTX) is currently under study for use in juvenile rheumatoid arthritis. One complication of MTX is hepatotoxicity. Although liver function tests may be abnormal with its use, in this setting they do not correlate well with the development of hepatic fibrosis. Periodic liver biopsy is required to monitor for the hepatotoxic changes secondary to MTX. We describe and discuss the case of a 17-year-old woman who developed evidence of hepatic fibrosis after 3 years of MTX therapy.