Cotyledon and binucleate cell nitric oxide synthase expression in an ovine model of fetal growth restriction.

Heat exposure early in ovine pregnancy results in placental insufficiency and intrauterine growth restriction (PI-IUGR). We hypothesized that heat exposure in this model disrupts placental structure and reduces placental endothelial nitric oxide synthase (eNOS) protein expression. We measured eNOS protein content and performed immunohistochemistry for eNOS in placentas from thermoneutral (TN) and hyperthermic (HT) animals killed at midgestation (90 days). Placental histomorphometry was compared between groups. Compared with the TN controls, the HT group showed reduced delivery weights (457 +/- 49 vs. 631 +/- 21 g; P < 0.05) and a trend for reduced placentome weights (288 +/- 61 vs. 554 +/- 122 g; P = 0.09). Cotyledon eNOS protein content was reduced by 50% in the HT group (P < 0.03). eNOS localized similarly to the vascular endothelium and binucleated cells (BNCs) within the trophoblast of both experimental groups. HT cotyledons showed a reduction in the ratio of fetal to maternal stromal tissue (1.36 +/- 0.36 vs. 3.59 +/- 1.2; P< or = 0.03). We conclude that eNOS protein expression is reduced in this model of PI-IUGR and that eNOS localizes to both vascular endothelium and the BNC. We speculate that disruption of normal vascular development and BNC eNOS production and function leads to abnormal placental vascular tone and blood flow in this model of PI-IUGR.

Hepatoblastoma in a neonate: a hypervascular presentation mimicking hemangioendothelioma.

Congenital heart failure in the neonate supported by classic imaging findings may allow the implementation of medical therapy for presumed hemangioendothelioma without obtaining a tissue diagnosis. This case report describes a neonate with these classic clinical and radiographic findings but who underwent surgery for failing medical treatment and was diagnosed as having a hepatoblastoma by pathology. This case supports the need to obtain tissue confirmation before beginning medical therapy.

Cystic renal lymphangiectasia presenting as renal insufficiency in childhood.

Cystic renal lymphangiectasia is an unusual cause of cystic renal disease in childhood. We present a case of bilateral cystic renal lymphangiectasia in a 7-year-old boy who presented with asymptomatic renal insufficiency and anemia with decreased erythropoietin production. The clinical features of this condition and the diagnostic approach are reviewed. Although rare, this disorder should be considered in the differential diagnosis of cystic renal disease.

Picornavirus infection in early murine gestation: significance of maternal illness.

To evaluate whether maternal illness following picornavirus infection during pregnancy adversely affects placental and fetal health, mice were inoculated with the GDVII strain of Theiler's murine encephalomyelitis virus or control cell lysate during days 4-7 of gestation. Gross appearance, histopathology and viral culture, and in situ hybridization positivity of placentae and fetuses from ill GDVII-infected, healthy GDVII-infected and control mice were compared. Twenty of 34 (59 per cent) GDVII-infected dams became clinically ill. More placenta-fetus pairs from ill mice were grossly abnormal (68 per cent) than from well GDVII-infected (51 per cent;P< 0.01) or control mice (9 per cent;P< 0.001). Virus was detected by in situ hybridization in 73 per cent of placentae and 29 per cent of fetuses from sick GDVII-infected dams, and in 85 per cent of placentae and 19 per cent of fetuses from healthy GDVII-infected mice (differences not significant). Histological abnormalities consisting of necrosis or an increase in hyaline tissue in the vascular labyrinth layer were similarly frequent in placentae from ill and well GDVII-infected mice (58 per cent versus 67 per cent, P=0.5). Viral RNA, inflammation and necrosis were evident in the heart, great vessels, brain and spinal cord of GDVII-infected fetuses. Infection with GDVII in early pregnancy produces a high rate of gross placental and fetal abnormalities. The rate of gross abnormalities exceeds the incidence of fetal infection and more closely parallels the rates of infection and histopathology in the placenta, suggesting that much of the damage to placenta-fetus pairs is a consequence of placental infection. In addition, the occurrence of viral-induced maternal illness is associated with additive risk to placental and fetal health not explained by an increased rate of placental or fetal infection.

Protection of murine gestational tissues from picornavirus infection in the preimplantation period.

Mice were inoculated with Theiler's murine encephalomyelitis virus (TMEV) on gestational days 1-3 (pre-implantation) or days 4-5 (peri- or post-implantation) or with control cell lysate (days 1-5). Dams were subsequently sacrificed between days 11-14 of gestation, and placentae and fetuses were harvested. Few placentae from dams inoculated with virus on days 1-3 were positive by virus culture (2 per cent) or in situ hybridization (6 per cent), and no fetuses were positive by either technique. In contrast, most placentae from dams inoculated with virus on days 4-5 were virus-positive by culture (96 per cent) or in situ hybridization (100 per cent), and a moderate number of fetuses were also positive (30 per cent by culture, 19 per cent by in situ hybridization). Necrosis was present more frequently in placentae from mice inoculated with virus on days 4-5 (55 per cent) than in placentae from dams inoculated with virus on days 1-3 (19 per cent) or with control cell lysate (18 per cent). Viral infection, mononuclear inflammation and cell necrosis were identified in the heart and great vessels of TMEV-infected fetuses. These results indicate that gestational tissues are largely protected from viral infection before implantation. After implantation, gestational tissues are more readily infected and damaged by maternal picornavirus infection.

Astroblastoma: ultrastructural observations on a case of high-grade type.

An astroblastoma of high-grade type arising in the brain of a 3-year-old child is reported. The first description of the ultrastructural, immunohistochemical, and cytogenetic findings in this rare tumor variant are presented.

Liver disease in Navajo neuropathy.

OBJECTIVE: To describe clinical and histologic features of liver disease in infants and children with Navajo neuropathy (NN). METHODS: Physicians at Navajo Area Indian Health Service facilities and neurologists and gastroenterologists at regional referral hospitals were surveyed for identification of patients born between 1980 and 1994 with known or suspected NN. Clinical records and liver histologic findings were reviewed. RESULTS: Liver disease was present in all children with NN. Three clinical phenotypes of NN were observed, based on age at presentation and course: infantile NN presented in 5 infants before 6 months of age with jaundice and failure to thrive and progressed to liver failure before 2 years of age; childhood NN presented in 6 children between 1 and 5 years of age with liver dysfunction, which progressed to liver failure and death within 6 months; and classical NN presented in 9 children with variable onset of liver disease but progressive neurologic deterioration. Liver histologic findings were characterized by multinucleate giant cells, macrovesicular and microvesicular steatosis, pseudo-acini, inflammation, cholestasis, and bridging fibrosis and cirrhosis. Cases of all 3 phenotypes occurred within the same kindred. CONCLUSIONS: Liver disease is an important component of NN and may be the predominant feature in infants and young children. We propose changing the name of this disease to Navajo neurohepatopathy.

Congenital pulmonary venous stenosis presenting as persistent pulmonary hypertension of the newborn.

Congenital pulmonary venous stenosis (CPVS) has been previously described in older infants and children, typically manifesting as failure to thrive with congestive heart failure and subsequent respiratory deterioration. We report on 2 cases of CPVS which presented during the immediate newborn period as severe persistent pulmonary hypertension of the newborn.

Fulminant Epstein-Barr viral hepatitis: orthotopic liver transplantation and review of the literature.

Acute hepatic failure caused by primary Epstein-Barr virus (EBV) infection has been reported in the literature in 16 cases, with an overall mortality of 87%. We report a case of fulminant hepatic failure in an immunocompetent young girl caused by primary EBV infection that was treated by orthotopic liver transplantation. After transplantation she has been treated with low-dose immunosuppression, a pooled gammaglobulin preparation containing anti-EBV antibodies, and anti-viral therapy. The patient is presently doing well 2 years after transplantation without evidence of clinical EBV infection, primary immunodeficiency, or lymphoproliferative disease.

Severe aortic regurgitation with mechanical prosthetic valve replacement in pauciarticular juvenile rheumatoid arthritis.

We describe a patient with pauciarticular juvenile rheumatoid arthritis with aortic insufficiency who underwent successful aortic valve replacement with a mechanical prosthetic valve.

Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts.

Extrahepatic biliary atresia (EHBA) and choledochal cysts (CDC) are important causes of obstructive jaundice in pediatric patients. Viruses in general, and reoviruses in particular, have long been considered as possible etiologic agents responsible for inciting the inflammatory process that leads to these infantile obstructive cholangiopathies. In an effort to determine whether reovirus infection is associated with these disorders, we used a sensitive and specific reverse-transcriptase polymerase chain reaction (RT-PCR) technique designed to amplify a portion of the reovirus L1 gene segment from extracts of liver and/or biliary tissues. These tissues were obtained at the time of liver biopsy or surgical procedures from 23 patients with EHBA, 9 patients with CDC, and 33 patients with other hepatobiliary diseases. Hepatic and biliary tissues obtained at autopsy from 17 patients who died without known liver or biliary disease were also analyzed. Reovirus RNA was detected in hepatic and/or biliary tissues from 55% of patients with EHBA and 78% of patients with CDC. Reovirus RNA was found also in extracts of hepatic and/or biliary tissue from 21% of patients with other hepatobiliary diseases and in 12% of autopsy cases. The prevalence of reovirus RNA in tissues from patients with EHBA and CDC was significantly greater than that in patients with other hepatobiliary diseases (chi2 P = .012 EHBA vs. OTHER, P = .001 CDC vs. OTHER), or AUTOPSY cases (chi2 P = .006 EHBA vs. AUTOPSY, P < .001 CDC vs. AUTOPSY).

Intravascular ultrasonic characteristics and vasoreactivity of the pulmonary vasculature in children with pulmonary hypertension.

We sought to describe the morphologic characteristics of pulmonary arteries by intravascular ultrasound (IVUS) in children with and without pulmonary hypertension to compare these anatomic findings with those of pulmonary wedge angiography, and to determine the relation between these structural findings and functional reactivity to pulmonary vasodilators. Direct evaluation of pulmonary vascular structure in children with pulmonary hypertension with current imaging techniques has been limited and little is known about the relation between structural and functional characteristics of the pulmonary vasculature. In 23 children undergoing cardiac catheterization (15 with pulmonary hypertension and 8 controls) we performed IVUS and pulmonary wedge angiography of the distal pulmonary arteries in the same lobe. IVUS was performed in 44 pulmonary arteries measuring 2.5 to 5.0 mm internal diameter with a 3.5Fr 30-MHz IVUS catheter. We assessed vasoreactivity to inhaled nitric oxide (NO) and oxygen in 13 of 15 children with pulmonary hypertension. Baseline pulmonary vascular resistance (PVR) was greater in the 15 children with pulmonary hypertension than in the 8 controls (9.5+/-1.9 vs 1.5+/-0.3 U x m2, p <0.05). NO lowered PVR in patients with pulmonary hypertension (p <0.05). IVUS studies in patients with pulmonary hypertension showed a thicker middle layer, wall thickness ratio, and diminished pulsatility than did those in controls (p <0.05). The inner layer was not visualized by IVUS in any control patient, but was seen in 9 of 15 patients with pulmonary hypertension. Pulmonary artery wedge angiography correlated with baseline mean pulmonary artery pressure and PVR as well as with IVUS findings of wall thickness ratio and inner layer thickness. The inner layer was not visualized by IVUS in any patient with grade 1 wedge angiograms or in 86% of patients with grade 2 wedge angiograms. All patients with grade 4 and 80% of patients with grade 3 wedge angiograms had a visible inner layer. Vasoreactivity to NO and oxygen did not correlate with structural assessment of the pulmonary vasculature by IVUS. Structural changes in the pulmonary arteries in children with pulmonary hypertension can be directly visualized by IVUS, but are not predictive of NO-induced pulmonary vasodilation. IVUS examination of pulmonary arteries may complement current techniques utilized in the evaluation of children with pulmonary hypertension.

Adverse effects of maternal enterovirus infection on the fetus and placenta.

Gestational outcome in a murine model of congenital enterovirus infection was evaluated. Pregnant mice were inoculated intravenously with Theiler's murine encephalomyelitis virus (TMEV), a murine enterovirus, or with BHK 21 cell lysate (control) at 6-7 days of gestation (early) and sacrificed 6 or 12 days later, and their placentas and fetuses were studied. High rates of gross and histologic abnormalities (50%-87%) were seen in placentas and fetuses from dams infected with TMEV and sacrificed 6 days later. TMEV-infected dams sacrificed 12 days after inoculation had lower rates of placental-fetal abnormalities (25%-57%) but an additional 42% rate of complete pregnancy loss. Pregnancy loss (9%) and placental-fetal abnormalities (4%-7%) were uncommon in control animals. Rates of fetal abnormalities and placental infection in infected dams exceeded fetal viral infection, suggesting that TMEV infection adversely affects pregnancy either directly by fetal damage or indirectly by placental compromise.

Intra-operative radiation therapy in pediatric neuroblastoma.

External beam irradiation (EBRT) has been shown to improve response rates and event-free survival in children with neuroblastoma and regional lymph node metastases. Irradiation during surgical exposure (intra-operative radiotherapy, IORT) with displacement of adjacent radiosensitive organs out of the treatment field allows for more precise delineation of the target volume and significantly reduces the amount of normal tissue exposed to irradiation. We have incorporated IORT into the treatment regimen of 24 children with neuroblastoma between the years of 1983-1991. IORT was directed to any residual tumor or the tumor bed; the median dose of radiation was 1,000 cGY, equivalent to 3,000 cGY of conventional EBRT. There were 11 males and 13 females. Two patients had stage II, 12 patients had stage III, and 10 patients had stage IV disease. Ten children received IORT for suspected recurrent or persistent neuroblastoma. Twelve patients were disease-free survivors following IORT with a median follow-up of 54 months. For those patients with stage III disease, seven children were disease-free survivors, while only three of 10 patients with stage IV disease survived (median follow-up 30 months). Disease-free Survival (DFS) correlated with the achievement of local tumor control in children with both stage III and IV neuroblastoma. There was limited morbidity and no episodes of obstructive uropathy were encountered. We conclude that IORT appears to be well tolerated and may have therapeutic benefit for a select group of patients with neuroblastoma. IORT merits future exploration by prospective study.

Fatal meconium aspiration in spite of appropriate perinatal airway management: pulmonary and placental evidence of prenatal disease.

OBJECTIVE: Our purpose was to summarize eight cases of fatal meconium aspiration syndrome where pathologic review showed evidence of chronic prenatal disease and to compare these findings with those of a group of control infants and fetuses who died of other causes. STUDY DESIGN: A 15-year retrospective chart review identified the infants who died of meconium aspiration within 48 hours of life and who also had autopsies performed. Neonatal pulmonary and available placental pathologic findings are described from these study infants and are compared with published norms and with autopsy results from a group of control infants and fetuses. RESULTS: Seven of the eight study infants underwent suctioning of the trachea immediately after birth. In all eight cases the neonatal lungs demonstrated histologic evidence of significant hypoxic changes of a chronic nature with onset before birth. The available placentas showed variable but significant abnormalities that support a case for subacute or chronic in utero compromise. CONCLUSIONS: As in other reports, there is evidence that meconium aspiration may be a prenatal rather than a postnatal disease. However, this is the first study that presents evidence on the basis of both pulmonary and placental pathologic findings and reinforces the importance of placental examinations in complicated pregnancies.

Balamuthia mandrillaris meningoencephalitis presenting with acute hydrocephalus.

The leptomyxid amoeba Balamuthia mandrillaris, previously believed to be a harmless soil-inhabiting organism, is now known to be a rare but consistently lethal cause of meningoencephalitis in humans. We report a case of amebic meningoencephalitis caused by B. mandrillaris which presented as a febrile illness with acute hydrocephalus.

Fulminant hepatitis associated with centrilobular hepatic necrosis in young children.

OBJECTIVE: To describe fulminant hepatic failure (FHF) in children in the United States with clinical and histopathologic features distinctly different from those typical of FHF. PATIENTS: Seven young children were seen in early 1994 with encephalopathy, coagulopathy, and elevated aminotransferase levels. Liver failure was preceded by a prodromal viral illness that resulted in a period of fasting without dehydration. Unlike the majority of children with FHF, these patients had serum bilirubin levels < 171 mumol/L (10 mg/dl). All children had received therapeutic doses of acetaminophen during the prodromal illness. HISTOPATHOLOGIC FINDINGS: Histologic findings included zonal necrosis of hepatocytes in a centrilobular distribution, which is characteristic of toxic liver injury but is atypical for viral hepatitis and sporadic non-A non-B hepatitis. OUTCOME: Six patients recovered spontaneously, and one died of complications of liver failure and fungal sepsis. The cause of this disorder remains unknown, but we postulate a viral or environmental insult that preferentially damages zone 3 hepatocytes. The potential for this injury may have been augmented by ingestion of therapeutic doses of acetaminophen while patients were in a fasted state. The prognosis was good compared with typical FHF in children and correlated with the degree of liver necrosis on histologic examination.

Anastomotic ulceration: a late complication of ileocolonic anastomosis.

Symptomatic ulceration developed at a previous ileocolonic anastomosis in six children. In the neonatal period all patients had had necrotizing enterocolitis that required resection of the terminal ileum, ileocecal valve, and proximal portion of the colon. Gross or occult rectal bleeding, with or without pain and diarrhea, began 5 1/2 years after successful resection and ileocolonic anastomosis. The cause of the ulcers is unknown. They appear inflammatory, both grossly and histologically, but have been uniformly unresponsive to antiinflammatory medications, antibiotics, and immunosuppressive medication. Surgical revision of the anastomosis and ulcer resection in five patients have resulted in rapid recurrence in four. Thirteen similar cases have been reported in the English-language literature. We conclude that ulceration is a long-term complication of neonatal resection of the terminal ileum and ascending colon with ileocolonic anastomosis.