Decreased kainate receptor binding in the arcuate nucleus of the sudden infant death syndrome.

The human arcuate nucleus is postulated to be homologous to ventral medullary surface cells in animals that participate in ventilatory and blood pressure responses to hypercarbia and asphyxia. Recently, we reported a significant decrease in muscarinic cholinergic receptor binding in the arcuate nucleus in victims of the sudden infant death syndrome compared with control patients that died of acute causes. To test the specificity of the deficit to muscarinic cholinergic binding, we examined kainate binding in the arcuate nucleus in the same database. We assessed 3H-kainate binding to kainate receptors with tissue receptor autoradiography in 17 brainstem nuclei. Analysis of covariance was used to examine differences in binding by diagnosis, adjusted for postconceptional age (the covariate). Cases were classified as SIDS, 47; acute control, 15; and chronic group with oxygenation disorder, 17. (Acute controls are infants who died suddenly and unexpectedly and in whom a complete autopsy established a cause of death). The arcuate nucleus was the only region in which there was a significant difference in the age-adjusted mean kainate binding between the SIDS group (37+/-2 fmol/mg tissue) and both the acute controls (77+/-4 fmol/mg tissue) (p < 0.0001) and the chronic group (69+/-4 fmol/mg tissue) (p < 0.0001). There was a positive correlation between the density of muscarinic cholinergic and kainate binding in the SIDS cases only (R = 0.460; p = 0.003). The neurotransmitter deficit in the arcuate nucleus in SIDS victims involves more than one receptor type relevant to carbon dioxide and blood pressure responses at the ventral medullary surface.

Decreased serotonergic receptor binding in rhombic lip-derived regions of the medulla oblongata in the sudden infant death syndrome.

The sudden infant death syndrome (SIDS) is postulated to result from a failure of homeostatic responses to life-threatening challenges (e.g. asphyxia, hypercapnia) during sleep. The ventral medulla participates in sleep-related homeostatic responses, including chemoreception, arousal, airway reflex control, thermoregulation, respiratory drive, and blood pressure regulation, in part via serotonin and its receptors. The ventral medulla in humans contains the arcuate nucleus, in which we have shown isolated defects in muscarinic and kainate receptor binding in SIDS victims. We also have demonstrated that the arcuate nucleus is anatomically linked to the nucleus raphé obscurus, a medullary region with serotonergic neurons. We tested the hypothesis that serotonergic receptor binding is decreased in both the arcuate nucleus and nucleus raphé obscurus in SIDS victims. Using quantitative autoradiography, 3H-lysergic acid diethylamide (3H-LSD binding) to serotonergic receptors (5-HT1A-D and 5-HT2 subtypes) was measured blinded in 19 brainstem nuclei. Cases were classified as SIDS (n = 52), acute controls (infants who died suddenly and in whom a complete autopsy established a cause of death) (n = 15), or chronic cases with oxygenation disorders (n = 17). Serotonergic binding was significantly lowered in the SIDS victims compared with controls in the arcuate nucleus (SIDS, 6 +/- 1 fmol/mg tissue; acutes, 19 +/- 1; and chronics, 16 +/- 1; p = 0.0001) and n. raphé obscurus (SIDS, 28 +/- 3 fmol/mg tissue; acutes, 66 +/- 6; and chronics, 59 +/- 1; p = 0.0001). Binding, however, was also significantly lower (p < 0.05) in 4 other regions that are integral parts of the medullary raphé/serotonergic system, and/or are derived, like the arcuate nucleus and nucleus raphé obscurus, from the same embryonic anlage (rhombic lip). These data suggest that a larger neuronal network than the arcuate nucleus alone is involved in the pathogenesis of SIDS, that is, a network composed of inter-related serotonergic nuclei of the ventral medulla that are involved in homeostatic mechanisms, and/or are derived from a common embryonic anlage.

Brainstem 3H-nicotine receptor binding in the sudden infant death syndrome.

Maternal cigarette smoking during pregnancy has been shown to be a major risk factor for the sudden infant death syndrome (SIDS). We hypothesized that SIDS is associated with altered 3H-nicotine binding to nicotinic receptors in brainstem nuclei related to cardiorespiratory control and/or arousal. We analyzed 3H-nicotine binding in 14 regions in SIDS and control brainstems using quantitative tissue receptor autoradiography. Three groups were analyzed: SIDS (n = 42), acute controls (n = 15), and a chronic group with oxygenation disorders (n = 18). The arcuate nucleus, postulated to be important in cardiorespiratory control and abnormal in at least some SIDS victims, contained binding below the assay detection limits in all (SIDS and control) cases. We found no significant differences among the 3 groups in mean 3H-nicotine binding in the 14 brainstem sites analyzed. When a subset of the cases were stratified by the history of the presence or absence of maternal cigarette smoking during pregnancy, however, we found that there was no expected increase (upregulation) of nicotinic receptor binding in SIDS cases exposed to cigarette smoke in utero in 3 nuclei related to arousal or cardiorespiratory control. This finding raises the possibility that altered development of nicotinic receptors in brainstem cardiorespiratory and/or arousal circuits put at least some infants, i.e. those exposed to cigarette smoke in utero, at risk for SIDS, and underscores the need for further research into brainstem nicotinic receptors in SIDS in which detailed correlations with smoking history can be made.

Bilateral juvenile granulosa cell tumors in a 4-month-old dysmorphic infant. A clinical, histologic, and ultrastructural study.

Juvenile granulosa cell tumors were encountered within bilateral cystic ovarian masses in a 4-month-old infant. The child was the product of a consanguinous pregnancy, and manifested poor growth, relative microcephaly, facial asymmetry, and a malformed left ear. There was no history of gestational drug or hormone ingestion, and no evidence of abnormal endocrine activity after birth, however, the serum alpha-fetoprotein level was mildly elevated. The tumors were well defined by sonography and there was no evidence of metastasis. Histologically, a dense proliferation of round to oval tumor cells showed considerable individual cell necrosis and frequent microcyst formation. There was no evidence of luteinization and only mild nuclear pleomorphism. Immunoperoxidase study failed to reveal alpha-fetoprotein. Ultrastructural study supported the granulosa cell nature of the tumor, but a few cells contained bundles of intracytoplasmic filaments. There has been no evidence of recurrent disease during a 16-month follow-up period, and serial alpha-fetoprotein determinations have remained in the reference range. Comparison with two previously reported bilateral juvenile granulosa cell tumors suggests that this tumor occurs in young infants, and is amenable to conservative therapy.

Epidemiology of sudden infant death syndrome in American Indians.

A 7-year retrospective study of sudden infant death syndrome in Oklahoma Indians failed to support previous observations of a markedly elevated rate among the American Indians compared with the white population. The rate of sudden infant death syndrome in Oklahoma Indians was 2.32/1,000 live births. The rates of sudden infant death syndrome among white infants (1.8/1,000) and black infants (3.11/1,000) were similar to those reported in previous studies. Males had consistently higher rates of sudden infant death syndrome regardless of race.

Common pulmonary vein atresia: the role of extracorporeal membrane oxygenation.

Common pulmonary vein atresia is a rare form of cyanotic congenital heart disease in which the pulmonary veins join to form a blind confluence that does not communicate with the heart or the major systemic veins. Twenty-one cases have been reported since the lesion was first described in 1962; only two patients with this lesion have survived. Over a 4-year period, common pulmonary vein atresia was diagnosed in five newborns referred to the San Diego Regional Extracorporeal Membrane Oxygenation Program. All five improved dramatically as a result of venoarterial bypass. Congenital heart disease was diagnosed at autopsy in the initial case and by cardiac ultrasound and/or catheterization in the others. Surgical repair was attempted in three neonates; all three required continued extracorporeal membrane oxygenation support postoperatively because of pulmonary hypertension and severe pulmonary parenchymal disease. One infant died of respiratory insufficiency at 3 months of age. The other two survived and were discharged from the hospital. The diagnostic and therapeutic dilemmas posed by this lesion and the life-saving potential for extracorporeal membrane oxygenation in this rapidly fatal cardiac anomaly are the bases of this report.

Effect of sleep state and position on the incidence of obstructive and central apnea in infants.

Sixty-four infants with a history of apnea were studied to determine the effects of sleeping position and sleep state (rapid eye movement [REM]) v (non-rapid eye movement [NREM]) on the occurrence of central and obstructive apneas. All-night polysomnographic studies were conducted on each infant, and the spontaneous occurrence of central and obstructive apneic events was determined in the prone, supine, and side positions. Sleeping position did not significantly affect the rate or duration of central or obstructive apneas. Furthermore, neither central nor obstructive apneic episodes were significantly altered by sleep state. These data suggest that, in spite of an ostensible predisposition to upper airway obstruction in the supine position and during rapid eye movement sleep, neither sleeping position nor sleep state appears to affect the rate of duration of apneic events.

Female infant with oncocytic cardiomyopathy and microphthalmia with linear skin defects (MLS): a clue to the pathogenesis of oncocytic cardiomyopathy?

A infant girl had red stellate skin lesions on the cheeks and neck, and mildly short palpebral fissures. Her skin abnormality was typical of microphthalmia with linear skin defects (MLS), a newly recognized syndrome consisting of congenital linear skin defects and ocular abnormalities in females monosomic for Xp22. She died suddenly and unexpectedly at age 4 months; the cause of death was ascribed to oncocytic cardiomyopathy. Oncocytic cardiomyopathy occurs only in young children, who present with refractory arrhythmias leading to cardiac arrest. The coexistence of two rare conditions, one of which is mapped to the X chromosome, and an excess of affected females with oncocytic cardiomyopathy, make it likely that oncocytic cardiomyopathy is also X-linked, with Xp22 being a candidate region. Overlapping manifestations in the two conditions (ocular abnormalities in cases of oncocytic cardiomyopathy and arrhythmias in MLS) offer additional support for this hypothesis.

Diphenylhydantoin-induced hypersensitivity reaction with interstitial nephritis.

A 10-year-old black girl had an episode of diphenylhydantoin(DPH)-induced exfoliative dermatitis, lymphadenopathy, hepatitis, peripheral eosinophilia, and transient renal failure. The findings of specific lymphocyte sensitization of DPH, a clinically typical delayed hypersensitivity reaction, multinucleated histiocytes in the renal interstitium, and negative renal immunofluorescence studies for immune reactants indicate that the child's renal injury was at least partially cell-mediated.

Germ cell neoplasms of head and neck soft tissues: a pathologic spectrum of teratomatous and endodermal sinus tumors.

Germ-cell neoplasms, in particular teratomas with immature and mature somatic type tissues, are some of the most commonly found tumors in children. Approximately 5% of these neoplasms appear in one of several extracranial sites in the head and neck region. This study reports the clinical, pathologic and immunohistochemical findings in six germ-cell neoplasms occurring in the neck and facial areas. A mass was recognized at birth in five children, and the sixth patient was 2 1/2 years old at diagnosis. Four of the six neoplasms contained one or another element of endodermal sinus tumor; two of these had a mixed pattern of endodermal sinus tumor and teratoma. The other two cases were purely teratomas. The serum alpha-fetoprotein was known to be elevated in three children whose tumors had endodermal sinus elements; it returned to normal level in two of the children, but remained high in the one fatal case. Placental alkaline phosphatase and alpha-fetoprotein were demonstrated immunohistochemically in two of the three cases, with available tissue containing endodermal sinus tumor. Teratomatous metastases in ipsilateral cervical lymph nodes were found in one patient with a pure teratoma; that patient is disease-free one year after surgery. Only nine previous examples of endodermal sinus tumor have been reported in the head and neck region, exclusive of the central nervous system. There is one other case in the literature of a congenital cervicothyroidal teratoma with metastatic disease. These six neoplasms illustrate the clinical and pathologic spectrum in this nosologically homogeneous, but morphologically diverse, category of tumors.

Adenovirus myocarditis: retrospective diagnosis by gene amplification from formalin-fixed, paraffin-embedded tissues.

Understanding the pathogenesis of viral myocarditis is linked to the availability of sensitive assays to detect viruses in clinical material. Recent advances in molecular techniques permit direct detection of viral-specific nucleic acid in tissue samples. This report describes a protocol for DNA extraction and amplification of adenovirus genome from formalin-fixed, paraffin-embedded human tissues that detects as little as 10 copies of viral genome in a background of 0.5 micrograms of human DNA. This sensitive assay permitted the examination of archived tissues to establish a retrospective diagnosis of adenoviral myocarditis in two pediatric patients.

Vasoactive intestinal polypeptide in cardiac myxoma.

A case of left atrial myxoma is reported in which tumor tissue was found to contain high levels of vasoactive intestinal polypeptide. This finding further supports the concept that myxomas are true neoplasms and may explain some of the poorly understood clinical manifestations of this tumor.

Molecular identification of viruses in sudden infant death associated with myocarditis and pericarditis.

A subset of infants dying suddenly and unexpectedly have myocarditis with or without pericarditis found at autopsy. To address whether viruses known to cause infantile myocarditis and pericarditis might be present in such infants, we examined myocardium, liver and skeletal muscle for the presence of genomic sequences from adenovirus, cytomegalovirus, enterovirus and echovirus 22/23 in infants enrolled in a comprehensive evaluation protocol. We studied eight infants who died suddenly and unexpectedly with histologic evidence of myocarditis and/or pericarditis detected at postmortem examination. One infant with myocarditis and pericarditis had adenovirus genome detected in the myocardium. In an additional infant with severe pericarditis alone, enterovirus genome was detected in the liver. Although echovirus 22/23 has been associated with myopericarditis in young infants, no previous studies have used molecular methods to search for the genomic sequences of these viruses in clinical samples. No echovirus 22/23 genome was detected in the patients reported here. The significance of enterovirus and adenovirus genome in the tissues of two patients dying suddenly and unexpectedly remains speculative but raises the possibility that pathogenic viruses may cause little or no clinical symptoms and yet be contributory to sudden death in young infants.

Subdural hematoma following open-heart operations.

Six patients who died following open-heart operations were found at postmortem examination to have acute subdural hematomas. On the basis of the clinical and postmortem findings, two factors in the pathogenesis of the hemorrhage are postulated. In the presence of intraoperative heparin administration, significant hematoma formation may result from damage to the bridging dural veins from minor, inadvertent head trauma or alterations in cerebral volume from fluid shifts. Manipulation of the head in patients who have been given heparin should be undertaken with extreme care, particularly in infants. In any patient with neurological dysfunction who has also had an open-heart operation, the possibility of an expanding subdural hematoma must be considered.

Second report of a translocation involving 19q13.4 in a mesenchymal hamartoma of the liver.

Cytogenetic study of a mesenchymal hamartoma of the liver detected a balanced translocation between chromosomes 11 and 19 in a 6-month-old male whose constitutional karyotype was normal. The chromosome 19 breakpoint, 19q13.4, appears to be identical to one of the breakpoints identified in the only other mesenchymal hamartoma studied with cytogenetic methods.

Unbalanced translocation resulting in the loss of the chromosome 17 short arm in an osteoblastoma.

We report results of the first cytogenetic study of an osteoblastoma. Cells from the tumor were characterized by a three-way unbalanced translocation involving chromosomes 15, 17, and 20. As a consequence of the translocation, most of one chromosome 17 short arm appears to have been lost. This loss suggests the possibility that loss of 17p DNA sequences may be involved in early changes leading to neoplastic proliferation of osteoblasts.

Hepatoblastoma characterized by trisomy 20 and double minutes.

Karyotypic study of two hepatoblastomas revealed trisomies for chromosome 20 and the presence of double minutes (dmin). These cases are the second and third examples of trisomy 20 in hepatoblastoma and are the first examples of dmins in this rare childhood tumor.

Presence or absence of trisomy 11 is correlated with histologic subtype in congenital mesoblastic nephroma.

Fluorescence in situ hybridization utilizing a probe for the alpha satellite repeat sequence on chromosome 11 was used to detect variations in the number of chromosomes 11 in 24 formalin-fixed, paraffin-embedded congenital mesoblastic nephromas. Evidence of trisomy 11 was found in nearly half of the tumors. More importantly, the presence of trisomy 11 was associated with the cellular histologic variant of this tumor.

Developmental morphometry of the vagus nerve in the opossum.

Developmental morphology of the vagus nerve has been described for placental but not marsupial mammals such as the opossum which undergo even greater postnatal maturation. In the present study, the cervical vagus nerve of opossums from the seventh postnatal day to the adult were compared after 3% glutaraldehyde immersion, postfixation in osmium tetroxide and staining with uranyl acetate and lead citrate. At 7 days of age, axons were unmyelinated. Only 4 myelinated axons were present at the 25th postnatal day and by 50 days of age only 11% of adult values were reached. The number of Schwann cells increased from 105 at age 7 days up to 640 in the adult. The number of myelin lamellae surrounding the largest axons increased from 9 at 25 days up to 102 +/- 9 at adulthood. In the newborn kitten and rabbit, the number of myelinated vagal fibers comprised 10% (n = 326) and 18% (n = 653), respectively, of that reached in the adult animal. Comparable values are not obtained in the opossum until the 50th postnatal day.

Pulmonary vasculitis with hemorrhage in anaphylactoid purpura.

We report a 14-year-old female with anaphylactoid purpura (AP) who developed pulmonary hemorrhage with acute vasculitis on lung biopsy. She improved with pulse methylprednisolone, daily prednisone and ventilatory assistance. Pulmonary vasculitis is a rare but serious manifestation of AP.