Glycosaminoglycan metabolism defects and atherosclerosis: frequent association of endothelial dysfunction in patients with Mucopolysaccharidosis.

Cardiovascular lesions, including coronary artery stenosis, are frequently associated and can cause sudden death in patients with genetic defects of glycosaminoglycan (GAG) metabolism. Early diagnosis of coronary artery lesions is difficult, although potentially lifesaving. Histopathological similarities between atherosclerotic changes in adults and in patients with genetic GAG metabolism defects have been known. Atherosclerosis is the result of a complex process involving metabolism of GAGs and proteoglycans preceded by endothelial dysfunction as a key event. Decreased nitric oxide (NO) bioavailability is considered the hallmark of endothelial dysfunction. Reduced NO synthase (NOS) has been reported in atherosclerotic arteries. Impairment in reactive hyperemia-digital peripheral arterial tonometry (RH-PAT) with EndoPAT has been validated to correlate coronary microvascular function in patients with atherosclerosis. RH-PAT is thought to reflect endothelial NO production. Immunohistological staining of endothelial NOS was performed in the stenotic lesions in the coronary artery of a 3-year-old patient with Mucopolysaccharidosis-I, showing decreased activities. This prompted a study to measure endothelial function in patients with GAG metabolism defects for early diagnosis of endothelial dysfunction in the coronary arteries as an early sign of coronary artery changes. Evaluation by RH-PAT in 30 patients with variable genetic defects in GAG metabolism revealed significantly decreased Reactive Hyperemia Indexes compared with 12 controls. Evaluation of endothelial function with RH-PAT in patients with GAG metabolism defects may detect coronary artery lesions that can be underdiagnosed by the other measures such as coronary angiography. Use of this method may prove vital in the management of patients with GAG metabolism defects.

Unequivocal identification of brown adipose tissue in a human infant.

We report the unique depiction of brown adipose tissue (BAT) by magnetic resonance imaging (MRI) and computed tomography (CT) in a human 3-month-old infant. Based on cellular differences between BAT and more lipid-rich white adipose tissue (WAT), chemical-shift MRI and CT were both capable of generating distinct signal contrasts between the two tissues and against surrounding anatomy, utilizing fat-signal fraction metrics in the former and x-ray attenuation values in the latter. While numerous BAT imaging experiments have been performed previously in rodents, the identification of BAT in humans has only recently been described with fusion positron emission and computed tomography in adults. The imaging of BAT in children has not been widely reported and, furthermore, MRI of human BAT in general has not been demonstrated. In the present work, large bilateral supraclavicular BAT depots were clearly visualized with MRI and CT. Tissue identity was subsequently confirmed by histology. BAT has important implications in regulating energy metabolism and nonshivering thermogenesis and has the potential to combat the onset of weight gain and the development of obesity. Current findings suggest that BAT is present in significant amounts in children and that MRI and CT can differentiate BAT from WAT based on intrinsic tissue properties.

Infant with Clinical Evidence of Pulmonary Hypoplasia: A Case Report.

Pulmonary hypoplasia is the incomplete development of lung tissue. A reduced number of lung cells, airways, and alveoli is the hallmark and can be seen unilaterally or in both lungs. The diagnosis, however, is usually made upon pathologic examination. Here we have presented a case of a term infant presenting with severe hypoxemic respiratory failure. Despite optimizing medical and respiratory management, the infant passed away at 22 hours of life. On autopsy, she was discovered to have bilateral diaphragmatic eventrations, which is a rare cause of secondary pulmonary hypoplasia. She also was found to have some other minor abnormalities on autopsy but no unifying cause for the eventrations and other abnormalities was elucidated.

Two-year outcome of infants weighing 600 grams or less at birth and born 1994 through 1998.

OBJECTIVE: To assess the neurologic and developmental outcome at 2 years of age in preterm infants with birth weights 600 g or lower. METHOD: We conducted a retrospective review from January 1994 through December 1998 for placental histopathology, maternal factors, neonatal intensive care unit course, growth, neurologic/special sense status, and development at 2 years of age corrected for prematurity. RESULTS: Of the 104 neonates weighing 600 g or less, 24 survived to nursery discharge (23%). Two infants died of chronic lung disease after discharge, and 21 of the remaining 22 infants (95%) returned for follow-up. Placental pathology was available for 21 (95%); acute inflammation was present in 67%, and other abnormalities occurred in 76%. Mean birth weight was 537 (430-600) g, and mean gestational age was 24 (22-27) weeks. At birth, 55% were below the tenth percentile for birth weight. At nursery discharge and 2 years of age, 94% were below the tenth percentile for weight, length, and head circumference. Nineteen of 21 (90%) infants were abnormal on neurodevelopmental follow-up. Major problems were cerebral palsy, blindness, gastrostomies, and ventriculoperitoneal shunts. CONCLUSION: Abnormal placental histology was present in all but one infant, suggesting fetal injury before birth. Only eight of 20 infants with chorioamnionitis were diagnosed clinically, and all infants had a complicated course. We found a high incidence of intrauterine growth restriction and an almost universal pattern of impaired postnatal growth with extremely poor neurodevelopmental outcome at 2 years of age.

Causes of nursery death beyond the neonatal period.

OBJECTIVE: To investigate causes of death in infants who died after 28 days, beyond the neonatal period but before discharge from the nursery, to establish their clinical courses and causes of death and to attempt to find criteria for earlier identification of these infants. METHODS: We identified 30 such infants (12% of nursery deaths) from 1993 through 1998 and conducted a retrospective review of their records including placental pathology and autopsy reports when available. In all, 14 infants who weighed or = 880 g died of diverse congenital anomalies, including five with nonhemolytic hydrops and four with pulmonary hypoplasia. One infant without congenital anomaly weighed 3290 g. Support for this severely asphyxiated infant was withdrawn after 103 days because of progressive cortical atrophy. The remaining 14, the largest of which weighed 860 g, died of complications of prematurity, which we termed postponed neonatal deaths (PND). They followed a typical course of progressive multiple organ failure. All received assisted ventilation and postnatal steroids, developed chronic lung disease, and were on ventilation at the time of death. Renal insufficiency occurred late in the course. Acute infections and renal failure were the major proximal causes of death. When compared with surviving controls the PND were less likely to have received antenatal steroids and received more inotropic agents for cardiovascular support and more amphotericin for fungal infection; surgery for perforated bowel was confined to the PND. CONCLUSIONS: The incidence of postneonatal nursery deaths has not changed in more than 20 years remaining at 11 to 12% of nursery deaths. Congenital anomaly was a prominent cause of death (50%). When infants without congenital anomalies (PND) were compared to surviving controls, no differences were found, which could reliably identify PND early in their course. The only potentially preventable factor was lack of antenatal steroid exposure in the PND.

Brown adipose tissue in the buccal fat pad during infancy.

BACKGROUND: The buccal fat pad (BFP) is an encapsulated mass of adipose tissue thought to enhance the sucking capabilities of the masticatory muscles during infancy. To date, no conclusive evidence has been provided as to the composition of the BFP in early postnatal life. OBJECTIVE: The purpose of this study was to examine whether the BFP of neonates and infants is primarily composed of white adipose tissue (WAT) or brown adipose tissue (BAT). MATERIALS AND METHODS: The percentage of fat in the BFP in 32 full-term infants (16 boys and 16 girls), aged one day to 10.6 months, was measured using magnetic resonance imaging (MRI) determinations of fat fraction. RESULTS: BFP fat fraction increased with age (r = 0.67; P<.0001) and neonates had significantly lower values when compared to older infants; 72.6 ± 9.6 vs. 91.8 ± 2.4, P<.0001. Multiple regression analysis indicated that the age-dependent relationship persisted after accounting for gender, gestational age, and weight percentile (P = .001). Two subjects (aged one and six days) depicted a change in the MRI characteristics of the BFP from primarily BAT to WAT at follow-up examinations two to six weeks later, respectively. Histological post-mortem studies of a 3 day and 1.1 month old revealed predominantly BAT and WAT in the BFP, respectively. CONCLUSION: The BFP is primarily composed of BAT during the first weeks of life, but of WAT thereafter. Studies are needed to investigate the contributions of BAT in the BFP to infant feeding and how it is altered by postnatal nutrition.

Human BAT possesses molecular signatures that resemble beige/brite cells.

Brown adipose tissue (BAT) dissipates chemical energy and generates heat to protect animals from cold and obesity. Rodents possess two types of UCP-1 positive brown adipocytes arising from distinct developmental lineages: "classical" brown adipocytes develop during the prenatal stage whereas "beige" or "brite" cells that reside in white adipose tissue (WAT) develop during the postnatal stage in response to chronic cold or PPARγ agonists. Beige cells' inducible characteristics make them a promising therapeutic target for obesity treatment, however, the relevance of this cell type in humans remains unknown. In the present study, we determined the gene signatures that were unique to classical brown adipocytes and to beige cells induced by a specific PPARγ agonist rosiglitazone in mice. Subsequently we applied the transcriptional data to humans and examined the molecular signatures of human BAT isolated from multiple adipose depots. To our surprise, nearly all the human BAT abundantly expressed beige cell-selective genes, but the expression of classical brown fat-selective genes were nearly undetectable. Interestingly, expression of known brown fat-selective genes such as PRDM16 was strongly correlated with that of the newly identified beige cell-selective genes, but not with that of classical brown fat-selective genes. Furthermore, histological analyses showed that a new beige cell marker, CITED1, was selectively expressed in the UCP1-positive beige cells as well as in human BAT. These data indicate that human BAT may be primary composed of beige/brite cells.

Developmental regulation of p66Shc is altered by bronchopulmonary dysplasia in baboons and humans.

RATIONALE: The p66(Shc) adapter protein antagonizes mitogen-activated protein, or MAP, kinase, mediates oxidative stress, and is developmentally regulated in fetal mouse lungs. OBJECTIVES: To determine if p66(Shc) is similarly regulated in primates and in bronchopulmonary dysplasia (BPD), which results from oxidative injury to immature lungs. METHODS: Normal and injured lungs from humans and baboons were evaluated by Western analysis and immunohistochemistry. MEASUREMENTS AND MAIN RESULTS: In baboons, p66(Shc) decreased 80% between 125 and 175 days' gestation (p = 0.025), then doubled after term delivery at 185 days (p = 0.0013). In the hyperoxic 140-day fetal baboon BPD model, p66(Shc) expression persisted, and its localization shifted from the epithelium of gestational controls to the mesenchyme of diseased lungs, coincident with expression of proliferating cell nuclear antigen and cleaved poly(adenyl ribose) polymerase, a marker of apoptosis. Treatment with the antibombesin antibody 2A11 attenuated BPD, reduced cell proliferation, increased p66(Shc) expression 10.5-fold, and preserved epithelial p66(Shc) localization. p66(Shc) also decreased during normal human lung development, falling 87% between 18 and 24 weeks' gestation (p = 0.02). p66(Shc) was expressed throughout 18-week human lungs, became restricted to scattered epithelial cells by 24 weeks, and localized to isolated mesenchymal cells after term delivery. In contrast, p66(Shc) remained prominent in the epithelium of lungs with acute injury or mild BPD, and in the mesenchyme of lungs with severe disease. p66(Shc) localized to tissues expressing proliferating cell nuclear antigen and cleaved poly(adenyl ribose) polymerase. CONCLUSIONS: p66(Shc) expression, cell proliferation, and apoptosis are concomitantly altered during lung development and in BPD.

A rare presentation of Pompe disease with massive hypertrophic cardiomyopathy at birth.

We report a term infant with Pompe disease presenting in the immediate newborn period. The infant was born at 40 weeks' gestation, weighing 3600 g to a 32 year-old black female. Infant presented at delivery with massive hypertrophic cardiomyopathy and pulmonary hypertension. Diagnosis was confirmed by low alpha-glucosidase activity. The histopathology and electron microscopic findings were consistent with Pompe disease. This is the second reported case of Pompe disease presenting at delivery.