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Biomedical subjects

J J Volpe

Publications and source records attributed to J J Volpe.

At least 55 records · Page 3Linked to original sources
PubMed1996

Strokes in children.

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Cerebrovascular Disorders↗
PubMed1995

Cerebral oxygen supply and utilization during infant cardiac surgery.

The survival of infants with congenital heart disease has improved dramatically. However, the incidence of neurological injury in infants surviving cardiac surgery remains considerable. These neurological sequelae are attributable at least in part to hypoxia-ischemia/reperfusion, which inevitably accompanies infant heart surgery with deep hypothermia, cardiopulmonary bypass, and circulatory arrest. To begin to identify mechanisms of brain injury during infant cardiac surgery, we used near-infrared spectroscopy to study the relationship between cerebral intravascular (hemoglobin) and mitochondrial (cytochrome aa3) oxygenation in 63 infants (aged 1 day to 9 months) undergoing deep hypothermic repair of congenital heart defects, throughout the intraoperative period. Moreover, we assessed the effect of postnatal age on these changes. The cerebral concentration of oxidized cytochrome aa3 decreased from the onset of deep hypothermic cardiopulmonary bypass, despite apparent abundant intravascular oxygenation manifested by a simultaneous increase in the cerebral concentration of oxyhemoglobin. During this interval infants older than 2 weeks had a greater decrease in oxidized cytochrome aa3 than did infants 2 weeks old or younger. During deep hypothermic circulatory arrest, cerebral levels of oxidized cytochrome aa3 remained depressed while those of oxyhemoglobin declined. With reperfusion following circulatory arrest, the recovery of oxidized cytochrome aa3 was delayed, despite a rapid recovery of intravascular oxygenation (HbO2). After rewarming and 60 minutes of reperfusion, only 46% of infants recovered to the baseline level of cerebral oxidized cytochrome aa3. These findings demonstrate a paradoxical dissociation of changes in intravascular and mitochondrial oxygenation during hypothermic cardiopulmonary bypass; a pronounced decrease of mitochondrial oxygenation is established during induction of hypothermia and a delay in recovery of mitochondrial oxygenation occurs following circulatory arrest. These effects were more pronounced in infants older than 2 weeks than in younger infants. The data suggest potentially deleterious impairments of intrinsic mitochondrial function or of delivery of intravascular oxygen to the mitochondrion or both, effects previously undetected and apparently influenced by cerebral maturation.

Brain↗
PubMed1995

Oligodendroglial development in human fetal cerebrum.

We have successfully established mixed glial cell primary cultures prepared from individual fetal human brains (15-18 weeks' gestation in age). Cultures were maintained for as long as 3 months in either 10% fetal calf serum (FCS) or serum-free chemically defined medium (CDM). By morphological and immunohistochemical criteria, the precursor cell for human oligodendrocytes (O-2A cell) was identified. This cell exhibited the bipolar morphology and A2B5-positive (A2B5+) immunoreactivity typical of the O-2A precursor cell. With time in culture, cells possessing a stellate morphology appeared, some of which stained with the O4 antibody, indicative of cell differentiation in the oligodendroglial lineage. At yet older culture age, arborized cells bearing the O1 (galactocerebroside, GC) immunohistochemical marker and displaying the morphological characteristics typical of more mature oligodendrocytes were found, confirming their oligodendroglial identity. Oligodendroglial differentiation was supported best by CDM rather than FCS. To complement these observations, double immunofluorescent studies were performed on parietal sections from human fetal brains at 20 to 22 weeks of gestation. Bipolar A2B5+, multipolar A2B5+/O4+, and arborized A2B5-/O1+ cells were found, thus confirming the presence of oligodendrocytes in human fetal brain at this stage of prenatal development and consistent with the observations made in cell culture.

Brain↗
PubMed1994

Brain injury in the premature infant--current concepts.

The magnitude of the problem of brain injury in the premature infant, and particularly the prevention of that injury, is enormous. Approximately 50,000 infants are born yearly in the United States with a birthweight < or = 1,500 g. Approximately 85% of these infants survive, and of the survivors, approximately 5-15% exhibit major spastic motor deficits, grouped under the rubric "cerebral palsy," and an additional 25-50% exhibit less prominent development disabilities, particularly school failure. Moreover, epidemiological studies show that in recent years the prevalence of cerebral palsy in infants of low birth weight, i.e., birth weight < or = 1,500 g, has increased, probably as a secondary result of the ever increasing survival rates for these fragile small infants.

Animals↗
PubMed1993

Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms, and prevention.

Periventricular white matter injury, the principal variety of brain injury of the human premature infant, involves differentiating oligodendroglia. Nothing is known of the biochemical mechanism of oligodendroglial death in this disorder. Because an early event in periventricular white matter injury is ischemia-induced axonal disruption and because such axonal destruction could lead to a marked increase in local concentrations of glutamate, we evaluated the vulnerability of differentiating oligodendroglia to glutamate in a culture model. Oligodendroglia were isolated from mixed-glial primary cultures by a selective detachment technique and grown in a primary culture under conditions that lead to differentiation. These oligodendroglia were found to be highly vulnerable to glutamate-induced cell death. The EC50 for glutamate for a 24 hr exposure was approximately 200 microM, comparable to the value reported for neurons in conventional cerebral cortical cultures. Astrocytes, in contrast, were shown to be resistant to as much as 5 mM glutamate. Study of glutamate receptor antagonists and glutamate transport substrates showed that the glutamate-induced oligodendroglial death was not related to a receptor mechanism, as operates in neurons, but rather was secondary to glutamate uptake by the oligodendroglia. Glutamate transport by high-affinity, sodium-dependent and by sodium-independent systems was shown. The central importance of glutamate uptake for the toxic effect of glutamate was shown by total prevention of the oligodendroglial toxicity by the simultaneous inhibition of glutamate uptake by the specific inhibitor D,L-threo-beta-hydroxyaspartate. Subsequent observations showed that the toxicity of glutamate was mediated by free radical attack, the consequence of glutathione depletion, apparently caused by the action of a glutamate-cystine exchange mechanism that results in cystine and thereby glutathione depletion. Thus, addition of cystine or cysteine totally prevented the glutamate toxicity to oligodendroglia. Second, glutamate exposure led to cystine efflux. Third, glutathione levels decreased markedly in cells exposed to glutamate, and this marked decrease preceded the loss of cell viability. Fourth, glutamate toxicity could be prevented totally by exposure to different free radical scavengers, vitamin E and idebenone. The data thus show that glutamate is highly toxic to oligodendroglia. Moreover, the findings raise the possibilities that such glutamate toxicity is operative in the oligodendroglial cell death associated with ischemic processes that disrupt axons, such as periventricular white matter injury of the premature infant, and that novel therapies directed against glutamate transport, glutathione depletion, and free radical attack might be beneficial in prevention of that injury.

Animals↗
PubMed1993

Cerebral oxygen metabolism in newborns.

OBJECTIVE: A better understanding of the developmental changes in brain energy metabolism that occur in human neonates is critically important for designing rational treatment strategies that ensure an adequate supply of nutrients to the brain and minimize deleterious side effects of therapeutic interventions in sick newborns. METHODS: Cerebral metabolic rate for oxygen (CMRO2) was measured with positron emission tomography in 11 sick newborns of different gestational ages. RESULTS: In five preterm infants, mean hemispheric CMRO2 was 0.06 to 0.54 mL 100 g-1 min-1. Two of these preterm infants with virtually absent CMRO2 (0.06 mL 100 g-1 min-1) had minimal or no evidence of parenchymal brain injury detected in the newborn period. In six term infants, mean hemispheric CMRO2 was 0.0 to 1.3 mL 100 g-1 min-1. Two with no neurological disease had mean hemispheric CMRO2 of 0.4 and 0.7 mL 100 g-1 min-1 and were normal at 6 and 7 months, respectively. CONCLUSIONS: CMRO2 in four newborns who had minimal or no detectable brain injury was considerably below the threshold for brain viability in adults of 1.3 mL 100 g-1 min-1. This indicates that energy requirements in fetal and newborn brain are minimal or can be met by nonoxidative metabolism.

Brain↗
PubMed1992

Glycoprotein processing is required for completion but not initiation of oligodendroglial differentiation from its bipotential progenitor cell.

The role of N-linked glycoproteins in the development of oligodendroglia has been studied in a culture system that initially contains the progenitor cell for oligodendroglia and type 2 astrocytes. The progenitor cells, derived from mixed glial primary cultures of newborn rat cerebrum, were studied under culture conditions that we have shown previously to induce oligodendroglial differentiation. Castanospermine was used to inhibit processing of N-linked glycoproteins by its inhibitory action on glucosidase I, the enzyme responsible for the initial trimming of glucose residues from the glucosylated high mannose core oligosaccharide derived from the dolichol pathway. Exposure to castanospermine had no effect on the initial commitment of the progenitors to oligodendroglial differentiation, i.e. 95% of both control and castanospermine-treated cells became galactocerebroside (GC) positive. However, the developmental inductions of 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) and glycerol-3-phosphate dehydrogenase (GPDH) and the elaboration of a network of fine interconnecting processes were prevented by the castanospermine exposure. No effect of castanospermine on cell number was observed. A major effect of the inhibitor on glycoprotein processing was manifested by an accumulation of high mannose glycoproteins, of abnormal oligosaccharide structure, compatible with the inhibition of glucosidase I.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Establishment of a culture system for the study of oligodendroglial development: complementary effects of boiled serum and astrocyte extract.

Mixed glial primary cultures derived from neonatal rat brain were used to isolate the progenitor glial cell with the capacity to differentiate into oligodendroglia or type 2 astrocytes depending on the culture medium. Subcultures composed primarily of this progenitor were utilized, first, to study the regulation of oligodendroglial differentiation by two factors added to chemically defined medium (CDM), i.e. boiled fetal calf serum (FCS) and cellular extract of type 1 astrocytes, and, second, to devise culture conditions that would cause the progenitor cells to differentiate virtually exclusively along oligodendroglial lines (judged by immunologically identified expression of galactocerebroside; GC) and with high specific and total activity of the oligodendroglial enzymes, 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) and glycerol-3-phosphate dehydrogenase (GPDH). Addition of untreated FCS to CDM of the progenitors resulted in 6 days in richly cellular, mixed glial cultures composed of slightly more GFAP-positive astrocytes than oligodendroglia. Addition of boiled FCS to CDM of the progenitors resulted in 6 days in cultures composed almost exclusively (95%) of GC-positive cells and with high specific activity of CNP. This effect of boiled serum, compared to untreated serum, was related to virtual elimination of astrocytes, in the presence of continued differentiation to GC-positive oligodendroglia. Addition of type 1 astrocyte extract as well as boiled FCS to CDM was necessary to generate high specific activity of GPDH. Additionally, the total number of oligodendroglia increased 2-fold when astrocyte extract as well as boiled FCS was added to the CDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Brain injury in the premature infant--current concepts of pathogenesis and prevention.

Brain injury in the premature infant and, particularly, the prevention of that injury is an enormous problem. With modern neonatal intensive care, approximately 85% of very low birth weight infants survive, and of these survivals, approximately 5-15% exhibit major spastic motor deficit, grouped under the rubric, 'cerebral palsy', and an additional 25-50% exhibit less prominent developmental disabilities, particularly school failure.

Brain Injuries↗
PubMed1991

Positron emission tomography in newborn infants.

Positron emission tomography (PET) is a technique that permits the noninvasive in vivo measurement of a variety of cerebral physiologic and biochemical processes. Numerous complex methodologic and technical features must be considered when PET is applied to the study of the newborn's cerebral physiology and neurologic disease. Although the application of PET to newborn infants is still in its formative stages, important information regarding perturbations of cerebral blood flow in neurologic diseases has been obtained and striking developmental changes in cerebral metabolism are apparent.

Blood Volume↗
PubMed1990

Glutamine synthetase activity of developing astrocytes is inhibited in vitro by very low concentrations of lead.

This study has dealt with the inhibition by lead of glutamine synthetase (GS) activity in homogenates of mixed glial primary cultures, 95% enriched in differentiating astrocytes. A 70% inhibition was observed with a lead concentration of only 2.5 microM. Prevention of the inhibition by addition of EDTA or dithiothreitol is compatible with the conclusion that the effect is mediated by binding of lead ion to sulfhydryl moieties of the enzyme. Among several other cations tested, only mercury, which has a similarly high binding affinity for sulfhydryl moieties, inhibited the enzyme. The inhibitory effect of lead was relatively specific, since no inhibition of another astrocytic marker enzyme, lactate dehydrogenase, of the oligodendroglial marker enzyme, 2',3'-cyclic nucleotide 3'-phosphohydrolase, or of the plasma membrane marker, Na,Ka-ATPase, was observed with concentrations of lead that produced a 70% decrease of GS. Because of the critical role of GS in regulation of extracellular glutamate, the findings raise the possibility that glutamate-induced neuronal injury is involved in the genesis of the cognitive defects associated with chronic low-level lead exposure in young children.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗