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Biomedical subjects

J J Volpe

Publications and source records attributed to J J Volpe.

At least 91 records · Page 5Linked to original sources
PubMed1989

Movement disorder of premature infants with severe bronchopulmonary dysplasia: a new syndrome.

A previously unrecognized, striking movement disorder has been observed in 10 premature infants with severe bronchopulmonary dysplasia. Chronic hypoxemia, hypercarbia, bronchospasm, and inadequate nutrition were present in all. The movement disorder developed from approximately the third postnatal month. The dominant movements involve the limbs, neck, trunk, and oral-buccal-lingual structures. The limb movements were most prominent distally and consisted of rapid, random, jerky movements (similar to chorea) and "restless" movements (similar to akathisia). Similar movements of the neck and face were observed; tongue movements had a "darting" quality. The oral-buccal-lingual movements were similar to the dyskinesia of older patients. Movements were exacerbated during episodes of respiratory failure and attenuated during sleep. All infants exhibited feeding disorders, largely due to tongue movements. In 3 infants treated with clonazepam, there was striking improvement in motor function, including feeding. The natural history was partial or complete resolution or a static course. Thus, of the 7 surviving infants, the movements were absent (without therapy) at 15, 18, and 30 months of age. In the remaining 4 infants (3 of whom receive clonazepam), the movements, though attenuated, persisted at 6, 12, 15 and 21 months of age, respectively. Neuropathologically, 1 infant showed neuronal loss with astrocytosis in caudate, putamen, globus pallidus, and thalamus. These data defined a previously unrecognized extrapyramidal movement disorder of infants with severe bronchopulmonary dysplasia; pathogenesis may be related to chronic hypoxemia.

Bronchopulmonary Dysplasia↗
PubMed1988

Cerebral blood flow requirement for brain viability in newborn infants is lower than in adults.

Measurements of regional cerebral blood flow (CBF) with positron emission tomography in adult humans with cerebrovascular disease have demonstrated consistently that values below 10 ml/(100 gm.min) occur only in infarcted brain. Although experimental data suggest that the newborn brain may be more resistant to ischemic injury than the adult brain, the minimum CBF necessary to sustain neuronal viability in newborn infants is unknown. We have measured CBF with positron emission tomography in 16 preterm and 14 term newborn infants and have determined the relationship between CBF and subsequent brain function as assessed by neurological examination and developmental assessment. The range of mean CBF in the preterm infants was 4.9 to 23 ml/(100 gm.min) and the range of mean CBF in the term infants was 9.0 to 73 ml/(100 gm.min). Five preterm infants and one term infant with mean CBF less than 10 ml/(100 gm.min) survived. Three of these 5 preterm infants, with mean CBF of 4.9, 5.2, and 9.3 ml/(100 gm.min), respectively, have normal neurological examinations and Bayley Scales of 80 or greater at 6, 6, and 24 months of age, respectively. One (mean CBF 6.9) has normal cognitive development (Bayley 103) and a mild spastic diplegia at age 19 months, and one infant (mean CBF 6.2) has a left hemiparesis and a Binet IQ score of 70 at age 33 months. The term infant, with a mean CBF of 9.0 ml/(100 gm.min), was developing normally when he died of sepsis at age 5 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain↗
PubMed1988

Dolichol-linked oligosaccharide and glycoprotein biosyntheses in glial cells in primary culture: development and enzymatic correlates.

Primary cultures of cerebral glia derived from neonatal rat brain were utilized to determine 1) the developmental changes of dolichol-linked oligosaccharide and N-linked glycoprotein biosyntheses, 2) the enzymatic correlates of these developmental changes, and 3) the temporal relations between the biosyntheses of dolichol-oligosaccharide and N-linked glycoproteins and the biochemical expression of astrocytic and oligodendroglial differentiation. Marked, parallel developmental increases in the rates of incorporation of [3H]glucosamine into both dolichol-oligosaccharide and glycoprotein were observed, with maximal rates achieved after 9-10 days in culture and little change occurring over the next 10 days in culture. Concerning the enzymatic correlates, dolichol kinase exhibited a moderate developmental increase with a maximum at 5 days in culture, whereas the activities of the three critical enzymes that utilize dolichyl phosphate in the synthesis of the dolichol-linked oligosaccharide, i.e., N-acetylglucosaminylphosphotransferase (GlcNAc-1-P transferase), mannosylphosphoryldolichol (Man-P-Dol) synthase, and glucosylphosphoryldolichol (Glc-P-Dol) synthase, reached maxima after 6-9 days in culture. Both the activity of Man-P-Dol synthase in vitro and the rate of formation of its product, Man-P-Dol, in intact cells were shown to correlate closely with the rates of oligosaccharide and glycoprotein biosyntheses. An important regulatory role for Man-P-Dol synthase and its product, Man-P-Dol, was suggested further by the demonstration of a maturation-dependent activation by Man-P-Dol of GlcNAc-1-P transferase, the first committed step in the pathway. Two enzymatic markers of astrocytic (glutamine synthetase) and oligodendroglial (2',3'-cyclic nucleotide 3'-phosphohydrolase) differentiation exhibited marked developmental increases in activity with onset at the time of attainment of peak rates of dolichol-oligosaccharide and glycoprotein biosyntheses. Importance of the latter processes for glial differentiation is suggested.

Animals↗
PubMed1988

Dolichyl phosphate: rapid increase and predominant form of brain dolichol compounds during early brain development.

Of brain dolichol compounds, dolichyl phosphate is most critical since it serves as the carrier of saccharide moieties to be utilized for N-linked protein glycosylation. The objectives of the current study were to determine (1) whether the proportion of dolichyl phosphate to dolichol in brain is relatively large and/or changes with development, and (2) whether the subcellular distribution of these isoprenoid compounds differs and/or changes with development. A recently described, improved technique for isolation and quantitation of dolichyl phosphate was employed. The data show that in the first 4 weeks of postnatal life in the rat dolichyl phosphate is, in fact, the predominant form of total dolichol compounds in brain. Subsequently, concentrations of dolichol exceeded those of dolichyl phosphate in adult brain, particularly with aging. Dolichyl phosphate was found to be localized primarily in microsomes; dolichol was found in only small amounts in microsomes but was enriched in the fraction that contained lysosomes. The observations indicate that during early brain development, an active time period for differentiating events, many of which are mediated by glycoproteins, dolichyl phosphate is present in high concentration at the subcellular site of N-linked glycoprotein synthesis, i.e., endoplasmic reticulum.

Aging↗
PubMed1988

Neurologic aspects of bronchopulmonary dysplasia.

Thirty seven infants were identified with bronchopulmonary dysplasia (BPD). Their hospital records were examined and survivors evaluated to determine the neurologic aspects of BPD. Five infants exhibited progressive neurologic disease; nine infants, Five infants exhibited progressive neurologic disease; nine infants, nonprogressive neurologic disease; and 19, normal neurologic outcome. In four, neurologic outcome was indeterminate because of early death. Thus, evaluation of this population of infants with BPD has established two syndromes of neurologic disease--progressive and nonprogressive. The patients with nonprogressive neurologic disease exhibited static neurologic deficits identical to those described in earlier reports of outcome in infants with BPD. The infants with apparently progressive neurologic disease had clinical courses comparable to the fatal pattern of cerebral deterioration previously described. The syndromes appear to be distinct in etiology and clinical presentation. Intraventricular hemorrhage complicated by hemorrhagic intracerebral involvement appears the factor most clearly associated with nonprogressive neurologic disease. The etiology of the striking progressive neurologic syndrome could not be so clearly established but appears to be related to the course and treatment of BPD.

Analysis of Variance↗
PubMed1988

Seizures in the neonatal intensive care unit of the 1980s. Types, Etiologies, Timing.

A retrospective review was taken of 150 newborns with seizures evaluated at the same medical center and by the same investigator(s) from 1982 to 1987. The aims of the study were to determine in this current population the distribution of clinical seizure types, the distribution of causative etiologies, and the relation of etiology to the timing of onset of the seizures. Seizures were classified as subtle, multifocal clonic, generalized tonic, focal clonic, and myoclonic. Subtle (65% of total) and multifocal clonic seizures (54% of total) were the most common seizure types. Subtle seizures usually occurred in combination with other seizure types. Only one seizure type was related to gestational age, i.e., focal clonic seizures in the term infant. Hypoxic-ischemic encephalopathy (65% of total) was by far the most common etiology in both preterm and term infants. Seizures with hypoxic-ischemic encephalopathy occurred characteristically early in the neonatal period, i.e., 90 percent in the first 2 days of life. Moreover, 80 percent of all seizures in the first 2 days of life were related to hypoxic-ischemic encephalopathy.

Cerebral Hemorrhage↗
PubMed1987

Regulation of sterol synthesis and of 3-hydroxy-3-methylglutaryl coenzyme A reductase by lipoproteins in glial cells in primary culture.

Although plasma lipoproteins have been demonstrated to have a major role in regulating cholesterol biosynthesis in extraneural cells, no data concerning such regulation are available for developing brain, when cholesterol synthesis is especially active. Glial primary cultures derived from neonatal rat brain and by morphological and biochemical criteria essentially exclusively composed of astrocytes were utilized to examine such regulation. When the primary cultures, which had been maintained in 10% fetal calf serum, were placed in 10% lipoprotein-poor serum on day 7 of culture, an induction of sterol synthesis (1.6-2.2-fold) and of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase-specific activity (1.5-2-fold) resulted after 24 hr. Addition of low-density lipoprotein (LDL) to the 10% lipoprotein-poor serum prevented the induction of both sterol synthesis and HMG-CoA reductase. However, addition of high-density lipoprotein (HDL) to the 10% lipoprotein-poor serum caused a 1.5-2-fold further induction of sterol synthesis relative to that in cultures containing 10% lipoprotein-poor serum alone. In contrast to the glial primary cultures, cultures of C-6 glioma cells responded to replacement of 10% fetal calf serum with 10% lipoprotein-poor serum with much more marked increases of sterol synthesis and HMG-CoA reductase. Although, as with the primary cultures, addition of LDL to the C-6 glioma cell cultures prevented the increases in sterol synthesis and reductase activity, addition of HDL had no effect. Thus, these results indicate that in developing glial cells in primary culture, cholesterol synthesis and HMG-CoA reductase are capable of responsiveness to both LDL and HDL.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Dolichol kinase and the regulation of dolichyl phosphate levels in developing brain.

The developmental changes of dolichol kinase activity and dolichyl phosphate levels have been studied in rat brain. Because both dolichol kinase activity and dolichyl phosphate were enriched in microsomes, detailed study of this subcellular fraction was carried out. Dolichol kinase specific activity in brain microsomes increased postnatally 3-fold to a maximum at ca. 30 days of age. This increase was observed whether exogenous dolichol was present or not and whether Zn2+ or Ca2+ was utilized as the cation for the enzyme. Zn2+ was the most effective cation in developing brain, as we have shown previously for adult brain (Sakakihara, Y. and Volpe, J.J., J. Biol. Chem., 260 (1985) 15413-15419). Although the Vmax for the enzyme increased by three-fold with development, the Km for dolichol and for CTP did not change, indicating that the developmental increase was not related to an alteration in catalytic efficiency of the enzyme. A striking and parallel increase in dolichyl phosphate levels in brain microsomes was defined with development. Levels were lowest in one-day-old animals and then increased ca. 13-fold to a maximum at 30 days of postnatal age. The parallel increase in dolichol kinase activity and dolichyl phosphate levels in microsomes of developing brain suggests that dolichol kinase is the principal determinant of cellular levels of dolichyl phosphate, the critical intermediate in the dolichol-linked pathway to glycoproteins.

Animals↗
PubMed1987

Dolichol-linked glycoprotein synthesis in developing mammalian brain: maturational changes of the N-acetylglucosaminylphosphotransferase.

The enzyme UDP-N-acetylglucosamine:dolichyl phosphate, N-acetylglucosamine-1-phosphate transferase (GlcNAc-1-P transferase), the first committed step in the dolichol-linked oligosaccharide pathway for glycoprotein biosynthesis, has been studied in developing rat brain. The enzyme was shown to be localized in microsomes, particularly heavy microsomes, and to be activated by Mg2+ and inhibited by tunicamycin. Study of the enzyme with brain development demonstrated two prominent findings. First, the accentuation of enzymatic activity caused by addition of a saturating concentration of dolichyl phosphate was greater in brain of older (3-4 weeks of age and subsequently) animals (25-fold) than in brain of younger (less than two weeks of age) animals (10-fold). This difference suggests that dolichyl phosphate may be limiting for GlcNAc-1-P transferase activity in endoplasmic reticulum of the older animals. Second, a marked (3.5-fold) increase in activity occurred over a discrete time period (3-4 weeks of postnatal life) during brain development. That this increase reflected an increase in enzyme amount rather than in catalytic efficiency was suggested by kinetic studies. Coupled with our previous demonstrations of increases in brain dolichol, dolichol kinase activity, and dolichyl phosphate levels during approximately the same developmental period (Sakakihara, Y. and Volpe, J.J., Dev. Brain Res., 14 (1984) 225-262; Volpe, J.J. et al., Dev. Brain Res., in press), the data suggest a temporally discrete period of activation of the dolichol-linked pathway to glycoproteins. Whether the pathway is regulated coordinately or sequentially is a fertile topic for future study.

Aging↗
PubMed1987

Dolichol-linked glycoprotein synthesis in G1 is necessary for DNA synthesis in synchronized primary cultures of cerebral glia.

Primary cultures of newborn rat cerebrum, which are composed of glial cells (principally astroglia), were used for examining the relationship between dolichol-linked glycoprotein synthesis and DNA synthesis in developing cerebral glia. The cells were synchronized by reducing the content of fetal calf serum in the culture medium from 10 to 0.1% (vol/vol) for 48 h between days 4 and 6 in culture. Reversal of the quiescent state by return of the cultures to 10% serum causes a marked increase in DNA synthesis 12-24 h later. A sharp increase in glycoprotein synthesis (incorporation of [3H]mannose) occurred in the first 12 h after serum repletion, preceding the increase in DNA synthesis. Tunicamycin, an inhibitor of the dolichol-linked pathway to glycoprotein synthesis at the first committed step in oligosaccharide formation, promptly and completely prevented the increase in glycoprotein synthesis and, in addition, the subsequent increase in DNA synthesis. The effects of tunicamycin on glycoprotein and DNA syntheses were reversible, and no comparable effect on total protein synthesis was observed. When tunicamycin was added only during a temporally circumscribed period in G1, i.e., from 3 to 9 h after serum repletion, the increase in DNA synthesis between 12 and 24 h after repletion was still markedly inhibited, i.e., to approximately 45% of the value in untreated cultures. The data thus show that there is a requirement for dolichol-linked glycoprotein synthesis for the subsequent occurrence of DNA synthesis and that this requirement is expressed late in the G1 phase of the cell cycle.

Animals↗
PubMed1987

Cell cycle-specific requirement for mevalonate, but not for cholesterol, for DNA synthesis in glial primary cultures.

The requirement for the sterol biosynthetic pathway for the occurrence of DNA synthesis in glial cells and, in particular, the relative roles of cholesterol and of mevalonate have been studied. Primary cultures of developing glial cells were synchronized by reducing the content of fetal calf serum (FCS) in the culture medium from 10% to 0.1% (vol/vol) for 48 h between days 4 and 6 in culture. Reversal of the resulting quiescent state by the return of the cultures to 10% serum caused after 24 h a marked increase in DNA synthesis, and this increase was prevented by the simultaneous addition of mevinolin, a specific inhibitor of the sterol biosynthetic pathway at the 3-hydroxy-3-methylglutaryl coenzyme A reductase step, at the time of serum repletion. A dose-dependent reversal of the mevinolin inhibition of DNA synthesis occurred with simultaneous addition of mevalonate to the culture medium. The induction of DNA synthesis by serum repletion, its inhibition by mevinolin, and the reversal of the inhibition by mevalonate were unaffected by a 95% reduction in exogenous cholesterol produced by utilization of lipoprotein-poor serum (LPPS) rather than FCS. Similarly, return of quiescent cultures to 10% LPPS containing mevinolin and sufficient low-density lipoprotein (LDL) to raise the cholesterol concentration 80-fold failed to restore DNA synthesis. In addition, reversal of the mevinolin inhibition of DNA synthesis by mevalonate occurred despite the continuous presence of mevinolin if mevalonate was added as late as 12 h after serum repletion, but not if added after 16 h or more.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Oligodendroglial differentiation in glial primary cultures: requirement for mevalonate.

The oligodendroglial enzyme, 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP), is a valuable marker for expression of oligodendroglial differentiation in glial primary cultures, and the inducibility of this enzyme by dibutyryl-3',5'-cyclic AMP (dBcAMP) appears to be limited to immature or developing oligodendroglia. To investigate the relationship between the induction of CNP and the sterol biosynthetic pathway, primary cultures of glia dissociated from the brains of newborn rats were maintained in 10% fetal calf serum (FCS) and exposed to 1 mM dBcAMP on day 7 in culture. Cultures so treated for either 48 h or 72 h demonstrated a three- to fourfold induction of CNP specific activity. The magnitude of this induction was not affected when the cholesterol content of the culture medium was reduced by greater than 95% by placing the cultures in 10% lipoprotein-poor serum rather than 10% FCS during the exposure to dBcAMP. Mevinolin (10 microM), a specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of the sterol biosynthetic pathway, completely inhibited the induction of CNP by dBcAMP, while not affecting either the accumulation of cellular protein per flask or rate of protein synthesis. Simultaneous addition of mevalonate (20 mM) prevented the inhibition of the induction of CNP by mevinolin. However, simultaneous addition of low-density lipoprotein sufficient to increase the cholesterol content of the medium 80-fold failed to correct mevinolin's inhibition of the induction of CNP.(ABSTRACT TRUNCATED AT 250 WORDS)

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1987

Are venous circulatory abnormalities important in the pathogenesis of hemorrhagic and/or ischemic cerebral injury?

The venous circulatory changes in 12 intubated premature infants with fluctuations or elevations in arterial BP were studied. The objectives of the study were to determine whether important alterations in venous pressure occur in infants with fluctuations in arterial BP or with elevations in arterial BP associated with suctioning. Venous and arterial catheters were present in all infants. Perfusion pressure was derived from the difference between mean arterial BP and venous pressure. At rest, minimal change in arterial BP, venous pressure, and perfusion pressure was observed. Elevations in arterial BP were accompanied by pronounced changes in venous pressure. However, because the magnitude and the direction of the changes in venous pressure were not consistent, pronounced changes in perfusion pressure resulted. Fluctuations in arterial BP were associated with fluctuations in venous pressure, which also resulted in pronounced and continuous alterations in perfusion pressure. Induced muscle paralysis in two infants obliterated the changes in arterial BP, venous pressure, and perfusion pressure associated with suctioning. These data demonstrate that marked venous circulatory changes accompany common arterial circulatory abnormalities; such alterations on the venous side of the circulation may be important in the pathogenesis of neonatal hemorrhagic and/or ischemic injury.

Blood Pressure↗
PubMed1986

Intraventricular hemorrhage in extremely small premature infants.

The incidence, timing, severity, and outcome of intraventricular hemorrhage (IVH) were studied in extremely small premature infants with birth weights (BWs) between 500 and 700 g; 366 infants with BWs between 701 and 1500 g, admitted during the same period, served as a comparison group. Intraventricular hemorrhage occurred in 34 (62%) of 55 infants with BWs less than 700 g vs 91 (25%) of the 366 comparison infants. In the group with BWs less than 700 g, IVH occurred in the first 18 hours, from 19 to 72 hours, and after 72 hours of life in 62%, 20%, and 18% of the infants, respectively. In the comparison group, the occurrence for these periods was 13%, 82%, and 5%, respectively. The severity of IVH in infants with BWs less than 700 g was grade III (with or without intraparenchymal hemorrhage) in 97% of the lesions, but in the comparison group such severe IVH accounted for only 32% of the lesions. Intraventricular hemorrhage was a common contributor to death in the infants with BWs less than 700 g. Thus, in 24 infants who died before 72 hours of life, 21 infants (88%) had severe IVH. In addition, intracranial hemorrhage (four infants with IVH and two infants with intracerebellar hemorrhage) occurred late (days 8 to 25) and contributed to death in six of the infants with BWs less than 700 g. These data indicate that in comparison with larger premature infants, infants with BWs less than 700 g exhibit a higher incidence of IVH, which is more severe, occurs earlier, and is associated more often with a fatal outcome. In addition, late and lethal intracranial hemorrhage is also more likely to occur in these smaller infants.

Birth Weight↗