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Biomedical subjects

J J Volpe

Publications and source records attributed to J J Volpe.

At least 37 records · Page 2Linked to original sources
PubMed1999

Periventricular white matter injury in the premature infant is followed by reduced cerebral cortical gray matter volume at term.

Periventricular white matter injury, that is, periventricular leukomalacia (PVL), the dominant form of brain injury in the premature infant, is the major neuropathological substrate associated with the motor and cognitive deficits observed later in such infants. The nature of the relationship of this lesion to the subsequent cognitive deficits is unclear, but such deficits raise the possibility of cerebral cortical neuronal dysfunction. Although cortical neuronal necrosis is not a prominent feature of brain injury in premature infants, the possibility of a deleterious effect of PVL on subsequent cerebral cortical development has not been investigated. An advanced quantitative volumetric three-dimensional magnetic resonance imaging technique was used to measure brain tissue volumes at term in premature infants with earlier ultrasonographic and magnetic resonance imaging evidence of PVL (mean gestational age at birth, 28.7 +/- 2.0 weeks; n = 10), in premature infants with normal imaging studies (mean gestational age at birth, 29.0 +/- 2.1 weeks; n = 10), and in control term infants (n = 14). Premature infants with PVL had a marked reduction in cerebral cortical gray matter at term compared with either premature infants without PVL or normal term infants (mean +/- SD: PVL, 157.5 +/- 41.5 ml; no PVL, 211.7 +/- 25.4 ml; normal term, 218.8 +/- 21.3 ml). As expected, a reduction in the volume of total brain myelinated white matter was also noted (mean +/- SD: PVL, 14.5 +/- 4.6 ml; no PVL, 23.1 +/- 6.9 ml; normal term, 27.6 +/- 10.3 ml). An apparent compensatory increase in total cerebrospinal fluid volume also was found (mean +/- SD: PVL, 64.5 +/- 15.2 ml; no PVL, 52.0 +/- 24.1 ml; normal term, 32.9 +/- 13.5 ml). PVL in the premature infant is shown for the first time to be followed by impaired cerebral cortical development. These findings may provide insight into the anatomical correlate for the intellectual deficits associated with PVL in the premature infant.

Basal Ganglia↗
PubMed1999

Early detection of periventricular leukomalacia by diffusion-weighted magnetic resonance imaging techniques.

Periventricular leukomalacia (PVL), the principal form of brain injury in the premature infant, is characterized by overt focal necrotic lesions in periventricular white matter and less prominent, more diffuse cerebral white matter injury. The early detection of the latter, diffuse component of PVL is not consistently possible with conventional brain imaging techniques. We demonstrate the early detection of the diffuse component of PVL by diffusion-weighted magnetic resonance imaging (DWI). In a premature infant with no definite cerebral abnormality detectable by cranial ultrasonography or conventional magnetic resonance imaging, DWI showed a striking bilateral decrease in water diffusion in cerebral white matter. The DWI abnormality (ie, decreased apparent diffusion coefficient) was similar to that observed with acute cerebral ischemic lesions in adults. At 10 weeks of age, conventional magnetic resonance imaging and ultrasonography showed striking changes consistent with PVL, including the presence of small cysts. The observations indicate the importance of DWI in the early identification of the diffuse component of PVL and also perhaps the role of ischemia in the pathogenesis of the lesion.

Female↗
PubMed1999

Intracellular redox state determines whether nitric oxide is toxic or protective to rat oligodendrocytes in culture.

We found that several nitric oxide donors had similar potency in killing mature and immature forms of oligodendrocytes (OLs). Because of the possibility of interaction of nitric oxide with intracellular thiols, we tested the effect of the nitrosonium ion donor S-nitrosylglutathione (SNOG) in OL cultures in the setting of cystine deprivation, which has been shown to cause intracellular glutathione depletion. Surprisingly, the presence of 200 microM SNOG completely protected OLs against the toxicity of cystine depletion. This protection appeared to be due to nitric oxide, because it could be blocked by hemoglobin and potentiated by inclusion of superoxide dismutase. We tested the effect of three additional NO* donors and found that protection was not seen with diethylamine NONOate, a donor with a half-life measured in minutes, but was seen with dipropylenetriamine NONOate and diethylaminetriamine NONOate, donors with half-lives measured in hours. This need for donors with longer half-lives for the protective effect suggested that NO* was required when intracellular thiol concentrations were falling, a process evolving over hours in medium depleted of cystine. These studies suggest a novel protective role for nitric oxide in oxidative stress injury and raise the possibility that intracerebral nitric oxide production might be a mechanism of defense against oxidative stress injury in OLs.

Animals↗
PubMed1998

Maturation-dependent vulnerability of oligodendrocytes to oxidative stress-induced death caused by glutathione depletion.

Death of oligodendrocyte (OL) precursors can be triggered in vitro by cystine deprivation, a form of oxidative stress that involves depletion of intracellular glutathione. We report here that OLs demonstrate maturation-dependent differences in survival when subjected to free radical-mediated injury induced by glutathione depletion. Using immunopanning to isolate rat preoligodendrocytes (preOLs), we generated highly enriched populations of preOLs and mature OLs under chemically defined conditions. Cystine deprivation caused a similar decrease in glutathione levels in OLs at both stages. However, preOLs were completely killed by cystine deprivation, whereas mature OLs remained viable. Although the glutathione-depleting agents buthionine sulfoximine and diethylmaleate were more potent in depleting glutathione in mature OLs, both agents were significantly more toxic to preOLs. Glutathione depletion markedly increased intracellular free radical generation in preOLs, but not in mature OLs, as indicated by oxidation of the redox-sensitive probe dihydrorhodamine 123. The antioxidants alpha-tocopherol, idebenone, and glutathione monoethylester prevented the oxidation of dihydrorhodamine in cystine-depleted preOLs and markedly protected against cell death. When the intracellular glutathione level was not manipulated, preOLs were also more vulnerable than mature OLs to exogenous free radical toxicity generated by a xanthine-xanthine oxidase system. Ultrastructural features of free radical-mediated injury in glutathione-depleted preOLs included nuclear condensation, margination of chromatin, and mitochondrial swelling. These observations indicate that preOLs are significantly more sensitive to the toxic effects of glutathione depletion and that oligodendroglial maturation is associated with decreased susceptibility to oxidative stress.

Animals↗
PubMed1998

Neurologic outcome of prematurity.

Brain injury in the premature infant is an extremely important problem, in part because of the large absolute number of infants affected yearly. The 2 principal brain lesions that underlie the neurological manifestations subsequently observed in premature infants are periventricular hemorrhagic infarction and periventricular leukomalacia. The emphases of this article are the neuropathological features, pathogenesis, and potential means of prevention of these 2 lesions. Recent work suggests that the ultimate goal, prevention of the lesions, is potentially achievable. Periventricular hemorrhagic infarction may be avoidable by prevention of germinal matrix-intraventricular hemorrhage, and periventricular leukomalacia by detection of impaired cerebrovascular autoregulation, prevention of impaired cerebral blood flow, and interruption of the cascade to oligodendroglial cell death by such agents as free radical scavengers.

Brain↗
PubMed1998

Quantitative magnetic resonance imaging of brain development in premature and mature newborns.

Definition in the living premature infant of the anatomical and temporal characteristics of development of critical brain structures is crucial for insight into the time of greatest vulnerability of such brain structures. We used three-dimensional magnetic resonance imaging (3D MRI) and image-processing algorithms to quantitate total brain volume and total volumes of cerebral gray matter (GM), unmyelinated white matter (WM), myelinated WM, and cerebrospinal fluid (CSF) in 78 premature and mature newborns (postconceptional age, 29-41 weeks). Total brain tissue volume was shown to increase linearly at a rate of 22 ml/wk. Total GM showed a linear increase in relative intracranial volume of approximately 1.4% or 15 ml in absolute volume per week. The pronounced increase in total GM reflected primarily a fourfold increase in cortical GM. Unmyelinated WM was found to be the most prominent brain tissue class in the preterm infant younger than 36 weeks of postconceptional age. Although minimal myelinated WM was present in the preterm infant at 29 weeks, between 35 and 41 weeks an abrupt fivefold increase in absolute volume of myelinated WM was documented. Extracerebral and intraventricular CSF was readily quantitated by this technique and found to change minimally. The application of 3D MRI and tissue segmentation to the study of human infant brain from 29 to 41 weeks of postconceptional age has provided new insights into cerebral cortical development and myelination and has for the first time provided means of quantitative assessment in vivo of early human brain development.

Body Composition↗
PubMed1998

Recovery of congenital isolated pharyngeal dysfunction: implications for early management.

The authors describe a case of severe congenital dysphagia caused by isolated pharyngeal dysfunction to highlight the clinical variability in the time to spontaneous recovery of this syndrome. The infant demonstrated recovery at 2 months of age, much earlier than previously reported examples. This case assists in the definition of this syndrome. This diagnosis should be considered in the evaluation of infants with congenital dysphagia.

Cisapride↗
PubMed1998

Brain injury in the premature infant: overview of clinical aspects, neuropathology, and pathogenesis.

Brain injury in the premature infant is an extremely important problem, in part because of the large absolute number of infants affected yearly. The two principal brain lesions that underlie the neurological manifestations subsequently observed in premature infants are periventricular hemorrhagic infarction and periventricular leukomalacia. The emphases of this article are the neurology, neuropathology, and pathogenesis of these two lesions. Recent work suggests that the ultimate goal, prevention of the lesions, is potentially achievable. Periventricular hemorrhagic infarction may be preventable by prevention of germinal matrix/intraventricular hemorrhage, and periventricular leukomalacia, by detection of impaired cerebrovascular autoregulation, prevention of impaired cerebral blood flow, and interruption of the cascade to oligodendroglial cell death by such agents as free-radical scavengers.

Brain Injuries↗
PubMed1998

Microstructural development of human newborn cerebral white matter assessed in vivo by diffusion tensor magnetic resonance imaging.

Alterations of the architecture of cerebral white matter in the developing human brain can affect cortical development and result in functional disabilities. A line scan diffusion-weighted magnetic resonance imaging (MRI) sequence with diffusion tensor analysis was applied to measure the apparent diffusion coefficient, to calculate relative anisotropy, and to delineate three-dimensional fiber architecture in cerebral white matter in preterm (n = 17) and full-term infants (n = 7). To assess effects of prematurity on cerebral white matter development, early gestation preterm infants (n = 10) were studied a second time at term. In the central white matter the mean apparent diffusion coefficient at 28 wk was high, 1.8 microm2/ms, and decreased toward term to 1.2 microm2/ms. In the posterior limb of the internal capsule, the mean apparent diffusion coefficients at both times were similar (1.2 versus 1.1 microm2/ms). Relative anisotropy was higher the closer birth was to term with greater absolute values in the internal capsule than in the central white matter. Preterm infants at term showed higher mean diffusion coefficients in the central white matter (1.4 +/- 0.24 versus 1.15 +/- 0.09 microm2/ms, p = 0.016) and lower relative anisotropy in both areas compared with full-term infants (white matter, 10.9 +/- 0.6 versus 22.9 +/- 3.0%, p = 0.001; internal capsule, 24.0 +/- 4.44 versus 33.1 +/- 0.6% p = 0.006). Nonmyelinated fibers in the corpus callosum were visible by diffusion tensor MRI as early as 28 wk; full-term and preterm infants at term showed marked differences in white matter fiber organization. The data indicate that quantitative assessment of water diffusion by diffusion tensor MRI provides insight into microstructural development in cerebral white matter in living infants.

Anisotropy↗
PubMed1998

Near infrared spectroscopy detects cerebral ischemia during hypotension in piglets.

We have previously reported concordant changes in cerebral intravascular oxygenation measured by near infrared spectroscopy (NIRS) and mean arterial blood pressure (MAP) in premature infants. We hypothesized that the cerebral oxygenation changes are caused by MAP-induced alterations in cerebral blood flow (CBF) and studied these parameters in neonatal piglets (n = 6). Changes in cerebral intravascular oxygenation were measured by NIRS from the hemoglobin difference (HbD) signal (oxyhemoglobin-deoxyhemoglobin). CBF was measured by the radioactive microsphere technique. The cerebral circulation was also monitored by Doppler determinations of CBF velocity (time average mean velocity) in the anterior cerebral artery. Hypotension to <50% of baseline MAP was achieved by a ligature around the ascending aorta. Arterial oxygenation was maintained constant by mechanical ventilation. As observed in our studies of premature infants, cerebral HbD and MAP showed concordant changes. Hypotension was accompanied by significant decreases both in CBF (42.8 +/- 12.5% of baseline p < 0.01) and HbD (-65.0 +/- 22.0 micromol/L x dpf, p < 0.01). HbD was significantly correlated with MAP (p < 0.05) and time average mean velocity (p = 0.01). Importantly, decreases in cerebral total hemoglobin (HbT), a measure of cerebral blood volume, did not correlate significantly with decreases in MAP. We conclude that 1) decreases in cerebral intravascular oxygenation, as assessed by NIRS, observed with decreases in MAP reflect a decline in CBF, and hence oxygen delivery, 2) the HbD signal is more sensitive to changes in CBF than the HbT signal, and 3) NIRS recordings may have clinical utility in detecting cerebral ischemia.

Animals↗
PubMed1998

Neonatal neurologic evaluation by the neurosurgeon.

This article focuses on the cornerstone of the evaluation of infants with a potential neurosurgical disorder, that is, the neonatal neurologic examination. A systematic clinical approach is described with emphasis on the most common abnormalities encountered and the unique characteristics of the clinical neurologic assessment of the newborn. The value of the clinical evaluation is emphasized not only for diagnosis but also for estimation of prognosis.

Humans↗
PubMed1998

Prognosis for development in the newborn requiring neurosurgical intervention.

The long-term prognosis of the newborn infant destined for neurosurgery may depend in large part on preexisting neurologic disturbances. The ability to delineate preoperatively the likely long-term neurologic outcome of such infants facilitates the formulation of optimal interventions and the prediction of likely benefit of a specific intervention and addresses parental concerns for the likely outcome with and without neurosurgical intervention. This article describes two fundamental approaches, using clinical observations or laboratory investigations for delineating such a prognosis. Clinically important factors include the underlying cause, the extent of associated parenchymal injury, and the nature of comorbid factors, particularly those of cerebrovascular and dysgenetic origin. Other important prognostic factors include the age at presentation, the rate of progression, and timing of intervention. The use and limitations of current structural brain imaging, electrophysiologic and perfusion studies, and newer neurodiagnostic techniques are discussed.

Central Nervous System Diseases↗
PubMed1997

Brain injury in the premature infant--from pathogenesis to prevention.

Brain injury in the premature infant is an extremely important problem, in part because of the large absolute number of infants affected yearly. The two principal brain lesions that underlie the neurological manifestations subsequently observed in premature infants are periventricular hemorrhagic infarction and periventricular leukomalacia. The emphases of this article are the neurology, neuropathology and pathogenesis of these two lesions. Recent work suggests that the ultimate goal, prevention of the lesions, is potentially achievable. Periventricular hemorrhagic infarction may be preventable by prevention of germinal matrix-intraventricular hemorrhage, and periventricular leukomalacia, by detection of impaired cerebrovascular autoregulation, prevention of impaired cerebral blood flow and interruption of the cascade to oligodendroglial cell death by such agents as free radical scavengers.

Brain Diseases↗
PubMed1997

Intraventricular urokinase for the treatment of posthemorrhagic hydrocephalus.

This case series pilot study assessed the safety of intraventricular urokinase administration, alternating with cerebrospinal fluid (CSF) drainage. A secondary objective was to comment on whether this therapy achieves fibrinolysis, and whether this fibrinolysis is sufficient to prevent progression of hydrocephalus to requirement for ventriculoperitoneal shunt. Six preterm infants with progressive posthemorrhagic hydrocephalus requiring treatment with a ventricular drain received an infusion of intraventricular urokinase alternating with CSF drainage for 3 days. Of the 6 treated patients, the median gestation at birth was 26.5 weeks and the median age at treatment was 30 days. One patient had an elevation in CSF erythrocyte count most likely due to successful clot lysis. One patient had an elevated CSF leukocyte count consistent with transient meningeal irritation. No other side effects were noted. Fibrinolysis was achieved in the CSF, as documented by markedly elevated D-dimer levels. Clot size diminished ultrasonographically. However, all 6 patients eventually required a ventriculoperitoneal shunt. We conclude that intermittent infusion of intraventricular urokinase alternating with periods of CSF drainage is probably a safe way to achieve a fibrinolytic state. However, when administered at the relatively late point in the neonatal course when a ventricular drain is required, this fibrinolytic state is not sufficient to decrease the requirement for ventriculoperitoneal shunt.

Age of Onset↗
PubMed1997

Brain injury in the premature infant. Neuropathology, clinical aspects, pathogenesis, and prevention.

There are two principal lesions that underlie brain injury and the neurologic manifestations in the premature infant: periventricular hemorrhagic infarction and periventricular leukomalacia. Both of these lesions may be potentially preventable: periventricular hemorrhagic infarction by preventing germinal matrix-IVH, and periventricular leukomalacia by detecting impaired cerebrovascular regulation with near-infrared spectroscopy, preventing the impaired cerebral blood flow and interrupting the cascade to oligodendroglial cell death, perhaps by such agents as free-radical scavengers. Prenatal magnesium sulfate also may be valuable. The greatest progress toward prevention has been made regarding periventricular hemorrhagic infarction, but the advent of new technologies, especially near-infrared spectroscopy, and of new insights into the cellular basis for oligodendroglial vulnerability provide hope for prevention of periventricular leukomalacia.

Brain Diseases↗
PubMed1996

Cystine deprivation induces oligodendroglial death: rescue by free radical scavengers and by a diffusible glial factor.

In this study we examined the effect on oligodendroglial survival of exogenous cystine deprivation. Oligodendroglia isolated from mixed glial primary cultures derived from brains of 1-day-old rats, and then grown for 3 days, were markedly dependent on extracellular cystine for survival. The EC50 values for cystine for a 24-h exposure ranged from 2 to 65 microM. After 6 h of cystine deprivation, the cellular glutathione level decreased to 21 +/- 13% of the control. Free radical scavengers (alpha-tocopherol, ascorbate, idebenone, and N-tert-butyl-alpha-phenylnitrone) were protective against cystine deprivation but had no effect on the glutathione level. An iron chelator, desferrioxamine mesylate, also was protective. These findings suggest that intracellular hydroxyl radicals are important for this toxicity. In contrast to the observations in 3-day-old cultures, the dependence on exogenous cystine for cell viability was not observed consistently in oligodendroglia cultured for 6 days before the onset of cystine deprivation. Several observations suggested that this loss of cystine dependence was due to a diffusible factor. Sensitivity to the toxicity of cystine deprivation in day 6 cultures increased as the volume of medium was increased from 0.3 to 2 ml. Furthermore, preincubation of cystine-depleted medium with astrocyte cultures eliminated the toxicity of the cystine deprivation. HPLC assay of the conditioned cystine-depleted medium showed no significant change in cystine or cysteine concentration. We conclude that oligodendroglia are highly susceptible to cystine deprivation in day 3 cultures and that this susceptibility is due to the accumulation of intracellular free radicals in the setting of glutathione depletion. The resistance of day 6 oligodendroglial cultures is caused at least in part by a diffusible factor.

Animals↗
PubMed1996

Cerebral oxygenation measured by near infrared spectroscopy during cardiopulmonary bypass and deep hypothermic circulatory arrest in piglets.

Near infrared spectroscopy (NIRS) shows large changes in cerebral oxyhemoglobin (Hbo2), deoxyhemoglobin (Hb), and oxidation state of cytochrome aa3 (Cyto2) in infants undergoing cardiopulmonary bypass and deep hypothermic circulatory arrest (CPB-DHCA). To evaluate the physiologic significance of these clinical NIRS measurements, we applied the technique in a piglet model of CPB-DHCA. After an initial stabilization period on CPB, animals (n = 8) were cooled to 15 degrees C, subjected to DHCA for 1 h, then reperfused with rewarming and monitored for 180 min. NIRS measurements were compared with determinations of cerebral blood flow (CBF). During cooling, Cyto2 decreased markedly, whereas Hbo2 increased. DHCA was associated with a sharp decrease in Hbo2, a corresponding increase in Hb, and a smaller, less consistent further decrease in Cyto2. NIRS measurements recovered toward baseline with reperfusion. CBF decreased during cooling and recovered to baseline levels with reperfusion. These findings are consistent with existing human data and show that 1) cooling is associated with increased oxygenation of cerebral hemoglobin despite a reduction in CBF; 2) Cyto2 becomes more reduced during cooling, consistent with a net cellular oxygen deficit; and 3) DHCA is associated with rapid cerebral hemoglobin deoxygenation and a small further reduction of Cyto2.

Animals↗