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Biomedical subjects

D P Younkin

Publications and source records attributed to D P Younkin.

At least 19 recordsLinked to original sources
PubMed2001

Silent infarction as a risk factor for overt stroke in children with sickle cell anemia: a report from the Cooperative Study of Sickle Cell Disease.

OBJECTIVE: To determine whether children with homozygous sickle cell anemia (SCD) who have silent infarcts on magnetic resonance imaging (MRI) of the brain are at increased risk for overt stroke. METHODS: We selected patients with homozygous SCD who (1) enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD) before age 6 months, (2) had at least 1 study-mandated brain MRI at age 6 years or older, and (3) had no overt stroke before a first MRI. MRI results and clinical and laboratory parameters were tested as predictors of stroke. RESULTS: Among 248 eligible patients, mean age at first MRI was 8.3 +/- 1.9 years, and mean follow-up after baseline MRI was 5.2 +/- 2.2 years. Five (8.1%) of 62 patients with silent infarct had strokes compared with 1 (0.5%) of 186 patients without prior silent infarct; incidence per 100 patient-years of follow-up was increased 14-fold (1.45 per 100 patient-years vs 0.11 per 100 patient-years, P =.006). Of several clinical and laboratory parameters examined, silent infarct was the strongest independent predictor of stroke (hazard ratio = 7.2, P =.027). CONCLUSIONS: Silent infarct identified at age 6 years or older is associated with increased stroke risk.

Anemia, Sickle Cell↗
PubMed1997

Factor V Leiden mutation: an unrecognized cause of hemiplegic cerebral palsy, neonatal stroke, and placental thrombosis.

Activated protein C resistance caused by an Arg506Gln mutation in the factor V gene (factor V Leiden mutation) is the most common cause of familial thrombosis. This mutation is associated with arterial and venous thromboembolic disease in neonates, infants, and children, but is not a significant risk factor for ischemic stroke in adults. We report on 3 babies with different neonatal cerebrovascular disorders including ischemic infarction and hemorrhagic stroke who are heterozygous for factor V Leiden mutation. One infant had multiple thrombi in the fetal placental vasculature. This is the first reported association between hemiplegic cerebral palsy, placental thrombosis, and factor V Leiden mutation. We suspect that activated protein C resistance may be an important cause of in utero cerebrovascular disease and hemiplegic cerebral palsy.

Brain Ischemia↗
PubMed1995

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors mediate excitotoxicity in the oligodendroglial lineage.

We demonstrate by reverse transcriptase-polymerase chain reaction and Southern blotting that an immortalized rat oligodendroglial cell line (CG-4) expresses the non-N-methyl-D-aspartate (non-NMDA) glutamate receptor (GluR) genes GluR2-7, KA-1, and KA-2 and that nonimmortalized cells of the rat oligodendroglial lineage express the GluR1-3, GluR5-7, KA-1, and KA-2 genes. Lactic dehydrogenase release assays show that both immortalized and nonimmortalized cells of the oligodendroglial lineage are damaged by a 24-h exposure to 500 microM kainate or 5 mM L-glutamate, but not by a 24-h exposure to up to 10 mM alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA). Damage is prevented by the non-NMDA GluR channel inhibitor 6-cyano-7-nitroquinoxaline-2,3-dione and is also averted if Ca2+ is removed from the culture medium. Cyclothiazide, which blocks desensitization of AMPA-preferring GluRs, increases cytotoxicity of kainate as well as inducing toxicity of AMPA. We conclude that cells of the oligodendroglial lineage express a population of AMPA-preferring and possibly also kainate-preferring GluR channels that are capable of mediating Ca(2+)-dependent excitotoxicity and that AMPA-induced cytotoxicity is blocked by desensitization of AMPA-preferring GluRs.

Animals↗
PubMed1993

Inducible expression of neuronal glutamate receptor channels in the NT2 human cell line.

Glutamate receptor (GluR) channels are responsible for a number of fundamental properties of the mammalian central nervous system, including nearly all excitatory synaptic transmission, synaptic plasticity, and excitotoxin-mediated neuronal death. Although many human and rodent neuroblast cell lines are available, none has been directly shown to express GluR channels. We report here that cells from the human teratocarcinoma line NT2 are induced by retinoic acid to express neuronal N-methyl-D-aspartate (NMDA) and non-NMDA GluR channels concomitant with their terminal differentiation into neuron-like cells. The molecular and physiologic characteristics of these human GluR channels are nearly identical to those in central nervous system neurons, as demonstrated by PCR and patch clamp recordings, and the cells demonstrate glutamate-induced neurotoxicity.

2-Amino-5-phosphonovalerate↗
PubMed1993

Magnetic resonance spectroscopy in hypoxic-ischemic encephalopathy.

In vivo magnetic resonance spectroscopy (MRS) allows repetitive, noninvasive measurement of cerebral metabolites, including ATP, phosphocreatine (PCr), inorganic phosphate (Pi), intracellular pH, lactate, and N-acetyl aspartate. MRS has been used extensively to study cerebral metabolic changes in neonatal neurologic disorders. In babies with severe hypoxic-ischemic encephalopathy, PCr decreases and Pi increases, causing a fall in PCr/Pi and PCr/ATP, and a rise in Pi/ATP. These changes correlate with neurodevelopmental outcome. Decreased ATP is only seen in extremely severe hypoxic-ischemic encephalopathy and is usually associated with death in the neonatal period. Serial MRS studies may be helpful in selecting babies who would benefit from interventional treatment. Ongoing advances in MRS technology will permit localized, multinuclear spectroscopy, improving our ability to identify cerebral metabolic changes.

Brain Ischemia↗
PubMed1992

[Metabolic kinetics in the brains in infants with IUGR, respiratory distress syndrome, seizures and asphyxia].

31-P magnetic resonance spectroscopy (MRS) allows noninvasive measurements of cerebral phosphorus compounds: ATP, phosphocreatine (PCr), inorganic phosphate (Pi), phosphomonoesters (PME) and phosphodiesters (PDE). In this paper we reported our MRS data from the brains of infants with intrauterine growth retardation, respiratory distress syndrome, neonatal seizures or neonatal asphyxia, and discussed the possibilities to prevent brain damage due to these perinatal troubles.

Adenosine Triphosphate↗
PubMed1987

The effect of hematocrit and systolic blood pressure on cerebral blood flow in newborn infants.

The effects of hematocrit and systolic blood pressure on cerebral blood flow were measured in 15 stable, low birth weight babies. CBF was measured with a modification of the xenon-133 (133Xe) clearance technique, which uses an intravenous bolus of 133Xe, an external chest detector to estimate arterial 133Xe concentration, eight external cranial detectors to measure cephalic 133Xe clearance curves, and a two-compartmental analysis of the cephalic 133Xe clearance curves to estimate CBF. There was a significant inverse correlation between hematocrit and CBF, presumably due to alterations in arterial oxygen content and blood viscosity. Newborn CBF varied independently of systolic blood pressure between 60 and 84 mm Hg, suggesting an intact cerebrovascular autoregulatory mechanism. These results indicate that at least two of the factors that affect newborn animal CBF are operational in human newborns and may have important clinical implications.

Blood Pressure↗
PubMed1987

31P-NMR studies of cerebral metabolic changes during graded hypoxia in newborn lambs.

We measured cerebral phosphocreatine (PCr), inorganic phosphate (Pi), ATP, and intracellular pH (pHi) with in vivo phosphorus nuclear magnetic resonance (NMR) during 10- to 15-min periods of reversible hypoxic hypoxia in 20 newborn lambs (1-11 days). There was a significant correlation between arterial O2 partial pressure (PaO2) and the PCr/Pi ratio or pHi; however, between PaO2 130-33 mmHg, metabolite changes were not significant. PCr/Pi and pHi decreased significantly when PaO2 was lowered below 33 and 28 mmHg, respectively. After recovery, metabolite ratios and pHi returned to base-line values within 5 min. During the early phases of hypoxia and recovery, there were large fluctuations in metabolites and pHi, indicating that mitochondrial reactions were not in a steady state. After several minutes of hypoxia or recovery, PCr/Pi and pHi stabilized, suggesting steady state kinetics for mitochondrial respiration. NMR is extremely sensitive to changes in mitochondrial oxygenation, and stable PCr/Pi and pHi indicate that O2 tension in cerebral mitochondria of the newborn lamb is constant between PaO2 of 30 and 140 mmHg.

Adenosine Triphosphate↗
PubMed1987

31P NMR studies in Duchenne muscular dystrophy: age-related metabolic changes.

To evaluate possible progressive metabolic changes in Duchenne muscular dystrophy, we used 31P nuclear magnetic resonance spectroscopy to measure high-energy phosphate compounds and phosphorylated diesters (PDE) in resting gastrocnemius muscle of 14 Duchenne patients and 10 normal boys. The patients had higher inorganic phosphate (Pi), intracellular pH, and PDE; and lower phosphocreatine (PCr) and PCr/Pi ratio; ATP was not significantly different. The patients showed significant age-related decreases in PCr and PCr/Pi, and increases in Pi and PDE, but ATP did not change. In normal boys, ATP increased with age, but PCr and Pi did not. These studies imply progressive metabolic deterioration in Duchenne dystrophy.

Adenosine Triphosphate↗
PubMed1986

Magnetic resonance spectroscopy of normal and diseased muscles.

Phosphorus magnetic resonance spectroscopy (P MRS) affords and innovative approach to the study of the oxidative enzyme content of normal and diseased muscles. Examples of the evaluation of the enzyme content of normal muscles by an exercise protocol are provided. The protocol affords a hyperbolic work/cost profile, the Vmax of which is calculated by the reciprocal plots giving the enzyme content and the "effective Michaelis constant" with an evaluation of the resting metabolism. This steady state protocol clearly illustrates enzyme adaptation, on the one hand, and tissue atrophy particularly in the case of tissue injury, Duchenne's dystrophy, and genetic deletion of specific enzymes, on the other hand. The method is rapid, safe, and affords a quantitative evaluation of the disease process and possibilities for following appropriate therapies. So far, approx 1000 examinations of normal and diseased human limbs have been carried out in our laboratory in over the past four years.

Acidosis↗
PubMed1986

Cerebral metabolic effects of neonatal seizures measured with in vivo 31P NMR spectroscopy.

In vivo phosphorus 31 nuclear magnetic resonance (31P NMR) spectroscopy was used to evaluate changes in cerebral high-energy phosphate compounds in 8 infants with seizures. During the study 4 babies had seizures that caused a 50% decrease in the phosphocreatine to inorganic phosphate (PCr/Pi) ratio. Focal seizures caused lateralized decreases in the PCr/Pi ratio; generalized seizures caused bilateral decreases. Postictal spectra had increased PCr/Pi ratios, presumably due to postictal inhibition. Interictal 31P NMR spectra were normal. One patient's seizures were successfully treated with intravenously administered phenobarbital during NMR data acquisition, causing an immediate increase in the PCr/Pi ratio from 0.7 to 1.2. These studies indicate that cerebral PCr concentration decreases by approximately 33% and that oxidative metabolism increases by approximately 45% during neonatal seizures. Five babies had PCr/Pi ratios of less than 0.8 during seizures and subsequently developed long-term neurological sequelae, which suggests that neonatal seizures may cause or exacerbate cerebral injury by increasing cerebral metabolic demands above energy supply.

Adenosine Triphosphate↗
PubMed1985

Neurologic manifestations of the organoid nevus syndrome.

Prominent neurologic abnormalities were observed in six patients with epidermal or linear sebaceous nevi (organoid nevi). These cases were remarkable for unilateral facial nevi, cognitive impairment, seizures, and focal or lateralized epileptic EEG abnormalities. Additional manifestations included the onset of seizures in the neonatal period, unilateral hypsarrhythmia or Lennox-Gastaut EEG pattern, hemiparesis, asymmetric macrocephaly, and somatic growth disturbances. The full expression of this disorder was not apparent at birth, but emerged gradually during infancy. The neurologic abnormalities in these patients were attributed to unilateral or asymmetric malformations of the CNS as demonstrated by computed tomography. A lateralized disorder of neuroectodermal proliferation, differentiation, and migration could account for both the cutaneous and neurologic abnormalities in this disorder. The striking clinical similarities in these patients suggest a close link between epidermal and linear sebaceous nevi.

Abnormalities, Multiple↗