Donald Younkin

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

Abstract: 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 µM kainate or 5 mMl‐glutamate, but not by a 24‐h exposure to up to 10 mMα‐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 Ca2+‐dependent excitotoxicity and that AMPA‐induced cytotoxicity is blocked by desensitization of AMPA‐preferring GluRs.

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.

Expression of Non-NMDA Glutamate Receptor Channel Genes by Clonal Human Neurons

Abstract: Treatment of the human teratocarcinoma line NTera2/c1.D1 (NT2) with retinoic acid induces terminal neuronal differentiation. In a previous study, we found that the neurons obtained in this way express functional N‐methyl‐d‐aspartate (NMDA) and non‐NMDA glutamate receptor channels. We now show by reverse transcriptase‐polymerase chain reaction and Southern blotting that these neurons transcribe each of the nine known non‐NMDA glutamate receptor genes (GluR1‐7, Ka‐1, and Ka‐2) and that four of these genes (GluR2, GluR6, GluR7, and Ka‐1) are also transcribed by undifferentiated NT2 cells. Patch clamp studies demonstrate that individual non‐NMDA glutamate receptor channels are readily isolated from NT2‐derived neurons and that these channels are potently modulated by the desensitization blocker cyclothiazide. NT2‐derived neurons are susceptible to kainate excitotoxicity but are not injured by prolonged exposure to α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate. We expect that the NT2‐derived human neuronal culture system will facilitate studies of human neuronal non‐NMDA glutamate receptor channels and of the pathophysiology of neuronal excitotoxicity.

Cerebral hernodynamics in the diagnosis of normal pressure hydrocephalus

We studied the effect of CSF drainage on cerebral blood flow (CBF) in normal pressure hydrocephalus (NPH) and non-NPH dementia using the 133Xenon inhalation technique. Dementia patients had lower CBF than matched elderly normals. Flow values for NPH and non-NPH patients did not differ before or after CSF drainage. CBF did not increase after lumbar puncture, and these measurements were not useful in predicting the outcome of ventricular shunt surgery. Postoperative CBF didnot increase after successful shunting.

Noninvasive Method of Estimating Human Newborn Regional Cerebral Blood Flow

A noninvasive method of estimating regional cerebral blood flow (rCBF) in premature and full-term babies has been developed. Based on a modification of the xenon-133 inhalation rCBF technique, this method uses eight extracranial NaI scintillation detectors and an i. v. bolus injection of xenon-133 (∼0.5 mCi/kg). Arterial xenon concentration was estimated with an external chest detector. Cerebral blood flow was measured in 15 healthy, neurologically normal premature infants. Using Obrists method of two-compartment analysis, normal values were calculated for flow in both compartments, relative weight and fractional flow in the first compartment (gray matter), initial slope of gray matter blood flow, mean cerebral blood flow, and initial slope index of mean cerebral blood flow. The application of this technique to newborns, its relative advantages, and its potential uses are discussed.

Superficial temporal‐middle cerebral artery anastomosis Effects on vascular, neurologic, and neuropsychological functions

In 44 patients, we studied the effects of superficial temporal-middle cerebral artery anastomosis on cerebral blood flow (CBF), neurologic examination, and cognitive functions. At 3 months, there was significant improvement in all variables. At 9 months, CBF was no longer significantly greater, but neurologic examination and cognitive functions had further improved. Patients with TIA had significant postoperative decreases in TIA frequency and did not progress to stroke, but had no significant changes in any variable. In stroke patients, we could not separate the effects of surgery from the natural evolution of changes in CBF and examination after stroke. None of the preoperative measurements predicted postoperative clinical improvement.

Propranolol therapy for shuddering attacks

d e m y e 1 i n a t in g po 1 y n e u r o p a t h y , t h a t “The process in g of immunoglobulin appears to be sufficiently rigorous that HIV or hepa t i t i s should not be t ransmi t ted by in t ravenous immunoglobulin. Thus far there are no other known complications from this treatment.” In our patient, the dose administered was as used previously,’ and plasma protein electrophoresis 3 days after his final dose of Intragam showed an elevated gamma globulin level. Although blood viscosity was within the normal range when tested, it is likely to have been elevated at the time of Intragam infusion and the patient’s stroke. We believe the patient’s altered blood viscosity and hemorrheology contributed significantly to the thrombogenesis and stroke. (An alternative explanation that was not evaluated in our patient was the possibility that the gamma globulin therapy altered the level of activity of clotting factors o r platelet aggregability, which could have similarly contributed to the patient’s stroke.) With increasing use of intravenous gamma globulin preparations in different patient groups, additional side effects will become apparent and should be reported. When considering intravenous gamma globulin therapy in older patients with known cerebrovascular disease or vascular risk factors, consideration should be given to reducing the dose because of the possibility of cardiac overload and plasma hyperviscosity with predisposition to thrombogenesis.

Regional variations in human newborn cerebral blood flow

Regional differences in the local cerebral metabolic rate of glucose have been reported in newborn infants. This study was performed to determine if comparable differences exist in neonatal regional cerebral blood flow (rCBF). In 21 infants, rCBF was measured with a modified xenon 133 (133Xe) clearance technique by means of eight extracranial detectors positioned over four homologous regions (frontal, parietal, temporal, and occipital). The rCBF was lowest in the frontal region, higher in the parietal region, and highest in the temporal and occipital regions. Regional differences in rCBF may be caused by regional differences in brain development and function.

Nuclear magnetic resonance: An overview of its spectroscopic and imaging applications in pediatric patients

Magnetic resonance (MR) is a technique that permits the noninvasive evaluation of morphologic features and function based on the distribution of protons and other selected elements. We present a basic description of MR and illustrate both 31P-MR spectroscopy and proton imaging applications in pediatric patients. The applications of these techniques are diverse, and are presented concisely in an attempt to give pediatricians an overview of this new technology and its potential role in patient management.

Phenobarbital‐induced dyskinesia in a neurologically impaired child

A 2-year-old child with known neurologic impairment developed a dyskinesia soon after starting phenobarbital therapy for seizures. Known causes of movement disorders were eliminated after evaluation. On repeat challenge with phenobarbital, the dyskinesia recurred. Phenobarbital should be added to the list of anticonvulsant drugs that can cause movement disorders.