Temporal processing deficits in remediation-resistant reading-impaired children.

There is considerable interest in whether a deficit in temporal processing underlies specific learning and language disabilities in school-aged children. This view is particularly controversial in the area of developmental reading problems. The temporal-processing hypothesis was tested in a sample of normal children, 9-11 years of age, and in a sample of age-matched children with reading impairments, by assessing temporal-order discrimination. Five different binary temporal-order tasks were evaluated in the auditory and visual sensory modalities. Other basic discrimination abilities for single auditory stimuli were also assessed, including just noticeable differences (JNDs) for frequency and intensity and a simple threshold detection task. In these tasks, the temporal dimension was the duration of the individual stimuli (20 and 200 ms). All data were obtained using forced- choice psychophysical methods, either in a single-track adaptive format or using psychometric functions. The results from these experiments showed that children with reading impairments had deficits in temporal-order discrimination, but these effects were not modality specific. These same children also had significantly elevated frequency and intensity JNDs and their performance on these tasks were not dependent on stimulus duration. No group differences were observed on the threshold detection task, and the derived measurements of temporal integration (i.e. the threshold difference between the 20- and 200-ms stimuli) were considered normal, averaging 11.7 dB. As a whole, discrimination deficits observed in the reading-impaired group only occurred with suprathreshold stimuli. The deficits were neither modality specific nor temporal (duration) specific.

Effect of allopurinol on hypoxia-induced modification of the NMDA receptor in newborn piglets.

The present study tests the hypothesis that pretreatment with allopurinol, a xanthine oxidase inhibitor, will prevent modification of the NMDA receptor during cerebral hypoxia in newborn piglets. Eighteen newborn piglets were studied. Six normoxic control animals were compared to six untreated hypoxic and six allopurinol (20 mg/kg i.v.) pretreated hypoxic piglets. Cerebral hypoxia was induced by lowering the FiO2 to 0.05-0.07 for 1 hour and tissue hypoxia was confirmed biochemically by the measurement of ATP and phosphocreatine. Brain cell membrane Na+,K+-ATPase activity was determined to assess membrane function. Na+,K+-ATPase activity was decreased from control in both the untreated and treated hypoxic animals (46.0+/-1.0 vs 37.9+/-2.5 and 37.3+/-1.4 micromol Pi/mg protein/hr, respectively, p < 0.05). [3H]MK-801 binding was determined as an index of NMDA receptor modification. The receptor density (Bmax) in the untreated hypoxic group was decreased compared to normoxic control (1.09+/-0.17 vs 0.68+/-0.22 pmol/mg protein, p < 0.01). The dissociation constant (Kd) was also decreased in the untreated group (10.0+/-2.0 vs 4.9+/-1.4 nM, p < 0.01), indicating an increase in receptor affinity. However, in the allopurinol treated hypoxic group, the Bmax (1.27+/-0.09 pmol/mg protein) was similar to normoxic control and the Kd (8.1+/-1.2 nM, p < 0.05) was significantly higher than in the untreated hypoxic group. The data show that the administration of allopurinol prior to hypoxia prevents hypoxia-induced modification of the NMDA receptor-ion channel binding characteristics, despite neuronal membrane dysfunction. By preventing NMDA receptor-ion channel modification, allopurinol may produce a neuromodulatory effect during hypoxia and attenuate NMDA receptor mediated excitotoxicity.

Effect of allopurinol on NMDA receptor modification following recurrent asphyxia in newborn piglets.

The present study tests the hypothesis that repeated episodes of asphyxia will lead to alterations in the characteristics of the N-methyl-d-aspartate (NMDA) receptor in the brain cell membrane of newborn piglets and that pre-treatment with allopurinol, a xanthine oxidase inhibitor, will prevent these modifications. Eighteen newborn piglets were studied. Six untreated and six allopurinol treated animals were subjected to eight asphyxial episodes and compared to six normoxic, normocapneic controls. Brain cell membrane Na+,K+-ATPase activity was determined to assess membrane function. Na+,K+-ATPase activity was decreased from control following asphyxia in both the untreated and treated animals (47.7+/-3.2 vs. 43.0+/-2.2 and 41.0+/-5.3 micromol Pi/mg protein/h, p<0.05, respectively). 3H-MK-801 binding studies were performed to measure NMDA receptor binding characteristics. The receptor density (Bmax) in the untreated asphyxia group was decreased compared to control animals (0.80+/-0.11 vs. 1.13+/-0.33, p<0.05); furthermore, the dissociation constant (Kd) was also decreased (3.8+/-0.7 vs. 9.2+/-2.2, p<0.05), indicating an increase in receptor affinity. In contrast, Bmax in the allopurinol treated asphyxia group was similar to control (1. 06+/-0.37); and Kd was higher (lower affinity) than in the untreated group (6.5+/-1.4, p<0.05). The data indicate that recurrent asphyxial episodes lead to alterations in NMDA receptor characteristics; and that despite cell membrane dysfunction as seen by a decrease in Na+,K+-ATPase activity, allopurinol prevents modification of NMDA receptor-ion channel binding characteristics induced by repeated episodes of asphyxia.

Effect of propentofylline on free radical generation during cerebral hypoxia in the newborn piglet.

The present study tests the hypothesis that propentofylline, an adenosine re-uptake inhibitor, will reduce free radical generation during cerebral hypoxia. Ten newborn piglets were pretreated with propentofylline (10 mg/kg), five of which were subjected to hypoxia, while the other five were maintained at normoxia. Five untreated control piglets underwent the same conditions. Hypoxia was induced through a decrease in FiO2 to 0.11 and documented biochemically by a decrease in ATP and phosphocreatine levels. Free radical formation in the cortex was detected directly using electron spin resonance spectroscopy with a spin trap technique. Results demonstrate that free radicals, corresponding to the alkoxyl radical, increased significantly following hypoxia, and that this increase was inhibited by pretreatment with propentofylline. Conjugated dienes, a lipid peroxidation product, also increased following hypoxia and were subsequently inhibited by propentofylline. The administration of propentofylline also significantly limited the hypoxia-induced decrease in tissue levels of ATP and phosphocreatine. These data demonstrate that pretreatment with propentofylline decreased free radical generation and lipid peroxidation as well as preserved high energy phosphates during cerebral hypoxia.

Purine metabolism and inhibition of xanthine oxidase in severely hypoxic neonates going onto extracorporeal membrane oxygenation.

The effect of allopurinol to inhibit purine metabolism via the xanthine oxidase pathway in neonates with severe, progressive hypoxemia during rescue and reperfusion with extracorporeal membrane oxygenation (ECMO) was examined. Twenty-five term infants meeting ECMO criteria were randomized in a double-blinded, placebo-controlled trial. Fourteen did not receive allopurinol, whereas 11 were treated with 10 mg/kg after meeting criteria and before cannulation, in addition to a 20-mg/kg priming dose to the ECMO circuit. Infant plasma samples before cannulation, and at 15, 30, 60, and 90 min, and 3, 6, 9, and 12 h on bypass were analyzed (HPLC) for allopurinol, oxypurinol, hypoxanthine, xanthine, and uric acid concentrations. Urine samples were similarly evaluated for purine excretion. Hypoxanthine concentrations in isolated blood-primed ECMO circuits were separately measured. Hypoxanthine, xanthine, and uric acid levels were similar in both groups before ECMO. Hypoxanthine was higher in allopurinol-treated infants during the time of bypass studied (p = 0.022). Xanthine was also elevated (p < 0.001), and uric acid was decreased (p = 0.005) in infants receiving allopurinol. Similarly, urinary elimination of xanthine increased (p < 0.001), and of uric acid decreased (p = 0.04) in treated infants. No allopurinol toxicity was observed. Hypoxanthine concentrations were significantly higher in isolated ECMO circuits and increased over time during bypass (p < 0.001). This study demonstrates that allopurinol given before cannulation for and during ECMO significantly inhibits purine degradation and uric acid production, and may reduce the production of oxygen free radicals during reoxygenation and reperfusion of hypoxic neonates recovered on bypass.

Brain cell membrane function during hypoxia in hyperglycemic newborn piglets.

To test the hypothesis that acute hyperglycemia reduces changes in cell membrane structure and function during cerebral hypoxia in the newborn, brain cell membrane Na+,K(+)-ATPase activity and levels of membrane lipid peroxidation products were measured in four groups of anesthetized, ventilated newborn piglets: normoglycemia/normoxia (control, group 1, n = 12), hyperglycemia/normoxia (group 2, n = 6), untreated hypoxia (group 3, n = 10), and hyperglycemia/hypoxia (group 4, n = 7). Hyperglycemia (blood glucose concentration 20 mmol/L) was induced using the glucose clamp technique. The hyperglycemic glucose clamp was maintained for 90 min before onset of hypoxia and throughout the period of hypoxia. Cerebral tissue hypoxia was induced in groups 3 and 4 by reducing fraction of inspired oxygen for 60 min and was documented by a decrease in the ratio of phosphocreatine to inorganic phosphate as measured using 31P-nuclear magnetic resonance spectroscopy. Blood glucose concentration during hypoxia in hyperglycemic hypoxic animals was 20.7 +/- 1.2 mmol/L, compared with 10.3 +/- 1.7 mmol/L in untreated hypoxic piglets (p < 0.05). Peak blood lactate concentrations were not significantly different between the two hypoxic groups (8.4 +/- 2.8 mmol/L versus 7.8 +/- 1.6 mmol/L). In cerebral cortical membranes prepared from the untreated animals, cerebral tissue hypoxia caused a 25% reduction in Na+,K(+)-ATPase activity compared with normoxic controls and an increase in conjugated dienes and fluorescent compounds, markers of lipid peroxidation. In contrast, Na+,K(+)-ATPase activity and levels of lipid peroxidation products in hyperglycemic hypoxic animals were not significantly different from the values in control normoxic animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of nordihydroguaiaretic acid on cerebral blood flow and metabolism during hypoxia in newborn piglets.

Nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, was investigated for its effect on cerebral blood flow (CBF) and cortical oxygen consumption during hypoxia in 9 anesthetized, ventilated newborn piglets. CBF was measured by radioactive microspheres while brain cortical metabolism was evaluated by continuous 31P-NMR spectroscopy. Five piglets were treated with NDGA (3 mg/kg i.v. in 50% ethanol as vehicle) prior to hypoxia and had CBF measured before NDGA (control), 15 min after NDGA (baseline) and then after 15 and 45 min of hypoxia following NDGA. Another 4 piglets were treated with vehicle (2 ml/kg 50% ethanol) under the same protocol. In the NDGA-treated piglets, cerebral cortical O2 consumption for a given PCr/Pi was significantly increased (p < 0.05) compared to non-NDGA. Since NDGA inhibits production of vasoconstricting leukotrienes during hypoxia, cortical capillary beds otherwise constricted may be perfused following NDGA, thus increasing the O2-consuming tissue area.

Effect of allopurinol on uric acid levels and brain cell membrane Na+,K(+)-ATPase activity during hypoxia in newborn piglets.

Oxygen-free radicals generated by xanthine oxidase during hypoxia-ischemia may result in cellular injury through harmful effects on membrane phospholipids. The present study investigated the effect of administration of allopurinol, an inhibitor of xanthine oxidase, on free-radical generation and brain cell membrane injury during hypoxia by inhibiting the breakdown of hypoxanthine to uric acid. Brain cell membrane Na+,K(+)-ATPase activity and lipid peroxidation products (conjugated dienes and fluorescent compounds) were determined as indices of brain membrane function and structure. Cerebral oxygenation was continuously monitored during hypoxia by 31P-NMR spectroscopy. Plasma and brain tissue levels of uric acid were measured to evaluate xanthine oxidase activity and purine degradation. Na+,K(+)-ATPase activity decreased significantly in both hypoxic groups; however, the allopurinol-treated hypoxic group showed a smaller decrease than the untreated hypoxic group (47.3 +/- 4.9 vs. 42.0 +/- 2.7 mumol Pi/mg protein/h, P < 0.05), respectively. Conjugated dienes increased significantly in the untreated hypoxic compared to control animals (0.070 +/- 0.045 vs. 0.004 +/- 0.006 mumol/g brain, P < 0.05), with the allopurinol-treated animals having intermediate values (0.053 +/- 0.039 mumol/g brain). Fluorescent compounds were lower in the allopurinol-treated hypoxic group compared to the untreated hypoxic group (0.79 +/- 0.19 vs. 1.06 +/- 0.60 micrograms/quinine sulfate/g brain, P < 0.05). Measurements of serum and brain tissue uric acid were significantly lower during hypoxia in the allopurinol-treated compared to the untreated group (30.3 +/- 15.6 vs. 45.7 +/- 10.6 microM (P < 0.05) and 1.69 +/- 0.97 vs. 4.27 +/- 2.37 nmol/g (P < 0.05), respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Protective effect of MgSO4 infusion on nmda receptor binding characteristics during cerebral cortical hypoxia in the newborn piglet.

This study tests the hypothesis that magnesium, a selective non-competitive antagonist of the NMDA receptor, will attenuate hypoxia-induced alteration in NMDA receptors and preserve MK-801 binding characteristics during cerebral hypoxia in vivo. Anesthetized, ventilated and instrumented newborn piglets were divided into three groups: normoxic controls were compared to untreated hypoxic and Mg(2+)-treated hypoxic piglets. Cerebral hypoxia was induced by lowering the FiO2 to 5-7% and confirmed biochemically by a decrease in the levels of phosphocreatine (82% lower than control). The Mg(2+)-treated group received MgSO4 600 mg/kg over 30 min followed by 300 mg/kg administered during 60 min of hypoxia. Plasma Mg2+ concentrations increased from 1.6 +/- 0.1 mg/dl to 17.7 +/- 3.3 mg/dl. 3H-MK-801 binding was used as an index of NMDA receptor modification. The Bmax in control, hypoxic and Mg(2+)-treated hypoxic piglets was 1.09 +/- 0.17, 0.70 +/- 0.25 and 0.96 +/- 0.14 pmoles/mg protein, respectively. The Kd for the same groups were 10.02 +/- 2.04, 4.88 +/- 1.43 and 8.71 +/- 2.23 nM, respectively. The Bmax and Kd in the hypoxic group were significantly lower compared to the control and Mg(2+)-treated hypoxic groups, indicating a preservation of NMDA receptor number and affinity for MK-801 during hypoxia with Mg2+. The activity of Na+, K+ ATPase, a marker of neuronal membrane function, was lower in the hypoxic group compared to the control and Mg(2+)-treated hypoxic groups. These findings show that MgSO4 prevents the hypoxia-induced modification of the NMDA receptor and attenuates neuronal membrane dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoxia-induced modification of the N-methyl-D-aspartate receptor in the brain of the newborn piglet.

The effect of hypoxia on the N-methyl-D-aspartate (NMDA) receptor/ion channel complex in the brain cell membrane of the newborn piglet was studied. Experiments were conducted on newborn piglets, 2-4 days of age, that were anesthetized and mechanically ventilated. Hypoxic hypoxia was induced in the experimental group by lowering the FiO2 to 5-7%. The control group was ventilated under normoxic conditions. Tissue hypoxia was documented biochemically by decreased levels of ATP and phosphocreatine (PCr) in the hypoxic group (52% and 81% lower than the normoxic group, respectively). [3H]MK-801 binding characteristics (Bmax = number of receptors, Kd = dissociation constant) were used as an index of NMDA receptor modification. In hypoxic brains, Bmax decreased from the control level of 1.13 +/- 0.15 pmol/mg protein to 0.68 +/- 0.23 pmol/mg protein (P < 0.01) and the Kd value decreased (reflecting increased affinity) from 9.46 +/- 1.68 nM in the control brains to 4.87 +/- 1.42 nM (P < 0.01) in the hypoxic brains. The Na+,K(+)-ATPase activity, an index of brain cell membrane function, decreased from a control value of 46.5 +/- 0.4 to 40.5 +/- 2.3 mumol inorganic phosphate (Pi) mg protein/h (P < 0.005) during hypoxia. The results of this study indicate that hypoxia in newborn piglets modifies the NMDA receptor in the cerebral cortex, resulting in an increased affinity of the receptor channel. Hypoxia-induced modification of the NMDA ion/receptor complex may be a potential mechanism of cerebral excitotoxicity.

Selective sensitivity of synaptosomal membrane function to cerebral cortical hypoxia in newborn piglets.

The effect of hypoxia on the structure and function of the synaptosomal membranes and myelin fraction (glial cells, neuronal cells bodies and axonal membranes) was investigated by measuring Na+,K(+)-ATPase activity and levels of lipid peroxidation products in cerebral cortical synaptosomal membranes and myelin fractions obtained from newborn piglets. Hypoxic hypoxia was induced and cerebral hypoxia was documented as a decrease in the ratio of phosphocreatine to inorganic phosphate (PCr/Pi) using 31P-NMR spectroscopy. PCr/Pi decreased from baseline of 2.93 +/- 0.76 to 0.61 +/- 0.36 during hypoxia. The synaptosomal membrane Na+,K(+)-ATPase activity decreased from a control value of 56.6 +/- 3.7 to 40.4 +/- 6.0 mumol Pi/mg protein/h during hypoxia. The level of conjugated dienes increased from zero (reference value) to 4.5 +/- 2.7 nmol/mg lipid and the level of fluorescent compounds increased from 23.5 +/- 2.2 to 92.6 +/- 46.4 ng quinine sulfate/mg lipid in the synaptosomal membranes during hypoxia. No change in myelin fraction Na+,K(+)-ATPase activity or levels of lipid peroxidation products were noted. These data indicate that synaptosomal membranes, rich in polyunsaturated fatty acids, are more susceptible to oxygen free radical mediated lipid peroxidative damage during hypoxia.

Posthemorrhagic hydrocephalus. Use of an intravenous-type catheter for cerebrospinal fluid drainage.

STUDY OBJECTIVE: To report a 9-year experience with the treatment of posthemorrhagic hydrocephalus (PHH) with the use of an easily inserted external ventricular drain. DESIGN: A case series with a retrospective review of hospital records and cranial ultrasound results, from 1981 through 1989, in all infants with PHH. INTERVENTION: A previously defined method of identification and bedside management of PHH was applied. If infants reached 2 kg of body weight and PHH recurred, a ventriculoperitoneal shunt was inserted. RESULTS: A total of 70 procedures were performed in 24 patients, and all were associated with a decrease in head circumference and ventricular size on ultrasound scan. One infection occurred, and only 12 infants required a ventriculoperitoneal shunt. CONCLUSIONS: This technique compared favorably with other methods of intervention to avoid early placement of a ventriculoperitoneal shunt in preterm infants and offered the advantage of consistently decreasing ventricular size. A multicenter-controlled trial will be needed to compare the safety and efficacy of therapies for PHH.