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Improvement of brain function in hemodialysis patients treated with erythropoietin.

To evaluate the effects of recombinant human erythropoietin (rHuEPO) on brain function, 15 chronic hemodialysis patients were studied by event-related P300, stimulus-related evoked potentials, and trailmaking before (hematocrit 22.7%) and after rHuEPO (hematocrit 30.6%). P300 peak latency elicited by a tone discrimination paradigm improved (391 before vs. 366 ms after; Cz = vertex; P less than 0.01) confirming beneficial effects on cerebral cognitive processing. P300 amplitude (13.6 vs. 15.8 microV; P = 0.06) and trailmaking tended to improve (55 vs. 43 s). P300 measures were influenced by low hemoglobin levels before rHuEPO (P less than 0.01), suggesting that severe anemia may contribute to uremic brain dysfunction. Furthermore, decrease of stimulus-related auditory brainstem I-V interpeak latency (4.28 before vs. 4.17 ms after; P less than 0.05) and increase of somatosensory N20/P25 amplitude (4.8 vs. 7.0 microV; P less than 0.05) pointed to improvement of sensory pathways by mechanisms unrelated to cognition. Brain dysfunction in chronic hemodialysis patients may, beside other factors, in part be caused by severe anemia and can be improved by rHuEPO treatment.

Anemia

Blood glucose and brain function: interactions with CNS cholinergic systems.

We recently found that glucose injections attenuate amnesia and hyperactivity produced by scopolamine, a muscarinic antagonist. The present study examined whether glucose would augment behavioral effects produced by a muscarinic agonist, physostigmine. In experiment I, doses were first determined for which neither glucose (10 mg/kg) nor physostigmine (0.05 mg/kg) altered scopolamine-induced hyperactivity. However, combined glucose-physostigmine injections significantly reduced scopolamine hyperactivity. Experiment II evaluated the effects of glucose on physostigmine-induced tremors. Glucose (10, 100, and 250 mg/kg) or saline injections were given 20 min before physostigmine injections (0.4 or 0.05 mg/kg). Observations of glucose effects on the severity of physostigmine-induced tremors were then obtained at 5-min intervals for 25 min after physostigmine injections. Glucose (100 mg/kg) significantly facilitated the onset of tremors when injected before either dose of physostigmine, and augmented (at 100 and 250 mg/kg) tremor severity when injected before the lower dose of physostigmine. These findings indicate that glucose can facilitate the actions of a cholinergic agonist on two behaviors, locomotor activity and tremors, adding support to the view that circulating glucose levels can modulate central cholinergic function. More generally, the results provide additional evidence that circulating glucose levels can influence brain function.

Animals

Iron in brain function and dysfunction with emphasis on Parkinson's disease.

Metals such as lead, zinc, copper, aluminum and manganese have been implicated in neuropsychiatric disorders. However, until fairly recently the role of iron in brain function was rather obscure, because little attention was paid to its metabolism in the brain. It is now apparent that maintenance of brain iron homoeostasis is important for the normal functioning of his organ. Most of the studies have been directed towards the cognitive and attentional deficit resulting from nutritional iron deficiency. Evidence so far suggests subsensitivity of striatal dopamine neurotransmission. By contrast the selective increase in free iron in the substantia nigra pars compacta of parkinsonian brains is thought to initiate oxidative stress, from iron-induced liberation of cytotoxic oxygen free radicals. Such radicals are known to promote membrane fluidity, alteration in cellular calcium homoeostasis, lipid peroxidation and finally cell death in systemic organs. Evidence supporting similar processes being responsible for nigrostriatal dopamine neuron degeneration in Parkinson's disease is now becoming available. Such possibilities afford the development of neuroprotective drugs as a means to retard the progression of this disorder. These include other selective monoamine oxidase B inhibitors, iron chelators with the ability to cross the blood-brain barrier, selective calcium channel antagonists and mitochondrial electron transport system protectors.

Anemia, Hypochromic

Functional brain imaging in pediatrics.

With the development of noninvasive tomographic imaging techniques, it is now possible to measure local chemical and physiologic functions in various body organs. Studies of local cerebral glucose metabolism in infants and children using positron emission tomography (PET) have provided important information on human brain functional development and plasticity. The clinical application of functional neuroimaging techniques in the management of pediatric neurologic disorders has yielded encouraging results. In children with intractable epilepsy being considered for surgical intervention, PET is highly sensitive in localizing focal areas of cortical dysplasia, heterotopias, and other migrational defects corresponding to surface electrographic localization of epileptogenic regions. Expanding PET technology provides a new approach that holds great promise in the diagnosis and management of brain disorders in children.

Brain

Effect of tunicamycin on the expression of functional brain neurotransmitter receptors and voltage-operated channels in Xenopus oocytes.

The role of N-glycosylation on the expression of functional brain neurotransmitter receptors and voltage-operated channels was studied by injecting Xenopus oocytes with mRNA from rat brain or chick optic lobe, and culturing them in the presence or absence of tunicamycin, an inhibitor of asparagine linked glycosylation. Electrophysiological recordings were then made to assess the amounts of functional receptors and channels present in the oocyte membrane. The appearance of gamma-aminobutyric acid (GABA) receptors and voltage-activated Na+ channels was profoundly reduced. In contrast, the functional expression of kainate receptors, and voltage-activated K+ and Ca2+ channels was much less affected. Thus, it seems that kainate receptors, and K+ and Ca2+ channels can be expressed and function normally without being glycosylated. On the other hand, GABA receptors and Na+ channels may need to be N-glycosylated in order to function properly, or to ensure their correct insertion into the membrane.

Amino Acids

[Effects of propentofylline (HWA285) on recovery of brain function following total cerebral ischemia (TCI) in dogs].

We examined the effects of a xanthine derivative, propentofylline, on recovery of brain function following TCI in 23 adult mongrel dogs. TCI was produced by clamping ascending aorta with aortoatrial bypass formation. The dogs were divided into 3 groups: preischemic administration (0.3 mg.kg-1.min-1, 30 min), post-ischemic administration (0.5 mg.kg-1.min-1, 6h) and control. The progress of recovery of EEG, respiration, reflexes, motor functions, arousal state and behavior were observed for 7 days after TCI and the latter 5 functions were analysed using neurologic deficit score (NDS). Propentofylline shortened the time necessary for reappearance of EEG after the starting of recirculation but could not improve the NDS.

Animals

Level of ischemia and brain functions in the Mongolian gerbil in vivo.

The Mongolian gerbil (Meriones unguiculatus) provides a very useful animal model to study the effects of ischemia on brain functions. In this model it is possible to induce two levels of ischemia in the same animal. Thus, monitoring the brain in vivo in real-time will provide meaningful information regarding the development of ischemic injury as well as the follow-up during the recirculation period. The aims of the study were as follows: (1) To elucidate the mechanism behind the development of ischemic depolarization under unilateral and bilateral carotid artery occlusion. (2) To exclude the possibility that removal of the dura mater will affect the results. (3) To correlate the kinetics of the recovery processes to the level of ischemia. We tested the correlation between energy depletion level (evaluated by intramitochondrial NADH redox state) and the development of ischemic depolarization (ID) and vasospasm (evaluated by extracellular K+, DC potential and 366 nm reflectance changes, respectively) under partial and complete ischemia (induced by unilateral or bilateral carotid artery occlusion) using the multiparametric monitoring system (MPA). In 12 out of 32 gerbils monitored by the MPA, the dura mater remained intact, while in the other 20, it was removed very gently before connecting the MPA to the brain. Two types of responses to unilateral carotid artery occlusion were recorded and the gerbils were divided into groups according to the development of the ID. In a third group of 5 gerbils we tested the effect of 1-5 min of bilateral occlusion on the various parameters monitored.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals

Sensitivity to chlorpromazine effects on brain function of schizophrenics and normals. A preliminary report.

For the purpose of quantitative demonstration of the sensitivity to chlorpromazine (CPZ) effects on brain functions of schizophrenics and normal subjects, polygraphic recordings of electroencephalogram (EEG) and electrodermal response (EDR) were performed before and 3 h after oral administration of 25 mg of CPZ: percent time waking EEG (per cent W-EEG) and number per minute of EDR were measured during the resting period and the period of calculation. In 10 normal adult subject, both per cent W-EEG and number of EDR showed remarkable decrease after CPZ administration. In 22 schizophrenics, however, per cent W-EEG showed no significant decrease after CPZ administration. Number of EDR in schizophrenics during the period of calculation did not show any significant decrease. The neural mechanism underlying the lower sensitivity to CPZ effects in schizophrenics was discussed.

Adolescent

[Brain function and blood flow velocity in the middle cerebral artery in subarachnoid hemorrhage: evaluation with multimodality evoked potentials (MEPs) and transcranial Doppler (TCD) ultrasound].

Brain dysfunction and blood flow velocity changes in the middle cerebral artery (MCAFV) were studied in 59 patients with ruptured cerebral aneurysms presenting subarachnoid hemorrhage. Brain function and blood flow velocity were evaluated by multimodality evoked potentials (MEPs) consisting of ABR, SEP and VEP as reported, and transcranial Doppler (TCD) ultrasound. The abnormality on MEPs were graded into 4 grades. Nearly normal, mildly abnormal, moderately abnormal and severely abnormal. The results on MEP study were compared with clinical Hunt and Hess (H. H) grade or Fisher's CT group of subarachnoid hemorrhage in 44 patients. MCAFV was measured in 15 patients and mean velocity as well as CO2 reactivity and effect of head elevation were studied. Control value of MCAFV was 64 +/- 13 cm/sec in 50 healthy adults. CO2 reactivity was determined by K values obtained from the modified formula of cerebral blood flow by Olesen et al. MEP grade in H. H grade III and IV patients showed, on admission, variations in their grades in comparison with those in H. H grade I II and V patients. There was no definite correlation between the abnormality in MEPs and the degree of subarachnoid hemorrhage in Fisher's group 3 and 4 patients. When the surgical results in early and late operation in H. H grade III and IV patients were compared, it was shown that the outcome was favourable in early operated patients of H. H grade III if initial MEP grades were between I-III.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Molecular diversity of glutamate receptors and implications for brain function.

The glutamate receptors mediate excitatory neurotransmission in the brain and are important in memory acquisition, learning, and some neurodegenerative disorders. This receptor family is classified in three groups: the N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-kainate, and metabotropic receptors. Recent molecular studies have shown that many receptor subtypes exist in all three groups of the receptors and exhibit heterogeneity in function and expression patterns. This article reviews the molecular and functional diversity of the glutamate receptors and discusses their implications for integrative brain function.

Amino Acid Sequence

Methadone effects on brain functioning and type A and B CNV shapes.

Twelve male outpatients participating in a methadone maintenance treatment program were evaluated for the effects of acute administration of methadone on brain functioning (contingent negative variation or CNV), attention performance (reaction time and continuous performance test), and psychophysiological activity (heart rate and eye blink rate). Individual differences in response to methadone were assessed by classifying patients into two groups on the basis of basal CNV shapes: Type A (quick rise time) and type B (slow rise time). Methadone produced a pattern of increased electrical brain activity (CNV) and enhanced attention performance in type B patients and elevated heart rate and lowered eye blink rate in type A subjects. Results are interpreted in terms of the distraction-arousal and the eye blink-hedonia hypotheses.

Adult

Relationships between measures of brain functions and general intelligence.

Relationships between measures of general intelligence (Wechsler-Bellevue Verbal IQ, Performance IQ, and Full-scale IQ) and a measure designed to reflect adequacy of brain functions (Halstead Impairment Index) were studied using a control group and groups with left, right and generalized cerebral lesions. The results confirmed earlier findings of (1) differential levels of Verbal and Performance intelligence depending on damage of the left or right cerebral hemisphere; and (2) the greater general sensitivity of the Impairment Index than IQ values to brain damage. Comparative data suggested particularly that IQ values may underestimate brain-dependent adaptive abilities among non-brain-damaged subjects. A significant relationship between IQ values and the Impairment Index was present. This finding permitted evaluation of use of a differing cut-off Impairment Index, as an indicator of cerebral damage, depending on the subject's IQ level. The results suggested that increased accuracy in classifying subjects as brain-damaged might be achieved using a cutting Impairment Index of .4 or greater when the IQ value is 100 or more and .5 or greater when the IQ value is below 100.

Adult

Effect of acute doses of controlled-release carbamazepine on clinical, psychomotor, electrophysiological, and cognitive parameters of brain function.

The neurotoxic effect of acute doses of carbamazepine controlled-release (CBZ-CR) divitabs (800, 1,200, and 1,600 mg) was assessed on clinical, psychomotor, electrophysiological, and cognitive parameters of brain function in 10 healthy volunteers in a double-blind, randomised, placebo-controlled, phase I study. Significant changes compared to placebo were demonstrated for the clinical scales, ataxia (AT), convergence of the near-point (CNP), peak saccadic velocity (PSV), critical flicker fusion (CFF), spectral analysis of the EEG, and brainstem auditory evoked potential (BAEP) tests. Digit repetition, digit symbol substitution, Sternberg memory scanning time, Sternberg choice reaction time, saccadic latency, and saccadic accuracy showed important negative findings. Significant clinical tolerance to side effects developed within 20 to 33 h after CBZ-CR dosage during a period in which the mean CBZ blood levels remained virtually unchanged. CBZ-CR, 800, 1,200, and 1,600 mg yielded low, medium, and high therapeutic blood levels, respectively, for +10 to +33 h after dosage without the development of severe clinical side effects.

Adult

Functional brain asymmetry and murine systemic lupus erythematosus.

The role of brain lateralization in antibody production was studied in a murine systemic lupus erythematosus model. Male and female New Zealand black mice that spontaneously produce pathogenic auto-antibodies directed against red blood cells and DNA, were divided into right- and left-handers using a paw preference test, and anti-erythrocyte and anti-DNA antibody production was repeatedly determined. In females, antibodies against erythrocytes and double-stranded DNA appeared earlier in left-handers. These results provide the first evidence of an association between a functional brain asymmetry and auto-antibody production and suggest the involvement of the central nervous system in the pathogenesis of autoimmune processes.

Aging

[Effect of a high-intensity radiation exposure on brain function in monkeys. Postradiation changes in central coordination of brain bioelectrical processes].

In experiments with Macaca fascicularis exposed to high-energy electrons (45 Gy, 6.5 Gy/s) revealed were early changes in the coherent spectrum of EEG semihemispheric leads. These changes were displayed by the increased interrelation between slow-wave fluctuations and decreased coherence within the mid- and high-frequency EEG-rhythms band. The relationship was noted between the changes observed and the clinical symptoms features of early radiation response as well as the dynamics of the CNS functions of exposed animals. Postirradiation changes in the intracellular bioelectric interaction are considered as one of the manifestations of the systemic response of the brain to the harmful effect of radiation.

Animals

High-altitude mountaineering and brain function: neuropsychological testing of members of a Mount Everest expedition.

Concern has been raised regarding the possibility that hypoxic conditions encountered during high-altitude mountaineering may have lasting harmful effects on the human brain. Members of an expedition to Mount Everest completed a series of neuropsychological tests before and after the expedition. Exposure to altitudes above 7,200 m was limited to a maximum of four consecutive nights, separated by rest periods at lower altitudes. No significant decline in performance was observed on any test. The subjects also completed a short series of tests at different altitudes during the expedition. No significant deterioration was observed at altitudes up to 7,500 m. There do not appear to be lasting harmful effects on brain function under these conditions.

Altitude

Growth hormone, somatomedin and prolactin--relationship to brain function.

In recent years it has been found that the brain of several mammals including have receptors for somatomedin both IGF-I and II and measurable hGH has been identified in human brain tissue. IGF-II has been determined in CSF. The presence of these hormones in brain tissue seems to be of developmental and functional importance as experimental studies in frogs, tadpoles and rats showed that injection of growth hormone enhanced brain growth and increased the ratio of neurons to glia. In man early initiation of hGH therapy to children with hGH (who have a less than normal head circumference) induced a fast catch-up growth of the head and improved their IQ. The data available seems to indicate that growth hormones and/or the somatomedins play an important role in the early brain development, maturation and function. In case of hereditary or congenital GH-RH, hGH or somatomedin deficiency, the effectiveness of therapy seems age limited similar to hypothyroidism. The finding of prolactin receptors in human brain and the report of a child with congenital hypoprolactinemia who had mild mental retardation raises the possibility that also prolactin plays a role in brain function.

Animals

Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis.

1. It has been established that chronic hyperammonaemia, whether caused by portacaval shunting or other means, leads to a variety of metabolic changes, including a depression in the cerebral metabolic rate of glucose (CMRGlc) increased permeability of the blood-brain barrier to neutral amino acids, and an increase in the brain content of aromatic amino acids. The preceding paper [Jessy, DeJoseph & Hawkins (1991) Biochem. J. 277, 693-696] showed that the depression in CMRGlc caused by hyperammonaemia correlated more closely with glutamine, a metabolite of ammonia, than with ammonia itself. This suggested that ammonia (NH3 and NH4+) was without effect. The present experiments address the question whether ammonia, in the absence of net glutamine synthesis, induces any of the metabolic symptoms of cerebral dysfunction associated with hyperammonaemia. 2. Small doses of methionine sulphoximine, an inhibitor of glutamine synthetase, were used to raise the plasma ammonia levels of normal rats without increasing the brain glutamine content. These hyperammonaemic rats, with plasma and brain ammonia levels equivalent to those known to depress brain function, behaved normally over 48 h. There was no depression of cerebral energy metabolism (i.e. the rate of glucose consumption). Contents of key intermediary metabolites and high-energy phosphates were normal. Neutral amino acid transport (tryptophan and leucine) and the brain contents of aromatic amino acids were unchanged. 3. The data suggest that ammonia is without effect at concentrations less than 1 mumol/ml if it is not converted into glutamine. The deleterious effect of chronic hyperammonaemia seems to begin with the synthesis of glutamine.

Amino Acids