Applying a multidimensional autoregressive model to some bio-phenomena (i. e. EEG, EMG, heart rate variability and postural sways, etc.), the dynamic mono- and multivariate higher-order activities, each of which consisted of some first- and second-order component activities, can be described in frequency and time-pattern as the power spectral density or frequency responses and impulse responses. Some of these activities were manifested in the brain and cardio-respiratory systems during ontogenic development. Along with these changes of activities, there was a change in the information-carring capacity of the brain during ontogeny. This implies that the entropy of EEG activity diminishes during maturation of the brain.
Modern mathematical techniques, developed in the area of information theory, are invaluable. It seems reasonable to assume that along these lines we shall achieve further progress in research on normal and impaired brain mechanisms and behavior in the human infant and child.

View full abstract

The process of lesion repair in the dramatically developing fetal brain shows a distinctive feature from that in the developed normal brain. The reason for the difference probably can be clarified by the anatomic features of the fetal brain.
First, a wide extracellular space, which is necessary for the cell motility when a brain develops, preexists in the fetal brain.
Secondly, it is also important that there are no cell-to-cell junctions in a fetal brain and each cell can freely locomote. Therefore, necrotized neuroblasts can be easily removed as they are “in the normal condition” by macrophages.
As the astrocytes, which play an extremely important role in the developed adult brain for the repair of lesion, are still before gliogeneses or under differentiation in the fetal brain, there is little or no astrocytosis as compared with the developed brain. Therefore, the lesion repair process results in the production of a malformed brain.

View full abstract

The basic idea for the realization of effective statistical data analysis is illustrated with an example. The use of statistical models is explained and the feasibility of objective comparison of the models by an information criterion AIC is demonstrared. Further, the possibility of practical use of Bayesian models for complex data analysis is explained. Finally, the necessity of cooperation between the experts of respective fields and statisticians for further development of statistical data analysis is mentioned.

View full abstract

This symposium was focused on pathogenetic analysis on dynamic changes of intracranial pathology in the perinatal period and pervention of fetal and neonatal brain damage. New and valuable results were reported in topics of cerebral blood flow dynamics in the fetus and neonate, imaging modalites in the fetus and neonate, metabolic parameters, neurophysiological function, and pathological analysis.

View full abstract

In oder to obtain quantitative data concerning the changes of fetal cerebral blood flow occurring in relation to hypoxia and acidemia, we evaluated correlations between fetal blood gases and blood flow velocity waveforms in fetuses.
A total of 24 Doppler examinations were carried out to investigate the waveforms of middle cerebral and umbilical arteries in 17 intrauterine growth retardation (IUGR) fetuses. Within 24 hours after blood flow measurements, cordocentesis was performed and umbilical venous blood gases and pH were determined. There was a significant positive correlation between the gestationally adjusted resistance index value [delta SD (RI)] for middle cerebral artery and P_o2 or pH, while a negative correlation was noted between the middle cerebral artery delta SD (RI) and P_co2. The umbilical artery delta SD (RI) and pH showed a negative correlation, but there was no correlation between the umbilical artery delta SD (RI) and P_co2 or P_co2. In the presence of partly compensated respiratory acidosis, the delta SD (RI) for middle cerebral artery was still high, while that for umbilical artery did not increase although P_o2, was reduced.These findings suggest that blood flow changes in fetal middle cerebral and umbilical arteries are different in IUGR. Middle cerebral artery blood flow may respond directly to changes in P_o2. Furthermore, fetal acid-base disorders may modify the relationship between blood flow changes and fetal P_o2.

View full abstract

An accurate and safe method for measuring cerebral blood flow in infants is important to the study of neonatal neurology. The use of Doppler ultrasound for the assessment of neonatal cerebral circulation has a great potential, because it is non-invasive and portable. The advantages of the technique have allowed it to be widely used.
Doppler ultrasound has been used for the assessment of newborn cerebral hemodynamics by a number of groups for various pathophysiological conditions. The factors influencing the cerebral blood flow velocity include cerebral blood flow, cerebrovascular resistance and the diameter of the vessel. It is important to understand how physiological variables influence changes in the cerebral blood flow velocity in infants with neurological problems.

View full abstract

In order to reveal whether or not brain impairment occurs in the human fetus during the intrauterine period, we described three term fetuses, having successful prenatal diagnosis of localized brain lesion, through the real-time ultrasound observation of in utero behavioral patterns. Movement of extremities, breathing movement, alternation of REM (rapid eye movement) and NREM (non-rapid eye movement) periods, and the concurrence of regular mouthing movement with the NREM period were used as parameters. Despite normal breathing movement patterns, in case 1, there were no movements observed in any of the four extremities, thereby suggesting impairment of the spinal cord at and below C₅. This diagnosis was compatible with the neonatal MRI findings which showed a well circumscribed hyperintensity located at C_5-6. In case 2, the repeated lack of breathing movement was noted, combined with the absence of alternation of the REM/NREM period, implying a lesion involved the pons and/or medulla oblongata. Our diagnosis was in good accordance with the actual neonatal CT findings, which showed a calcified lesion spreading from the pons to medulla oblongata. As for case 3, although movement of extremities, breathing movement and REM/NREM period alternation were all found to be within the normal range, there was no concurrence between regular mouthing and the NREM period. This suggested impairment of brain function responsible for NREM sleep, located from the pons through the thalamocortical connection to the cerebral hemisphere. Neonatal CT were found to be in agreement, by indicating a lesion, diffusely involving the cerebral white matter.

View full abstract

During five years from 1985 to 1989, serial brain echography was performed in 399 preterm infants with gestation less than 35 weeks at Kitasato University Hospital. Twenty-eight (7.0%) infants without periventricular hemorrhage were revealed as having spastic cerebral palsy by neurodevelopmental evaluation in later infancy. Of these 28 infants, the following neonatal brain echographic findings were obtainedcystic periventricular leukomalacia in 14, and persistent periventricular echogenicity without cystic formation in 4. However, neonatal brain echograms were completely normal in 10 infants.
Magnetic resonance (MR) studies were performed to find cerebral lesions in all 28 infants. Periventricular high intensity areas on T₂ weighted images, irregularity of ventricular wall, ventricular dilatation, decreased volume in periventricular white matter and thinning of the posterior body of corpus callosum were common findings in those infants, and compatible with the MR findings of periventricular leukomalacia (PVL). Therefore our infants with no brain echo abnormality might have had small PVL lesions not detected by brain echography. The reliability of brain echography is still controversial in the diagnosis of nonhemorrhagic PVL. Careful follow up is essential even in the infant with no brain echo abnormality.

View full abstract

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.

View full abstract

EEGs were recorded serially throughout the neonatal period and auditory brainstem responses (ABRs) in the late neonatal period in 105 preterm infants with the gestational age of less than 33 weeks and birth weights of less than 1, 750g in order to study the relation between abnormal findings and neurological outcome.
A study of serial EEG recordings revealed that a disorganized pattern following severe depression of background EEG activities was closely associated with deep white matter injuries detected by ultrasonography and that infants showing such features are likely to suffer from cerebral palsy. On the other hand, a dysmature pattern was often observed following prolonged mild depression, although no abnormalities were apparent on ultrasonography. This EEG pattern was more often associated with mental impairment. Any findings of ABRs were not associated with adverse outcome.
We conclude that serial EEG recordings during the neonatal period in preterm infants are useful in clarifying the extent and nature of brain injury as well as future developmental problems.

View full abstract

This study is an overview of 2, 515 consecutive autopsies on newborn infants who died during the first 28 days of life at the Hospital for Sick Children, Toronto, during the period 1970-1989. The infants were grouped into 2 categories according to their gestational age and then subdivided into the groups of early (0-6 days) and late (7-28 days) neonatal deaths. In this overview trends in the occurrence of neuropathological observation were documented. In each 5-year time period and each gestational group the following diagnoses were recorded; hypoxic-ischemic neuronal changes, periventricular leukomalacia, infarction, kernicterus, meningitis, and hemorrhage (subependymal, parenchymal, choroidal). In these 20 years, the mortality in preterm infants has decreased due to a fall in the incidence of subependymal/intraventricular hemorrhage, kernicterus and meningitis. In contrast, the rate of mortality in term infants has increased due to a higher frequency of hypoxic-ischemic neuronal necrosis and choroid plexus hemorrhage.

View full abstract

Peroxisomes in higher animals had been considered as a fossil organelle. But, the discovery of peroxisomal fatty acid β-oxidation system in 1976 revived a great deal of interest. In the last decade, peroxisomes have been shown to have an important role in the lipid metabolism. In accord with this progress, the presence of peroxisome diseases has been established. The peroxisomal disorders recognized at present comprise 12 different diseases, with neurological involvements in 10 of them. Recent studies have identified at least eight complementation groups in peroxisome-deficiency disorders, and indicated that currently used clinical categories do not represent distinct genotypes.

View full abstract

Peroxisomes contain hydrogen peroxide-forming oxidase (s) and catalase. Mammalian peroxisomes had been considered as a fossil organelle, since other important metabolism was not found. The discovery of a new fatty acid β-oxidation system in rat liver peroxisomes in 1976 revived a great deal of interest of this organelle. Biochemical features and molecular aspects of individual enzymes of this system are summarized. It has also been elucidated that peroxisomes have important roles in biosynthesis of cholesterol, bile acids, and plasmalogens. These metabolisms together with some oxidases are summarized briefly.

View full abstract

Peroxisome, an ubiquitous subcellular organelle in eukaryotes, functions in many crucial pathways in metabolisms such as catabolism by β-oxidation of very long chain fatty acids, biosynthesis of etherglycerolipids, and metabolism of cholesterol. To address the question how peroxisomes are assembled in eukaryotic cells, we discuss here two topics undertaken in our laboratory. Peroxisomes are formed by posttranslational assembly mechanism; peroxisomal proteins are synthesized on free polysomes in the cytosol, mostly at their final sizes. This implies that topogenic signal (s) for import of newly synthesized polypeptides into peroxisomes reside in the internal sequence of proteins. Peroxisome-targeting signal has been noted in vivo and in vitro for enzymes such as luciferase and acyl-CoA oxidase (AOX). The topogenic signal resides at the extreme C-terminus and comprises tripeptide -Ser-Lys-Leu-COOH (SKL). Further experiments have strongly suggested that the SKL motif, Ser/Ala-Lys/Arg/His-Leu-COOH commonly found at C -termini of many peroxisomal proteins, functions as a peroxisome-targeting signal.
Among several human genetic peroxisomal disorders, cerebrohepatorenal syndrome (Zellweger syndrome) is a typical, severe disease with absence of peroxisome, where a peroxisome assembly is likely to be defective. We isolated three mutants (Z24, Z65, and ZP92), recessive to wild-type cell and mutually com-plementary, of Chinese hamster ovary (CHO) cells that resemble the fibroblasts from Zellweger patients. To investigate molecular mechanism of peroxisome assembly and primary defects of human peroxisome-defi-cient disorders, we searched for the genes encoding factors that complement dysfunctions of CHO cell mutants. The mutants transfected with a pcD2-rat liver cDNA library were selected in the presence of G418. Revertant cells in which assembly of peroxisomes had been restored were selected by the P12/UV method. We have cloned a cDNA encoding a 35-kDa peroxisomal integral membrane protein (termed peroxisome assembly factor-1, PAF-1) that restores peroxisome biogenesis and complements the defects of peroxisomal functions in the mutant Z65.

View full abstract

Neuropathology of peroxisomal disorders showed polymicrogyria in the cerebral and cerebellar cortices, neuronal heterotopia in the cerebral white matter, dysplasia of the inferior olivary nucleus and subependymal cyst in 6 cases of Zellweger syndrome (ZS), and diffuse loss of myelin sheath and mild polymicrogyria in a case of neonatal adrenoleukodystrophy. Developmental immunohistochemistry of catalase, acyl-CoA oxidase and ketoacyl-CoA thiolase revealed that positive reaction appears with neuronal and glial maturation. Diffuse dysmyelination may be related to maldevelopment of oligodendroglia, and migration disorder to abnormality of endothelial cells or radial glia, because both cells were positively stained in fetuses of 20 weeks of gestation and endothelial cells were rarely stained in ZS.

View full abstract

Peroxisome-deficient disorders including Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease are characterized by hypotonia, psychomotor delay, hepatomegaly and dysmorphism. Multiple peroxisomal enzymes are deficient in these disorders probably due to the defect of transport machinery of enzymes. Defects of β-oxidation enzymes causes an accumulation of very-long-chain fatty acids, which is closely related to the pathogenesis. Catalase, a marker enzyme of peroxisome, is distributed in the cytosol. Immunocytochemical staining of peroxisomes using anti-catalase is a useful tool for prenatal and postnatal diagnosis. Although the primary etiology of peroxisomal deficiency has not been determined, genetic heterogeneity was clarified by complementation studies. At least 8 genes are involved in the formation of functional peroxisomes.

View full abstract