Tatsuro Izumi

Variation of the ganglioside compositions of human milk, cow’s milk and infant formulas

The ganglioside compositions of human milk, cows milk and infant formulas were compared. The results showed that there was a drastic change in the ganglioside composition from the colostrum to later human milk, and that both the patterns and contents of gangliosides in human milk, cows milk and infant formulas differed markedly. In human milk, the total lipid-bound sialic acid level was two times higher than those in cows milk and infant formulas. The major ganglioside in the later human milk, GM3 (27.7%), was only a minor component in the colostrum, cows milk and infant formulas (3.3, 2.8 and 0.4-2.6%, respectively). GD3 represented 49.0, 61.0 and 72.4-86.6%, respectively, of the colostrum, cows milk and infant formulas, compared to 31.8% of the later human milk gangliosides. Another four gangliosides, which were assumed to be c-series gangliosides, were detected in the colostrum and the later human milk. They represented 33-38% of total lipid-bound sialic acid, and were tentatively designated as GX1, GX2, GX3 and GX4, respectively. However, only GX1 and GX2 were observed in cows milk and infant formulas. The variation of the gangliosides in human and cows milk, and infant formulas might have some biological significance regarding neonatal brain development, allergies, infant growth and non-immunoglobulin prophylactic activities against some bacterial toxins.

Chronological changes in the ganglioside composition of human milk during lactation

The normal chronological changes in the ganglioside composition of human milk during lactation were examined by means of a high-performance thin-layer chromatography (HPTLC) micro-method with 1 ml of milk from each lactation. Six human milk ganglioside compositions were found, which were designated as GM3, GD3, GX1, GX2, GX3 and GX4. GX1-GX4, which had not been described previously, were tentatively assumed to be gangliosides of the c-series because they did not react to the GA1 antibody after sialidase treatment. GD3 was the major composition of the colostrum (GD3, 42-56%; GM3, 2.22-6.5%). GM3 increased sharply at eight days postpartum (GD3, 32.22%; GM3, 27.79%) and then increased gradually after eight days until examined at seven weeks postpartum (GM3/GD3, 0.84-2.67). The newly found GX1-GX4 showed some variability in the percentage composition between individuals, and there were no distinct differences between the colostrum and the later milk. The drastic compositional changes in GM3 and GD3 during lactation might have some biological significance, such as in immunological activity, somatic growth and the nervous system.

Heterozygous GLDC and GCSH gene mutations in transient neonatal hyperglycinemia

Transient neonatal hyperglycinemia is clinically or biochemically indistinguishable from nonketotic hyperglycinemia at onset. In the case of transient neonatal hyperglycinemia, the elevated plasma and cerebrospinal fluid glycine levels are normalized within 2 to 8 weeks. To elucidate the pathogenesis of transient neonatal hyperglycinemia, we studied three patients by screening mutations in the genes that encode three components of the glycine cleavage system. Heterozygous mutations were identified in all of the three patients, suggesting that transient neonatal hyperglycinemia develops in some heterozygous carriers for nonketotic hyperglycinemia.

Transient nonketotic hyperglycinemia in an asphyxiated patient with pyridoxine-dependent seizures

An asphyxiated neonate with pyridoxine-dependent seizures and associated transient nonketotic hyperglycinemia is reported. Frequent seizures and their resultant hypoxic-ischemic insult may have led to the elevation of the cerebrospinal fluid glycine level in this patient. Early diagnosis and treatment of pyridoxine-dependent seizures is essential for an improved neurologic outcome.

Ganglioside patterns in neuroepithelial tumors of childhood

To elucidate a relationship between neuronal anaplasia, tumor proliferation, and ganglioside contents, we quantified gangliosides by HPTLC in tumors of neuroepithelial tissues at different grade, i. e. peripheral primitive neuroectodermal tumor (PPNET, grade IV), ependymoma (EPEN, grade III), neuroblastoma (NB, grade IV), and dysembryoplastic neuroepithelial tumor (DNT, grade I). PPNET, the most undifferentiated tumor examined had lowest concentration of total lipid-bound sialic acid. GM3 was the major ganglioside in all undifferentiated tumors (46-72.7% of total lipid-bound sialic acid). GD3 was an another component in PPNET and EPEN (7.2-17.3%). Concentration of a complex gangliosides GM1 was decreased in all tumor tissues and those of GT1a, GD1b and GT1b were decreased in tumors of high grade. The results suggest that the composition of gangliosides could be of considerable value in refining the classification of neuroepithelial tumors in infancy and childhood.

Prospective study of nesidioblastosis in newborns and infants: hypoglycemic seizures, epileptogenesis and the significance of the C-peptide suppression test in pancreatectomy.

The long‐term follow‐up of chronic hyperinsulinemic seizures, epileptogenesis and other neurological complications in five patients who were treated with conservative therapy followed by pancreatectomy during the neonatal period and infancy, who were confirmed to have diffuse nesidioblastosis are described. The reaction pattern of the C‐peptide (CPR) suppression test and its relation to the final extent of pancreatectomy was examined in four patients. The chronological change in electro‐encephalography (EEG) and its epileptogenesis was also examined in each patient during hyperinsulinemic hypoglycemia, and during normoglycemia in a long‐term post‐pancreatectomy follow‐up. All patients demonstrated several types of hypoglycemic seizures, ranging from apnea, erratic seizures, partial seizures evolving to generalized/unilateral tonic‐clonic or tonic seizures, myoclonic seizures and EEG abnormalities. Four of five patients still suffered from epilepsy at the age of 4–22 years. The reaction pattern of the CPR suppression test showed dichotomy, with a hyper‐reactive pattern in two patients who required total pancreatectomy to control hypoglycemia, and a suppression pattern in two other patients treated with 90–95% pancreatectomy.

Limited dorsal myeloschisis associated with multiple vertebral segmentation disorder.

A 3-year-old girl was admitted to our department with spina bifida occulta. At birth, thoracic dysplasia with severe respiratory dysfunction and a soft pedunculated mass connecting with an intradural mass were noted. The patient did not start to walk and partial removal of the intradural mass was performed via a laminectomy of the fused vertebrae. There was no boundary between the spinal cord and the mass and the histological diagnosis of this mass was connective tissue. The anomalies in this case were considered to be multiple vertebral segmentation disorder (MVSD) and limited dorsal myeloschisis. The coincidence of these anomalies might suggest the causal genesis of MVSD.

Normal Developmental Changes in Carotid Artery Diameter Measured by Echo-Tracking

We examined the developmental changes in carotid arterial diameter and its change with pulsatile pressure in infants and children using the phase-locked echo-tracking method. The mean, maximum systolic, and minimum diastolic carotid arterial diameter and pulsating diameter changes were measured in 95 healthy children aged 1 month to 13 years. The mean, maximum, and minimum carotid arterial diameter increase significantly and exponentially with age, body weight, height, and body surface area, and the correlation coefficient was highest with body surface area. The change in carotid arterial diameter with pulse pressure increased gradually until 2 to 3 years of age. Our results suggest that the maturational changes in carotid diameter and the dynamic changes in the diameter reflect changes in the carotid-cerebral circulatory system. The noninvasive measurement of the carotid diameter and pulsating diameter changes by a phase-locked echo-tracking method is useful for examining carotid-cerebral circulatory disorders.

Influence of Concomitant Anticonvulsants on Serum Concentrations of Clonazepam in Epileptic Subjects: An Age- and Dose-Effect Linear Regression Model Analysis

This study investigates the interactions between clonazepam and concomitant antiepileptic drugs, and the underlying problems associated with collecting and analysing data. The influence of concomitant carbamazepine, phenytoin, valproic acid and zonisamide, on the steady-state serum concentration of clonazepam were investigated by a multiple linear regression analysis in 51 epileptic in-patients under 20 years-of-age, receiving chronic clonazepam monotherapy or polytherapy. The proposed age- and dose-effect model accurately described clonazepam pharmacokinetics (multiple correlation coefficient 0–884), indicating that the serum concentration of clonazepam was positively correlated with the dose of clonazepam and negatively correlated with the dose of carbamazepine and valproic acid, but not of phenytoin or zonisamide, in an age-related manner.

Evaluation of Clonazepam Pharmacokinetics in Epileptic Children Receiving Monotherapy or Polytherapy, and the Influences of Concomitant Antiepileptic Drugs on the Serum Concentration of Clonazepam

We investigated the relationship between the steady-state serum concentration of clonazepam and the daily dose per weight in epileptic children under 12 years of age who were receiving chronic monotherapy or polytherapy. We also examined the effects of the concurrent administration of other antiepileptic drugs, including phenobarbital (PB), phenytoin (PHT), carbamazepine (CBZ), zonisamide (ZNS), and valproic acid (VPA), on the serum concentration of clonazepam by multiple linear regression analysis. The clonazepam concentration in the same daily dose and the concentration/dose ratio were lower in the polytherapy group than in the monotherapy group. The clonazepam concentration was noted to be positively proportional to the dose of clonazepam and was negatively affected by the addition of PB, PHT, and CBZ, but not of ZNS or VPA. The present results suggest that the differences of clonazepam pharmacokinetics in the monotherapy and polytherapy are associated with the effects of PB, PHT, and CBZ on the serum concentration of clonazepam.