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Based on the clinical course of a 16-year-old boy with type I Crigler-Najjar syndrome, we estimated the threshold concentration of unbound bilirubin, as assayed by the horseradish peroxidase method, that apparently induces toxicity to the brain. Before the age of 15, the patient did not manifest any neurological or behavioural dysfunction despite increased bilirubin in serum. The binding affinity and the binding capacity of the patient's serum albumin for bilirubin determined when he was about 14 years old were 108(mol/L)−1and 1·01 to 1·04 mol/L, respectively. These values were nearly the same as those of normal controls reported in the literature. The total bilirubin binding capacity was greater than the patient's total bilirubin concentration, showing that his serum albumin was not saturated with bilirubin. The reserve bilirubin binding capacity (RBBC) was estimated to be 158 μmol/L and the unbound bilirubin concentration to be 15·1 nmol/L. Concentration of unbound bilirubin peaked at 21·7 nmol/L at the age of 15 years and 11 months, i.e. 2 months before the onset of difficulties in walking and speaking. At this time, the RBBC was estimated as −64 μmol/L. A peak concentration of total bilirubin, 811 μmol/L, was observed during the period of rapid loss of the ability to walk or speak. At the age of 16 years and 1 month the RBBC decreased to −98 μmol/L and the unbound bilirubin concentration to 18·8 nmol/L. Following phototherapy, the patient's neurological state returned to normal; he could speak and walk normally. At the age of 16 years and 2 months the RBBC returned to 105 μmol/L and unbound bilirubin decreased to 16·6 nmol/L. These results suggest that maintaining the concentration of unbound bilirubin at < 20 nmol/L and the total bilirubin concentration at lower than the binding capacity of serum albumin is important for prevention of neurological deficits in Crigler-Najjar syndrome. The upper limit of unbound bilirubin in such an older patient was nearly the same as that reported for newborns.

We attempted to delineate the events leading to hypomyelination in the brain of thelittle mouse, a promising murine model of isolated growth hormone deficiency. At 20 days of age, the mutant mouse brain weighed less than its normal counterpart, and this difference in brain weight persisted. Increase in CNPase activity was found to be suppressed in the cerebrum throughout the developmental stage, but not in the other parts of the brain. Differences in cerebral DNA content between thelittle and normal mice first became apparent on the 10th day of age. Thereafter, the rate of increase in thelittle brain consistently lagged behind the normal. [3H]Thymidine incorporation into the DNA fraction in vivo on the 7th day of age, when glial cell proliferation in the normal cerebrum is most active, was approximately half that of the controls in all parts of thelittle brain. These findings indicate that the hypomyelination of the mutant cerebrum might result from reduced oligodendroglial proliferation due to growth hormone deficiency.

The Long-Evans cinnamon (LEC) rat is an animal model of human Wilson's disease. The hepatic copper content of LEC rats increased in an age-dependent manner from 4–5 days of age and was maintained at a high level from 15–16 weeks of age. The renal copper content of LEC rats showed a tendency to increase from 10 weeks of age and increased rapidly from 15 weeks of age. No difference in whole-brain copper concentration was observed between LEC and Long-Evans agouti (LEA) rats. LEC rats treated with D-penicillamine and trienthine-2HCl had reduced liver dysfunction. These agents reduced the hepatic copper content by 1/2–2/3 and the renal copper content to within the normal range. They also decreased the copper content of hair and nails, and there was also a good correlation between the copper content of liver and white hair. J. Trace Elem. Exp. Med. 10:49–59, 1997. © 1997 Wiley-Liss, Inc.

It is well known that procaterol has more potent antiallergic properties than previous β-stimulants. Thirteen children with asthma who could be controlled for 2 months with a regular procaterol aerosol given 4 times/day (10 μg/dose) were studied. Histamine challenges were performed before and an average of 5 months after the consecutive treatment. No significant differences were seen in peak expiratory flow values. PC20 increased significantly from 132.9 ± 127.7 μg/ml to 762.4 ± 1205.7 μg/ml after 5 months. These results suggest that asthmatic children who can be controlled with regular use of the β-stimulant procaterol are likely to have a decreased bronchial hyperresponsiveness.

Glycine cleavage activity was compared in the livers from three cases of ketotic hyperglycinemia (two cases of propionic acidemia and one case of methylmalonic acidemia) and three controls. In one case of propionic acidemia, glycine cleavage activity (5.2 nmole/mg protein/hr) was normal in the liver obtained at biopsy when the patient was well controlled by the treatment with low protein diet (0.8 g/kg/day) and the level of serum glycine was lowered to normal. In the two other cases of ketotic hyperglycinemia, glycine cleavage activity was significantly reduced in the liver obtained at autopsy when the patients died in the state of metabolic acidosis. Its activity in the liver of one case of propionic acidemia (0.7 nmole/mg protein/hr) was 6–26 of that in controls (2.7–10.8 nmole/mg protein/hr), and 2–7 in a case of methylmalonic acidemia (0.2 nmole/mg protein/hr).

Glycine cleavage activity was compared in the livers from three cases of ketotic hyperglycinemia (two cases of propionic acidemia and one case of methylmalonic acidemia) and three controls. In one case of propionic acidemia, glycine cleavage activity (5.2 nmole/mg protein/hr) was normal in the liver obtained at biopsy when the patient was well controlled by the treatment with low protein diet (0.8 g/kg/day) and the level of serum glycine was lowered to normal. In the two other cases of ketotic hyperglycinemia, glycine cleavage activity was significantly reduced in the liver obtained at autopsy when the patients died in the state of metabolic acidosis. Its activity in the liver of one case of propionic acidemia (0.7 nmole/mg protein/hr) was 6–26% of that in controls (2.7–10.8 nmole/mg protein/hr), and 2–7% in a case of methylmalonic acidemia (0.2 nmole/mg protein/hr).Analysing of the individual components of the glycine cleavage system, a marked decrease in the activity of H-protein was revealed in the livers of the both patients; it (0.2 nmole/mg protein/ hr) was only 3–4% of that in controls (4.9–6.3 nmole/mg protein/ hr). These findings suggest that the reduction of the glycine cleavage system in the liver of ketotic hyperglycinemia occurs secondarily as speculated previously and is caused mainly by a decrease of H-protein activity.Speculation: The reduction of glycine cleavage activity in ketotic hyperglycinemia may be caused at first by an inactivation of H-protein. Subsequently the activities of other components of the glycine cleavage system may be decreased.

Computed tomography revealed bilateral hypodensity of the thalamus in three patients with acute encephalopathy. In two cases the abnormal findings on CT persisted and were associated with severe neurological sequelae.

Kawasaki disease (KD) is an acute type of systemic vasculitis characterized by a remarkable activation of the inflammatory response. Most KD patieents were complicated with the liver dysfunction in the acute phase. To investigate the pathogenesis of the l iver dysfunction, we measured the serum levels of inflammatory cytokines including interleukin (IL)-6, interferon-?, tumor necrosis factor-a, transforming growth factor-ß, IL-10, or vascular endothelial growth factor (VEGF), which were re lated with the pathogenesis of the vasculitis, and the serum levels of albumin and C-reactive protein (CRP) as the indicator of the acute inflammatory response in 35 KD patients. The nineteen of 35 KD patients (54.3%) suffered liver dysfunction (AST50 IU). Neither albumin nor CRP were significantly elevated in the serum of patients with liver dysfunction compared with those without liver dysfunction. Of the measured cytokines, only VEGF was significantly elevated in the patients with liver dysfuncti on compared with patients without liver dysfunction (p<0.05). We presume that this high level of serum VEGF was caused with the thrombocytosis of KD disease. These results suggest that the liver dysfunction in the acute phase of KD was induced via end o thelial cells activated by VEGF.