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Biomedical subjects

H Igisu

Publications and source records attributed to H Igisu.

At least 73 records · Page 4Linked to original sources
PubMed1987

Cumulative toxicity potential of methomyl aerosol by repeated inhalation.

There are few investigations concerning the cumulative toxicity of agricultural chemicals by repeated inhalation. In this study, Wistar male rats were exposed to methomyl powder (mass median aerodynamic diameter, 4.4 microns) for a single 4-hr exposure, or for 4 hr/day, 5 days/week for 3 months. The average exposure concentrations were controlled at 9.9 mg/m3 for the single exposure and at 14.8 mg/m3 for repeated exposures by a dust generator consisting of a continuous fluidized bed with an overflow pipe and a screw feeder. After the repeated exposures, plasma and red cell cholinesterase activities, and lipid concentrations of the rat lungs were measured and histopathological examinations were performed. There was no evidence of cumulative effects on the red cell cholinesterase activity, histopathological changes and lipid concentration in 3-month repeated inhalation.

Aerosols↗
PubMed1986

Inhibition of cytochrome c oxidase by psychosine (galactosylsphingosine).

Pi uptake and acetoacetate formation were suppressed by psychosine (galactosylsphingosine) in rat liver mitochondria. Besides, reduced form of cytochrome c increased in the reaction mixture which contained psychosine. Using reduced form of cytochrome c as substrate, less than 5 microM of psychosine (0.1 mumoles/mg of mitochondrial protein) inhibited cytochrome c oxidase by more than 50%. The inhibition was completely reversed by 1% human serum albumin. Thus, a lipid which is produced in the brain has a powerful and yet reversible inhibitory effect on an enzyme of cellular respiration.

Acetoacetates↗
PubMed1984

Progressive accumulation of toxic metabolite in a genetic leukodystrophy.

Progressive accumulation of a cytotoxic metabolite, galactosylsphingosine (psychosine), was found in the brain of the twitcher mouse, a mutant caused by genetic deficiency of galactosylceramidase. Similar abnormal accumulation was also found in the brain of the genetic galactosylceramidase deficiency disease in the dog and in human patients (globoid cell leukodystrophy or Krabbe disease). Galactosylphingosine was absent in the brains of normal and heterozygous mice. The finding provides support for the psychosine hypothesis as the biochemical pathogenetic mechanism of globoid cell leukodystrophy. Analogous mechanisms may be important in the pathogenesis of other genetic lysosomal diseases.

Animals↗
PubMed1984

Glycolipids of the spinal cord, sciatic nerve, and systemic organs of the twitcher mouse.

The glycolipid composition of the spinal cord, sciatic nerve, kidney, liver and lung of twitcher mice, neurological mutants caused by a genetic deficiency of galactosylceramidase activity, was analyzed during development. No abnormal increase of galactosylceramide or sulfatide was detected in the spinal cord and the sciatic nerve at any age. Galactosylceramide and sulfatide in the whole tissue were in fact decreased in the spinal cord toward later stages of the disease. These findings were qualitatively similar but quantitatively milder than those in the genetically and enzymatically equivalent human disease, globoid cell leukodystrophy (Krabbe disease). Lactosylceramide was abnormally increased in both the spinal cord and the sciatic nerve, but glucosylceramide was increased only in the sciatic nerve. In contrast, there was a massive accumulation of galactosylceramide in the systemic organs. The hydroxy-fatty acid-containing (HFA-) galactosylceramide was predominant in all organs. In the kidney at 42 days. HFA-galactosylceramide was 50-fold and the non-hydroxy-fatty acid-containing (NFA-) galactosylceramide 5-fold higher than the normal levels. Although the absolute amount of galactosylceramide in the liver and lung was much smaller, it was also increased greatly in the twitcher mouse. Lactosylceramide was slightly to moderately increased in the systemic organs but there was no abnormality in glucosylceramide. The analytical findings in the twitcher kidney were in sharp contrast to those in the human disease, in which no abnormal accumulation of galactosylceramide occurs. The abnormal accumulation of the substrate for the deficient enzyme is more consistent with the concept of "lysosomal storage disease". Even though the underlying genetic defect is the same, its consequences show clear species differences.

Animals↗
PubMed1984

Murine globoid cell leukodystrophy: the twitcher mouse. An ultrastructural study of the kidney.

Kidneys of 5- to 45-day-old twitcher mice were studied by light and electron microscopy. No abnormalities were detected with the light microscope. However, at the ultrastructural level, several types of cytoplasmic inclusions were found in epithelial cells with increasing frequency with age. The characteristic inclusions of globoid cell leukodystrophy, identical with those observed in the central nervous system, were confined to epithelial cells of the thin limbs of the loop of Henle. They were present on day 5 in epithelial cells of the thin limbs of the loop of Henle in the papillae of developing kidneys and, after day 20, became more widely distributed in both descending and ascending thin limbs of long loops and in descending thin limbs of short loops. Occasionally, these characteristic inclusions were found within the lumen. Thus, although the twitcher mouse is an authentic model of human globoid cell leukodystrophy, the massive increase in renal galactosylceramide and the finding of inclusions in the twitcher mouse's kidney contrast sharply with the lack of similar changes in man.

Animals↗
PubMed1984

Analysis of galactosylsphingosine (psychosine) in the brain.

A sensitive and specific analytical procedure has been developed for determination of galactosylsphingosine (psychosine) in the brain. The method takes advantage of two unusual properties of psychosine--the strong positive charge and the reactivity of the free amino group. It involves lipid extraction, separation from other lipids on a cation-exchange column (AG-50W), elimination of the last trace of galactosylceramide by silicic acid chromatography, dansylation of psychosine, Florisil and DEAE-Sephadex chromatography, and finally, fluorescent densitometry of dansylated psychosine separated by thin-layer chromatography. The detection limit is 5-10 ng/100 mg brain tissue when the standard procedure is followed exactly. Reliable determination can be made for 50 ng/100 mg or higher in the presence of 200,000-fold excess of other lipids and in the presence of 40,000-fold excess of galactosylceramide. The sensitivity can be increased fivefold by using a larger aliquot for the final determination. This analytical procedure has been successfully applied to demonstrate abnormal accumulation of psychosine in the brain in human, canine, and murine genetic galactosylceramidase deficiencies (globoid cell leukodystrophy).

Animals↗
PubMed1983

Abnormal accumulation of galactosylceramide in the kidney of twitcher mouse.

The kidney tissue of the twitcher mice, a neurological mutant caused by a genetic deficiency of galactosylceramidase, contains enormously increased amounts, up to 50 times normal, of galactosylceramide. The finding is in sharp contrast with those in the enzymatically equivalent human disease, globoid cell leukodystrophy (Krabbe disease), in which no specific abnormal accumulation of galactosylceramide occurs despite the same genetic block in the catabolic pathway. This indicates that the same genetic defect can result in entirely different consequences in different species. Caution must be exercised even when "authentic animal models" are utilized for studies of human diseases.

Animals↗
PubMed1983

The twitcher mouse: an ultrastructural study on the oligodendroglia.

Morphological alterations of oligodendroglia were investigated in the spinal cord of the twitcher mouse, an authentic murine model of human globoid cell leukodystrophy (GLD) from day 5 to day 45 postnatal (p.n.). Typical inclusions were seen in the perikarya as well as the processes of oligodendroglia after day 10 with increasing frequency. The majority of the inclusions was non-crystalloid but rather needle-like or slender tubular in appearance. Ultrastructural features of cellular degeneration became first noticeable on days 25-30 in the oligodendroglial cytoplasm. These consisted of an increased number of microtubules and/or smooth cisterns, dispersed ribosomes, alteration of endoplasmic reticulum forming stacked lamellae or whorls, vesiculation or vacuolation of cytoplasm. The number of degenerating oligodendroglia increased in the older twitcher mice, so did the degenerating myelin sheath. However, even on day 45, when globoid cells became conspicuous in subpial and perivascular regions, many oligodendroglia and myelin sheaths were still well preserved. These observations suggested that oligodendroglial degeneration resulted in the degeneration of myelin sheaths but globoid cells appeared even before morphological evidence of myelin degeneration, presumably in response to the biochemical alterations resulted from the deficiency of galactosylceramidase.

Age Factors↗
PubMed1983

Lipids of developing brain of twitcher mouse. An authentic murine model of human Krabbe disease.

Brains of the newly discovered neurological mutant of the mouse, twitcher, were analysed from birth to the terminal stage of the disease for major tissue constituents and the lipid composition. A genetic deficiency of galactosylceramidase is the underlying cause of this mutant. The affected mice failed to gain body weight after 20 days (30 per cent of normal at 42 days) but the brain weight was much less affected (85 per cent of normal at 42 days). The water content and the four major fractions, chloroform-methanol insoluble residue, chloroform-methanol soluble protein, upper phase solids and total lipid, were essentially unaltered except that the total lipid was reduced slightly towards the terminal stage. Among lipids, only galactolipids, galactosylceramide and sulphatide were abnormal in the twitcher brain. Galactosylceramide was decreased at 37 and 42 days whereas decrease in sulphatide occurred earlier from 25 days, resulting in an increased ratio of galactosylceramide to sulphatide. The analytical abnormalities found in the twitcher brain are qualitatively similar to and quantitatively milder than those in the brain of human patients with globoid cell leukodystrophy (Krabbe disease), of which the twitcher is an enzymatically authentic animal model. The secondary abnormalities observed in brains of human patients as the result of tissue devastation were generally not present in the twitcher brain. Mouse brains contain relatively little myelin. As the pathology in twitcher is greatest in the spinal cord and brainstem (Duchen et al., 1980), the fact that the changes in twitcher brains are quantitatively milder than those of human patients may partly reflect the relative amount of myelin in the two species. While more detailed studies of some specific constituents, such as galactosylsphingosine, and of other tissues, such as the peripheral nervous system and the kidney, will have to be performed, the present results serve as the reference for comparison between the human and murine galactosylceramidase deficiency states and for future experiments with the twitcher mutant, which is an invaluable tool for studies of globoid cell leukodystrophy.

Animals↗
PubMed1983

Murine globoid cell leukodystrophy (the twitcher mouse). The presence of characteristic inclusions in the kidney and lymph nodes.

Ultrastructural investigations were carried out on the kidney, lung, liver, spleen, lymph nodes and adrenal gland of the twitcher mouse, a recently discovered authentic murine model of human globoid cell leukodystrophy (GLD). The characteristic cytoplasmic inclusions identical to those found in the glial and globoid cells in the central nervous system (CNS) were observed in the epithelial cells of the thin limbs of the loops of Henle in the kidney and also in the macrophages in the lymph nodes. Such inclusions were not detected in the systemic organs in a case of human GLD. This fact may indicate an important species difference between the human and murine forms of GLD, although the genetic enzymatic defect is the same.

Animals↗
PubMed1982

Glycosylceramide synthesis in the developing spinal cord and kidney of the twitcher mouse, an enzymatically authentic model of human Krabbe disease.

UDP-galactose:ceramide galactosyltransferase activity was assayed in the spinal cord and kidney of the recently discovered neurological mutant, the twitcher mouse, which is an enzymatically authentic model of human globoid cell leukodystrophy (Krabbe disease). The activity in the spinal cord was essentially normal during the early myelination period up to 15 days. There was a slight reduction at 20 days. At 25 and 33 days, the galactosyltransferase activity was drastically reduced compared to controls. In contrast, the galactosyltransferase activity in the kidney of twitcher mice remained normal throughout the developmental stages examined. Activity of the control enzyme UDP-glucose:ceramide glucosyltransferase was always normal in both the spinal cord and kidney. Thus, reduction of galactosylceramide synthesis occurs in the CNS secondarily to the pathological alteration of the oligodendroglia. No such reduction occurs in the kidney, at least for the last step of galactosylceramide synthesis. Reduced synthesis as the result of metabolic regulation in the presence of the catabolic block is therefore unlikely to be the cause of the lack of abnormal accumulation of galactosylceramide in the kidney of patients with globoid cell leukodystrophy.

Animals↗
PubMed1981

Erythrocyte membrane in myotonic dystrophy. A study with acetylcholinesterase.

Erythrocyte membrane in myotonic dystrophy (MyD) was studied with respect to acetylcholinesterase (AchE), an enzyme localized on the external surface of the membrane. The activity was determined over the temperature range of 7-41 degrees C (in hemolysates) and 25-41 degrees C (in ghosts). The activity, the transition temperature in the Arrhenius plots, and the activation energy either above or below the transition temperature did not differ between MyD and controls. The Hill coefficient for the inhibition by fluoride was approximately 1 in MyD and in controls at 13, 25 and 37 degrees C. The dose of fluoride for 50% inhibition of the enzyme activity differed between different temperatures but not between MyD and controls. There seems to be no gross abnormality in AchE or its environment in erythrocyte membrane in MyD.

Acetylcholinesterase↗
PubMed1981

Na+ + K+ ATPase of erythrocyte membranes in Duchenne muscular dystrophy.

We studied the Na+ + K+ ATPase activity of erythrocyte membranes from patients with Duchenne muscular dystrophy (DMD). Samples from patients and controls were obtained at almost the same time on the same day and processed simultaneously. Difference of anticoagulants, extent of washing the red cells, mechanical or osmotic disruption of the cells, presence or absence of EDTA in the washing solution of the ghosts, intentional removal of the peripheral proteins of the membranes, addition of DMD plasma to the assay system, and different temperatures of membrane storage caused no significant differences between DMD and control in Na+ + K+ ATPase or in response of the enzyme to ouabain.

Erythrocyte Membrane↗
PubMed1980

Erythrocyte acetylcholinesterase in Duchenne muscular dystrophy.

The activity and the activation energy (25--43 degrees C) of acetylcholinesterase did not differ between erythrocytes from patients with Duchenne muscular dystrophy (DMD) and controls. The Hill coefficient for the inhibition of the enzyme activity by fluoride was 1 in both groups. The dose of fluoride for 50% inhibition of the enzyme activity differed between samples prepared in different ways, but not between DMD and controls. The present results suggest that there is no gross abnormality in erythrocyte acetylcholinesterase or its environment in the erythrocyte membrane in DMD.

Acetylcholinesterase↗
PubMed1980

Beriberi neuropathy. Morphometric study of sural nerve.

Seven biopsied sural nerves from patients with beriberi were morphometrically evaluated. In teased fiber analysis the mean frequency of myelinated fibers showing axonal degeneration and segmental demyelination was 37.5 and 5.3%, respectively. In two cases with frequency of segmental demyelination higher than 5%, segmental demyelination was shown by statistical criteria to have occurred on certain fibers in a clustered fashion. Therefore, the segmental demyelination in beriberi may be secondary to axonal degeneration. Electromyographic findings and slow improvement of muscle weakness were compatible with axonal degeneration of motor fibers. Determinations of fiber densities revealed preferential decrease of the density of large myelinated fibers with the preservation of the density of small myelinated and unmyelinated fibers. The preferential nerve fiber involvement in beriberi was not associated with pain in the lower limbs and this fact is contrary to the expectation of the proponents of the gate control theory.

Adolescent↗