Neuroimaging findings in late infantile GM1 gangliosidosis

Late infantile GM1 gangliosidosis is an extremely rare metabolic disorder with clinical features of seizure and progressive motor and mental retardation without facial dysmorphism or visceral organomegaly. We report the CT and MR imaging findings in one infant, which included abnormalities of the cerebral cortex, white matter, and deep nuclei.     

GM2 gangliosidosis B1 variant: biochemical and molecular characterization of hexosaminidase A

This paper, based on functional radiological knowledge of normal cervical spine kinematics, develops the hypothesis that compressive vertebral injury can be produced by abrupt reversal of curve between hyperflexed and hyperextended parts of the cervical spine. Reversal of curve occurs when the main vector of a compressive force passes between two centers of flexion-extension motion. The hypothesis more clearly explains reverse dislocation of fractured vertebrae than the current concept of Whitley and Forsyth of motion of the head through an arc. The mechanism of injuries with characteristics of hyperflexion of one segment and hyperextension of an adjacent segment, e.g., in certain types of hangman's fractures, is better understood. The hypothesis is expected to be helpful in guiding experimental cervical spine injury, as it relates direction of force to level and type of the resulting vertebral injury.     

Clinical, ultrastructural and biochemical study of a case of GM1 type 2 gangliosidosis

Clinical, histological, ultrastructural and biochemical studies have been performed in a living 20-month-old infant with GM1-gangliosidosis type 2. Rectum, brain and liver biopsies were done. The histological and ultrastructural examination revealed the presence of cytoplasmic membranous bodies in the nervous system and a vacuolisation of the visceral parenchymatous cells, particularly histiocytes. The diagnosis was established by the finding of a generalized beta-galactosidase deficiency and an accumulation of GM1-ganglioside in brain. In leukocytes, the activity of p-nitrophenyl-beta-galactosidase was below 5%, and that of GM1-ganglioside beta-galactosidase below 1% of values obtained in controls. In cerebral tissue, GM1 ganglioside constituted 80% of total gangliosides; its concentration was 15 times that in age-matched controls. No accumulation of GM1 could be evidence in liver. Enzymatic examination of leukocytes obtained from the consanguineous parents revealed heterozygote values.     

Two siblings of type 3 GM1 gangliosidosis with different clinical features and different ages of onset

We experienced two siblings of type 3 GM1 gangliosidosis. A 33-year-old woman developed dysarthria, dysbasia and bradykinesia at around the age of 30. Her 28-year-old brother showed locomotor retardation and skeletal deformity in infancy. He lost the ability to stand walk at childhood, and developed progressive dystonia. The major neurologic manifestations were parkinsonian symptoms in the elder sister, and progressive dystonia in her brother. Both had markedly reduced beta-galactosidase activity in peripheral blood lymphocyte and were diagnosed as having type 3 GM1 gangliosidosis. Gene analysis revealed that these patients were homozygotes of the adult type mutant gene. The two siblings are unique in that the clinical manifestations and the age of onset of symptoms differed markedly between them despite the same mutant gene in both cases.     

Recombinant GM2-activator protein stimulates in vivo degradation of GA2 in GM2 gangliosidosis AB variant fibroblasts but exhibits no detectable binding of GA2 in an in vitro assay

OBJECTIVE: To examine choroidopathy in patients with Beh?et disease. DESIGN: Prospective clinical study. PARTICIPANTS: Thirty-three patients (63 eyes) with Beh?et disease. INTERVENTION: Patients underwent simultaneous indocyanine green (ICG) and fluorescein angiography with a double detector of scanning laser ophthalmoscopy. MAIN OUTCOME MEASURES: Angiographic findings recorded on videotapes were evaluated. The relation of angiographic findings with systemic activity and aqueous inflammation was also analyzed. RESULTS: Fluorescein angiography showed leakage in varying degrees from retinal vessels in 30 patients (53 eyes, 84%). The ICG angiographic findings were choroidal vascular wall staining in 16 eyes (25%), hyperfluorescent spots in 42 eyes (66%) and hypofluorescent plaques in 22 eyes (35%), both of which were not evident with fluorescein, leakage from choroidal vessels in 3 eyes (5%), and irregular filling of choriocapillaris in 11 eyes (17%). These findings did not have a statistically significant correlation with the presence or absence of aqueous inflammation or oral aphthous ulcerations. CONCLUSIONS: The patients with Beh?et disease showed choroidal abnormalities, which could be revealed only by ICG angiography, but not with funduscopy or fluorescein angiography. Simultaneous ICG and fluorescein angiography would be useful for examining choroidal lesions in Beh?et disease.     

Transport of GM1 and GM1 inner ester across an in vitro model of the blood-brain barrier

Gangliosides, especially GM1, attenuate the in vivo damage caused by various neurotoxins. The chemically neutral inner ester of GM1 may be a better cytoprotective agent against some neurotoxins than the parent GM1 compound, because it may cross the blood-brain barrier (BBB) more easily than the anionic GM1. Using an in vitro bovine brain endothelial cell model of the BBB, we show the inner ester more readily transverse the tight junction barrier of this model than does GM1. Further, it is demonstrated that the GM1 inner ester is stable for several hours at pH values between 7.0 and 8.2 at 37 degrees C. Finally, the results illustrate that the BBB model may be useful for testing other gangliosides and their various derivatives for increased ability to cross the BBB.     

Thymic sarcoma in childhood

Sarcoma of the thymus is exceedingly rare, especially in children. We report a case of thymic sarcoma in a child, including the imaging findings which have not been previously described.     

Ganglioside GM1 attenuates scopolamine-induced amnesia in rats and mice

We evaluated ethanol- and HCl-induced mucosal damages in developing rats. The degree of damage induced by ethanol and HCl was greatest in 1-week-old rats and decreased significantly with age until 4 weeks; thereafter it increased again. To evaluate the effect of weaning on the maturational changes in mucosal defense, we compared ethanol-induced mucosal damage among three groups of newborn rats: (1) receiving milk only; (2) receiving only rat chow from 14 days of age, and (3) having free access to milk and chow. There were no significant differences at 18 and 21 days of age. The mucus thickness increased with age until 8 weeks and was not affected by weaning. In conclusion, developmental changes occur in gastric mucosal protection in rats. Weaning does not have a significant effect on these changes.     

Construction of a recombinant feline herpesvirus type 1 expressing Gag precursor protein of feline immunodeficiency virus

Arthritis of dislocation is a unique form of degenerative joint disease involving the shoulder. It seems that a larger number of patients who develop arthritis of dislocation have had prior instability repairs. In studying large numbers of patients, several factors seem to recur. Careful, repeated examinations of both symptomatic and asymptomatic shoulders may uncover subtle subluxations; examination of other peripheral joints may reveal evidence of hyperlaxity and multidirectional instability. With understanding of the nature, direction, and extent of the instability patterns, more appropriate stabilization procedures may diminish the incidence of arthritis of dislocation. Today's techniques and the surgical management of instabilities obviate the need for hardware, which has been shown to have a significant impact on the occurrence of this arthritis. Surgeons should realize the potentials and risks of arthroscopic stabilization procedures, and only after satisfactory analysis should these procedures be done by orthopedic surgeons in general. Many new techniques for shoulder stabilization are now in the armementarium of the arthroscopist, but more time is needed to see if they will influence the development of arthritis of instability. When arthritis of dislocation does develop, shoulder arthroplasty is reasonable, despite the young age of patients. In the technique of joint replacement for this condition, specific surgical principles must be kept in mind. Preservation of deltoid function is paramount. Restoration of muscle length and tension relationships are critical for successful functional outcomes. Component positioning and orientation must account for the bone loss and alterations in soft tissue tension and quality. No shoulder replacement, no matter how well performed, will be successful without adequate physician-directed rehabilitation.     

Properties and functions of feline herpesvirus type 1 glycoproteins

Feline herpesvirus type 1 (FHV-1) is a causative agent of feline viral rhinotracheitis and belongs to the subfamily Alphaherpesvirinae of the family Herpesviridae. Since first isolated in 1958 by Crandell and Maurer, FHV-1 is distributed worldwide and is the most clinically significant agent for respiratory infections in cats. In this review, we describe the recent findings with properties and functions of FHV-1 glycoproteins, especially hemagglutinins.     

Monosialoganglioside GM1 inhibits neurotoxicity after hypothermic circulatory arrest

BACKGROUND/AIM: A herbal medicine, Sho-saiko-to (TJ-9), has recently been orally administered to patients with chronic liver disease in Japan and has been reported to inhibit the development of hepatocellular carcinoma. The aim of this study was to investigate whether TJ-9 has an inhibitory effect on the development of preneoplastic lesions and liver fibrosis in rats. METHODS: The effects of the TJ-9 were examined using the choline-deficient L-amino acid-defined (CDAA) diet-induced liver fibrosis model in 16-week-old male Wistar rats. RESULTS: TJ-9 (1% w/w) prevented fibrosis, as indicated by reduced hydroxyproline content in the liver and inhibition of the increase in a serum marker of fibrosis (hyaluronic acid), without reducing the increase in serum alanine aminotransferase and aspartate aminotransferase. TJ-9 also reduced the expression of type III procollagen alpha 1 mRNA in the liver, as well as the proliferation of myofibroblast-like cells (activated stellate cells, activated Ito cells). Furthermore, TJ-9 reduced the number of preneoplastic lesions, detected as enzyme-altered (glutathione S-transferase placental form-positive) lesions, in the liver. CONCLUSIONS: These results indicate that the herbal medicine Sho-saiko-to (TJ-9) prevents fibrosis as well as preneoplastic lesions, not by inhibiting hepatocyte cell death but by inhibiting the activation of stellate cells, which are considered to be the main collagen-producing cells, leading to a reduction in the development of preneoplastic lesions.     

Ultrastructural study of plasma membrane GM1 in neuroectodermal cells using cholera-peroxidase

Cholera toxin was coupled to peroxidase to yield a highly specific marker for GM1 gangliosides. Study of embryonic brain cells in culture revealed intense binding of cholera-peroxidase by plasma membranes of both neurons and glial cells. In contrast, long-term monolayer glioblastoma cultures, including one producing C-type virus, revealed virtually no labelling of their plasma membranes. Such cells were shown to be capable of incorporating exogenously applied GM1 into their plasma membranes. Studies with fixed brain and synaptosomal fractions were in accord with results on embryonic brain cells in culture, and autoradiographic findings with 125I cholera supported observations made utilizing cholera-peroxidase. From our studies there is some indication that long-term propagation in vitro alters the plasma membrane GM1.     

Effect of ganglioside (GM1) on memory in senescent rats

We investigated the effects of aerosolized prostacyclin (PGI2) administration on hemodynamics and pulmonary gas exchange in 8 patients with severe respiratory failure and acute pulmonary hypertension. Nebulization of epoprostenol (5 ng/kg body weight for 15 min) decreased mean pulmonary blood pressure from 41.2 +/- 6.7 mm Hg (mean +/- SD, before administration) to 36.1 +/- 6 mm Hg < or = 15 min (p < 0.05). The effect was reversed 10 min after discontinuation of PGI2 (40.9 +/- 6.3 mm Hg). Pulmonary vascular resistance index (339 +/- 138 dynes.s.cm-5.m2, before administration) was significantly (p < 0.05) reduced < or = 15 min (260 +/- 89 dynes.s.cm-5.m2) and increased again after discontinuation of PGI2 (341 +/- 142 dynes.s.cm-5.m2). The ratio of arterial oxygen to the fraction of inspired oxygen (PaO2/FiO2) increased from 119 +/- 34 mm Hg (before administration) to 163 +/- 76 mm Hg (15 min after initiation of administration p < 0.05) and was reduced after PGI2 discontinuation (116 +/- 35 mm Hg). Heart rate, mean blood pressure, central venous pressure, and pulmonary arterial wedge pressure remained unchanged, whereas cardiac index was slightly reduced. We assume that PGI2 aerosolization is a beneficial technique, applied with a ventilator nebulization system. The beneficial effect might be caused by selective pulmonary vasodilatation in well-ventilated areas of the lung.     

Ethanol disordering of GM1-enriched short-sleep synaptosomal plasma membranes

The Long-Sleep (LS) and Short-Sleep (SS) mouse synaptosomal plasma membranes differ in ethanol sensitivity at superficial membrane regions, which corresponds with the behavioral response of the mice to ethanol hypnosis. The only significant difference between these synaptosomal plasma membranes is the synaptosomal monosialoganglioside (GM1) content, LS > SS. Here, GM1 was examined as a parameter for increasing membrane sensitivity to ethanol effects in the ethanol-resistant SS membranes. Synaptosomal plasma membranes from SS mice were allowed to incorporate exogenous GM1. Membrane order was then studied at the surface, intermediate, and interior regions of the membranes by delayed Fourier transform proton NMR in the presence and absence of perdeuterated ethanol. Differences in membrane order were observed in all three membrane regions with increasing perdeuterated ethanol concentrations depending on the synaptosomal GM1 content.     

Anti-idiotypic monoclonal antibodies to GM1 identify ganglioside binding proteins

Ganglioside stimulated neurite outgrowth may be due to ganglioside binding to membrane proteins or to intercalation into the membrane. To test that ganglioside binding proteins could be found on neuronal surfaces, anti-idiotypic ganglioside monoclonal antibodies (AIG mAbs) were generated to mimic the biological properties of the GM1 ganglioside. The AIG mAbs were identified by their ability to bind to a known GM1 binding protein, the beta-subunit of cholera toxin. For the two AIG mAbs studied, AIG5 and AIG20, binding to beta-CT was blocked most strongly by GM1. This data also suggests that AIG5 and AIG20 mimic different but overlapping epitopes of the ganglioside GM1. Western blotting and immunoprecipitation of mammalian tissues reveals four potential ganglioside binding proteins of molecular weight 93, 66, 57, and 45 kDa. Immunocytochemistry demonstrates neuronal surface label with the AIG mAbs, which suggests that gangliosides, enriched on the neuronal surface membrane, are co-localized with putative ganglioside binding proteins. In bioassays, the AIG mAbs promote neuronal sprouting. This shows that these antibodies can be used to study the biological effects of ganglioside binding to neuronal surface proteins, and the role of gangliosides in the activation of neurite outgrowth.     

Heritability and biochemistry of gangliosidosis in emus (Dromaius novaehollandiae)

The progeny of two emu breeder pairs, which had a history of producing offspring with gangliosidosis, were monitored for 15 mo. DNA fingerprinting revealed that individuals in each breeder pair were not related to each other. One breeder pair had 13 progeny that reached or exceeded the age of 1 mo, and six of these progeny developed gangliosidosis. The mean age at which these affected emus were euthanatized, with distinct neurologic disease, or died was 5.7 mo. The second emu pair had 13 progeny, seven of which developed gangliosidosis, with a mean age of euthanasia/death of 4.6 mo. Affected emus died or were euthanatized from 2 to 8 mo of age. The primary clinical sign in the affected emus was mild to severe ataxia. Severe hemorrhage into the body cavity or the muscles of the thigh was noted in 8 of 13 of the affected emus. Brain ganglioside levels were evaluated in six of the affected emus and six controls. Significant increases (P < 0.05) in gangliosides GM1 and GM3 were noted, with 2.3- and 4.9-fold increases in these two gangliosides, respectively, in affected emus. Furthermore, the diseased emu brains contained ganglioside GM2, whereas this monosialoganglioside was undetectable in the brains of normal controls. Total mean brain ganglioside sialic acid in affected emus was increased 3.3-fold in comparison with controls. Serum chemistries revealed elevated cholesterol and decreased uric acid levels in affected emus. Gangliosidosis in emus is an inherited disease process that, in the current study, caused 50% mortality in the progeny of two emu breeder pairs. The elimination of this lethal gene from emu breeder stock is essential for the long-term economic viability of the United States emu industry.     

Influence of endogenous GM1 ganglioside on TrkB activity, in cultured neurons

To establish direct linkage between the ethanol-inducible cytochrome P450, CYP2E1, ethanol hepatotoxicity, and lipid peroxidation, a HepG2 cell line which expresses human CYP2E1 was established by retroviral infection. Ethanol produced a time-and concentration-dependent cytotoxicity to HepG2 cells expressing the CYP2E1 but not to control cells. The ethanol toxicity was prevented by inhibitors of CYP2E1 and antioxidants. In a similar manner, addition of a polyunsaturated fatty acid such as arachidonic acid produced toxicity to the cells expressing CYP2E1 but not the control cells. Toxicity was associated with enhanced lipid peroxidation and was prevented by antioxidants. The ethanol and arachidonic acid toxicity was apoptotic in nature and was associated with activation of Caspases I and III. The toxicity and apoptosis could be prevented by peptide inhibitors of ICE and by transfection with a plasmid containing the cDNA for human Bcl-2. These results show that this HepG2 cell model can be used to establish a CYP2E1-dependent ethanol hepatotoxicity system, and that induction of a state oxidative stress appears to play a central role in the CYP2E1-dependent apoptosis and cytotoxicity.