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ABSTRACT: Pontocerebellar hypoplasia exhibits a diverse range of etiologies, including six known autosomal recessive, single gene disorders. We describe a molecularly confirmed case of pontocerebellar hypoplasia type 4, a rare and severe neonatal phenotype with a novel TSEN54 mutation, presenting with polyhydramnios, hypertonia, and early neonatal death. The patient manifested severe hypoplasia of the cerebellum and brainstem. The neuropathologic findings in pontocerebellar hypoplasia type 4 develop late in gestation, and therefore prenatal diagnosis with ultrasonography is of limited use. Establishing a molecular diagnosis in the proband is critical for allowing couples to plan future pregnancies.
Pediatric Neurology 09/2011; 45(3):185-8. · 1.52 Impact Factor
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ABSTRACT: Recent findings that a novel polyunsaturated fatty acid, β-oxa 23:4n-6, inhibits adhesion molecule expression on vascular endothelial cells and leukocyte adhesion led us to examine its ability to inhibit the development of atherosclerosis in the apoE-deficient (apoE) mouse. The mice were kept on normal chow or a high-fat/high-cholesterol diet for various periods and treated with either vehicle or β-oxa 23:4n-6 by the intraperitoneal route. The hearts and aortae were isolated and lesion development at the aortic root was determined. Morphometric assessment revealed that lesion development was a function of compensatory aortic enlargement, suggesting that measurement of plaque size per se is the appropriate assessment of lesion size. Using this criterion, we found that atherosclerosis development was reduced in response to β-oxa 23:4n-6, plaque size by 74% and aortic cross-sectional area by 62%, under an optimized regime. The number of foam cells per unit tissue area in the lesions of β-oxa 23:4n-6-treated mice was significantly reduced by 37.5%. The blood levels of β-oxa23:4n-6 in these mice exceeded the concentrations previously found to inhibit adhesion molecule expression in cultured endothelial cells. These data show that β-oxa23:4n-6 protects against experimental atherosclerosis, most likely by reducing the number of infiltrating monocytes.
Journal of cardiovascular pharmacology 10/2010; 56(4):431-9. · 2.83 Impact Factor
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ABSTRACT: MPS IIIA is a lysosomal storage disorder caused by mutations in the sulphamidase gene, resulting in the accumulation of heparan sulphate glycosaminoglycans (HS GAGs). Symptoms predominantly manifest in the CNS and there is no current therapy that effectively addresses neuropathology in MPS IIIA patients. Recent studies in MPS IIIA mice have shown that rhodamine B substrate deprivation therapy (SDT) (also termed substrate reduction therapy/SRT) inhibits GAG biosynthesis and, improves both somatic and CNS disease pathology. Acute overexposure to high doses of rhodamine B results in liver toxicity and is detrimental to reproductive ability. However, the long-term effects of decreasing GAG synthesis, at the low dose sufficient to alter neurological function are unknown. A trans-generational study was therefore initiated to evaluate the continuous exposure of rhodamine B treatment in MPS IIIA mice over 4 generations, including treatment during pregnancy. No alterations in litter size, liver histology or liver function were observed. Overall, there are no long-term issues with the administration of rhodamine B at the low dose tested and no adverse effects were noted during pregnancy in mice.
Molecular Genetics and Metabolism 101(2-3):208-13. · 3.19 Impact Factor
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ABSTRACT: MPS IIIA is a lysosomal storage disorder caused by mutations in the sulphamidase gene, resulting in the accumulation of heparan sulphate glycosaminoglycans (HS GAGs). Symptoms predominantly manifest in the CNS and there is no current therapy that effectively addresses neuropathology in MPS IIIA patients. Recent studies in MPS IIIA mice have shown that rhodamine B substrate deprivation therapy (SDT) (also termed substrate reduction therapy/SRT) inhibits GAG biosynthesis and, improves both somatic and CNS disease pathology. Acute overexposure to high doses of rhodamine B results in liver toxicity and is detrimental to reproductive ability. However, the long-term effects of decreasing GAG synthesis, at the low dose sufficient to alter neurological function are unknown. A trans-generational study was therefore initiated to evaluate the continuous exposure of rhodamine B treatment in MPS IIIA mice over 4 generations, including treatment during pregnancy. No alterations in litter size, liver histology or liver function were observed. Overall, there are no long-term issues with the administration of rhodamine B at the low dose tested and no adverse effects were noted during pregnancy in mice.
Molecular Genetics and Metabolism.
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ABSTRACT: N-Acetylcysteine (NAC), being both a mucolytic agent and a thiol-containing antioxidant, may affect the establishment and maintenance of H. pylori infection within the gastric mucus layer and mucosa. Agar and broth dilution susceptibility tests determined the MIC of H. pylori strain SSI to NAC. H. pylori load in SSI strain-infected C57BL mice was determined as colony forming units per gram of gastric tissue. Gastritis assessment was scored and gastric surface hydrophobicity was determined by contact angle measurement. MICs of NAC were 5 to 10 and 10 to 15 mg/ml using the agar dilution and broth dilution methods, respectively. NAC (120 mg per day for 14 days) reduced the H. pylori load in mice by almost 1 log compared with sham treatment. Pretreatment with NAC (40 mg/day) also significantly reduced the H. pylori load but did not prevent H. pylori colonization. Both H. pylori infection and NAC reduced the surface hydrophobicity of murine gastric mucosa. No significant differences were observed in the gastritis scores of H. felis- or H. pylori-infected mice receiving either NAC or sham treatments. This study demonstrates that NAC inhibits the growth of H. pylori in both agar and broth susceptibility tests and in H. pylori-infected mice. NAC did not alter the severity of H. pylori- or H. felis-induced gastritis.
Digestive Diseases and Sciences 49(11-12):1853-61. · 2.12 Impact Factor
