| 11. |
- Hedera, P., et al.
(författare)
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Spastic paraplegia, ataxia, mental retardation (SPAR) : A novel genetic disorder
- 2002
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Ingår i: Neurology. - : American Academy of Neurology. - 0028-3878 .- 1526-632X. ; 58:3, s. 411-416
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To describe a kindred with a dominantly inherited neurologic disorder manifested either as uncomplicated spastic paraplegia or ataxia, spastic paraplegia, and mental retardation.Methods: Neurologic examinations and molecular genetic analysis (exclusion of known SCA and HSP genes and loci; and trinucleotide repeat expansion detection [RED]) were performed in six affected and four unaffected subjects in this family. MRI, electromyography (EMG), and nerve conduction studies were performed in three affected subjects.Results: The phenotype of this dominantly inherited syndrome varied in succeeding generations. Pure spastic paraplegia was present in the earliest generation; subsequent generations had ataxia and mental retardation. MRI showed marked atrophy of the spinal cord in all patients and cerebellar atrophy in those with ataxia. Laboratory analysis showed that the disorder was not caused by mutations in genes that cause SCA-1, SCA-2, SCA-3, SCA-6, SCA-7, SCA-8, and SCA-12; not linked to other known loci for autosomal dominant ataxia (SCA-4, SCA-5, SCA-10, SCA-11, SCA-13, SCA-14, and SCA-16); and not linked to known loci for autosomal dominant hereditary spastic paraplegia (HSP) (SPG-3, SPG-4, SPG-6, SPG-8, SPG-9, SPG-10, SPG-12, and SPG-13) or autosomal recessive HSP SPG-7. Analysis of intergenerational differences in age at onset of symptoms suggests genetic anticipation. Using RED, the authors did not detect expanded CAG, CCT, TGG, or CGT repeats that segregate with the disease.Conclusions: The authors describe an unusual, dominantly inherited neurologic disorder in which the phenotype (pure spastic paraplegia or spastic ataxia with variable mental retardation) differed in subsequent generations. The molecular explanation for apparent genetic anticipation does not appear to involve trinucleotide repeat expansion.The spinocerebellar ataxias (SCA) and hereditary spastic paraplegias (HSP), although clinically heterogeneous, typically are discerned as distinct syndromes: insidiously progressive ataxia of SCA typically is distinct from the insidiously progressive spastic gait disturbance of HSP.1-5⇓⇓⇓⇓ We identified a kindred with a unique, dominantly inherited neurologic disorder with features of both HSP and spastic ataxia. The most remarkable feature was the observation that different individuals exhibited different phenotypes within this family. Whereas affected members of the oldest generations exhibited pure spastic paraplegia, affected members in the younger generations exhibited cerebellar ataxia, lower extremity spasticity, and variable mental retardation and subtle dystonia. We designate this novel Spastic Paraplegia, Ataxia, mental Retardation syndrome as SPAR. In this report, we describe the clinical features of this SPAR index family and present our findings supporting that SPAR is genetically distinct from known forms of autosomal dominant HSP and SCA and is not caused by an expanded trinucleotide repeat.
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| 12. |
- Li, Wei, et al.
(författare)
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3-Aminopropanal, formed during cerebral ischaemia, is a potent lysosomotropic neurotoxin
- 2003
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Ingår i: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 371:2, s. 429-436
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Tidskriftsartikel (refereegranskat)abstract
- Cytotoxic polyamine-derived amino aldehydes, formed during cerebral ischaemia, damage adjacent tissue (the so-called 'penumbra') not subject to the initial ischaemic insult. One such product is 3-aminopropanal (3-AP), a potent cytotoxin that accumulates in ischaemic brain, although the precise mechanisms responsible for its formation are still unclear. More relevant to the present investigations, the mechanisms by which such a small aldehydic compound might be cytotoxic are also not known, but we hypothesized that 3-AP, having the structure of a weak lysosomotropic base, might concentrate within lysosomes, making these organelles a probable focus of initial toxicity. Indeed, 3-AP leads to lysosomal rupture of D384 glioma cells, a process which clearly precedes caspase activation and apoptotic cell death. Immunohistochemistry reveals that 3-AP concentrates in the lysosomal compartment and prevention of this accumulation by the lysosomotropic base ammonia, NH3, protects against 3-AP cytotoxicity by increasing lysosomal pH. A thiol compound, N-(2-mercaptopropionyl)glycine, reacts with and neutralizes 3-AP and significantly inhibits cytoxocity. Both amino and aldehyde functions of 3-AP are necessary for toxicity: the amino group confers lysosomotropism and the aldehyde is important for additional, presently unknown, reactions. We conclude that 3-AP exerts its toxic effects by accumulating intralysosomally, causing rupture of these organelles and releasing lysosomal enzymes which initiate caspase activation and apoptosis (or necrosis if the lysosomal rupture is extensive). These results may have implications for the development of new therapeutics designed to lessen secondary damage arising from focal cerebral ischaemia.
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| 16. |
- Yuan, Jinliang, et al.
(författare)
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Analysis of Fluid Flow and Heat Transfer for Proton Exchange Membrane Fuel Cells by an Extended Darcy Model
- 2002
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Ingår i: Progress in Transport Phenomena. - 2842993918 ; , s. 837-842
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Konferensbidrag (refereegranskat)abstract
- By using a three dimensional computational method, gas flow and heat transfer have been investigated and analyzed for both cathode / anode ducts of proton exchange membrane fuel cells. The Brinkman- Forchheimer-extended Darcy model is employed to investigate the flow inside the porous layer of the duct. Effects of inertial coefficient, together with permeability, effective thermal conductivity, thickness of the porous layer, on gas flow and heat transfer are studied.
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