Combined use of free and pedicled skin flaps for the reconstruction of extremities in high voltage electrical injury.
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Adult↗
Biomedical subjects
A Salviati
Publications and source records attributed to A Salviati.
Neuropathology of cognitively normal elderly.
Despite general agreement about the boundaries of Alzheimer disease (AD), establishing a maximum limit for Alzheimer-type pathology in cognitively intact individuals might aid in defining more precisely the point at which Alzheimer pathology becomes clinically relevant. In this study, we examined the neuropathological changes in the brains of 39 longitudinally followed. cognitively normal elderly individuals (24 women, 15 men; age range 74-95, median 85 years). Neuropathological changes of the Alzheimer type were quantified by determining neurofibrillary tangle (NFT) staging by the method of Braak and Braak and by quantification of the abundance of diffuse, cored, and neuritic plaque burden using the scheme developed by the Consortium to Establish a Registry for Alzheimer Disease (CERAD). Vascular, Lewy body, and argyrophilic grain pathology were also assessed. We found 34 subjects (87%) with a Braak stage <IV; 32 subjects (82%) with less than moderate numbers of cored plaques and 37 subjects (95%) with less than moderate numbers of tau-positive neuritic plaques. Many subjects had moderate or frequent diffuse plaques (n = 19, 49%). By the National Institute on Aging-Reagan Institute (NIA-RI) criteria, none of our cases met criteria for high "likelihood" of AD. Four met NIA-RI criteria for intermediate "likelihood." Seven cases met CERAD criteria for possible AD. Nineteen met Khachaturian criteria for AD. Only 1 subject had neocortical Lewy bodies. Small, old infarcts were common, but no subjects had more than 2 of these and none had a single large infarction. Thus, the majority of individuals who are cognitively normal near the time of their death have minimal amounts of tau-positive neuritic pathology (Braak stage <IV and neuritic plaques <6 per x100 field in the most affected neocortical region). The few subjects with more severe AD pathology can be expected based on incidence rates of AD in the very elderly.
Aged↗
Myelin oligodendrocyte glycoprotein polymorphisms and multiple sclerosis.
A detailed analysis of the coding sequences of myelin oligodendrocyte glycoprotei (MOG) gene was performed in multiple sclerosis (MS) patients and in control individuals and three new polymorphisms are described: T636C, nt 571+77C-->T (IVS 4), and nt 710-44A-->G (IVS 6). Screening studies demonstrated that T636C was present in three MS patients and in no control individual and that polymorphisms nt 571+77C-->T (IVS 4), and nt 710-44A-->G (IVS 6), were present with no significant frequency differences in MS patients and control individuals. No mutations were found after sequencing the coding sequences of the extracellular domain of MOG gene in 20 MS patients and 20 control individuals. Screening studies were also performed for known polymorphisms: G15A, Val142Leu, nt 571+68A-->G (IVS 4), and 571+92C-->G (IVS 4). Polymorphism Val 142 Leu, which is linked to nt 571+68A-->G (IVS 4), resulted under-represented in MS patients.
Axons↗
A novel 4-bp deletion creates a premature stop codon and dramatically decreases HEXB mRNA levels in a severe case of Sandhoff disease.
We present the molecular genetic analysis of an infantile-onset Sandhoff disease patient. Genomic DNA amplification, heteroduplex analysis, cloning and sequencing revealed a 4-bp deletion in exon 4 (497 DeltaAGTT). The result is a frameshift mutation that leads to a stop codon in exon 5. This mutation is associated with a dramatic decrease of HEXB mRNA levels.
Base Sequence↗
Myelin oligodendrocyte glycoprotein (MOG) polymorphisms and adrenoleukodystrophy.
We describe four novel sequence variants in the Myelin Oligodendrocyte Glycoprotein (MOG) gene. A total of six sequence variants of the MOG gene were identified in eleven out of 44 ALD patients investigated: G15A, CTC repeat in exon 1, Val142Leu, Val145Ile, 551+68A-->G and 551+77C-->T. Screening studies demonstrated that all these polymorphisms are present in 50 unaffected control male individuals of the same population and in the different phenotypes of ALD patients, indicating that they do not contribute to phenotype variability in ALD.
Adrenoleukodystrophy↗
Novel consensus sequence for the Golgi apparatus casein kinase, revealed using proline-rich protein-1 (PRP1)-derived peptide substrates.
Previous studies have shown that the Golgi apparatus casein kinase (G-CK) recognizes phosphoacceptor sites specified by the triplet SXE/Sp, which is found in several phosphoproteins, besides casein itself. In the present study, we report that G-CK can phosphorylate, with comparable efficiency, sequences surrounding Ser-22 of salivary proline-rich protein-1 (PRP1), which do not conform to the SXE/Sp motif. By using a series of peptide substrates derived from the PRP1 Ser-22 site, we also have shown that the optimal consensus sequence recognized by G-CK in this case was SXQXX(D/E)3, where the acidic residues at positions n+5 to n+7 and, to a lesser extent, the glutamine residue at position n+2 are the critical determinants.
Amino Acid Sequence↗
Detection of mutations in the ALD gene (ABCD1) in seven Italian families: description of four novel mutations.
The study describes the mutations causing adrenoleukodystrophy in seven Italian families. Four missense mutations leading to amino acid substitutions, two frameshift mutations leading to a premature termination signal, and a splicing mutation were identified. Mutations 2014C>T (P543L), 2053A>G (Q556A), 673-674insCC, and 1874+1G>A are described for the first time in this report. Mutations 1638C>T (R418W), 1588G>A(R401Q), and 1801-1802delAG are already known to be link to ALD.
ATP Binding Cassette Transporter, Subfamily D, Mem↗
Two novel frameshift mutations in the adrenoleukodystrophy gene in Italian patients.
Two novel frameshift adrenoleukodystrophy mutations in two families were identified: a complex dinucleotide deletion/tetranucleotide insertion at 1116 TC-->GAGA (codon 244 [serine]) and an AG deletion at nucleotide 1462 (codon 359 [glutamic acid]). Both mutations are predicted to cause premature termination of protein synthesis. The patients were affected by childhood cerebral adrenoleukodystrophy and by adrenomyeloneuropathy with mild Addison disease, respectively.
Adrenoleukodystrophy↗
Two novel missense mutations causing adrenoleukodystrophy in Italian patients.
The authors present two new missense mutations in exon 1 of the adrenoleukodystrophy (ALD) gene. The first, a C813T transition, results in the substitution Pro143 Ser in the third putative transmembrane domain of the adrenoleukodystrophy protein (ALDP) in an adult onset case. The second, a de novo C709T transition, results in a substitution Ser 108 Leu between the second and the third putative transmembrane segments, in a childhood case.
ATP Binding Cassette Transporter, Subfamily D, Mem↗
Mutations associated with very late-onset metachromatic leukodystrophy.
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Age of Onset↗
Neuroaxonal dystrophy with dystonia and pallidal involvement.
Infantile neuroaxonal dystrophy (INAD) is an autosomal recessive disease of infantile onset, characterised by progressive clinical course, multi-systemic involvement and widespread presence of dystrophic axons in both the central and peripheral nervous system. Clinical, neurophysiological and neuroradiological criteria of the disease are established, but the occurrence of atypical cases is known. Since the availability of molecular markers is still lacking, diagnostic evidence in vivo is provided by the presence of specific axonal lesions distally in the peripheral nerve fibres. In two children who had a protracted course of the disease with dystonic postures of the upper limbs and showed dystrophic axons following sural nerve biopsy, bilateral pallidal hypointensity was observed after T2-weighted MRI scans. These findings are consistent with iron deposition, and are usually observed in Hallervorden-Spatz syndrome (HSS), a condition which is also characterised by dystrophic axons diffusely present in the central nervous system, but without peripheral nervous system involvement. These observations raise the issue of different phenotypes of INAD, and are consistent with the existence of intermediate forms between INAD and HSS. Altered mechanisms of iron storage and transport to and from the cellular compartments may play a role in the pathogenesis of the disease.
Axons↗
Transduced fibroblasts and metachromatic leukodystrophy lymphocytes transfer arylsulfatase A to myelinating glia and deficient cells in vitro.
Metachromatic leukodystrophy (MLD) is a lysosomal storage disease, caused by deficiency of arylsulfatase A (ASA), that manifests primarily in the white matter of the nervous system. Currently, no specific treatment exists that will reverse its fatal outcome. Replacement therapy has been hampered by the blood-brain barrier (BBB). To circumvent this problem we designed an ex vivo gene therapy strategy that includes the retrovirus-mediated ASA transduction of cells, such as activated lymphocytes, that are able to traverse the BBB or other membranes of the CNS. For this purpose, two recombinant retroviruses based on the pLXSN vector were produced, containing the wild-type ASA cDNA or a pseudodeficiency ASA cDNA, which encodes a smaller enzyme with normal activity. After transduction, ASA activity increased more than 100-fold in fibroblasts from an MLD patient. Furthermore, ASA-transduced MLD PBLs expressed 30 times higher ASA activity when compared with control PBLs. Moreover, cell culture experiments demonstrated that transduced fibroblasts could efficiently transfer ASA to deficient cells across a transwell barrier, whereas transduced MLD lymphocytes could transfer ASA to deficient fibroblasts only by direct cell-to-cell contact. Finally, ASA was taken up by normal oligodendrocytes and Schwann cells, the target myelinating glial cells for therapy in MLD. These data suggest possible short-term strategies for transfer of ASA into the CNS via transduced autologous cells while long-term strategies, related to autologous transduced bone marrow transplant, take effect in patients.
Cerebroside-Sulfatase↗
Splicing mutation causes infantile Sandhoff disease.
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Alternative Splicing↗
Molecular genetic characterization of two metachromatic leukodystrophy patients who carry the T799G mutation and show different phenotypes; description of a novel null-type mutation.
Metachromatic leukodystrophy (MLD) is an autosomal recessive storage disease caused by deficiency of the lysosomal enzyme, arylsulfatase A. Two common mutations causing MLD have been characterized and correlations between phenotype and genotype have been established. A third common mutation, T799G, has also been identified in European MLD patients, and is associated with the late-onset forms of the disease. We report the molecular analysis of two Italian MLD patients, with juvenile and adult onset of the disease, respectively, who carried the T799G mutation in compound heterozygosity with different null mutations. A novel rapid mutation detection method is demonstrated for patient screening. One patient has a novel mutation, a T553C [corrected] transition that results in the substitution of Pro for Leu at codon 135, and produces no enzymatic activity in transfection experiments.
Adult↗
A novel mutation which represents the fifth non-pathogenic polymorphism in the coding sequence of the arylsulfatase A gene.
A novel mutation, a C-->T transition at nucleotide 455 of the coding sequence of the ARSA gene, was found in a control individual during the search for metachromatic leukodystrophy mutations. Its distribution in three different populations was examined. The frequency of the T allele was 0.058, 0.025 and 0.033, in Italian, German and Greek populations, respectively. The mutation results in no amino acid substitution and can be identified as it creates a a polymorphic site for the restriction endonuclease N/aIII.
Cerebroside-Sulfatase↗
Effects of long-term conduction block on membrane properties of reinnervated and normally innervated rat skeletal muscle.
1. Do motoneurons regulate muscle extrajunctional membrane properties through chemical (trophic) factors in addition to evoked activity? We addressed this question by comparing the effects of denervation and nerve conduction block by tetrodotoxin (TTX) on extrajunctional acetylcholine (ACh) sensitivity and action potential resistance to TTX in adult rats. 2. We applied TTX to sciatic or tibial nerves for up to 5 weeks using an improved blocking technique which completely suppresses conduction but avoids nerve damage. 3. Reinnervation by TTX-blocked axons had no effect on the high ACh sensitivity and TTX resistance induced by nerve crush. 4. Long-lasting block of intact nerves (up to 38 days) induced extrajunctional changes as pronounced as after denervation. At shorter times (3 days), however, denervation induced much larger changes than TTX block; such a difference is thus only transiently present in muscle. 5. The effects of long-lasting block were dose dependent. Dose levels (6.6 micrograms day-1) corresponding to those used in the literature to block the rat sciatic nerve induced muscle effects much smaller than those induced by denervation, confirming published data. Our novel finding is that equal effects are obtained using doses substantially higher (up to 10.5 micrograms day-1). For the soleus it was necessary in addition to apply the TTX directly to the smaller tibial nerve. 6. The TTX-blocked nerves were normal in their histological appearance and capacity to transport anterogradely 3H-labelled proteins, to release ACh in quantal and non-quantal form or cluster ACh receptors and induce functional ectopic junctions on denervated soleus muscles. 7. We conclude that muscle evoked activity is the physiological regulator of extrajunctional membrane properties. Chemical factors from the nerve do not appear to participate in this regulation. The stronger response to denervation at short times only is best accounted for by factors produced by degenerating nerves.
Acetylcholine↗
Sensory involvement in X-linked spino-bulbar muscular atrophy (Kennedy's syndrome): an electrophysiological study.
Electrophysiological findings were studied in a family with spino-bulbar muscular atrophy (SBMA): the subjects were three male patients aged 58, 38 and 34 years and two female carriers aged 63 and 28 years. Diagnosis was proven at the molecular genetic level. Electromyography in the males showed spontaneous activity and neurogenic reorganization of the motor unit; motor nerve conduction was normal. Sensory action potentials were variably reduced in amplitude, but some were completely normal. Somatosensory evoked potentials, from both the upper and lower limbs, were invariably abnormal because involvement of the central pathways was observed. These findings are in agreement with histological investigations documenting lesions in the posterior columns. Brain-stem acoustic evoked potentials showed an increase in wave I latency. The electrophysiological data provide further evidence of the extent of sensory damage either in the central or the peripheral nervous system in SBMA patients, who otherwise have a constant clinical presentation of progressive motor neuron disease.
Adult↗
Familial cavernous hemangioma with atypical neuroimaging.
Three members of the same family were studied, all of whom had multiple intracerebral cavernous angiomas for which a dominant autosomal inheritance was hypothesised. The proband suffered from headaches, and physical examination revealed evident right hemiparesis. The second case started with a hemorrhagic cerebral stroke and the third was asymptomatic on neurological examination. Nuclear magnetic resonance (NMR), performed in two of the three cases, showed lesions whose number and extent were not radiologically characteristic of cavernous angioma. A cerebral biopsy of the proband enabled the diagnosis to be made. Despite the recent introduction of NMR, the nosological classification of familial forms can be difficult when the radiological lesions are atypical. In such cases, cerebral biopsy is not only a valid diagnostic aid, but is also indispensable for obtaining adequate genetic information.
Brain↗