PubMed Health⌕ Search

Biomedical subjects

A C Ludolph

Publications and source records attributed to A C Ludolph.

At least 73 records · Page 4Linked to original sources
PubMed1999

Do the benefits of currently available treatments justify early diagnosis and treatment of amyotrophic lateral sclerosis? Arguments against.

Recent in vitro and experimental animal studies strongly indicate that motor neuron diseases, like other neurodegenerative diseases, may be preceded by a long preclinical period. Clinical studies have suggested that the beneficial effects of neuroprotection in human amyotrophic lateral sclerosis (ALS) may be due to a preferential effect on early phases of the disease. However, the aim of this article is to review the potential arguments that there is no justification for early neuroprotective treatment of ALS. Controversies concerning the clinical neuroprotective effects of riluzole in mice and humans exist. Side effects of riluzole are emphasized and the data that appear to indicate that ALS has a long preclinical period are questioned. On the basis of these doubts and skepticisms, we conclude that it may be premature to treat ALS early without addressing the major objections in future studies in a controlled manner.

Amyotrophic Lateral Sclerosis↗
PubMed1998

5'-heterogeneity of the human excitatory amino acid transporter cDNA EAAT2 (GLT-1).

TWO novel transcripts of the human excitatory amino acid transporter EAAT2 (GLT-1) were cloned using PCR cloning techniques. Comparative sequence analysis of the 5'-untranslated region (UTR) of five EAAT2 transcripts led to the definition of five putative 5'-untranslated exons that are combined in a variable manner. Alternative splicing is a likely mechanism for the 5' complexity of the EAAT2 cDNA. The potential functional meaning of this finding such as differential expression of the EAAT2 transcripts in the central nervous system remains to be demonstrated.

ATP-Binding Cassette Transporters↗
PubMed1998

Alternative splicing of the glutamate transporter EAAT2 (GLT-1).

The human glutamate transporter EAAT2 (GLT-1) is of major importance for synaptic glutamate reuptake, and reportedly, a candidate gene for neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease and epilepsy. Here we report the polymerase chain reaction (PCR) cloning of two novel EAAT2 transcripts, named EAAT2-C1 and EAAT2-C2, which originate from alternative splicing of the human EAAT2 gene. EAAT2-C1 results from skipping of the protein coding exon eight. In contrast, EAAT2-C2 is characterized by usage of internal splice sites in the exons five and six. The splicing events lead to a deletion of 45 and 107 amino acids, respectively, located in the C-terminal and central part of the putative protein.

ATP-Binding Cassette Transporters↗
PubMed1998

Phenotypic expression of the DYT1 mutation: a family with writer's cramp of juvenile onset.

Recently, the mutation causing early-onset generalized torsion dystonia has been identified as a GAG deletion in the gene for an adenosine triphosphate-binding protein named torsinA. We describe a German family with 5 clinically affected individuals carrying this mutation. In at least 4 of the 5 patients, the disease presented as a dystonic writer's cramp during late childhood or adolescence, which affected sequentially both sides but did not progress to a generalized form of dystonia. We conclude that familial writer's cramp may be a manifestation of the DYT1 mutation.

Adolescent↗
PubMed1998

The EAAT2 (GLT-1) gene in motor neuron disease: absence of mutations in amyotrophic lateral sclerosis and a point mutation in patients with hereditary spastic paraplegia.

OBJECTIVES: To investigate if sequence alterations of the excitatory amino acid transporter gene EAAT2 (GLT-1) may be a contributory factor to the pathogenesis of motor system degeneration. EAAT2 serves as a candidate gene as its reduced expression was reported in patients with amyotrophic lateral sclerosis (ALS). Furthermore, neurolathyrism, a motor neuron disease clinically related to hereditary spastic paraplegia (HSP), has been associated with an exogenous excitotoxin. METHODS: Sequence alterations were screened for in the coding region of EAAT2 in 55 patients with ALS and one family with autosomal dominant HSP (AD-HSP). RESULTS: In ALS, no sequence alteration in the EAAT2 gene have been found. Interestingly, a heterozygous A79G mutation of the EAAT2 gene was detected in two of seven affected patients with AD-HSP in the same kindred. The absence of cosegregation with the familial disease showed that the detected variant was not the cause of disease. The A79G sequence variant was not found in 55 patients with ALS or in 50 non-neurological controls. CONCLUSION: The allelic variant of the EAAT2 gene in conjunction with the primary gene defect may be a modifying factor for the highly variable AD-HSP phenotype.

Adult↗
PubMed1998

Amyotrophic lateral sclerosis and glutamate.

Amyotrophic lateral sclerosis is a progressive fatal disorder devastating the spinal cord and brain in humans. Excitotoxicity has been suggested to be involved in the pathogenesis of amyotrophic lateral sclerosis. This hypothesis has driven a wealth of basic research and stimulated development of neuroprotective therapies for chronic neurodegenerative disorders. As a result of these efforts, riluzole, an antiglutamatergic drug, has been established in the therapy of amyotrophic lateral sclerosis. A transgenic mouse showing features of amyotrophic lateral sclerosis has been subsequently engineered enabling studies of the disease in vivo. However, despite considerable progress, the etiology of amyotrophic lateral sclerosis remains obscure and the disturbances in excitatory neurotransmission should by no means be regarded as exclusive to the pathogenesis of the disease.

Journal Article↗
PubMed1997

Genomic organization of the human excitatory amino acid transporter gene GLT-1.

We present the genomic structure of the human glutamate transporter GLT-1 coding region, the intronic sequences adjacent to the exons, and oligonucleotide primer sequences for single strand conformational analysis. The exon-intron boundaries were determined using long-distance PCR and direct sequencing. The human GLT-1 coding region is composed of 10 exons spanning > 50 kb of genomic DNA. The exons range from 127 to 251 bp in length. The intron lengths vary considerably from 2.2 kb to > 15 kb. These data provide the basis for implementing a comprehensive screen for genetic alterations in the human GLT-1 gene using genomic DNA as a template.

ATP-Binding Cassette Transporters↗
PubMed1997

[Molecular biology findings in amyotrophic lateral sclerosis].

At presently, the etiology and pathogenesis of amyotrophic lateral sclerosis (ALS) are unknown. In recent years, the genetic background of hereditary motor neuron diseases has been partly defined. In particular, these advances represent an opportunity to improve our understanding of the pathogenesis of the familial and sporadic forms of ALS and thus provide a basis for rational therapeutic approaches. In this article, recent findings on the pathogenesis of the familial form of ALS and their implications for the sporadic form are discussed.

Amyotrophic Lateral Sclerosis↗
PubMed1997

Increased hypoxic tolerance by chemical inhibition of oxidative phosphorylation: "chemical preconditioning".

A short ischemic episode preceding sustained ischemia is known to increase tolerance against ischemic cell death. We report early-onset long-lasting neuroprotection against in vitro hypoxia by preceding selective chemical inhibition of oxidative phosphorylation: "chemical preconditioning." The amplitude of CA1 population spikes (psap) in hippocampal slices prepared from control animals (control slices) was 31 +/- 27% (mean +/- SD) upon 45-min recovery from 15-min in vitro hypoxia. In slices prepared from animals treated in vivo with 20 mg/kg 3-nitropropionate (3-np) 1-24 h prior to slice preparation (preconditioned slices), psap improved to 90 +/- 15% (p < 0.01). Posthypoxic oxygen free radicals were reduced to 65 +/- 10% (mean +/- SD) of control in preconditioned slices (p < 0.05). Posthypoxic neuronal density improved from 52 +/- 15% (mean +/- SD) in control slices to 97 +/- 23% in preconditioned slices (p < 0.001). Glibenclamide, an antagonist at KATP-channels, partly reversed increased hypoxic tolerance. We conclude that chemical preconditioning induces early-onset long-lasting tolerance against in vitro hypoxia. Ultimately, this strategy may be applicable as a neuroprotective strategy in humans.

Adenosine Triphosphate↗
PubMed1997

Decreased N-acetyl-aspartate/choline ratio and increased lactate in the frontal lobe of patients with Huntington's disease: a proton magnetic resonance spectroscopy study.

BACKGROUND: Both the effect of the mutation and the pathogenesis of Huntington's disease are unknown and a lack of biological markers for the natural history of the disease impedes the evaluation of novel therapeutic approaches. METHODS: Proton magnetic resonance spectroscopy was carried out on a frontal region of the cortex in 17 patients with clinically overt Huntington's disease and four asymptomatic gene carriers. RESULTS: Eight of 17 (47%) clinically affected patients with Huntington's disease and each of the asymptomatic carriers had lactate peaks in the frontal cortex which were not present in controls. The N-acetyl-aspartate/choline (NAA/Ch) ratio was significantly reduced in the symptomatic patients indicating the presence of neuronal loss. The reduction was related to the clinical severity of the disease and was absent in the asymptomatic carriers. CONCLUSION: The finding of lactate peaks supports the hypothesis that disturbed cerebral energy metabolism contributes to the pathogenesis of Huntington's disease.

Adult↗
PubMed1997

Chemical preconditioning: a cytoprotective strategy.

Brief ischemic or hypoxic episodes may increase or decrease tolerance towards subsequent severe ischemia in heart and brain. A similar phenomenon is observed after mild chemical inhibition of oxidative phosphorylation--chemical preconditioning. We have shown that chemical preconditioning can be induced by chemical inhibition of mitochondrial complex I and mitochondrial complex II. With a time interval of three hours between chemical pretreatment and massive inhibition of oxidative phosphorylation, recovery of population spike amplitude in hippocampal region CA1 after stimulation of the Schaffer collaterals was 31 +/- 9% in controls, 98 +/- 14% after i.p. treatment with 1 mg/kg body weight haloperidol, an inhibitor of mitochondrial complex I and 90 +/- 7% with pretreatment with 3-np, an inhibitor of mitochondrial complex II. Activation of ATP regulated potassium channels partakes in mediating the preconditioning effect. We conclude that chemical preconditioning is a practical prophylactic pharmacologic strategy to increase hypoxic tolerance.

Animals↗
PubMed1996

NMDA-antagonists reverse increased hypoxic tolerance by preceding chemical hypoxia.

Glutamate antagonists mitigate hypoxic damage upon acute inhibition of energy metabolism. The goal of this study was to investigate their effect on increased hypoxic tolerance induced by preceding chemical inhibition of energy metabolism. While recovery of population spike amplitude (psap) is 30% of onset in slices prepared from control animals (15 min hypoxia, 45 min recovery), recovery exceeds 90% in slices prepared from animals that underwent mild chemical hypoxia in vivo by treatment with 20 mg/kg 3-nitropropionic acid 1 h prior to slice preparation (p-slices). In p-slices perfused for 5 min with D(-)-2-amino-5-phosphonopentanoic acid (APV) (100 microM) 45 min prior to hypoxia, recovery declines to 42 +/- 13% (mean +/- SEM). In contrast, posthypoxic recovery after similar perfusion with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (10 microM) is 72 +/- 15% (P < 0.05). We conclude that increased hypoxic tolerance is abolished by N-methyl-D-aspartate (NMDA)-antagonists but not non-NMDA-antagonists.

2-Amino-5-phosphonovalerate↗
PubMed1996

Skin involvement in amyotrophic lateral sclerosis.

BACKGROUND: Patients with sporadic amyotrophic lateral sclerosis (ALS) show disorganised collagen and elastin of the dermis. We looked for inflammatory alterations to cutaneous blood vessels. PATIENTS AND FINDINGS: Seven patients with sporadic ALS were investigated; five were confined to bed, but none had bedsores. Light and electron microscopy of skin showed an oedematous dermis with collagen fibrils of irregular diameter. Small blood vessels were characterised by duplicated basement membranes and deposition of beta-amyloid protein, the main component of the neuronal and non-neuronal amyloid deposits in Alzheimer's disease. These skin changes were seen in all degrees of disability, but none was found in age-matched and sex-matched controls. INTERPRETATION: The skin in ALS is characterised by a distinctive pattern of alterations of connective tissue and blood vessels. Examination of skin in an additional and easily accessible investigation which may help elucidate the pathogenesis of ALS.

Amyloid beta-Peptides↗
PubMed1996

NADH in the pyramidal cell layer of hippocampal regions CA1 and CA3 upon selective inhibition and uncoupling of oxidative phosphorylation.

N2-laser-induced fluorescence in combination with the time and spectral resolution of fluorescent NADH molecules allows on-line measurement of relative NADH concentration with high spatial resolution (diameter of optical fibre 200 microns, lambda(exc) = 337 nm, lambda(det) = 460 nm). Energy metabolism was impaired in submerged rat hippocampal slices using the inhibitors amytal, 3-nitropropionate (3-np), sodium cyanide (1 mM each) and the uncoupling agent 2,4-DNP (200 microM). A microprocessor-controlled repeated positioning of the optical fibre in CA1 and CA3 pyramidal cell layers, and CA1 stratum radiatum (CA1SR). Time-dependently, NADH fluorescence increased reversibly upon perfusion with amytal and cyanide. It was unchanged by perfusion with 3-np for 40 min and rapidly decreased upon perfusion with 2,4-DNP. The CA1/CA3 ratio of NADH fluorescence mildly decreased to 0.92 +/- 0.04 (mean +/- S.D.) at 10 min (P < 0.05) and 0.89 +/- 0.05 at 20 min (P < 0.01) upon perfusion with amytal. The CA1/CA3 ratio increased to 1.56 +/- 0.28 at 10 min (P < 0.01) and 1.29 +/- 0.35 at 20 min (P < 0.05) upon application of 2,4-DNP. Fluorescence in CA1SR was similar to fluorescence in CA1 upon perfusion with 2,4-DNP and similar to CA3 upon perfusion with amytal. We conclude that NADH fluorescence can be measured with high regional selectivity and specificity in hippocampal slices. Selective inhibition of mitochondrial complex I and uncoupling of energy metabolism differentially impair NADH concentration in different hippocampal areas.

2,4-Dinitrophenol↗
PubMed1996

The glial glutamate transporter complementary DNA in patients with amyotrophic lateral sclerosis.

Here, we report a mutation screening by single-stranded conformational analysis of the astroglial human brain glutamate transporter (HBGT) II complementary DNA in patients with amyotrophic lateral sclerosis. The conformational analysis data indicate a lack of sequence variations in the HBGT II coding region in 6 patients with amyotrophic lateral sclerosis and the same number of nonneurological control subjects. In both groups, three variants of the HBGT II 5' untranslated region were isolated. We have no evidence that the reported complementary DNA variants are disease specific.

ATP-Binding Cassette Transporters↗