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T Gasser

Publications and source records attributed to T Gasser.

At least 55 records · Page 3Linked to original sources
PubMed2002

Glial cell line-derived neurotrophic factor up-regulates GTP-cyclohydrolase I activity and tetrahydrobiopterin levels in primary dopaminergic neurones.

Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurones against toxic and physical damage. In addition, GDNF promotes differentiation and structural integrity of dopaminergic neurones. Here we show that GDNF can support the function of primary dopaminergic neurones by triggering activation of GTP-cyclohydrolase I (GTPCH I), a key enzyme in catecholamine biosynthesis. GDNF stimulation of primary dopaminergic neurones expressing both tyrosine 3-monooxygenase and GTPCH I resulted in a dose-dependent doubling of GTPCH I activity, and a concomitant increase in tetrahydrobiopterin levels whereas tyrosine 3-monooxygenase activity was not altered. Actinomycin D, asan inhibitor of de novo biosynthesis, abolished any GDNF-mediated up-regulation of GTPCH I activity. However, GTPCH I mRNA levels in primary dopaminergic neurones were not altered by GDNF treatment, suggesting that the mode of action for that up-regulation is not directly connected to the regulation of GTPCH I transcription. We conclude that GDNF, in addition to its action in structural differentiation, also promotes differentiation regarding expression and enzymatic activity of a crucial component in the dopaminergic biosynthetic pathway.

Animals↗
PubMed2002

Pramipexole in patients with Parkinson's disease and marked drug resistant tremor: a randomised, double blind, placebo controlled multicentre study.

OBJECTIVE: To compare the tremorlytic properties of pramipexole, a non-ergoline dopamine agonist to those of placebo as add on medication in patients with Parkinson's disease. METHODS: Eighty four patients with early or advanced Parkinson's disease and marked, drug resistant tremor under a stable and optimised antiparkinsonian medication were included in a double blind, randomised, placebo controlled, multicentre study and assigned to add on treatment (7 week dose titration interval, 4 week maintenance period) with either pramipexole (n=44) or placebo (n=40) as adjunct. The primary end point was the absolute change in tremor score, defined as the sum of tremor related items (16, 20, 21) of the unified Parkinson's disease rating scale (UPDRS) in "on" periods. Secondary end points included the percentage change in tremor score, the absolute and percentage changes in long term EMG tremor registration, and the change in tremor self rating scales. Safety and tolerability were assessed on the basis of adverse events, laboratory tests, ECG, and vital signs. RESULTS: Pramipexole was significantly superior to placebo with a difference between treatment groups in the mean absolute change in tremor score of -4.4 (95% confidence interval (95% CI) -6.2 to -2.5) (p<0.0001), corresponding to a difference in the mean percentage change of -34.7% in favour of pramipexole. The secondary end points were consistent with the significant change in tremor score and provided further evidence for the benefit of pramipexole compared with placebo. Long term EMG registration as an objective measure showed a difference in mean absolute change in tremor occurrence of -15.2% (95%CI -21.4 to -9.0) (p<0.0001), and a difference in the mean percentage change of -45.7% in favour of pramipexole. The treatment effects increased during dose titration and remained stable during the 4 week maintenance dose period until the end of the study. The average daily pramipexole dose during maintenance was 4.1 (SD 0.9) mg. Safety analysis showed an increased rate of fatigue, insomnia, nausea, abdominal pain, and headache under pramipexole, comparable with previous studies. CONCLUSION: Pramipexole proved to be an effective agent for patients with Parkinson's disease and drug resistant tremor.

Administration, Oral↗
PubMed2002

[HER-2 and TOP 2A gene amplifications in urinary bladder carcinoma].

The HER-2/neu gene is frequently amplified in bladder cancer. Topoisomerase 2 Alpha (TOP2A) which is located nearby the HER-2/neu gene is an important molecular target for several anti cancer drugs. The frequency of TOP2A amplification in urinary bladder cancer is unknown. It was the aim of this study to determine the frequency of HER-2 and TOP2A amplification in urinary bladder cancer and to evaluate the association of these amplifications with tumor phenotype. For this purpose a tissue microarray containing 768 pTa, 425 pT1 and 571 pT2-4 carcinomas was analyzed by fluorescence in situ hybridization (FISH). Amplifications of both genes were significantly associated with advanced tumor stage and high grade. HER-2 amplification was found in 1.6% of pTa, 7.2% of pT1 and 13.8% of pT2-4 carcinomas (p < 0.0001). HER-2 amplification was present in only 1.1% of grade 1 and 0.8% of grade 2 tumors but in 14.2% of grade 3 tumors (p < 0.0001). TOP2A amplification was present in 0.7% pTa, 1.8% pT1 and 3.4% pT2-4 carcinomas (p < 0.0001). TOP2A was found in none of the grade 1, in 0.2% of grade 2 and 3.8% of grade 3 tumors (p < 0.0001). 1% of all analyzed tumors had simultaneously high level amplification of TOP2A and HER-2. Amplification of both genes were significantly associated with tumor specific survival if all tumors were analyzed together. Given the high frequency of HER-2 amplification in urinary bladder cancer, some of these tumors may respond favorable to Herceptin therapy. The TOP2A amplification status may influence response to anthracyclin treatment.

Antigens, Neoplasm↗
PubMed2001

Neuropathology of two members of a German-American kindred (Family C) with late onset parkinsonism.

We present genealogical and longitudinal clinical observations and autopsy findings of a previously reported kindred, Family C (German-American), with late-onset autosomal dominant parkinsonism with evidence for linkage on chromosome 2p13. The clinical phenotype includes the cardinal features of idiopathic Parkinson's disease. In addition, postural tremor and dementia are detected in some individuals. Two members of the kindred, one affected and one unaffected have recently come to autopsy. The unaffected family member was an 82-year-old woman whose brain showed only mild age-related pathology and no evidence of subclinical Lewy body disease. In contrast, the affected family member was an 83-year-old man whose brain had neuronal loss, gliosis and Lewy bodies in the substantia nigra and other monoaminergic brain stem nuclei, as well as the basal forebrain and amygdala. Lewy bodies and Lewy neurites had a distribution typical of cases of idiopathic Parkinson's disease. Thus, the clinical and pathological findings in this family with autosomal dominant parkinsonism are similar to those of sporadic Parkinson's disease.

Aged↗
PubMed2001

[A comparison of cholinesterase inhibitors and ginkgo extract in treatment of Alzheimer dementia].

AIM: To compare the effectiveness of second-generation cholinesterase inhibitors (donepezil, rivastigmine, metrifonate) with that of the special ginkgo extract EGb 761R in Alzheimer's disease. METHOD: Analysis of the effect on cognition with the aid of the ADAS-cog.scale, placebo-adjusted, within six months; statistical evaluation of the effect using the confidence interval for the potential mean improvement. RESULTS: All medications are statistically significantly superior to placebo. The mean improvement is larger for the cholinesterase inhibitors than for the ginkgo extract. In the statistically unfavorable case, the effect of the cholinesterase inhibitors is still appreciable, but not for the ginkgo extract. CONCLUSION: Until the results of direct comparative studies are available, the present results indicate a superior effect of cholinesterase inhibitors over the ginkgo extract in the treatment of mild to moderate Alzheimer's disease.

Aged↗
PubMed2001

NOTCH3 mutation involving three cysteine residues in a family with typical CADASIL.

Mutations in NOTCH3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary angiopathy causing stroke and vascular dementia. All CADASIL mutations identified so far result in the loss or gain of one cysteine residue within epidermal growth factor (EGF)-like repeat domains. Here an in-frame deletion causing a loss of three cysteine residues within EGF repeat 6 is reported. These data are consistent with the hypothesis that the change toward an odd number of cysteine residues within a given EGF repeat and therefore an unpaired, reactive cysteine residue is the common and critical molecular event in CADASIL.

Adult↗
PubMed2001

Liposome-mediated gene transfer to fetal human ventral mesencephalic explant cultures.

The feasibility of non-viral gene transfer using liposomes is described for human fetal nigral tissue. Ventral mesencephalic explants from 6 to 12 week old fetuses were grown as free-floating roller tube cultures. For the transfection, a vector coding for beta-galactosidase driven by the Rous Sarcoma Virus promoter was used. The developmental stage of the human tissue, time in vitro and the amount of vector DNA used significantly influenced the transfection efficiency. Optimal transfection results were obtained with tissue from a 10 week old fetus, cultured for 4 days and transfected with mixtures containing 4 microg vector DNA. Histological analysis suggested that a specific population of ventral mesencephalic precursor cells were the target for the gene transfer. This finding might have implications for gene delivery and cell replacement strategies in Parkinson's disease.

Avian Sarcoma Viruses↗
PubMed2001

High-throughput tissue microarray analysis of 3p25 (RAF1) and 8p12 (FGFR1) copy number alterations in urinary bladder cancer.

Studies by comparative genomic hybridization revealed that the chromosomal regions 3p25 and 8p11-p12 are recurrently amplified in bladder cancer. To investigate the prevalence of DNA copy number alterations in these chromosomal regions and study their clinical significance, we used probes for the RAF1 (3p25) and FGFR1 (8p12) genes for fluorescence in situ hybridization. A tissue microarray containing 2317 tumors was analyzed. The analysis revealed RAF1 amplification in 4.0% and FGFR1 amplification in 3.4% of interpretable tumors. In addition, deletions were found at the 3p25 locus in 2.2% and at the 8p11-12 locus in 9.9% of interpretable tumors. Both amplifications and deletions of RAF1 and FGFR1 were significantly associated with high tumor grade (P < 0.0001), advanced stage (P < 0.0001), and poor survival (P < 0.05) if tumors of all of the stages where analyzed together. RAF1 amplifications were associated with subsequent tumor progression in pT1 carcinomas (P < 0.05). The marked differences in the frequency of all of the analyzed changes between pTa grade 1/grade 2 and pT1-4 carcinomas support the concept of these tumor groups representing different tumor entities.

Chromosomes, Human, Pair 3↗
PubMed2001

Origin of the mutations in the parkin gene in Europe: exon rearrangements are independent recurrent events, whereas point mutations may result from Founder effects.

A wide variety of mutations in the parkin gene, including exon deletions and duplications, as well as point mutations, result in autosomal recessive early-onset parkinsonism. Interestingly, several of these anomalies were found repeatedly in unrelated patients and may therefore result from recurrent, de novo mutational events or from founder effects. In the present study, haplotype analysis, using 10 microsatellite markers covering a 4.7-cM region known to contain the parkin gene, was performed in 48 families, mostly from European countries, with early-onset autosomal recessive parkinsonism. The patients carried 14 distinct mutations in the parkin gene, and each mutation was detected in more than one family. Our results support the hypothesis that exon rearrangements occurred independently, whereas some point mutations, found in families from different geographic origins, may have been transmitted by a common founder.

Age of Onset↗
PubMed2001

Microarrays of bladder cancer tissue are highly representative of proliferation index and histological grade.

The number of genes suggested to play a role in cancer biology is rapidly increasing. To be able to test a large number of molecular parameters in sufficiently large series of primary tumours, a tissue microarray (TMA) approach has been developed where samples from up to 1000 tumours can be simultaneously analysed on one glass slide. Because of the small size of the individual arrayed tissue samples (diameter 0.6 mm), the question arises of whether these specimens are representative of their donor tumours. To investigate how representative are the results obtained on TMAs, a set of 2317 bladder tumours that had been previously analysed for histological grade and Ki67 labelling index (LI) was used to construct four replica TMAs from different areas of each tumour. Clinical follow-up information was available from 1092 patients. The histological grade and the Ki67 LI were determined for every arrayed tumour sample (4x2317 analyses each). Despite discrepancies in individual cases, the grade and Ki67 information obtained on minute arrayed samples were highly similar to the data obtained on large sections (p<0.0001). Most importantly, every individual association between grade or Ki67 LI and tumour stage or prognosis (recurrence, progression, tumour-specific survival) that was observed in large section analysis could be fully reproduced on all four replica TMAs. These results show that intra-tumour heterogeneity does not significantly affect the ability to detect clinico-pathological correlations on TMAs, probably because of the large number of tumours that can be included in TMA studies. TMAs are a powerful tool for rapid identification of the biological or clinical significance of molecular alterations in bladder cancer and other tumour types.

Adenocarcinoma↗
PubMed2001

Inherited Myoclonus-dystonia syndrome: narrowing the 7q21-q31 locus in German families.

Genetic studies were performed in four German families with autosomal dominant myodonus-dystonia syndrome. Mutations in the D2 dopamine receptor gene, which have been implicated in this disorder, were excluded in all four families by linkage analysis and direct sequencing. All four families supported linkage to the second reported locus on chromosome 7q21 with a combined maximum multipoint lod score of 5.99. The observation of key recombinations in one family refined the disease locus to a 7.2 cM region flanked by the markers D7S652 and D7S2480.

Adolescent↗
PubMed2001

Cervical dystonia in monozygotic twins: case report and review of the literature.

We report on monozygotic male twins of German origin with early onset cervical dystonia. No other family members were affected. Although identical in age of onset and clinical course, there were phenotypic variations. While the second-born, more affected twin suffered from a symmetric retrocollis, the twin brother mainly presented with a spasmodic torticollis to the left. Dystonia remained focal in both siblings. A DYT1 gene deletion was excluded. Including our patients, hitherto only four twin pairs with idiopathic dystonia have been reported. Although dystonia in twins can be remarkably uniform in some cases, major differences in terms of disease progression, remissions, and disability may be found. These observations underline the role of inheritance in the pathogenesis of idiopathic dystonia but also indicate that some other factors contribute to the clinical presentation of dystonia.

Adult↗
PubMed2001

Genetics of Parkinson's disease.

Over the past few years, several genes for monogenically inherited forms of Parkinson's disease (PD) have been mapped and/or cloned. In a small number of families with autosomal dominant inheritance and typical Lewy-body pathology, mutations have been identified in the gene for alpha-synuclein. Aggregation of this protein in Lewy-bodies may be a crucial step in the molecular pathogenesis of familial and sporadic PD. On the other hand, mutations in the parkin gene cause autosomal recessive parkinsonism of early onset. In this form of PD, nigral degeneration is not accompanied by Lewy-body formation. Parkin-mutations appear to be a common cause of PD in patients with very early onset. Parkin has been implicated in the cellular protein degradation pathways, as it has been shown that it functions as a ubiquitin ligase. The potential importance of this pathway is also highlighted by the finding of a mutation in the gene for ubiquitin C-terminal hydrolase L1 in another small family with PD. Other loci have been mapped to chromosome 2p and 4p, respectively, in a small number of families with dominantly inherited PD, but those genes have not yet been identified. These findings prove that there are several genetically distinct forms of PD that can be caused by mutations in single genes. On the other hand, there is at present no direct evidence that any of these genes have a direct role in the aetiology of the common sporadic form of PD. Epidemiological, case control, and twin studies, although supporting a genetic contribution to the development of PD, all suggest a clear familial clustering only in a minority of cases. It is therefore widely believed that a combination of interacting genetic and environmental causes may be responsible in this majority of PD-cases. However, studies of gene-environment interactions have not yet produced any convincing results. Nevertheless, the elucidation of the molecular sequence of events leading to nigral degeneration in clearly inherited cases is likely to shed light also on the molecular pathogenesis of the common sporadic form of this disorder.

Chromosome Mapping↗
PubMed2001

Extensive myelitis associated with Mycoplasma pneumoniae infection: magnetic resonance imaging and clinical long-term follow-up.

Myelitis is a severe neurological complication associated with Mycoplasma pneumoniae infections. Little is known about the extent and the reversibility of this myelitis, and reports on the value of spinal imaging are inconclusive. To obtain more information on the diagnostic and prognostic value of spinal magnetic resonance imaging (MRI) we studied the clinical course and MRI long-term follow-up of two patients with extensive myelitis associated with M. pneumoniae infection. The neuroradiological findings were correlated with the clinical extent of the spinal syndrome, but their reversibility preceded clinical improvement. These preliminary findings indicate that follow-up spinal MRI may give valuable prognostic information in cases of M. pneumoniae associated myelitis and warrant further more systematic studies to ascertain the relationship between spinal MRI findings and prognosis.

Adult↗
PubMed2001

Autosomal-dominant Parkinson's disease linked to 2p13 is not caused by mutations in transforming growth factor alpha (TGF alpha) (short communication).

A susceptibility gene for Parkinson's disease (PD) with late onset and typical Lewy-body pathology maps to chromosome 2p13 (PARK3). In the present study we examined the gene for transforming growth factor alpha (TGF alpha), which is located in the PARK3-region, as a potential candidate gene. This polypeptide mitogen exerts trophic actions on dopaminergic neurons and TGF alpha-deficient mice have fewer dopaminergic neurons. We did not find mutations in the exonic or exon-flanking intronic sequences of index patients of two families linked to 2p13. This result excludes mutations in the coding region of TGF alpha as a cause for hereditary PD, but does not rule out a possible role of sequence variants in regulatory regions or splice sites.

Base Sequence↗
PubMed2001

Novel mutation in the TOR1A (DYT1) gene in atypical early onset dystonia and polymorphisms in dystonia and early onset parkinsonism.

Dystonia is a movement disorder involving sustained muscle contractions and abnormal posturing with a strong hereditary predisposition and without a distinct neuropathology. In this study the TOR1A (DYT1) gene was screened for mutations in cases of early onset dystonia and early onset parkinsonism (EOP), which frequently presents with dystonic symptoms. In a screen of 40 patients, we identified three variations, none of which occurred in EOP patients. Two infrequent intronic single base pair (bp) changes of unknown consequences were found in a dystonia patient and the mother of an EOP patient. An 18-bp deletion (Phe323_Tyr328del) in the TOR1A gene was found in a patient with early onset dystonia and myoclonic features. This deletion would remove 6 amino acids close to the carboxy terminus, including a putative phosphorylation site of torsinA. This 18-bp deletion is the first additional mutation, beyond the GAG-deletion (Glu302/303del), to be found in the TOR1A gene, and is associated with a distinct type of early onset dystonia.

Adolescent↗