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T Gasser

Publications and source records attributed to T Gasser.

At least 91 records · Page 5Linked to original sources
PubMed2000

Striatal dopamine transporter binding assessed by [I-123]IPT and single photon emission computed tomography in patients with early Parkinson's disease: implications for a preclinical diagnosis.

BACKGROUND: Specific binding to dopamine transporters may serve as a tool to detect early loss of nigrostriatal dopaminergic neurons in patients with Parkinson's disease. OBJECTIVE: To determine striatal dopamine transporter binding using the cocaine analogue [I-123]N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chl orophenyl) tropane ([I-123]IPT) and single photon emission computed tomography. PATIENTS AND METHODS: We studied 9 control subjects (mean age, 58 years; range, 41-69 years) and 28 patients with early Parkinson's disease (Hoehn and Yahr stages I [n = 14] and II [n = 14] [symptom duration, <5 years]; mean age, 55.5 years; range, 36-71 years). Single photon emission computed tomography was performed 90 minutes after injection of 120 to 150 MBq of radioactive [I-123]IPT. RESULTS: Specific striatal [I-123] IPT binding (mean +/- SD) was significantly reduced in patients with early Parkinson's disease (ipsilateral striatum: 4.09+/-0.97; range, 2.46-6.40; contralateral striatum: 3.32+/-0.76; range, 1.80-5.13) compared with controls (left striatum: 7.28+/-0.94; range, 5.78-8.81; right striatum: 7.41+/-1.28; range, 5.58-9.44). IPT binding ratios (mean +/- SD) were significantly lower in patients with Hoehn and Yahr stage II (ipsilateral striatum: 3.47+/-0.75; contralateral striatum: 2.96+/-0.73) compared with those with Hoehn and Yahr stage I (ipsilateral striatum: 4.72+/-0.75; contralateral striatum: 3.69+/-0.61) (P<.001). The ipsilateral striatum of patients with Hoehn and Yahr stage I showed a significant mean+/-SD reduction of IPT binding (ipsilateral striatum: 4.72+/-0.75) compared with either right or left striatum of controls (P<.001). Only in 1 patient was IPT binding to the ipsilateral striatum (ratio, 6.40) higher than the lowest value observed in the striatum of a control subject (ratio, 5.58). CONCLUSIONS: Use of [I-123] IPT and single photon emission computed tomography demonstrates a reduction of dopamine transporter binding in patients with early Parkinson's disease. Significantly reduced IPT binding already observed in the ipsilateral striatum of patients with Hoehn and Yahr stage I demonstrates the potential of this method to detect preclinical disease.

Adult↗
PubMed2000

Allelic loss at the D9S171 locus on chromosome 9p13 is associated with progression of papillary renal cell carcinoma.

Papillary renal cell carcinomas (RCCs) have characteristic clinical and morphological features that separate them from the more common clear cell RCCs. The details of the molecular changes in papillary RCC progression are not well understood. In this study, four highly polymorphic microsatellite markers [D9S970 (9p12-9p13), D9S171 (9p13), D9S1748 (9p21) and D9S156 (9p21)] were used to determine the frequency and prognostic significance of 9p deletions in 37 papillary RCCs. Allelic deletions were detected in eight cases (22%). The highest rate of loss of heterozygosity (LOH) was observed in 6 of 29 informative patients (21%) at the D9S171 locus on 9p13. Only two patients displayed allelic loss at D9S1748, which resides in close proximity to p16(INK4). Two of 24 informative papillary RCCs (8%) showed LOH for D9S970. LOH at D9S171 (9p13) was associated with short patient survival (p=0.008), independently of tumour grade and stage. These data suggest a tumour suppressor gene centromeric to 9p21 that may contribute to papillary RCC progression.

Carcinoma, Papillary↗
PubMed2000

The DYT1 GAG deletion is infrequent in sporadic and familial writer' s cramp.

A 3-base pair (GAG) deletion in the DYT1 gene has recently been found to be responsible for most cases of early-onset primary generalized dystonia. In some cases, this mutation has been associated with writer's cramp. To determine the frequency of this mutation in a larger series of patients, we examined 44 index patients with sporadic or familial (seven patients) writer's cramp for the presence of the DYT1 GAG deletion, including eight patients with segmental dystonia involving at least one upper limb. We found the mutation in none of these index patients, which confirms that isolated writer's cramp is only in rare cases a phenotypic manifestation of this mutation, even if a positive family history of writer's cramp is present.

Adult↗
PubMed2000

Autosomal-dominantly inherited forms of Parkinson's disease.

Today, a genetic contribution to the etiology of Parkinson's disease (PD) is generally accepted, based on the demonstration of a familial aggregation of the disease, as demonstrated by several case-control and twin-studies. However, most cases of PD appear to be sporadic, and in the majority of those with a positive family history, no clear mendelian mode of inheritance can be established. Therefore, a polygenic mode of inheritance or a multifactorial etiology is likely in these cases. On the other hand, a number of families have been identified, in whom parkinsonism is inherited as an apparently monogenic mendelian trait with high penetrance. In several of these families, the disease genes have been mapped and mutations have been identified in some of them. The first gene locus has been mapped to the long arm of chromosome 4 in a small number of families with autosomal-dominant inheritance and typical Lewy-body pathology (PARK 1), and mutations have been identified in the gene for alpha-synuclein in these kindreds. Two other loci in families with dominant inheritance have been mapped, to chromosome 2p13 (PARK 3) and to chromosome 4p, respectively. A gene causing autosomal recessive parkinsonism of juvenile onset has been mapped to chromosome 6 (PARK 2), and the causative gene has been identified and named parkin. Each of these genetically defined familial disorders share clinical characteristics that fulfill the criteria accepted for idiopathic Parkinson's disease but, as in sporadic PD, also show a variability of clinical expressions, both within and between families. At present, there is no direct evidence that any of these genes for familial Parkinsonian syndromes have a direct role in the etiology of the common sporadic form of PD. However, the elucidation of the molecular sequence of events leading to nigral degeneration in these inherited cases is likely to shed light also on the molecular pathogenesis of the common sporadic form of this disorder.

Chromosomes, Human, Pair 2↗
PubMed2000

[Typical anticipation in type 7 spinocerebellar ataxia].

Spinocerebellar ataxia type 7 (SCA7) belongs to the category of autosomal dominant cerebellar ataxias (ADCA). The clinical picture is characterised by progressive ataxia and macular degeneration. Other common signs are slow saccades, external ophthalmoplegia, and pyramidal tract signs. The disease is caused by the expansion of an unstable CAG trinucleotide repeat in the gene for ataxin 7 on chromosome 3. SCA7 is a rare disorder. The first case in Germany was described only recently. We report two additional patients, father and son, with the molecular genetic diagnosis of SCA7. The father carries a trinucleotide expansion of 42 CAG repeats, the son 51. Normal alleles range from 7 to 35 CAG repeats. Both patients show the typical picture with progressive ataxia and macular degeneration. We found a pronounced anticipation (earlier disease onset in subsequent generations), which is highly characteristic of CAG repeat disorders.

Adult↗
PubMed2000

High-throughput tissue microarray analysis of cyclin E gene amplification and overexpression in urinary bladder cancer.

Studies by comparative genomic hybridization revealed that the 19q13 chromosomal region is frequently amplified in bladder cancer. The cyclin E gene (CCNE), coding for a regulatory subunit of cyclin-dependent kinase 2, has been mapped to 19q13. To investigate the role of cyclin E alterations in bladder cancer, a tissue microarray of 2,317 specimens from 1,842 bladder cancer patients was constructed and analyzed for CCNE amplification by fluorescence in situ hybridization and for cyclin-E protein overexpression by immunohistochemistry. Fluorescence in situ hybridization analysis showed amplification in only 30 of the 1,561 evaluable tumors (1.9%). Amplification was significantly associated with stage and grade (P: < 0.0005 each). Immunohistochemically detectable cyclin E expression was strong in 233 (12.4%), weak in 354 (18.9%), and negative in 1, 286 of the 1,873 interpretable tumors. The majority (62.1%) of CCNE-amplified tumors were strongly immunohistochemistry-positive (P: < 0.0001). The frequency of protein expression increased from stage pTa (22.2%) to pT1 (45.5%; P: < 0.0001) but then decreased for stage pT2-4 (29.4%; P: < 0.0001 for pT1 versus pT2-4). Low cyclin E expression was associated with poor overall survival in all patients (P: < 0.0001), but had no prognostic impact independent of stage. It is concluded that cyclin E overexpression is characteristic to a subset of bladder carcinomas, especially at the stage of early invasion. This analysis of the prognostic impact of CCNE gene amplification and protein expression in >1,500 arrayed bladder cancers was accomplished in a period of 2 weeks, illustrating how the tissue microarray technology remarkably facilitates the evaluation of the clinical relevance of molecular alterations in cancer.

Adult↗
PubMed2000

Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary microangiopathic condition causing stroke in young adults. The responsible gene has recently been identified as the Notch3 gene. Notch3 encodes a large transmembrane receptor with 34 extracellularly localised epidermal growth factor-like (EGF) repeat domains. We screened 71 unrelated CADASIL families for mutations in two exons coding for the first five EGF-like repeats and found mutations in 70% of the families (n = 50). Two types of mutations were identified: 48 families (96%) had missense mutations and two families (4%) had small in-frame deletions. Seven mutations occurred multiple times. All of them are C to T transitions that affect CpG dinucleotides, suggesting that their multiple occurrence is due to the hypermutability of this sequence. All mutations, including the two deletions, result in the gain or loss of a cysteine residue, thus substantiating the pivotal role of an uneven number of cysteine residues within EGF-like repeat domains of Notch3 in the pathogenesis of CADASIL. To study the potential effects of these mutations 3D homology models of the first six EGF domains were generated on the basis of NMR data from human fibrillin-1. These models predict domain misfolding for a subset of mutations.

Amino Acid Sequence↗
PubMed2000

Epidemiology of drug exposure and adverse drug reactions in two swiss departments of internal medicine.

AIMS: To explore drug exposure, frequency of adverse drug reactions (ADRs), types of ADRs, predisposing risk factors and ADR-related excess hospital stay in medical inpatients. METHODS: Structured data regarding patient characteristics, 'events' (symptoms, laboratory results), diagnoses (ICD10) and drug therapy were collected using a computer-supported data entry system and an interface for data retrieval from electronic patient records. ADR data were collected by 'event monitoring' to minimize possible bias by the drug monitor. The causality of each event was assessed in relation to disease(s) and drug therapy. RESULTS: The analysis included 4331 (100%) hospitalizations. The median observation period was 8 days. The median number of different drugs administered per patient and day was 6 and varied between 4 (Q1 ) and 9 (Q3 ) different drugs in 50% of all hospital days. In 41% of all hospitalizations at least one disease-unrelated event could be possibly attributed to drug therapy. Clinically relevant ADRs occurred in 11% of all hospitalizations. In 3.3% of all hospitalizations ADRs were the cause of hospital admission. The incidence of possibly ADR-related deaths was 1.4. Factors predisposing for clinically relevant ADRs were female gender and polypharmacy. ADR-related excess hospital stay accounted for 8. 6% of hospital days. CONCLUSIONS: These data demonstrate the feasibility of the developed 'event monitoring' system for quantitative analysis of ADRs in medical inpatients. With increasing numbers of recorded patients the pharmacoepidemiological database provides a valuable tool to study specific questions regarding drug efficacy and safety in hospitalized patients.

Adverse Drug Reaction Reporting Systems↗
PubMed2000

Spontaneous growth in German children and adolescents with genetically confirmed Prader-Willi syndrome.

UNLABELLED: Height and weight in children with Prader-Willi syndrome, diagnosed by standard clinical criteria, follow a specific developmental pattern resulting in early childhood obesity, absent pubertal growth spurt and adolescent short stature. New molecular techniques (methylation analysis, fluorescence in situ hybridization) now allow the unequivocal diagnosis of Prader-Willi syndrome (PWS). We investigated the possibility of a bias in syndrome-specific growth standards based on clinically diagnosed patients by comparing these standards with new standards derived from 100 German patients with molecularly confirmed PWS, none of whom had received a growth-promoting therapy. Height centile curves of the German patients fall in the tall range of standards derived from American patients. This is mainly due to an elevation of the lower centile ranges in both sexes. When the height standards derived from German patients are compared to those of a large multinational cohort of patients, 78% of whom were not confirmed by genetic testing, only minor differences in the height centiles become apparent. The population background therefore does not appear to play a major role for the observed differences. In a marked proportion of patients a decreased sitting height/height ratio is found. This was usually associated with scoliosis. Weight standards from our study group show that after 14 y of age German girls with PWS are heavier than their American counterparts. Standards for the body mass index of German patients of both sexes are increased over normal reference standards (p < 0.0001) and do increase with age (boys: p = 0.0038; girls: p = 0.0004). PWS genotypes or sex had no apparent influence on SDS for height, weight and body mass index. CONCLUSIONS: Because of the observed differences to other growth standards, use of the newly constructed centile curves is advocated in German patients with molecularly confirmed PWS to avoid delay in the diagnosis of additional growth-compromising conditions.

Adolescent↗
PubMed2000

Body composition abnormalities in children with Prader-Willi syndrome and long-term effects of growth hormone therapy.

Obesity and hypothalamic GH deficiency contribute in different ways to the disturbances of body composition in Prader-Willi syndrome (PWS); while both increase the fat compartment, the reduction of lean tissue mass has been attributed mainly to GH deficiency. Therefore, body composition measured by dual-energy X-ray absorptiometry was prospectively studied in 12 overweight children with PWS and weight for height (WfH) SDS >0 before and during 3.5 years of treatment with hGH (0.037 mg/kg/day) on average. In the long term, there is a net reduction of body fat from 3.1 to 1.2 SD, with a minimum at the end of the second year of treatment. WfH SDS correctly reflects body fat mass and its changes. The initial deficit of lean mass (-1.6 SD) is counteracted by GH only during the first year of therapy (increase to -1.25 SD). But in the long term, GH therapy does not further compensate for this deficit, when lean mass is corrected for its growth-related increase. In conclusion, exogenous GH changes the phenotype of children with PWS: fat mass becomes normal, but, at least in the setting studied, GH is not sufficient to normalize lean tissue mass.

Absorptiometry, Photon↗
PubMed1999

Age and cause of death in mitochondrial diseases.

We report on the age and the causes of death in 16 patients with mitochondrial diseases. Nine patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) died at a mean age of 34 years and three patients with chronic progressive external ophthalmoplegia at a mean age of 56 years. The causes of death were cardiopulmonary failure (n = 5), status epilepticus (n = 4), aspiration pneumonia (n = 2), pulmonary embolism (n = 2), renal failure (n = 1), metabolic disturbance (n = 1), and unknown causes (n = 1). Thus, many patients in this series died of medical complications, some of which may be prevented.

Adolescent↗
PubMed1999

The Ile93Met mutation in the ubiquitin carboxy-terminal-hydrolase-L1 gene is not observed in European cases with familial Parkinson's disease.

Recently an Ile93Met mutation in the ubiquitin-carboxy-terminal-hydrolase-L1 gene (UCH-L1) has been described in a German family with Parkinson's disease (PD). The authors showed that this mutation is responsible for an impaired proteolytic activity of the UCH-L1 protein and may lead to an abnormal aggregation of proteins in the brain. In order to determine the importance of this or any other mutation in the coding region of the UCH-L1 gene in PD, we performed mutation analysis on Caucasian families with at least two affected sibs. We did not detect any mutations in the UCH-L1 gene, however, we cannot exclude mutations in the regulatory or intronic regions of the UCH-L1 gene since these regions were not sequenced. We conclude that the UCH-L1 gene is not a major gene responsible for familial PD.

Aged↗
PubMed1999

Quantitative MRI in CADASIL: correlation with disability and cognitive performance.

OBJECTIVE: To study correlations between total lesion load on brain MRI and clinical features, and to evaluate the influence of demographic variables on quantitative MRI variables in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). BACKGROUND: CADASIL is a hereditary form of small-vessel disease caused by mutations within the Notch3 gene. MRI abnormalities have been found both in asymptomatic and symptomatic CADASIL individuals. METHODS: Quantitative measurements on cerebral MRI were performed in 64 CADASIL individuals. MRI lesions were quantified using a semi-automated segmentation technique based on local thresholds. RESULTS: MRI total lesion volume correlated significantly with disability (Rankin Scale) on both T1- and proton density (PD)-weighted images. There was a significant inverse correlation between total lesion volume and overall cognitive performance as determined by the Mini-Mental State Examination. Age but not sex was correlated with lesion load both on T1- and PD-weighted images. There was no detectable influence of the Notch3 genotype on quantitative MRI variables. CONCLUSIONS: This study demonstrates correlations between MRI lesion volume and clinical characteristics in CADASIL. Longitudinal studies are now warranted to investigate whether quantitative MRI could be used as an adjunct outcome measure in future therapeutic trials in CADASIL.

Adult↗
PubMed1999

Spinocerebellar ataxia type 6: evidence for a strong founder effect among German families.

The authors found a strong geographic cluster of spinocerebellar ataxia type 6 (SCA6) families in the Northrhine-Westfalia area, suggesting a founder effect in the German SCA6 population. Genotyping with DNA markers linked to the CACNL1A4 gene on chromosome 19p13 revealed a common haplotype and shared allelic characteristics in the majority of German families. The observed founder effect may be related to the relative meiotic stability of CAG repeats in this type of autosomal dominant cerebellar ataxia.

Alleles↗
PubMed1999

GAG deletion in the DYT1 gene in early limb-onset idiopathic torsion dystonia in Germany.

We examined 57 patients with idiopathic torsion dystonia (ITD) for the 3-bp GAG deletion in the DYT1 gene on human chromosome 9q34. Three of five patients with early limb-onset ITD, one of them with a positive family history, tested positive for the mutation, as did one young patient with multifocal dystonia and a short course of the disease. Two patients with early-onset generalized dystonia beginning in the cervical muscles, as well as five other patients with multifocal, 14 patients with segmental, and 30 patients with focal cervical dystonia did not carry the mutation. This suggests that the GAG deletion is responsible for a major portion of cases of typical early limb-onset dystonia, but not for other types of dystonia, in our population.

Adolescent↗