PubMed Health⌕ Search

Biomedical subjects

Thomas Klockgether

Publications and source records attributed to Thomas Klockgether.

At least 55 records · Page 3Linked to original sources
PubMed2004

Diagnostic value of mitochondrial DNA mutation analysis in juvenile unilateral ptosis.

PURPOSE: To highlight the diagnostic relevance of mitochondrial DNA (mtDNA) mutation analysis in acquired juvenile unilateral upper eyelid ptosis. METHODS: A 13-year-old boy presented with acquired, slowly progressive unilateral ptosis. We performed ophthalmological and neurological examinations, laboratory testing, skeletal muscle biopsy including histological and histochemical investigations, biochemical analysis of respiratory chain enzymes in skeletal muscle homogenate and molecular genetic testing of skeletal muscle DNA. RESULTS: Though clinical, laboratory, histological and biochemical analyses did not reveal any hints suggesting a mitochondrial cytopathy, molecular genetic testing by Southern blot analysis of total DNA from skeletal muscle tissue showed a 5.8 kb mtDNA deletion thus proving the diagnosis of mitochondrial chronic progressive external ophthalmoplegia (CPEO). CONCLUSIONS: In patients with unexplained acquired juvenile unilateral ptosis, an underlying mitochondrial cytopathy should be considered even in cases of inconspicuous ancillary examinations comprising skeletal muscle histology and biochemistry. To establish the diagnosis, molecular genetic testing of DNA derived from skeletal muscle tissue is essential in those patients.

Adolescent↗
PubMed2004

Parkinson's disease: clinical aspects.

Parkinsonism is a clinical syndrome characterized by akinesia, muscular rigidity, and resting tremor. The most frequent cause of parkinsonism is Parkinson's disease (PD). Progressive loss of substantia nigra neurons together with the occurrence of Lewy bodies are considered essential neuropathological features of PD. Recent neuropathological studies suggest that nigral degeneration is only part of a more extended brain degeneration that starts in the medulla oblongata and then spreads to the mesencephalon and cerebral cortex. Correspondingly, the clinical symptoms occurring in PD go far beyond parkinsonism. Depending on the disease stage, autonomic dysfunction, olfactory disturbances, depression, and dementia are frequently encountered in PD. These neuropathological and clinical observations have major implications for future research in PD. In particular, the analysis of the properties that the neuronal cell types involved in PD have in common and that might make them susceptible to degeneration is essential.

Humans↗
PubMed2004

Lack of association between the interleukin-1 alpha (-889) polymorphism and early-onset Parkinson's disease.

An increasing number of studies have shown that an inflammatory process is part of Parkinson's disease (PD) brain pathology. Interleukin-1 (IL-1) is a multifunctional cytokine and is considered to contribute to several inflammatory diseases. Recently, we detected an associated risk in a subgroup of PD patients with a disease onset < 50 years and a C to T transition in the IL-1alpha promoter (-889). One-hundred-seventy-six German PD patients (42.1 +/- 6.4 years; 42.4% male) and 170 unrelated age-matched control individuals (40.4 +/- 8.7 years; 57.6% male) were investigated for the presence of the IL-1alpha (-889C/T) polymorphism. No significant difference in the allelic distribution of the analyzed IL-1alpha polymorphism has been found between PD and controls. We conclude that the C/T polymorphism in the IL-1alpha promoter region at -889 does not increase the risk to develop PD.

Adult↗
PubMed2004

Discriminatory features of acute transverse myelitis: a retrospective analysis of 45 patients.

Acute transverse myelitis (ATM) is a pathogenetically heterogeneous inflammatory disorder of the spinal cord. Therefore, the identification of clinical and paraclinical features providing clues of the underlying etiologies is needed. The clinical presentation, blood and cerebrospinal fluid (CSF) findings as well as magnetic resonance imaging (MRI) and neurophysiological features were retrospectively analyzed in 45 unselected consecutive patients with ATM. Parainfectious ATM was diagnosed in 38% of patients. The underlying infectious agent, however, was identified only in a minority of patients. In 36% of patients, the etiology remained uncertain ("idiopathic" ATM) and in 22% ATM was the first manifestation of possible multiple sclerosis (ATM-MS) according to recently published diagnostic criteria. Spinal cord MRI showed signal alterations in 96% of the patients. In ATM-MS, monosegmental involvement of the spinal cord was most frequent while spinal cord involvement of two or more segments was more common in ATM of other etiologies. Of particular note, neurophysiological examinations showed evidence of peripheral nervous system (PNS) involvement in 27% of patients with ATM but not in patients with ATM-MS. Therefore, neurophysiological evidence of PNS involvement may provide additional discriminatory features between ATM-MS and ATM of other etiologies.

Adolescent↗
PubMed2004

An interleukin-6 promoter variant is not associated with an increased risk for Alzheimer's disease.

Recent studies have implicated interleukin-6 (IL-6) in the pathogenesis of Alzheimer's disease (AD). Neuro-inflammatory processes surrounding the amyloid plaques contribute to the progression of AD-related neurodegeneration. IL-6 is a multifunctional inflammatory cytokine which possibly acts as a mediator in the local immune response in the brain of AD patients. In this study we investigated whether the risk of developing AD is altered in carriers of the C allele of a G/C polymorphism at position -174. 113 AD patients and 108 age- and gender-matched nondemented control subjects were analysed. Genotyping of IL-6 was performed using standard PCR and restriction fragment length polymorphism methods. The results were adjusted for age, gender and apolipoprotein E epsilon4 status. There was no evidence for an association between the polymorphism and the risk of developing AD. No evidence of an earlier age at onset for carriers of the C allele was evaluated. We conclude that IL-6 (-174) polymorphism does not influence the risk of developing AD in our cohort.

Aged↗
PubMed2004

Saccade velocity is controlled by polyglutamine size in spinocerebellar ataxia 2.

We assessed maximal saccade velocity (MSV) in 82 spinocerebellar ataxia type 2 (SCA2) patients and 80 controls, correlating it to disease duration, polyglutamine expansion size, age at onset, ataxia score, age, and sex. Little overlap with normal values was found even at earliest stages. Stepwise linear regression analysis showed that 60-degree MSV was strongly influenced by polyglutamine size and less by disease duration, whereas the reverse was found for ataxia score. Saccade velocity thus is a sensitive, quite specific, and objective endophenotype, useful to search polyglutamine modifier genes.

Adolescent↗
PubMed2004

The cystathionine beta-synthase (CBS) mutation c.1224-2A>C in Central Europe: Vitamin B6 nonresponsiveness and a common ancestral haplotype.

In homocystinuria due to cystathionine beta-synthase (CBS) deficiency, vitamin B6 response has been linked to distinct mutations and ruled out for others. The splice site mutation c.1224-2A>C leading to the deletion of exon 12 is predominantly found in patients from Central Europe, where it has been found on in average 14% of mutant alleles. In this study we analyzed the clinical picture in 17 CBS deficient carriers of c.1224-2A>C. Homozygotes for c.1224-2A>C did not respond to vitamin B6, while in compound heterozygotes the response to vitamin B6 depended on the mutation on the second allele. Maximum likelihood analysis revealed one common haplotype of the c.1224-2A>C alleles. Additionally, we report the four novel CBS mutations c.451G>A (p.Gly151?), c.740_769del (p.Lys247_Gly256del), c.862G>C (p.Ala288Pro) and c.1135C>T (p.Arg379Trp). In summary, the data of this study suggest that the CBS c.1224-2A>C allele confers vitamin B6 nonresponsiveness and that this mutant allele came from a common ancestor.

Alleles↗
PubMed2004

Cranial magnetic resonance imaging in genetically proven myotonic dystrophy type 1 and 2.

Cranial magnetic resonance imaging (MRI) in 19 German patients with genetically proven myotonic dystrophy Type 1 (DM1, n = 10) or Type 2 (DM2, n = 9) showed pathological findings consisting of white matter lesions (WML) and/or brain atrophy in 9/10 DM1 and 8/9 DM2 patients. Anterior temporal WML (ATWML) were exclusively seen in DM1 patients. Our findings indicate a high frequency of central nervous system (CNS) involvement in both disorders. However, temporopolar pathology, previously associated with intellectual dysfunction, seems to be restricted to DM1.

Adult↗
PubMed2004

Antiparkinsonian activity of Ro 25-6981, a NR2B subunit specific NMDA receptor antagonist, in animal models of Parkinson's disease.

N-methyl-D-aspartate (NMDA) receptor antagonists have antiakinetic and antidyskinetic effects in animals models of Parkinson's disease (PD). However, non-selective inhibition of NMDA receptors throughout the central nervous system may result in undesired effects such as ataxia and psychosis. We therefore studied Ro 25-6981, an activity-dependent antagonist of NMDA receptors containing the NR2B subunit which are predominantly expressed in the striatum. Ro 25-6981 induced contraversive rotations in 6-hydroxydopamine (6-OHDA)-lesioned rats without stimulating locomotion in normal rats and reversed parkinsonian symptoms in 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP)-treated common marmosets. Due to the small number of marmosets, there were no significant differences between Ro 25-6981 and vehicle though there was a significant trend toward differences, as shown by the Page test. Furthermore, Ro 25-6981 potentiated the action of levodopa in both species and attenuated the maximal levodopa response in 6-OHDA-lesioned rats chronically treated with levodopa without reducing the overall response. Ro 25-6981 also potentiated the action of the dopamine receptor agonists apomorphine, A68930 and quinpirole in 6-OHDA-lesioned rats. The present observations suggest a therapeutic potential of NR2B-selective NMDA receptor antagonists in the management of PD.

Animals↗
PubMed2003

Primary central nervous system lymphoma: results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy.

PURPOSE: To evaluate response rate, response duration, overall survival (OS), and toxicity in primary CNS lymphoma (PCNSL) after systemic and intraventricular chemotherapy with deferred radiotherapy. PATIENTS AND METHODS: From September 1995 to July 2001, 65 consecutive patients with PCNSL (median age, 62 years) were enrolled onto a pilot and phase II study evaluating chemotherapy without radiotherapy. A high-dose methotrexate (MTX; cycles 1, 2, 4, and 5) and cytarabine (ARA-C; cycles 3 and 6)-based systemic therapy (including dexamethasone, vinca-alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ARA-C. RESULTS: Sixty-one of 65 patients were assessable for response. Of these, 37 patients (61%) achieved complete response, six (10%) achieved partial response, and 12 (19%) progressed under therapy. Six (9%) of 65 patients died because of treatment-related complications. Follow-up is 0 to 87 months (median, 26 months). The Kaplan-Meier estimates for median time to treatment failure (TTF) and median OS were 21 months and 50 months, respectively. For patients older than 60 years, median survival was 34 months, and the median TTF was 15 months. In patients younger than 61 years, median survival and median TTF have not been reached yet; the 5-year survival fraction is 75%. Systemic toxicity was mainly hematologic. Ommaya reservoir infection occurred in 12 patients (19%), and permanent cognitive dysfunction possibly as a result of treatment occurred in only two patients (3%). CONCLUSION: Primary chemotherapy based on high-dose MTX and ARA-C is highly efficient in PCNSL. Response rate and response duration in this series are comparable to the response rates and durations reported after combined radiotherapy and chemotherapy. Neurotoxicity was infrequent.

Adult↗
PubMed2003

Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase.

Long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk for Alzheimer's disease (AD). To determine the mechanisms by which inflammation affects AD and how NSAIDs protect against it, we stimulated neuroblastoma cells stably transfected with amyloid precursor protein (APP) with proinflammatory cytokines, which increased the secretion of amyloid-beta and APP ectodomain. Addition of ibuprofen, indomethacin, peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, or cotransfection with PPARgamma cDNA reversed this effect. The inhibitory action of ibuprofen and indomethacin was suppressed by PPARgamma antagonists. Finally, we observed that the mRNA levels, expression, and enzymatic activity of beta-secretase were increased by immunostimulation and normalized by NSAIDs. In conclusion, proinflammatory cytokines activate beta-secretase, and NSAIDs inhibit this effect through PPARgamma.

Amyloid Precursor Protein Secretases↗
PubMed2003

The human MJD gene: genomic structure and functional characterization of the promoter region.

Machado-Joseph disease (MJD) is a progressive neurodegenerative disorder caused by expansion of a CAG motif within the translated region of the human MJD (hMJD) gene which has been mapped to chromosome 14q. In this study, the hMJD gene was identified in two overlapping bacterial artificial chromosome (BAC) clones and contained 11 exons resulting in a 6.14 kb transcript. The 5'-flanking region of the hMJD gene included a TATA-less promoter with GC-rich regions, a CCAAT box and multiple potential SP1 binding sites. Luciferase reporter assays performed in neuronal and non-neuronal human cell lines demonstrated a core promoter within the 200 bp region immediately upstream of the putative transcriptional start site (-89 according to the start codon). DNA-protein interactions defined by electrophoretic mobility shift assays (EMSA) revealed specific binding of nuclear proteins to the putative core promoter region.

5' Flanking Region↗
PubMed2003

Gene dosage-dependent effects of bcl-2 expression on cellular survival and redox status.

The human oncogene bcl-2 exerts protective functions in numerous models of apoptotic cell death and increased oxidative stress. We investigated the effects of inducible bcl-2 overexpression on cellular survival and redox status in dopaminergic rat pheochromocytoma PC 12 cells. Induction of high-level expression of bcl-2 in PC 12 cells resulted in generation of oxidative stress and cessation of growth by cell cycle arrest. Cell cycle arrest in bcl-2-overexpressing PC 12 cells was prevented by an inhibitor of extracellular signal-related kinase (ERK 1/2) activation. Protective effects of bcl-2 expression against L-DOPA neurotoxicity decreased with increasing amounts of bcl-2. Furthermore, high-level bcl-2 overexpression sensitized cells towards oxidative stress and glutathione depletion. Our data suggest that bcl-2 expression is beneficial only in a limited gene dosage range and that high-level expression of bcl-2 exerts potential deleterious effects.

Animals↗
PubMed2003

Lack of association of interleukin-10 promoter region polymorphisms with Alzheimer's disease.

There is increasing evidence that immune mechanisms are involved in the pathogenesis of Alzheimer's disease (AD). Recently, polymorphisms of the interleukin (IL)-1 and IL-6 genes were found to be associated with late-onset AD. The immunoregulatory IL-10 downregulates synthesis of pro-inflammatory cytokines such as IL-1. Current evidence suggests that some polymorphisms in the IL-10 promoter may have functional effects on IL-10 transcription. A total of 406 German AD patients (mean age 70.2+/-10.0 years, range 50-95 years, 42% female) and 251 unrelated non-demented control subjects (mean age 66.8+/-10.6 years, range 50-93 years, 38% female) were investigated for the presence of three polymorphisms in the IL-10 promoter region (-1087A/G, -824C/T, -597C/A). No significant differences in the allelic distribution of the analyzed IL-10 polymorphisms have been found between AD patients and controls. We conclude that polymorphisms in the IL-10 promoter region do not increase the risk of developing AD.

Aged↗