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W Kuhn

Publications and source records attributed to W Kuhn.

At least 55 records · Page 3Linked to original sources

Genetic influence on the development of Parkinson's disease.

In the last few years, the genetic contribution to Parkinson's disease has gained major attention and resulted in the identification of four gene loci in autosomal dominant and autosomal recessive Parkinson's disease. Several mutations in two genes have been shown to be responsible for neuronal cell death in Parkinson's disease. One of the gene products involved, alpha-synuclein, is a major component of Lewy bodies, the neuropathological feature of Parkinson's disease. In contrast, mutations in the parkin gene are associated with parkinsonism without Lewy body pathology. The elucidation of polygenic changes in the dopamine pathway, mitochondrial dysfunction, and of xenobiotic metabolism is technically now possible by means of association and genotype studies. The increasing knowledge of the pathogenesis of Parkinson's disease at a molecular level will have important implications for the development of individual therapeutic strategies to prevent disease progression.

Humans↗

Stromelysin-3 expression in invasive ovarian carcinomas and tumours of low malignant potential.

Stromelysin (ST)-3 is considered to be a marker of invasion and preinvasive lesions to indicate the likelihood of subsequent invasion. The expression of ST-3 has not been systematically studied in ovarian neoplasms. We studied 47 ovarian carcinomas and 49 ovarian tumours of low malignant potential (LMP) to see whether the expression of ST-3 correlated with any histopathologic features and, in the LMP tumours, whether its expression might be a prognostic indicator. All of the primary tumours and available metastases or implants were studied using immunohistochemistry (IHC) for ST-3 and, in 52 selected lesions, in situ hybridisation (ISH) using a cDNA probe. Expression of ST-3 was seen in 42 of 47 (89%) of the carcinomas and in 16 of 49 (33%) of the LMP cases. A significantly higher percentage of carcinomas than LMP tumours (P<0.00001) expressed ST-3 in the stroma adjacent to the tumour, with a correlation to increasing FIGO (International Federation of Gynecology and Obstetrics) tumour stage. ST-3 was expressed in the surrounding stroma of 1 of 8 LMP implants and 46 of 55 (84%) of the carcinoma metastases. The single LMP patient who died of tumour recurrence had ST-3 expression, but a significant prognostic impact was not found. The infrequent expression of ST-3 in LMP compared with carcinoma metastases appears to be more consistent with a peritoneal "field effect" than spread from the ovarian LMP tumour.

Adenocarcinoma, Mucinous↗

Altered redox state of platelet coenzyme Q10 in Parkinson's disease.

BACKGROUND: The reduced form of coenzyme Q10 (CoQ10) acts as a lipophilic antioxidant and participates in electron and proton transport of the respiratory chain in the inner mitochondrial membrane. An alteration in CoQ10 redox state may thus reflect a change in membrane electron transport and the effectiveness of defense against toxic reactive oxygen species such as hydrogen peroxide and superoxide. In Parkinson's disease alterations in the activities of complex I have been reported in substantia nigra and platelets. Deficiency of mitochondrial enzyme activities could affect electron transport which might be reflected by the platelet CoQ10 redox state. METHOD: We have determined concentrations of the reduced and oxidized forms of CoQ10 and the activity of monoamine oxidase B in platelets isolated from parkinsonian patients and age- and gender-matched controls. RESULTS: Platelet CoQ10 redox ratios (reduced CoQ10 to oxidized CoQ10) and the ratio of the reduced form, compared with total platelet CoQ10, were significantly decreased in de novo parkinsonian patients. Platelet CoQ10 redox ratios were further decreased by L-DOPA treatment (not significant), whilst selegiline treatment partially restored CoQ10 redox ratios. Monoamine oxidase activities in non-selegiline treated patients were similar to controls. INTERPRETATION: Our results either suggest an impairment of electron transport or a higher need for reduced forms of CoQ10 in the platelets of even de novo parkinsonian patients. However, the CoQ10 redox ratio was not correlated to disease severity, as determined by the Hoehn and Yahr PD disability classification, suggesting that this parameter may not be useful as a peripheral trait marker for the severity of PD but as an early state marker of PD.

Aged↗

Effects of apomorphine on visual functions in Parkinson's disease.

The effect of apomorphine on visual functions in Parkinson's disease (PD) was evaluated by use of a static contrast sensitivity test (VCTS charts), a colour discrimination test (Farnsworth-Munsell 100 Hue test) and the examination of achromatic and chromatic contour perception. 31 patients (14 male, 17 female; mean age 60.9 +/- 9.2 years) with idiopathic PD were tested before and after an individual dosage of subcutaneously applied apomorphine showing a significant effect on motor function during the whole experiment. The achromatic spatial contrast sensitivity improved significantly after apomorphine injection with respect to all spatial frequencies. The improvement of colour discrimination after apomorphine application was minimal and not statistically significant. The small advantage of apomorphine with respect to colour discrimination may be explained by negative cognitive side-effects of apomorphine interfering with the test performance. The achromatic contour perception before and after apomorphine injection was unaltered. The contour fusion latency for the green stimulus was shortened, the latency for the rest of the examined coloured stimuli was delayed (= normalized) after apomorphine application. We conclude that apomorphine may be used as a test-drug for the examination of the dopaminergic response of the visual system in patients with PD. The improvement of basal visual functions by dopaminergic stimulation with apomorphine underlines the role of dopamine deficiency for visual dysfunction in PD.

Aged↗

The activity of catechol-O-methyltransferase in parkinsonian patients with "on-off fluctuations".

Motor fluctuations complicate therapy in Parkinson's disease (PD). The mechanisms responsible for motor fluctuations such as the on-off type, are poorly understood. Differences of activity of various enzymes, such as Catechol-O-Methyltransferase (COMT, E.C.2.1.1.6.) may influence the appearance of motor fluctuations and the quantity of metabolic products of levodopa. Aim of this study was to compare erythrocyte COMT-activity in Parkinsonian patients without and with motor fluctuations from the on-off type. No significant differences in COMT-activity appeared in both groups. We conclude that activity differences in COMT-activity do not contribute to the appearance of motor fluctuations in Parkinson's disease.

Aged↗

Tolcapone increases maximum concentration of levodopa.

No significant increase of the maximum concentration (Cmax) of levodopa after addition of catechol-O-methyltransferase inhibitor tolcapone occurred in previous pharmacokinetic studies predominantly on healthy volunteers. We compared pharmacokinetics of levodopa in plasma before and after addition of tolcapone in 13 treated parkinsonian subjects under standardized conditions. We found a significant increase of Cmax of levodopa after the addition of tolcapone. This may represent one cause for the occurrence of dyskinesia previously early in the course of treatment with tolcapone.

Aged↗

Glutathione S-transferase polymorphism in Parkinson's disease.

Glutathione S-transferases (GSTs) are involved in the detoxification of endogenous or exogenous toxins, which may play a role in the pathogenesis of Parkinson's disease. We genotyped the Glutathione-S-Transferase isoenzymes GSTM1 and GSTT1 by polymerase chain reaction in order to evaluate different gene polymorphisms of these isoenzymes in 149 parkinsonian and 99 control subjects. No differences appeared between both groups regarding the frequencies of the homozygous deletion of GSTM1 (odds ratio 1.021; 95% CI [0.613; 1.699], p < 0.521 Fisher's exact test) and GSTT1 (odds ratio 1.514; 95% CI [0.811; 2.824], p < 0.127). Age of onset of PD did not correlate to GSTM1 and GSTT1 polymorphisms. These results do not support the hypothesis of a possible impact of GSTM1 and GSTT1 detoxification activities in the pathogenesis of Parkinson's disease.

Adult↗

Genetic analysis of immunomodulating factors in sporadic Parkinson's disease.

Immunomodulating factors have been shown to play a role in the pathogenesis of Parkinson's disease (PD) by biochemical methods. In order to investigate functionally important genes of the tumor necrosis factor alpha (TNFalpha) pathway we studied the frequency of DNA polymorphisms in the interleukin 6 (IL6), the TNFalpha, and the TNFalpha receptor 1 (TNFR1) genes in 264 sporadic German PD patients and in 183 age and sex matched German healthy controls. Analyzing the TNFalpha-308 polymorphism we found heterozygous individuals carrying alleles 1 and 2 more frequently in patients with a relative risk of 1.56 (p = 0.046, p(c) = 0.13, chi2 = 3.98). In contrast, the frequency of the B/2 haplotype described by the TNFR1-609 and TNFRI+36 polymorphisms was significantly decreased in our PD patients group (p = 0.0097, p(c) = 0.048, chi2 = 6.69) with a relative risk reduced to 0.52. Our results suggest an involvement of immunomodulating factors in the pathogenesis of sporadic PD as revealed by a molecular genetic approach.

Adjuvants, Immunologic↗

Correlation between tapping and inserting of pegs in Parkinson's disease.

BACKGROUND: Various investigators have developed complex quantitative instrumental procedures for objective assessment of parkinsonian motor impairment, since drawbacks of rating scales are interrater variability, subjective impression, and insensitivity to subtle modifications. OBJECTIVES: To determine whether performance of inserting of pegs and tapping (i) correlates with each other (ii) differentiates between parkinsonian subjects and healthy controls and (iii) reflects severity of Parkinson's disease (PD). SUBJECTS AND METHODS: In 157 previously untreated idiopathic parkinsonian patients and healthy controls, we measured (i) the total time taken to insert 25 pegs from a rack into a series of appropriate holes in a Purdue pegboard-like apparatus and (ii) the number of taps on a contact board with a contact pencil for a period of 32 seconds for assessment of fine motor skills. RESULTS: Results of both tests correlated with each other, differed between parkinsonian subjects and controls and reflected scored severity of PD. Better correlation with intensity of PD was noted with the Purdue pegboard-like task. CONCLUSION: Both tapping and inserting of pegs represent useful tools for objective evaluation of severity of PD. Peg insertion correlated better with disease severity. Both approaches may be useful in future clinical studies.

Adult↗

Elevated plasma levels of homocysteine in dystonia.

OBJECTIVE: Several case reports with dystonia and homocysteinuria suggest a putative pathogenetic importance of homocysteine for the development of dystonia. We investigated relations between plasma homocysteine, age, severity and duration of primary idiopathic torsion dystonia. SUBJECTS AND METHODS: We measured homocysteine levels in blood samples drawn from 24 subjects with dystonia and controls. RESULTS: Patients with dystonia (19.3 +/- 8.5, range 8.4-37 micromol/l) showed significantly (P= 0.008, t-test) increased levels of total homocysteine compared with age- and sex-matched controls (13.9 +/- 4.2, range 5.8-24.5 micromol/l). No significant influence of age and duration of dystonia appeared, but we found a significant trend for an association between severity of dystonia and homocysteine (P = 0.046, R = 0.41). CONCLUSIONS: Our study supports previous reports on subjects with dystonia with homocysteinuria. Neurotoxic effects and N-methyl-D-aspartate agonistic properties of homocysteine may hypothetically contribute to onset and severity of dystonia.

Adult↗

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Journal Article↗

Positron emission tomography using [(18)F]Fluorodeoxyglucose for monitoring primary chemotherapy in breast cancer.

PURPOSE: To address the role of positron emission tomography (PET) using [(18)F]fluorodeoxyglucose (FDG) to monitor primary (neoadjuvant) chemotherapy in patients with locally advanced breast cancer. PATIENTS AND METHODS: Quantification of regional FDG uptake of the breast acquired after the first and second courses of chemotherapy was compared with the baseline scan in 22 patients with a total of 24 breast carcinomas. To evaluate the predictive value of PET imaging, histopathologic response after completion of chemotherapy classified as gross residual disease (GRD) or minimal residual disease (MRD) served as the gold standard. RESULTS: Significant differences in tracer uptake between nonresponding tumors (GRD) and responding lesions (MRD) were observed (P <.05) as early as after the first course of chemotherapy. Tracer uptake showed little change in tumors with GRD found later in pathologic analysis but decreased sharply to the background level in most tumors with MRD. After the first course, all responders were correctly identified (sensitivity 100%, specificity 85%) by a standardized uptake value decrease below 55% of the baseline scan. At this threshold, histopathologic response could be predicted with an accuracy of 88% and 91% after the first and second courses of therapy, respectively. CONCLUSION: This study demonstrates that in patients with advanced breast cancer undergoing primary chemotherapy, FDG-PET differentiates responders from nonresponders early in the course of therapy. This may help improve patient management by avoiding ineffective chemotherapy and supporting the decision to continue dose-intensive preoperative chemotherapy in responding patients.

Adult↗

Long term results of definitive radiotherapy for cervical carcinoma using four applications of high dose rate afterloading.

BACKGROUND: In definitive radiotherapy for cervical carcinoma, combined modality treatment using external beam radiotherapy and brachytherapy is standard. Although the optimal number of afterloading applications is controversial, the majority of authors recommend three applications. METHODS: In this study, the authors investigated the use of 4 applications with iridium-192 afterloading with a dose of 7.5 grays (Gy). Standardized radiotherapy doses were adapted to the individual tumor anatomy using a prospective schedule. RESULTS: In the 73 study patients, actuarial and tumor-related 5-year survival rates by T classification were: T1b: 30% (100% cause specific survival); T2a: 55% (76% cause specific survival); T2b: 50% (60% cause specific survival); T3a: 50% (67% cause specific survival); T3b: 39% (50% cause specific survival); and T4a: 40% (40% cause specific survival). Morbidity, graded according to the National Cancer Institute's Common Toxicity Criteria (CTC) were low: CTC Grade 1: 7 patients (7.6%); CTC Grade 2: 7 patients (7.6%); CTC Grade 3: 1 patient (1.4%); and CTC Grade 4: 1 patient (1.4%). In a multivariate analysis, the T classification was the only significant independent prognostic factor for actuarial survival, tumor related (cause specific) survival, local tumor control and freedom of metastatic disease. The number of afterloading applications was an independent prognostic factor for local tumor control. CONCLUSIONS: Based on the long term results of the current study, external beam radiotherapy combined with 4 afterloading high dose rate applications (total of 30 Gy) appears to be clinically feasible and results in satisfactory survival rates and few side effects.

Adenocarcinoma↗

Nigral endothelial dysfunction, homocysteine, and Parkinson's disease.

We found increased levels of atherosclerosis-inducing homocysteine in parkinsonian patients with long-term application of levodopa compared with previously untreated parkinsonian patients and controls. We conclude that antiparkinsonian treatment with levodopa promotes occurrence of vascular disease in Parkinson's disease.

Aged↗

R- and S-salsolinol are not increased in cerebrospinal fluid of Parkinsonian patients.

Various investigators address an augmented synthesis of tetrahydroisoquinolines, such as salsolinol (SAL), or an increased N-methylation of these compounds as putative pathophysiologic mechanisms in Parkinson's disease (PD). Objectives of this study were (1) the evaluation of a putative elevation of enantiomers (R-, S-) of SAL and (2) the investigation of relations between these metabolic precursors of neurotoxic N-methylated-SAL (NMSAL) and dopamine in cerebrospinal fluid of untreated de-novo Parkinsonian patients and age- and sex-matched healthy controls. Levels of R- and S-SAL and dopamine did not significantly (R-SAL: P = 0.75, S-SAL: P = 0.69, dopamine: P = 0.46) differ and dopamine did not correlate to R-SAL and S-SAL in both groups. We conclude, that central accumulation of R-NMSAL, which is neurotoxic to dopaminergic nigrostriatal neurons, is not due to elevated synthesis of R-SAL and/or S-SAL in PD.

Adult↗

Increased susceptibility to sporadic Parkinson's disease by a certain combined alpha-synuclein/apolipoprotein E genotype.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders affecting about 1% of Western populations older than age 50. The pathological hallmark of PD are Lewy bodies, that is, intracytoplasmic inclusion bodies in affected neurons of the substantia nigra. Recently, alpha-synuclein (alpha-SYN) has been identified as the main component of Lewy bodies in sporadic PD, suggesting involvement in neurodegeneration via protein accumulation. The partially overlapping pathology of PD and Alzheimer's disease, as well as striking structural similarities of alpha-SYN and apolipoprotein E, which is a major risk factor for late-onset Alzheimer's disease, prompted us to investigate the influence of different alpha-SYN and apolipoprotein E alleles for developing sporadic PD. We performed association studies in 193 German PD patients and 200 healthy control subjects matched for age, sex, and origin. A polymorphism in the promoter region of the alpha-SYN gene (NACP-Rep1) as well as of the closely linked DNA markers D4S1647 and D4S1628 revealed significant differences in the allelic distributions between PD patients and the control group. Furthermore, the Apo epsilon4 allele but not the Th1/E47 promoter polymorphism of the apolipoprotein E gene was significantly more frequent among early-onset PD patients (age at onset, <50 years) than in late-onset PD. Regarding the combination of the Apo epsilon4 allele and allele 1 of the alpha-SYN promoter polymorphism, a highly significant difference between the group of PD patients and control individuals has been found, suggesting interactions or combined actions of these proteins in the pathogenesis of sporadic PD. PD patients harboring this genotype have a 12.8-fold increased relative risk for developing PD during their lives.

Aged↗