Biomedical subjects
Publications and source records attributed to T Müller.
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BACKGROUND: Exogenous glucagon rapidly stimulates insulin secretion. This test has been used to estimate insulin secretory capacity, which may predict oral glucose tolerance in patients after pancreas transplantation. METHODS: In 32 pancreas-kidney transplant recipients, in 10 nondiabetic kidney transplant recipients, and in 9 healthy control subjects, a glucagon stimulation test (1 mg i.v.) and a 75-g oral glucose tolerance test were performed with determination of glucose, insulin, and C-peptide profiles. RESULTS: Of 16 pancreas transplant recipients with the lowest insulin responses after glucagon, 7 had an impaired oral glucose tolerance, in contrast to 1 of 16 with high insulin responses (P=0.037). A low insulin response after glucagon was associated with significantly lower 120-min glucose concentrations (P=0.043) and a lower integrated incremental insulin response after oral glucose (P=0.006). CONCLUSIONS: In pancreas-kidney transplant recipients, a low insulin response after intravenous glucagon predicts a reduced insulin response after oral glucose and an impaired oral glucose tolerance. This simple test may be helpful in the follow-up of pancreas transplant recipients.
Recent association studies investigating polymorphisms in the alpha2-macroglobulin (A2M) gene provided evidence for an involvement of this protease inhibitor in the pathogenesis of Alzheimer's disease (AD). The partially overlapping pathology between AD and Parkinson's disease (PD) led us to investigate the role of A2M in PD. We performed association studies in a large sample of 328 German PD patients and 322 closely matched healthy controls. Analyzing the Val1000Ile polymorphism and a pentanucleotide deletion in the 5' splice site of exon 18 of the A2M gene we found an excess of homozygosity for the A2M deletion in early-onset PD (EOPD) patients (age at onset < 50 years) compared to late-onset PD (LOPD) patients (age at onset > 50 years; p = 0.008, p(p)c = 0.064, chi2 = 7.017). Therefore our data might indicate an age at onset modulating effect of the homozygous A2M deletion in PD.
We have developed a new microsystem for fast, automated studies of reactions and kinetics of single cells with biochemical or pharmacological agents. A cell spins in an external rotating electric field and the frequency dependence characterises the passive dielectric properties of membrane and cytoplasm. We use a planar microelectrode chip with microchannel (easily covered with a removable slip) for the application of frequencies exceeding 250 MHz to determine cytoplasmic properties in low and high conductivity electrolyte solutions. The laser tweezers serve as a bearing system, rotation is induced by microelectrodes and rotation speed is recorded automatically. This opens up new possibilities in biotechnology, e.g. for drug screening as demonstrated by measuring the influence of ionomycin on the passive dielectric properties of T-lymphoma cells. Additionally, a possible infrared-induced long-term cell damage could be observed by electrorotation and is discussed.
Recently, an Ile93Met substitution has been identified in the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene in a single German PD family with autosomal dominant inheritance. To determine whether mutations in the UCHL1 gene are causative for Parkinson's disease (PD) a detailed mutation analysis was performed in a large sample of German sporadic and familial PD patients. We found no disease-causing mutation in the coding region of the UCHL1 gene. Direct sequencing revealed six intronic polymorphisms in the UCHL1 gene. Analysis of an S18Y polymorphism in exon 3 of the UCHL1 gene in sporadic PD patients and controls showed carriers of allele 2 (tyrosine) significantly less frequent in patients with a reduced risk of 0.57 (CI = 0.36-0.88; p = 0.012, p(c) = 0.047, chi2 = 6.31). Our study shows that sequence variations in the coding region of UCHL1 are a rare event. A protective effect of a certain UCHL1 variant in the pathogenesis of sporadic PD is suggested, underlining the relevance of UCHL1 in neurodegeneration.
Background: Antiparkinsonian comedication and/or altered gastrointestinal motility and absorption influence plasma levels of levodopa. Another putative factor may represent body weight. The objective of our study was to examine the relationship between body weight and levodopa in plasma of parkinsonian patients.Methods: We enrolled 26 individuals into this trial on the resorption of levodopa. A standardized protocol was used, which eliminated influencing factors, such as comedication, activity, food and estimated levodopa plasma levels at fixed timepoints.Results: Levodopa amount (Spearman R=-0.48; p=0.013) and maximum concentration (Spearman R=-0.50; p=0.008) in plasma correlated negatively with body weight.Conclusion: Doses of levodopa should be considered in relation to body weight. Thus severe loss of weight may reduce the need for oral levodopa intake by parkinsonian subjects and may represent a putative factor in the occurrence of dyskineasia in these patients unless there is a concomitant reduction in the dose of oral levodopa.
The integrity of cell-cell contacts such as adherens junctions (AJ) and tight junctions (TJ) is essential for the function of epithelia. During carcinogenesis, the increased motility and invasiveness of tumor cells reflect the loss of characteristic epithelial features, including cell adhesion. While beta-catenin, a component of AJ, plays a well characterized dual role in cell adhesion and signal transduction leading to epithelial cell transformation, little is known about possible roles of tight junction components in signaling processes. Here we show that mutants of the TJ protein zonula occludens protein-1 (ZO-1), which encode the PDZ domains (ZO-1 PDZ) but no longer localize at the plasma membrane, induce a dramatic epithelial to mesenchymal transition (EMT) of Madin-Darby canine kidney I (MDCKI) cells. The observed EMT of these MDCK-PDZ cells is characterized by a repression of epithelial marker genes, a restricted differentiation potential and a significantly induced tumorigenicity. Intriguingly, the beta-catenin signaling pathway is activated in the cells expressing the ZO-1 PDZ protein. Ectopic expression of the adenomatous polyposis coli tumor suppressor gene, known to down-regulate activated beta-catenin signaling, reverts the transformed fibroblastoid phenotype of MDCK-PDZ cells. Thus, cytoplasmic localization of the ZO-1 PDZ domains induces an EMT in MDCKI cells, most likely by modulating beta-catenin signaling.
Recently, four subtypes of the human phosphodiesterase type 4 (PDE4A-D) enzyme have been described. So far, only very few PDE4 subtype-selective inhibitors are known. Herein, we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC(50) values as low as 0.7 nM. SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D with an IC(50) value of 1 nM. Thus, compound 11 was 55, 175, and 1000 times more potent in inhibiting PDE4D over PDE4B, PDE4A, and PDE4C. In a Brown Norway rat model of allergic asthma, compound 11 when given by the oral route (1 mg/kg) reduced by more than 50% the influx of eosinophils, T-cells, and neutrophils into bronchoalveolar lavage fluid (BALF) samples obtained from antigen-challenged animals. Thus, PDE4D-selective inhibitors of the 1,7-naphthyridine class have the potential as an oral therapy for treating asthma.
Planar and three-dimensiònal multi-electrode systems with dimensions of 2 - 40 microm were fabricated by IC technology and used for trapping and aggregation of microparticles. To achieve negative dielectrophoresis (repelling forces) in aqueous solution, radiofrequency (RF) electric fields were used. Experimentally, particles down to 100 nm in diameter were enriched and trapped as aggregates in field cages and dielectrophoretic microfilters and observed using confocal fluorimetry. Theoretically, single particles with an effective diameter down to about 35 nm should be trappable in micron field cages. Due to the unavoidable Ohmic heating, RF electric fields can induce liquid streaming in extremely small channels (12 microm in height). This can be used for pumping and particle enrichment but it enhances Brownian motion and counteracts dielectrophoretic trapping. Combining Brownian motion with ratchet-like dielectrophoretic forces enables the creation of Brownian pumps that could be used as sensitive separation devices for submicron particles if liquid pumping is avoided in smaller structures.
Phenotypes of individuals with the mitochondrial A3243G mutation and amount of mutant DNA in different tissues can be very variable, but the proportion of mutant DNA was consistantly lower in blood than muscle in previously studied patients. We detected the A3243G mutation in a 54-year-old patient with cardiomyopathy and hearing loss, where the amount of mutant DNA was higher in blood (19%) than in muscle (6%). This shows that the level of A3243G mutation is not always lower in rapidly dividing tissues such as blood than in muscle, as has been presumed until now.
The aim is to describe a general approach to determining important electrode positions when measured electro-encephalogram signals are used for classification. The approach is exemplified in the frame of the brain-computer interface, which crucially depends on the classification of different brain states. To classify two brain states, e.g. planning of movement of right and left index fingers, three different approaches are compared: classification using a physiologically motivated set of four electrodes, a set determined by principal component analysis and electrodes determined by spatial pattern analysis. Spatial pattern analysis enhances the classification rate significantly from 61.3 +/- 1.8% (with four electrodes) to 71.8 +/- 1.4%, whereas the classification rate using principal component analysis is significantly lower (65.2 +/- 1.4%). Most of the 61 electrodes used have no influence on the classification rate, so that, in future experiments, the setup can be simplified drastically to six to eight electrodes without loss of information.
Consensus could be reached that there is overwhelming evidence of preclinical neuroprotection. However, the evidence of neuroprotection/neurorescue under clinical conditions is limited. Lessons from clinical trials designed to show neuroprotection (selegiline, amantadine, dopamine agonists) demonstrate that with the drugs available neuroprotection/neurorescue has to start as early as possible. A PET-controlled clinical trial with ropinirole shows that there seems to be a good chance for neuroprotection in the early phase of Parkinson's disease in patients treated from the very beginning of the disease while there is no such benefit in patients with a late start of a neuroprotective therapeutic strategy. Also long-term neuroprotection cannot be reached. Complicating factors to demonstrate clinical neuroprotection are discussed.
An attempt was made to establish a decision algorithm for the treatment of idiopathic Parkinson's disease at various stages and in different subgroups such as akinetic-rigid or tremor dominance type. We suggest treating young patients with selegiline and a dopamine agonist. In the tremor dominance type we use either budipine or a dopamine agonist. Due to levodopa-induced dyskinesia, we try to avoid levodopa in the early stages of the disease and use it only later in more advanced situations in a combination therapy with dopamine agonists. Since IPS is not only based upon dopamine deficiency but also on resulting glutamatergic overstimulation, we advocate the use of a glutamate antagonist such as amantadine or budipine. Catechol-O-methyl inhibitors are very helpful when wearing-off occurs. Anticholinergics are only used in the early stages of tremor-dominant IPS because we fear enhancing the risk of dementia.
We tested the hypothesis that altered phosphorylation of Ca2+ regulatory proteins contributes to contractile anomalies in cardiac hypertrophy. Cardiac hypertrophy was induced in rats by chronic s.c. administration of isoproterenol (Iso, 2.4 mg/kg/day) via osmotic minipumps. On day 2 of Iso treatment the expression of atrial natriuretic factor was increased, time of relaxation in isolated papillary muscles shortened and protein expression of phospholamban (PLB) and sarcoplasmic reticulum Ca2+-ATPase reduced. In addition, the phosphorylation state of PLB at serine-16 and threonine-17 was decreased from (arbitrary units) 2.3+/-0.3 to 1.1+/-0.2 and from 4.1+/-0.6 to 2.1+/-0.2, respectively. This was not accompanied by altered activity of PLB-phosphorylating protein kinases (protein kinase A or Ca2+/calmodulin-dependent protein kinase II), whereas the activity of types 1 and 2A protein phosphatases (PP1 and -2A respectively) was enhanced from 1.1+/-0.08 to 1.71+/-0.13 nmol/mg/min. Iso treatment did not alter the PP1/PP2A activity ratio and 1 nmol/l okadaic acid, a concentration which completely blocks the catalytic subunit of PP2A, inhibited about 40% of total PP activity in all groups studied. These data indicate that the activity of both PP1 and PP2A were increased. All effects of Iso treatment were abolished by co-administration of propranolol (29.7 mg/kg/day). It is concluded that dephosphorylation of PLB is due to enhanced activity of PP1 and PP2A. We suggest that chronic beta-adrenergic stimulation, which occurs in human cardiac hypertrophy and failure, can lead to increased activity of PPs. This may contribute to altered contractile responses in the hypertrophied heart.
Anemia secondary to mycophenolate mofetil (MMF) was recently described in experimental animals. A clinical association between MMF and anemia has been observed, but there are no proven reports. We describe a girl with chronic graft failure who developed erythroid aplasia under immunosuppression with MMF. She showed prompt resolution when MMF was discontinued and a recurrence of this clinical course when MMF was restarted. As re-challenge with a medication is the most definitive approach for showing a direct relationship between the drug and the side effect, this case clearly demonstrates that MMF can cause erythroid aplasia.
A major step in the elucidation of the pathogenesis of neurodegenerative disorders was the identification of a mutation in the alpha-synuclein gene in autosomal dominant Parkinson's disease (PD). Alpha-synuclein is the main component of Lewy bodies (LB), the neuropathological hallmark of PD. Moreover, a fragment of alpha-synuclein (NAC) is the second major component of amyloid plaques in Alzheimer's disease (AD). Recent studies of other neurodegenerative disorders such as dementia with LB (DLB), multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS) also revealed intracellular accumulations of alpha-synuclein in affected brain regions. This may indicate that these disorders partially share common pathogenic mechanisms. Recent data provide first insights into the physiological function of alpha-synuclein and support the concept of an essential role of alpha-synuclein in neurodegeneration. Increasing knowledge on the pathogenic molecular mechanisms of neurodegeneration and of the pathophysiological function of alpha-synuclein in particular may influence future development of therapeutic strategies in neurodegenerative disorders.
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.
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.