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Biomedical subjects

A Richter

Publications and source records attributed to A Richter.

At least 163 records · Page 9Linked to original sources
PubMed1999

Dynamics of gene expression revealed by comparison of serial analysis of gene expression transcript profiles from yeast grown on two different carbon sources.

We describe a genome-wide characterization of mRNA transcript levels in yeast grown on the fatty acid oleate, determined using Serial Analysis of Gene Expression (SAGE). Comparison of this SAGE library with that reported for glucose grown cells revealed the dramatic adaptive response of yeast to a change in carbon source. A major fraction (>20%) of the 15,000 mRNA molecules in a yeast cell comprised differentially expressed transcripts, which were derived from only 2% of the total number of approximately 6300 yeast genes. Most of the mRNAs that were differentially expressed code for enzymes or for other proteins participating in metabolism (e.g., metabolite transporters). In oleate-grown cells, this was exemplified by the huge increase of mRNAs encoding the peroxisomal beta-oxidation enzymes required for degradation of fatty acids. The data provide evidence for the existence of redox shuttles across organellar membranes that involve peroxisomal, cytoplasmic, and mitochondrial enzymes. We also analyzed the mRNA profile of a mutant strain with deletions of the PIP2 and OAF1 genes, encoding transcription factors required for induction of genes encoding peroxisomal proteins. Induction of genes under the immediate control of these factors was abolished; other genes were up-regulated, indicating an adaptive response to the changed metabolism imposed by the genetic impairment. We describe a statistical method for analysis of data obtained by SAGE.

Carbon↗
PubMed1999

Experimental versus numerical eigenvalues of a Bunimovich stadium billiard: a comparison.

We compare the statistical properties of eigenvalue sequences for a gamma=1 Bunimovich stadium billiard. The eigenvalues have been obtained in two ways: one set results from a measurement of the eigenfrequencies of a superconducting microwave resonator (real system), and the other set is calculated numerically (ideal system). We show influence of mechanical imperfections of the real system in the analysis of the spectral fluctuations and in the length spectra compared to the exact data of the ideal system. We also discuss the influence of a family of marginally stable orbits, the bouncing ball orbits, in two microwave stadium billiards with different geometrical dimensions.

Journal Article↗
PubMed1999

Anderson localization in a string of microwave cavities.

The field distributions and eigenfrequencies of a microwave resonator which is composed of 20 identical cells have been measured. With external screws the periodicity of the cavity can be perturbed arbitrarily. If the perturbation is increased a transition from extended to localized field distributions is observed. For very large perturbations the field distributions show signatures of Anderson localization, while for smaller perturbations the field distribution is extended or weakly localized. The localization length of a strongly localized field distribution can be varied by adjusting the penetration depth of the screws. Shifts in the frequency spectrum of the resonator provide further evidence for Anderson localization.

Journal Article↗
PubMed1999

Cerebrovascular reserve before and after vertebral artery angioplasty.

The selection of patients with severe vertebrobasilar artery stenosis for angioplasty is based mainly on clinical experience rather than on controlled data. We present a patient with severe vertebral artery stenosis in whom we could document the positive effect of angioplasty on posterior circulation hemodynamics by using transcranial Doppler sonography.

Aged↗
PubMed1999

The epidermal growth factor receptor and its ligand family: their potential role in repair and remodelling in asthma.

The bronchial epithelium acts as a physical barrier to the ingress of airborne irritants and plays an active role in the airways immune response, reacting to a range of environmental stimuli to enable interaction with immune and inflammatory cells. It is well established that mucosal damage and epithelial cell shedding are important features of inflammatory airways diseases such as asthma. Evidence now suggests that the repairing epithelium has the potential to contribute to disease chronicity through production of an array of soluble mediators and adhesion molecules. However, the biochemical mechanisms that control epithelial maintenance and repair are poorly understood, even though avoiding or reversing the changes in the airways which are likely to result from chronic inflammation and epithelial restitution remains a significant challenge in asthma therapy. The purpose of this review is to highlight the potential of the epidermal growth factor receptor (EGFR/c-erbB) and its ligands in restitution of the bronchial epithelium. This receptor tyrosine kinase plays a pivotal role in regulation of epithelial cell behaviour, having the capacity to elicit a broad spectrum of cellular responses ranging from migration or proliferation to differentiation and enhanced survival; it also has the ability to regulate expression of various inflammatory mediators, mucins, adhesion molecules, matrix proteins, and metalloproteinases which are relevant to the chronic disease phenotype.

Animals↗
PubMed1998

Commitment of individual Th1-like lymphocytes to expression of IFN-gamma versus IL-4 and IL-10: selective induction of IL-10 by sequential stimulation of naive Th cells with IL-12 and IL-4.

Commitment of Th lymphocytes to the Th1 phenotype, as characterized by the expression of the major proinflammatory cytokine IFN-gamma, may be critically involved in the establishment of chronic inflammation and inflammatory autoimmune disease. To date, it has been shown that in IL-12-stimulated murine Th cell lines containing a major fraction of Th1 cells, Th2 cells can be induced by IL-4 until about 2 wk after initial activation, but not later. Here we analyze, based on the magnetic isolation of viable Th1 cells according to their specific expression of IFN-gamma, the cytokine commitment of individual Th1 cells. After activation of naive Th cells with Ag and IL-12 for up to 5 wk, isolated IFN-gamma-producing cells were restimulated with Ag and IL-4. Within the first 3 to 4 wk of IL-12 stimulation, some IFN-gamma+ cells stopped expression of IFN-gamma when restimulated with IL-4. However, within only 1 to 2 wk of IL-12 stimulation, few IFN-gamma+ cells could be converted to produce IL-4. Others continued to express IFN-gamma and thus were already committed to a proinflammatory, Th1-like phenotype. Surprisingly, within 3 wk of IL-12 stimulation, many of the IFN-gamma-producing cells responded to IL-4 restimulation by expression of IL-10, but neither IFN-gamma nor IL-4, i.e., by conversion to a suppressive, anti-inflammatory phenotype.

Animals↗
PubMed1998

Structure-function studies of ligand-induced epidermal growth factor receptor dimerization.

We present a novel 96-well assay which we have applied to a structure-function study of epidermal growth factor receptor dimerization. The basis of the assay lies in the increased probability of EGFRs being captured as dimers by a bivalent antibody when they are immobilized in the presence of a cognate ligand. Once immobilized, the antibody acts as a tether, retaining the receptor in its dimeric state with a resultant 5-7-fold increase in binding of a radiolabeled ligand probe. When the assay was applied to members of the EGF ligand family, murine EGF, transforming growth factor alpha, and heparin-binding EGF-like growth factor were comparable with human EGF (EC50 = 2nM); betacellulin, which has a broader receptor specificity, was slightly less effective. In contrast, amphiregulin (AR1-84), which has a truncated C-tail and lacks a conserved leucine residue, was ineffective unless used at >1 microM. We further probed the involvement of the C-tail and the conserved leucine residue in receptor dimerization by comparing the activities of two genetically modified EGFs (the chimera mEGF/TGFalpha44-50 and the EGF point mutant L47A) and a C-terminally extended form of AR (AR1-90) with those of two other unrelated EGF mutants (I23T and L15A). The potency of these ligands was in the order EGF > I23T > mEGF/TGFalpha44-50 > L47A = L15A >> AR1-90 > AR1-84. Although AR was much worse than predicted from its affinity, this defect could be partially rectified by co-localization of the immobilizing antibody with heparin. Thus, it seems likely that AR cannot dimerize the EGFR unless other accessory molecules are present to stabilize its functional association with the EGFR.

Cell Line↗
PubMed1998

Human protein MCM6 on HeLa cell chromatin.

Minichromosome maintenance (Mcm) proteins perform essential functions regulating the replication of chromatin. Human cells, like other eukaryotic cells, express at least six Mcm proteins conserved in the central region. We have earlier described the primary structures of five human Mcm proteins, but the primary structure of the sixth human Mcm protein, MCM6, was identified only recently. We now use antibodies, specific for the MCM6 protein, to assess its intranuclear distribution. We find that a fraction of MCM6 protein occurs in the nucleosol, forming multiprotein complexes with other Mcm proteins. More importantly, we use for the first time micrococcal nuclease as a tool to investigate the association of MCM6 protein with chromatin. After short digestion times, a considerable fraction of the MCM6 protein is released from chromatin as a multiprotein complex that includes other Mcm proteins as well. In addition, fractions of MCM3 and MCM6 proteins are released by nuclease digestion as monomeric proteins indicating that at least these two Mcm proteins may also occur as single molecules on chromatin. The data also suggest that the chromatin regions with bound Mcm proteins are more vulnerable to nuclease attack than bulk chromatin and may therefore differ in the arrangement of nucleosomes.

Antibodies↗
PubMed1998

Quantitative EEG analysis of depth electrode recordings from several brain regions of mutant hamsters with paroxysmal dystonia discloses frequency changes in the basal ganglia.

Computerized EEG spectral analyses of depth electrode recordings from striatum (caudate/putamen; CPu), globus pallidus (GP), and parietal cortex (pCtx) were performed before and after dystonic attacks in freely moving mutant dt(sz) hamsters with paroxysmal dystonia. In these hamsters, sustained attacks of abnormal movements and postures can be reproducibly induced by stress, such as placing the animals in a new environment. Data recorded from mutant hamsters were compared with recordings from age-matched nondystonic control hamsters. The predominant EEG changes in CPu and GP of dystonic hamsters were significant decreases in the high-frequency beta2 range and there was a tendency to increase in delta and theta activities. These changes were seen both before and after onset of dystonic attacks, indicating a permanent disturbance of neural activities in the basal ganglia of dystonic animals. No such changes were seen in the pCtx. Furthermore, no epileptic or epileptiform activity was seen in any of the recordings, substantiating a previous notion from cortical and hippocampal recordings that paroxysmal dystonia in these mutant hamsters has no epileptogenic basis. The present finding of abnormal synchronization of neural activity in the CPu and GP of dystonic hamsters adds to the belief that the striatopallidal-thalamocortical circuit is the most likely site in which to search for the unknown defect in primary (idiopathic) dystonia. As suggested by this study, quantitative EEG analysis can increase the likelihood of detecting subtle EEG abnormalities in different types of idiopathic dystonia and thereby improves our understanding of the pathogenetic mechanisms of this movement disorder.

Animals↗
PubMed1998

[3H]-2-deoxyglucose uptake study in mutant dystonic hamsters: abnormalities in discrete brain regions of the motor system.

The genetically dystonic (dtSZ) hamster, an animal model of idiopathic paroxysmal dystonia, displays attacks of generalized twisting movements and abnormal postures of limbs and trunk either spontaneously or in response to mild stress. This experimental model may be helpful to give insights into the pathophysiology of idiopathic dystonia in man. In the present study, the regional uptake of [3H]-2-deoxyglucose (2-DG) was examined in brains (75 brain regions) of dtSZ hamsters during the expression of severe dystonia. 2-DG autoradiography revealed significant changes of 2-DG uptake in discrete brain regions of dtSZ hamsters compared with age-matched, nondystonic control hamsters. In dystonic hamsters, a dramatic increase of 2-DG uptake was observed in the red nucleus (159% over control). Furthermore, enhanced 2-DG uptake was found in the ventromedial, ventrolateral, and anteroventral nuclei of the thalamus (19-42%) and in the medial vestibular nucleus (23%). A significant decrease in 2-DG uptake in deep cerebellar nuclei (-30%) may be the result of decreased synaptic activity of GABAergic neurons within these structures resulting in enhanced excitatory output to red nucleus, thalamic, and vestibular nuclei. In dtSZ hamsters, the 2-DG uptake was not significantly altered overall within the basal ganglia. Significant increases of 14% were, however, found in discrete parts of the caudate putamen in which recent studies revealed changes of dopamine receptors. Altered neural activity within the basal ganglia may therefore contribute to increased 2-DG uptake in the ventral thalamic nuclei as well as to decreased 2-DG uptake (-13%) found in the reticular thalamic nucleus. Although the present data are in line with the concept that abnormal thalamocortical activity seems to be critically involved in the dystonic syndrome, altered activities in other motor areas than output structures of the basal ganglia, such as in the red nucleus, may contribute to clinical manifestation of dystonia in mutant hamsters.

Animals↗
PubMed1998

[Large Brunner adenoma in the duodenal bulb--a case report].

Benign, proliferative changes of the Brunner's gland are very rare and account for about 10% of duodenal bulb neoplasias. The authors present a case of Brunner's gland adenoma of unusual dimensions (12 x 5 x 2.5 cm). The patient presented with vague epigastric discomfort as isolated symptoms. In this case we performed surgical treatment, including a duodenotomy and polypectomy. Because they are localized in the submucosa small, superficial endoscopic biopsies may fail to confirm the diagnosis. Malignancy seems to occur only very rarely, with only 14 cases reported in the literature. As the majority of Brunner's adenomas are quite small, endoscopic polypectomy will confirm the diagnosis and cure the condition in most cases. Large symptomatic adenomas may require surgical resection.

Adenoma↗
PubMed1998

Pathology of idiopathic dystonia: findings from genetic animal models.

Dystonia is a common movement disorder which is thought to represent a disease of the basal ganglia. However, the pathogenesis of the idiopathic dystonias, i.e. the neuroanatomic and neurochemical basis, is still a mystery. Research in dystonia is complicated by the existence of various phenotypic and genotypic subtypes of idiopathic dystonia, probably related to heterogeneous dysfunctions. In neurological diseases in which no obvious neuronal degeneration can be found, such as in idiopathic dystonia, the identification of a primary defect is difficult, because of the large number of chemically distinct, but functionally interrelated, neurotransmitter systems in the brain. The variable response to pharmacological agents in patients with idiopathic dystonia supports the notion that the underlying biochemical dysfunctions vary in the subtypes of idiopathic dystonia. Hence, in basic research it is important to clearly define the involved type of dystonia. Animal models of dystonias were described as limited. However, over the last years, there has been considerable progress in the evaluation of animal models for different types of dystonia. Apart from animal models of symptomatic dystonia, genetic animal models with inherited dystonia which occurs in the absence of pathomorphological alterations in brain and spinal cord are describe. This review will focus mainly on genetic animal models of different idiopathic dystonias and pathophysiological findings. In particular, in the case of the mutant dystonic (dt) rat, a model of generalized dystonia, and in the case of the genetically dystonic hamster (dt(sz)), a model of paroxysmal dystonic choreoathetosis has been used, as these show great promise in contributing to the identification of underlying mechanisms in idiopathic dystonias, although even a proper animal model will probably never be equivalent to a human disease. Several pathophysiological findings from animal models are in line with clinical observations in dystonic patients, indicating abnormalities not only in the basal ganglia and thalamic nuclei, but also in the cerebellum and brainstem. Through clinical studies and neurochemical data several similarities were found in the genetic animal models, although the current data indicates different defects in dystonic animals which is consistent with the notion that dystonia is a heterogenous disorder. Different supraspinal dysfunctions appear to lead to manifestation of dystonic movements and postures. In addition to increasing our understanding of the pathophysiology of idiopathic dystonia, animal models may help to improve therapeutic strategies for this movement disorder.

Animals↗
PubMed1998

Regional alterations in neuronal activity in dystonic hamster brain determined by quantitative cytochrome oxidase histochemistry.

The neural mechanisms underlying idiopathic dystonia are currently unknown. Genetic animal models, such as the dt(sz) hamster, a model of idiopathic paroxysmal dystonia, may be helpful to providing insights into the pathophysiology of this common movement disorder. Recent metabolic mapping studies in the hamster model, using 2-deoxyglucose autoradiography, demonstrated altered 2-deoxyglucose uptake in motor areas such as the striatum, ventral thalamic nuclei, red nucleus, and deep cerebellar nuclei, during dystonic attacks. Whereas the 2-deoxyglucose method is thought to reflect mainly acute alterations of synaptic activity, determination of cytochrome oxidase activity has been suggested as a method of choice to examine sustained baseline changes in neuronal activity. Therefore, in the present study quantitative cytochrome oxidase histochemistry was used to identify chronic regional alterations in the absence of dystonic attacks in mutant hamsters. For comparison with recent 2-deoxyglucose studies, cytochrome oxidase activity was also determined during a dystonic attack, which was induced by mild stress. Cytochrome oxidase was determined in 109 brain regions of dystonic hamsters and non-dystonic, age-matched control hamsters. In the absence of a dystonic attack, a tendency to decreased cytochrome oxidase activity was found in most brain regions, possibly due to retarded brain development in mutant hamsters. Significant decreases in cytochrome oxidase activity were found in motor areas and limbic structures, such as hippocampus, piriform cortex, fundus striatum, globus pallidus, substantia nigra pars reticulata, mediodorsal nucleus of the thalamus, ventral pallidum, and interpositus nucleus of the cerebellum. After induction of a dystonic attack, the trend of decreased cytochrome oxidase activity disappeared, except in globus pallidus and interpositus nucleus of the cerebellum. Although the significant alterations in cytochrome oxidase activity in the absence of a dystonic attack were moderate, the data are in line with previous findings in the mutant hamsters, indicating that dysfunctions of the basal ganglia and their output nuclei are involved in the dystonic condition. Altered neural activity in limbic structures, found in the absence of dystonic attacks in mutant hamsters, may contribute to the stress-susceptibility of the animals.

Animals↗
PubMed1998

Autosomal recessive spastic ataxia of Charlevoix-Saguenay.

A form of autosomal recessive spastic ataxia unique to the Charlevoix-Saguenay area was clinically identified 20 years ago in patients from that region. This region of Québec, Canada, was once considered a genetic isolate. First noted at gait initiation, signs of ataxia slowly progress along with spasticity of the four limbs, slurred speech, and followed by distal amyotrophy. Early diagnosis relies on the presence of prominent myelinated fibers embedding retinal blood vessels at funduscopy and marked saccadic alteration of ocular smooth pursuit. Imaging of the posterior fossa shows cerebellar vermis atrophy and nerve conduction studies reveal loss of sensory and reduced motor conduction velocities. The clinical features are consistent with a developmental defect in myelination of both retinal and peripheral nerve fibers. The cause of this defect and the progressive axonal degeneration in the corticospinal and spinocerebellar tracts, as well as in the peripheral nerves is still unknown. Results of recent molecular genetic linkage analysis have located the gene locus to chromosome 13q12. Further research is needed to define where this hereditary spastic ataxia stands in the classification of the early onset spinocerebellar degenerations.

Ataxia↗
PubMed1998

GAA instability in Friedreich's Ataxia shares a common, DNA-directed and intraallelic mechanism with other trinucleotide diseases.

We show that GAA instability in Friedreich's Ataxia is a DNA-directed mutation caused by improper DNA structure at the repeat region. Unlike CAG or CGG repeats, which form hairpins, GAA repeats form a YRY triple helix containing non-Watson-Crick pairs. As with hairpins, triplex mediates intergenerational instability in 96% of transmissions. In families with Friedreich's Ataxia, the only recessive trinucleotide disease, GAA instability is not a function of the number of long alleles, ruling out homologous recombination or gene conversion as a major mechanism. The similarity of mutation pattern among triple repeat-related diseases indicates that all trinucleotide instability occurs by a common, intraallelic mechanism that depends on DNA structure. Secondary structure mediates instability by creating strong polymerase pause sites at or within the repeats, facilitating slippage or sister chromatid exchange.

Alleles↗
PubMed1998

Galactosylononitol and stachyose synthesis in seeds of adzuki bean. Purification and characterization of stachyose synthase.

Stachyose synthase (STS) (EC 2.4.1.67) was purified to homogeneity from mature seeds of adzuki bean (Vigna angularis). Electrophoresis under denaturing conditions revealed a single polypeptide of 90 kD. Size-exclusion chromatography of the purified enzyme yielded two activity peaks with apparent molecular masses of 110 and 283 kD. By isoelectric focusing and chromatofocusing the protein was separated into several active forms with isoelectric point values between pH 4. 7 and 5.0. Purified STS catalyzed the transfer of the galactosyl group from galactinol to raffinose and myo-inositol. Additionally, the enzyme catalyzed the galactinol-dependent synthesis of galactosylononitol from D-ononitol. The synthesis of a galactosylcyclitol by STS is a new oberservation. Mutual competitive inhibition was observed when the enzyme was incubated with both substrates (raffinose and ononitol) simultaneously. Galactosylononitol could also substitute for galactinol in the synthesis of stachyose from raffinose. Although galactosylononitol was the less-efficient donor, the Michaelis constant value for raffinose was lower in the presence of galactosylononitol (13.2 mm) compared with that obtained in the presence of galactinol (38.6 mm). Our results indicate that STS catalyzes the biosynthesis of galactosylononitol, but may also mediate a redistribution of galactosyl residues from galactosylononitol to stachyose.

Amino Acid Sequence↗