Biomedical subjects

W Günther

Publications and source records attributed to W Günther.

At least 19 recordsLinked to original sources

PubMed2005

[Differential indications for atypical neuroleptics: Amisulprid, Clozapin, Olanzapin, Quetiapin und Risperidon. Results of a pilot study of prescription habits in psychiatric clinical usage in the BRD].

With the introduction of atypical neuroleptics, the therapy of schizophrenia has been improved by a group of antipsychotic substances characterized by better tolerability concerning extrapyramidal side effects and higher efficiency against negative symptoms. However, these atypical antipsychotics are not a homogeneous class of drugs but rather represent a group of substances with very different neurobiologic, pharmacologic, and clinical features. This fact and the growing variety of available atypical neuroleptics illustrate the difficulty in choosing the "right" antipsychotic drug for each patient. The aim of this investigation was to evaluate preliminary empirical data for possible differential indication of atypical neuroleptics by a questionnaire-based survey of 192 physicians in ten psychiatric hospitals active in the biological psychiatry work group of the German Federal Directors' Conference.

Antipsychotic Agents↗

PubMed2003

Molecular approaches to brain tumour invasion.

In glioma cells, the stimulatory input of extracellular matrix components and an increased sensitivity to growth factors result in a high proliferative and migratory behaviour. Cell surface receptor interactions play pivotal roles in converging information about conditions in the environment immediately outside the cell. The transduced signal, in turn induces a response within the cell that provokes a specific behaviour. Cellular migration and cell proliferation are interwoven processes that share several common intracellular pathways. The major cross-links are the phosphoinositol phosphate regulating enzymes, PI-3 kinase and PTEN, the focal adhesion kinase (FAK) and the tumour suppressor p53. An understanding of the interaction between the molecular participants involved in migration and proliferation will promote the design of new treatments. A full understanding of the basis of the invasiveness of tumour cells remains elusive. Gene and protein expression are being studied, using modern techniques such as microarray analysis, SAGE and 2-D protein gels. Transient and permanent protein-protein interactions and recruitment of proteins to specialised cellular domains are equally important in regulating cellular invasion and presumably will attract more attention in future.

Animals↗

PubMed2003

Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids.

Temozolomide is an alkylating cytostatic drug that finds increasing application in the treatment of melanoma, anaplastic astrocytoma and glioblastoma multiforme. The compound is a prodrug that decomposes spontaneously, independent of an enzymatic activation step. DNA methylation induces futile mismatch repair cycles and depletion of the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase should then initiate programmed cell death. We show drug-dependent inhibition of tumour growth in a three-dimensional cell culture model of the glioma cell lines U87MG and GaMG. Migrational behaviour of the glioblastoma cells remained unaltered. However, coincubation of tumour spheroids with primary brain aggregates showed reduced tumour cell invasion into brain tissue in the presence of temozolomide. This was not achieved by slowing cellular migration, as temozolomide-treated cells displayed no reduced motility. By transferase-mediated dUTP nick-end labelling (TUNEL) of apoptotic nuclei, we found that the drug was able to induce apoptosis throughout the tumour cell spheroids. Apoptosis was highest in the core region of the spheroids. Repetitive application of sublethal doses of temozolomide to multicellular spheroids resulted in the development of drug resistance in GaMG cells. We suggest that temozolomide is a strong initiator of apoptosis in glioblastoma tumour cells in a spheroid cell culture system, when cells are already in a stressful environment.

Antineoplastic Agents, Alkylating↗

PubMed2003

Dose-dependent effects of in vivo antithymocyte globulin during conditioning for allogeneic bone marrow transplantation from unrelated donors in patients with chronic phase CML.

We conducted a dose-escalation study with antithymocyte globulin (ATG) in patients undergoing unrelated donor bone marrow transplantation (URD-BMT). This study analyzes the results for 97 patients with chronic myelogenous leukemia (CML) in first chronic phase. Median age was 36 years (16-51). In all, 40 patients were transplanted within 2 years after diagnosis and 57 later during disease. ATG-S (Fresenius) 20-120 mg/kg body weight (b.w.) was given prior to transplantation. A total of 31 patients received less than 60 mg/kg b.w. and 66 patients received 60 mg/kg b.w. or more. All patients except one were grafted with bone marrow, and graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporin A and methotrexate. Graft failure did occur in one patient. Grade II-IV acute GVHD developed in 56.7% and extensive chronic GVHD in 11.3% of the patients. The relapse rate was 13.4%. With a median follow-up of 5.8 years (1.5-12.1), 5-year disease-free and overall survival for all patients were 56 and 66%, and for patients transplanted within 2 years of diagnosis it was 72 and 82%. A lower dose of ATG was a significant risk factor for poor outcome. In summary, URD-BMT remains an excellent treatment option for patients with early phase CML, if a sufficient amount of ATG is included in the preparative regimen.

Adolescent↗

PubMed2002

New concepts about graft-versus-host and graft-versus-leukaemia-reactions. A summary of the 5th International Symposium held in Munich, 21 and 22 March 2002.

The Fifth International Symposium on Graft-versus-Host and Graft-versus-Leukemia Reactions was held on 21 and 22 March 2002 in the University Hospital (Klinikum Grosshadern) of the University of Munich. As in previous years, it was dedicated to the encounter of scientists and clinicians involved in hematopoietic cell transplantation. This year's symposium focused on the characterization of stem cells potentially expanding the use of hematopoietic stem cells and on gene therapy. The immunology section dealt with mechanisms of tolerance, and the characterization of minor histocompatibility antigens presented by major histocompatibility molecules. Further important topics were cytokines and dendritic cells. In 1 and 1/2 days of intense work, the invited speakers, chairmen, authors and an active audience experienced an exciting exchange of ideas and collaboration. Again, new impulses were given for basic research and clinical transplantation. The authors would like to express their deep appreciation and thanks to all participants of this symposium.

Animals↗

PubMed2002

Real-time-MR guidance for placement of a self-made fully MR-compatible atrial septal occluder: in vitro test.

PURPOSE: This in vitro study investigated the feasibility to visualize the placement of three different atrial septal occluder systems using real-time MR control. METHODS: The experiments were performed on an interventional 1.5 T high field whole body system. Real-time MR imaging was achieved by radial or spiral k-space filling in conjunction with the sliding window reconstruction technique yielding an imaging speed of 15 frames per second. The CardioSeal, Amplatzer Septal Occluder and a specially designed MR-compatible closure device were tested in a water bath. A punctured plastic wall served as model for the atrial septal defect. RESULTS: The delivery systems of the CardioSeal and Amplatzer Occluder were ferromagnetic and caused substantial artifacts, making the device placement impossible, even if the magnetic forces would have been acceptable. The self-made prototype caused only minor susceptibility artifacts allowing its visualization on the MR images. The MR imaging techniques applied enabled real-time control of the occluder including steering through the artificial septal foramen and visualization of the occluder deployment. CONCLUSION: Real-time MR imaging allows for guidance and placement of an MR-compatible septal occluder in vitro suggesting the feasibility to perform atrial septal occlusion under MR-guidance in vivo as well.

Heart Atria↗

PubMed2001

Bis(1,3,4-thiadiazolo)-1,3,5-triazinium halides. 2. Intramolecular ring transformation and synthesis of novel highly substituted guanidines.

Bis(1,3,4-thiadiazolo)-1,3,5-triazinium halides 6 can be easily attacked by nucleophiles at either the C(3a) or the C(4a) position of the central six-membered (cationic) ring. Nucleophilic attack leads to at least two reaction channels, one of which has been previously detected (pathway a) and leads to novel aminals 19. In this paper we report on a second channel (pathway b). Attack of primary or secondary amines 8 at C(3a) or C(4a) in 6 (and their analogues 7) leads to the weakly stabilized intermediates 14. A cascade of several proton shifts, ring openings, rearrangements, and ring closure processes is initiated which finally leads via 17 and 18 to novel highly substituted guanidines 9, 10, 12, and 13. Pathway b seems to be the result of well-balanced negative-hyperconjugative effects in 14 and/or 17 which control the highly selective opening of a relatively stable central 1,3,5-triazinium ring to yield the crucial intermediate 18. Some representatives of the guanidines have been characterized by X-ray analyses. Since some of the guanidines contain one or two chirality centers, an effort was made to investigate the stereochemistry of these compounds.

Journal Article↗

PubMed2001

Biosynthesis of the bicycloalternarenes, mixed terpenoids of Alternaria alternata.

By incorporation of [2-13C]-mevalonate, [1-13C]-acetate and [1-13C]-glucose we could reveal that the phytopathogenic fungus Alternaria alternata biosynthesized the mixed terpenoids bicycloalternarenes via the classic mevalonate pathway. The polyketid pathway does not participate in the biosynthesis of bicycloalternarenes, because there is no incorporation of [13C]-acetate into the C-ring of these compounds. The labelling pattern in this nonterpenoid part of bicycloalternarenes after feeding with [1-13C]-glucose and [U-13C6]-glucose, respectively, allows the assumption that metabolites of the shikimate pathway are involved.

Acetates↗

PubMed2001

Regioselective functionalization of starch: synthesis and 1H NMR characterization of 6-O-silyl ethers.

A high regioselective 6-O silylation of starch by using thexyldimethylchlorosilane (TDSCl, chlorodimethyl-(2,3-dimethylbut-2-yl)silane) as bulky silylating agent in the reaction system N-methylpyrrolidone (NMP)/ammonia was carried out and investigated. The control of the degree of substitution (DSSi), the control of the regioselectivity, and the control of the reaction pathway are described in detail. After peracetylation of the silyl ethers of starch, the distribution of the silyl and acetyl substituents was characterized not only in the anhydroglucose repeating units (AGU) but also in the nonreducing end groups (NEG) by means of multidimensional 1H NMR techniques. In both cases, the silyl substituents were detected exclusively in the 6-O position, and the acetyl groups in the 2-O and 3-O positions of the AGU and in the 2-O, 3-O, and 4-O positions of the NEG, respectively. The described 6-O-thexyldimethylsilyl (TDS) units are potentially protecting groups of the primary OH position of starches.

Acetylation↗

PubMed2001

Tissue distribution and subcellular localization of the ClC-5 chloride channel in rat intestinal cells.

ClC-5 is the Cl- channel that is mutated in Dent's disease, an X-chromosome-linked disease characterized by low molecular weight proteinuria, hypercalciuria, and kidney stones. It is predominantly expressed in endocytically active renal proximal cells. We investigated whether this Cl- channel could also be expressed in intestinal tissues that have endocytotic machinery. ClC-5 mRNA was detected in the rat duodenum, jejunum, ileum, and colon. Western blot analyses revealed the presence of the 83-kDa ClC-5 protein in these tissues. Indirect immunofluorescence studies showed that ClC-5 was mainly concentrated in the cytoplasm above the nuclei of enterocytes and colon cells. ClC-5 partially colocalized with the transcytosed polymeric immunoglobulin receptor but was not detectable together with the brush-border-anchored sucrase isomaltase. A subfractionation of vesicles obtained by differential centrifugation showed that ClC-5 is associated with the vacuolar 70-kDa H+-ATPase and the small GTPases rab4 and rab5a, two markers of early endosomes. Thus these results indicate that ClC-5 is present in the small intestine and colon of rats and suggest that it plays a role in the endocytotic pathways of intestinal cells.

Animals↗

PubMed2000

ClC-5 Cl- -channel disruption impairs endocytosis in a mouse model for Dent's disease.

Dent's disease is an X-linked disorder associated with the urinary loss of low-molecular-weight proteins, phosphate and calcium, which often leads to kidney stones. It is caused by mutations in ClC-5, a renal chloride channel that is expressed in endosomes of the proximal tubule. Here we show that disruption of the mouse clcn5 gene causes proteinuria by strongly reducing apical proximal tubular endocytosis. Both receptor-mediated and fluid-phase endocytosis are affected, and the internalization of the apical transporters NaPi-2 and NHE3 is slowed. At steady state, however, both proteins are redistributed from the plasma membrane to intracellular vesicles. This may be caused by an increased stimulation of luminal parathyroid hormone (PTH) receptors owing to the observed decreased tubular endocytosis of PTH. The rise in luminal PTH concentration should also stimulate the hydroxylation of 25(OH) vitamin D3 to the active hormone. However, this is counteracted by a urinary loss of the precursor 25(OH) vitamin D3. The balance between these opposing effects, both of which are secondary to the defect in proximal tubular endocytosis, probably determines whether there will be hypercalciuria and kidney stones.

Animals↗

PubMed2000

Increased anti-streptococcal antibodies in patients with Tourette's syndrome.

Infection or postinfectious phenomena have been postulated to play a role in the pathogenesis of children afflicted with the typical symptoms of Tourette's syndrome (TS). We investigated whether an increase of titers of antistreptococcal antibodies can be reproduced in our children with TS, and whether this increase is restricted to children. We examined the titers of two different antistreptococcal antibodies, antistreptolysin (ASL) and anitDNase B, both in children and adults. Titer s of ASO and antiDNase B were measured (1) in 13 children/adolescents suffering from TS and in an aged-matched comparison group;(2) in 23 adult patients, a comparison group of 23 aged-matched controls, and in another group of 17 aged-matched, non-medicated acute schizophrenics. ASO and antiDNase B titers were determined by laser nephelometry using a commercially available kit. Two antistreptococcal cut-off levels were compared (> 250 U/ml and 400 U/ml). As expected, increases ASO titers (>400 IU/ml) were found in a higher portion of children/adolescents with TS compared to controls. Regarding adults, titers >250 U/ml for both antistreptococcal antigens were found in significantly more TS patients than in schizophrenic patients or healthy control subjects. The mean values of ASO and antiDNase titers were significantly higher in both groups of TS patients compared to control children/adolescents, to the comparison groups of healthy adults and to schizophrenics. No difference in antistreptococcal titers was found between schizophrenics and the group of healthy adults. TS patients exhibited higher antistreptococcal titers than age-matched comparison groups of both children/adolescents and adults using different types of calculation. Our findings support the theory that a postinfectious immune mechanism may play a role in the pathogenesis of TS. The mechanism still needs to be elucidated.

Adolescent↗

PubMed2000

Bicycloalternarenes produced by the phytopathogenic fungus Alternaria alternata.

Eleven compounds, ACTG toxins A and B and nine new substances named bicycloalternarenes (BCAs), were isolated and characterized from the culture filtrate of the phytopathogenic fungus Alternaria alternata. Under acidic conditions, these mixed terpenoids convert to pairs of tricycloaltenarenes that can be used for identification of the native compounds. We could not confirm the phytotoxic effects reported with ACTG-toxins in the past. However, BCA 2 at concentrations of 10(-4) M strongly inhibited germination and growth of Spirodela polyrhiza turions.

Alkenes↗

PubMed1999

First-episode schizophrenics show normal duration and topography of quasistationary EEG segments as compared to controls, during rest as well as during active tasks.

In patients suffering from chronic schizophrenia, both altered temporospatial structure of the EEG and impaired activation during cognitive tasks have repeatedly been demonstrated. The present study evaluates whether similar abnormalities are present in drug-naive first-episode schizophrenics. The EEGs of 32 schizophrenic patients and of 52 healthy controls were recorded during a simple and a complicated motor task, a simple and a complicated auditory stimulus, and during resting periods between the tasks. The temporospatial characteristics were evaluated by adaptive segmentation of EEG, which decomposes an EEG into temporal segments of quasistationary activity. No differences in the temporal and topographic aspects of the EEGs were found between the first-episode schizophrenic patients and the controls, neither during the resting EEGs nor during active tasks. Moreover, the dynamic course of the EEGs, defined as the alternation between task-related changes of temporospatial patterns and the reappearance of resting patterns, was identical in patients and controls. The present findings suggest that while abnormal EEG power spectra seem a consistent finding in treated as well as in never-treated schizophrenics, altered temporospatial patterns and reduced task-related EEG changes are inconsistent signs.

Adult↗

PubMed1999

Planning dysfunction in schizophrenia: impairment of potentials preceding fixed/free and single/sequence of self-initiated finger movements.

To test the hypothesis of a planning dysfunction in schizophrenia using a precise temporal definition, the readiness potential (RP), a negative cortical wave preceding self-initiated movements and reflecting motor preparation processes, was studied in patients under stable medication and in controls. The supplementary motor area (SMA), known to be involved in the generation of the RP, has also been implicated in movement selection (fixed versus free) and complexity (single versus sequence). This is the first study using RP for the assessment of the influence of these factors on motor preparation in schizophrenics. Our results show that schizophrenics' RP amplitude is significantly lower than in controls at central and contralateral electrodes. However, RP amplitude increases with task difficulty in both groups, offering important new insight into classical SMA hypoactivation in schizophrenics performing motor tasks. Topographic analysis shows that RP amplitude is, for both groups, significantly higher in sequence than in single movements at fronto-central sites and higher for free than for fixed movements at centro-parietal sites. Finally, RP onset occurs significantly later in schizophrenics than in controls. These results support the view of a motor-preparation and decision-making dysfunction in schizophrenia. They are interpreted within the framework of a fronto-striatal disorder in this disease.

Adult↗

PubMed1999

Synergistic effects of heat and ET-18-OCH3 on membrane expression of hsp70 and lysis of leukemic K562 cells.

We previously reported that cell surface expression of hsp70, the major stress inducible member of the 70-kDa heat shock protein family, is inducible by nonlethal heat as well as by treatment with the membrane-interactive compound alkyl-lysophospholipid 1-octadecyl-2-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3) selectively on human tumor cell lines. Plasma membrane expression of hsp70 increases selectively the sensitivity of tumor cells to lysis and, therefore, might play an important role in the antitumor immune response. Here, we demonstrate that a combined treatment consisting of sublethal heat (41.8 degrees C) and a noncytotoxic concentration of ET-18-OCH3 (25 micrograms/mL) results in a synergistic increase in the amount of cell membrane-bound hsp70 on leukemic K562 cells and on freshly isolated bone marrow of a chronic myelogeneous leukemia (CML) patient, but not on peripheral blood lymphocytes or CD34+ hematopoietic progenitor cells of healthy human individuals. Under these conditions the repopulating capacity of progenitor cells was not influenced. The increased hsp70 membrane expression on leukemic K562 cells results in a significantly increased sensitivity to lysis mediated by natural killer cells. In contrast to leukemic cells, the lysis of peripheral blood lymphocytes and CD34+ progenitor cells that lack expression of hsp70 on their plasma membrane was not negatively influenced by this treatment. A nonspecific disruption of the plasma membrane could be excluded, because treatment with a nontoxic concentration of the detergent Tween20 did not have an influence on hsp70 cell surface expression or on the sensitivity to lysis. Our findings might have further clinical implications with respect to purging of bone marrow from patients suffering from leukemia at sublethal conditions to induce a tumor-selective immune response.

Adult↗

PubMed1999

Interdisciplinary clinical assessment of patients with illness attributed to environmental factors.

Patients with health problems attributed to environmental factors such as chemical pollutants and electromagnetic fields often do not present evidence of an environmental aetiology of their symptoms. It has been postulated, that their problems are due to disorders diagnosed by other medical disciplines, especially allergology and psychiatry. Our study was designed to subject these patients to a comprehensive diagnostic program involving several medical disciplines in order to achieve diagnoses appropriate to explain the patients' symptoms. Fifty patients consecutively referred to the department of environmental medicine in the university hospital of Aachen, Germany, were submitted to the following examinations: (i) environmental medicine (history, clinical examination, biological and/or ambient monitoring for environmental agents); (ii) allergological examination (history, clinical examination, skin tests); (iii) psychiatric examination (psychopathological examination, psychometric and neuropsychological testing). In addition, the patients were examined in other hospital departments according to the symptoms presented. The findings were discussed in case conferences attended by the physicians involved in order to achieve individual diagnoses. The numbers of patients to whom diagnoses were given by different medical disciplines are as follows: psychiatry (32 patients), dermatology (4), allergology (2), neurology (2), rheumatology (2), gynaecology (1), haematology (1). The most frequent mental disorders diagnosed by the psychiatrists were somatoform disorders (19), followed by schizophreniform and delusion disorders (7). In spite of extensive diagnostic efforts, patients with health problems attributed to the environment usually do not present sufficient evidence of an environmental aetiology of their symptoms. On the other hand the symptoms often meet the diagnostic criteria of other diseases, especially of mental disorders.

Adult↗

PubMed1998

ClC-5, the chloride channel mutated in Dent's disease, colocalizes with the proton pump in endocytotically active kidney cells.

Loss-of-function mutations of the ClC-5 chloride channel lead to Dent's disease, a syndrome characterized by low molecular weight proteinuria, hypercalciuria, and kidney stones. We show that ClC-5 is expressed in renal proximal tubule cells, which normally endocytose proteins passing the glomerular filter. Expression is highest below the brush border in a region densely packed with endocytotic vesicles, where ClC-5 colocalizes with the H+-ATPase and with internalized proteins early after uptake. In intercalated cells of the collecting duct it again localizes to apical intracellular vesicles and colocalizes with the proton pump in alpha-intercalated cells. In transfected cells, ClC-5 colocalizes with endocytosed alpha2-macroglobulin. Cotransfection with a GTPase-deficient rab5 mutant leads to enlarged early endosomes that stain for ClC-5. We suggest that ClC-5 may be essential for proximal tubular endocytosis by providing an electrical shunt necessary for the efficient acidification of vesicles in the endocytotic pathway, explaining the proteinuria observed in Dent's disease.

Chloride Channels↗