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Biomedical subjects

G Müller

Publications and source records attributed to G Müller.

At least 235 records · Page 13Linked to original sources
PubMed1996

Characterization of the molecular mode of action of the sulfonylurea, glimepiride, at adipocytes.

The possibility of an insulin-independent blood glucose decreasing activity of sulfonylureas was re-evaluated. Single dose studies in dogs with different sulfonylureas revealed a ranking in the ratio of plasma insulin release/blood glucose decrease with glimepiride exhibiting the lowest and glibenclamide the highest ratio. This ranking suggests that sulfonylureas have extrapancreatic activity and that this is most pronounced for glimepiride. Further evidence for this was derived from single dose studies in rabbits, euglycemic hyperinsulinemic clamp studies in rats and subchronic studies in manifestly diabetic KK-AY mice. Extrapancreatic activity of sulfonylureas as deduced from the ranking in vivo between glimepiride and glibenclamide directly on peripheral tissues would imply a similar ranking between the two drugs in glucose utilizing processes in isolated muscle and fat cells. Indeed, glimepiride exhibits a higher potency compared to glibenclamide with respect to stimulation of glucose transport, glucose transporter isoform 4 (GLUT4) translocation and lipid and glycogen synthesis in normal and insulin-resistant adipocytes and in muscle cells, as well as of the potential underlying signalling processes examined at the molecular level. The molecular basis for the sulfonylurea-induced increase of glucose transport and non-oxidative glucose metabolism may rely on the dephosphorylation of key metabolic proteins/enzymes, like GLUT4 as demonstrated in isolated rat adipocytes. Activation of certain serine/threonine-specific protein phosphatases by insulin has been postulated to be mediated by the mitogen-activated protein kinase (MAPK) pathway and phosphatidylinositol (P1)-3'-kinase. However, there was no evidence that these pathways are involved in the regulation of protein phosphatase activity by sulfonylureas. Binding and photoaffinity studies showed that glimepiride associates in a time- and concentration dependent non-saturable manner with detergent-insoluble complexes of the plasma membrane which may correspond to caveolae. This association seems to be based on the interaction of glimepiride with glycosyl-phosphatidylinositol (GPI) lipids and membrane protein anchors. These were found to be enriched in detergent-insoluble complexes together with a GPI-specific phospholipase (PLC), the caveolae-specific coast protein, caveolin, and acylated tyrosine kinases of the src family. Sulfonylureas were found to stimulate the GPI-PLC and tyrosine phosphorylation of caveolin. This is presumably caused by direct interaction of the sulfonylurea into caveolar glycolipids and stimulation of a caveolar src tyrosine kinase, respectively. In accordance with the higher potency of glimepiride in vivo and in glucose transport/metabolism in vitro, the EC50 values for GPI-PLC activation and caveolin phosphorylation were lower for glimepiride than those for glibenclamide. The stimulation of protein tyrosine phosphorylation by sulfonylureas via this pathway not involving the insulin signaling cascade may be coupled to activation of specific protein phosphatases regulating glucose transport and metabolism. The concentrations required in vitro were higher than the reported therapeutic plasma concentrations. However, provided that the observed time-dependent accumulation of glimepiride in caveolae of peripheral cells were of functional relevance for stimulation of glucose transport/metabolism and would also occur in vivo, due to the longer exposure times even at lower drug concentrations the insulin-independent blood glucose decreasing activity of sulfonylureas might become effective in vivo.

Adipocytes↗
PubMed1996

The spatial variation of the refractive index in biological cells.

With a phase microscope the phase shift of cells from type L 929 fibroblast and mitochondria from liver cells was measured. Compared to the total phase shift caused by the cell relative to vacuum (approximately 1400 nm) the single phase shift of the mitochondria (approximately 180 nm) is small. Only the nucleus and the membrane of the cell give a visibly different phase shift relative to the mean value of the cell. The Fraunhofer diffraction of the measured phase object is calculated. With a simplified scattering theory, i.e. Rayleigh-Gans Scattering, different phase objects are investigated and their differential cross section is discussed.

Animals↗
PubMed1996

Glucose-induced sequential processing of a glycosyl-phosphatidylinositol-anchored ectoprotein in Saccharomyces cerevisiae.

Transfer of spheroplasts from the yeast Saccharomyces cerevisiae to glucose leads to the activation of an endogenous (glycosyl)-phosphatidylinositol-specific phospholipase C ([G]PI-PLC), which cleaves the anchor of at least one glycosyl-phosphatidylinositol (GPI)-anchored protein, the cyclic AMP (cAMP)-binding ectoprotein Gce1p (G. Müller and W. Bandlow, J. Cell Biol. 122:325-336, 1993). Analyses of the turnover of two constituents of the anchor, myo-inositol and ethanolamine, relative to the protein label as well as separation of the two differently processed versions of Gce1p by isoelectric focusing in spheroplasts demonstrate the glucose-induced conversion of amphiphilic Gce1p first into a lipolytically cleaved hydrophilic intermediate, which is then processed into another hydrophilic version lacking both myo-inositol and ethanolamine. When incubated with unlabeled spheroplasts, the lipolytically cleaved intermediate prepared in vitro is converted into the version lacking all anchor constituents, whereby the anchor glycan is apparently removed as a whole. The secondary cleavage ensues independently of the carbon source, attributing the key role in glucose-induced anchor processing to the endogenous (G)PI-PLC. The secondary processing of the lipolytically cleaved intermediate of Gce1p at the plasma membrane is correlated with the emergence of a covalently linked high-molecular-weight form of a cAMP-binding protein at the cell wall. This protein lacks anchor components, and its protein moiety appears to be identical with double-processed Gce1p detectable at the plasma membrane in spheroplasts. The data suggest that glucose-induced double processing of GPI anchors represents part of a mechanism of regulated cell wall expression of proteins in yeast cells.

Carrier Proteins↗
PubMed1996

Phenylguanine found in urine after benzene exposure.

Comparative investigations with synthetic N7-phenylguanine were carried out to clarify whether this compound is eliminated via the urine of rats as a benzene-derived nucleic acid adduct. As sensitive methods for detecting trace amounts of the compound, gas chromatography-mass spectroscopy, high performance liquid chromatography, and two immunoassays (enzyme-linked immunosorbent assay and fluoroimmunoassay) with appropriate monoclonal antibodies were used. The results indicate the excretion of several benzene-related guanine adducts slightly different from N7-phenylguanine that may possibly be hydroxylated. These adducts differ also from (O6-, N2- and C8-phenylguanine, respectively.

Animals↗
PubMed1996

[Development of a measuring set-up for determination of light distribution of scattered light applicators for interstitial laser treatment].

In the medical setting, scattering dome applicators are used in various therapeutic and diagnostic procedures, e.g. laser-induced interstitial thermotherapy. The present study reports on the development of an automatic measuring system for determining the light distribution along the active end of scattering dome applicators. Using a stepper motor, the applicator is gradually moved into an integrating sphere, in which the light intensity is measured with a photodetector. It was shown the light distribution is determined mainly by the conditions under which the laser beam is coupled to the transmission fiber. The results made it possible to optimize the production of applicators, and showed that the set-up was suitable for quality control use.

Equipment Design↗
PubMed1996

Quantitative and qualitative analyses of proteoglycans in cartilage extracts by precipitation with 1,9-dimethylmethylene blue.

The dye 1,9-dimethylmethylene blue may be used for the specific and quantitative precipitation of sulphated glycosaminoglycans as well as proteoglycans from the extracts of articular cartilage. The consumption of the dye DMMB enables to determine the amount of the proteoglycans present in the extract, by measuring the decrease of the absorption at 595 nm. The precipitated complex of DMMB and proteoglycans is used for qualitative investigations into the electrophoretic mobility of the different proteoglycans in agarose slab gel and their immunological characterization after blotting. Because of its higher sensitivity and greater simplicity the method described in this report is a promising alternative to the procedure based on alcian blue.

Animals↗
PubMed1996

[Ischemic colitis after vascular surgery reconstruction of an abdominal aortic aneurysm].

Between 1978 and 1994, a total of 678 patients were operated on for infrarenal (abdominal) aortic aneurysm at the Department of Surgery of Lübeck Medical University. Rupture had occurred in 165 patients, 351 were treated electively, and 162 presented with severe symptoms but no rupture. Only CT, angiography and intraoperative judgement were used for diagnosis. Reconstruction of the inferior mesenteric artery (IMA) was performed only in exceptional cases. Severe ischemic colitis occurred in 1.03% (in no case following elective surgery, in 0.66% of patients presenting with symptoms, and in 3.6% of patients in whom rupture had occurred prior to the operation). Three patients presented with mild ischemia, two with grade B ischemic colitis and three with transmural infarction. One patient had to be operated on for ischemic colitis despite open reconstruction of the IMA. We conclude from our data that there is no need to reconstruct the IMA as a routine procedure; this topic has been a controversial issue in the literature. We do reimplant a patent IMA when there is only oozing from the IMA and/or a borderline perfusion of the sigma following the operation, with at least one open internal iliac artery. When rupture had occurred, reconstruction should be performed if there is the slightest suspicion because of the increased risk, but only if the patient's cardiopulmonary condition allows this to be done. Analysis of our patients with ischemic colitis demonstrates the importance of maintaining stable circulatory conditions to prevent intestinal ischemia. Further diagnostic procedures (Doppler ultrasound, measuring of oxygen saturation or pH) may identify more patients at risk, but at the moment we do not consider these to be routine procedures.

Aged↗
PubMed1996

[Laparoscopic abdomino-perineal rectum excision].

In the department of surgery at the Medical University of Luebeck 10 laparoscopic abdomino-perineal rectum resections were performed within 2 years. Using 3-4 working trocars the intraabdominal dissection of the rectum and sigmoid colon, complete lymphadenectomy with radicular dissection of the inferior mesenteric artery and vein, and dissection of the mesocolon and colon were accomplished. Following a conventional perineal excision the specimen was delivered through the perineal wound. The procedure is finished by establishing a conventional colostomy using the upper left trocar incision. The operation times ranged from 4 to 7.5 hours. The patients--51 to 82 years old--left hospital within 2 weeks after operation. 18 months after operation all patients operated with curative intention were still alive and tumor free except one patient, who died after a heart attack without any recurrent tumor. Two smaller, local stoma complications and one venous bleeding occurred postoperatively. There was no conversion to open surgery caused by intraoperative complications. The abdomino-perineal resection seems to be an ideal indication for laparoscopic surgery, because of its completely intraabdominal preparation, the excellent laparoscopic view into the small pelvis, the oncologic lymphadenectomy and the unproblematic delivery of the specimen.

Aged↗
PubMed1996

[Radiochemotherapy of non-small-cell bronchial carcinoma. A report of experience].

PURPOSE: To investigate the survival of patients with inoperable non-small-cell lung cancer treated with combined radiochemotherapy. Frequency of local progression versus systemic dissemination after radiotherapy respectively radiochemotherapy. Extend of the toxicity of a combined modality treatment. PATIENTS AND METHODS: 60 inoperable patients (42 M0- and 18 M1-stage) with non-small-cell lung cancer who had received combined radiochemotherapy (RT+CT) were examined retrospectively. Different drugs or drug combinations were used. The sequence of radiotherapy and chemotherapy also differed. The survival was compared to that of another group of patients who had received at least 50 Gy with definitive radiotherapy at the same period of time (RT: N = 135). The Karnofsky performance index (KPI) was on an average of 80% in both groups. The primary of patients with systemic disease was treated by radiation when it became symptomatic or when it showed an evident progression. RESULTS: The two investigated treatment groups were comparable regarding KPI, histology, stage, tumor dose and age. The survival was significantly better when chemotherapy was added to radiotherapy. The median survival times in months were as follows: M0: RT 10.6/RT+CT 14.7; M1: RT 6.0/ RT+CT 9.3. Local tumor control was the major problem with or without chemotherapy (local progression of about 70% in both groups). The toxicity of radiochemotherapy was acceptable (bone marrow toxicity WHO-grade 4: 10.5%: nausea WHO-grade 4: 3%). CONCLUSION: In the absence of medical contraindications and with a KPI of at least 70% a combined radiochemotherapy in patients with inoperable non-small-cell lung cancer seems to be possible even if high radiation doses are used. Randomized studies are necessary to prove the impact on survival of an additional chemotherapy.

Adult↗
PubMed1996

[Thermal stress on the inner ear in laser stapedotomy].

Apart from ablation properties at the stapes footplate, the degree of thermal stress of the inner ear is important when considering the suitability of pulsed lasers for stapedotomy. The aim of the present study was to compare the heating of cochlear structures with presently available pulsed laser systems during stapedotomy under reproducible conditions. Temperature increases and heat-exchange processes were examined in a physiologic model of the cochlea using various laser parameters effective for footplate perforations. With all systems, increases in energy density, number of pulses and resultant total energy led to higher temperatures. In the effective energy density range, the highest temperature increases achieved with the requisite number of pulses at a distance of 2 mm behind the footplate perforation were 30 degrees and 26 degrees C with the pulsed CO2 and Ho:YAG lasers, respectively. The lowest temperature recorded was 5.5 degrees C with the Er:YAG and <5 degrees C with the Er:YSGG laser. The excimer laser investigated at only one energy density showed maximum temperatures of 10 degrees C. With regard to possible inner ear damage from thermal stress during laser stapedotomy, the Er:YSGG laser can be used safely over a relatively broad energy density range. The Er:YAG laser investigated also appears suitable for stapedotomy when considering thermal effects. In contrast, application of the pulsed CO2 laser at parameters effective for stapedotomy leads to high temperatures and wide scattering to compromise its use. The Ho:YAG laser also appears to be unsuitable because of the higher energy density and pulse rate required for sufficient perforation and the resultant higher temperature increases in the perilymph. Although footplate perforations can be achieved with only slight temperature increases in the fluid of the cochlea model, the excimer laser does not seem to be appropriate for stapedotomy because of the long period of heat exposure required and the lower ablation rates at the stapes.

Body Temperature↗
PubMed1996

Is cytokine expression responsible for differences between allergens and irritants?

Irritant and allergic contact dermatitis are two very similar diseases, and differentiating between these two can be difficult clinically. Recently, cytokines have been identified as useful tools for differentiation. Thus, our laboratory has identified an early cytokine pattern in the induction phase of contact sensitivity that is specific for allergens and is not found after epicutaneous application of irritants or tolerogens. The up-regulation of the Langerhans' cell-derived signal interleukin (IL)-1 beta early after allergen application especially seems to be highly specific for contact allergens. This cytokine was also found to be essential for the development of epicutaneous sensitization because injection of an anti-IL-1 beta monoclonal antibody before epicutaneous application of an allergen prevented sensitization. Additionally, cytokines also seem to be involved in down-modulating an ongoing inflammatory reaction such as contact sensitivity. IL-10 especially was shown to inhibit the LC accessory functions and to down-modulate inflammatory cytokines. The homeostasis of proinflammatory and counterregulatory cytokines and their clinical implications are discussed in this review.

Allergens↗
PubMed1996

[Indications and results of surgically treated, with temporary vena cava filter managed patients].

Heavily injured patients, patients who underwent operations on pelvis, hips, abdomen or malignoma surgery, as well as gynaecology patients suffering from malignoma or previous deep femoral vein thrombosis in connection with pregnancy or obesity are at risk to suffer from pulmonary embolism with potentially lethal course. In a retrospective study we evaluated the advantage of the prophylactic use of temporary vena cava filters and their side effects. The indications were 18 cases of surgery, with known iliacal vein or cava thrombosis, 3 cases of pregnancy thromboses, and 1 high-dose heparinisation after acute pulmonary embolism without lysis. Additionally a postoperative lysis therapy was performed due to a life-threatening pulmonary embolism in 1 patient. 1 Cook filter (transfemoral), 3 Angiocor filters (transbrachial), and 19 Antheor filters (3 transjugular, 5 transfemoral, 11 transbrachial) were implanted. In these patients no clinically visible pulmonary embolism occurred under therapy, 3 thrombi were detected in the filter. Complications were caused either by the underlying therapy alone (1 lethal outcome of abdominal aortic aneurysm surgery), by the combination of therapy and cava filter implantation (1 case of arm haematoma, 1 ascending thrombosis) or by filter implantation alone (2 cases of v. subclavia thrombosis, 1 dislocation, 1 basket rupture). Since temporary cava filters have no secondary complications per se, their use seems justified as long as there is strict indication including presence of iliacal vein or cava thrombosis and risk of thrombi mobilisation.

Abdominal Neoplasms↗
PubMed1996

[Laparoscopy in diagnosis and therapy of advanced abdominal malignancies].

Fifty-seven patients with abdominal and retroperitoneal malignancies were examined by laparoscopy mainly to establish operability (n = 29), to gain histology (n = 20), or to carry out laparoscopic (assisted) palliative procedures. Early explorative laparoscopy is recommended if large tumours, ascites or metastases are suspected because of the high sensitivity in confirming inoperability.

Abdominal Neoplasms↗
PubMed1996

Induction of connexin 32 expression by potential embryonic signals in rabbit uterine epithelium.

Connexin 32 induction is found in rabbit uterine epithelium as a response to embryo recognition. Here we have chosen this connexin 32 expression as a cell biological marker to define the type of a locally acting embryonic signal. 17 beta-estradiol, onapristone, catechol estrogen (4-hydroxy-estradiol), prostaglandins E2 and F2 alpha, db-cAMP, and glass beads as mechanical stimuli were given to pseudopregnant animals on day 4, 5 or 6 posthuman chorionic gonadotropin (hCG). The induction of connexin 32 corresponded to the time of implantation at days 6-8 post-hCG by immunohistochemistry and Northern blot analysis. Untreated pseudopregnant animals started to express connexin 32 on day 8 post-hCG. In animals treated with 4-hydroxy-estradiol, 17 beta-estradiol or prostaglandins, connexin 32 expression started 1 day earlier (day 7 post-hCG) and led to an enhanced connexin 32 expression on day 8 post-hCG compared to control animals. The antigestagen, onapristone, as well as cAMP did not alter the endogenous program. Mechanical stimuli led to a high expression of connexin 32 starting at day 7 post-hCG whereas in pregnancy the blastocyst induces connexin 32 expression from day 6 postcoitum onwards. Combination of mechanical stimuli with 17 beta-estrogen advanced the induction to day 6 post-hCG. We conclude that a mechanical stimulus in combination with 17 beta-estradiol induces connexin 32 synthesis in a similar manner as compared to the blastocyst during pregnancy.

Animals↗
PubMed1995

Glucose induces amphiphilic to hydrophilic conversion of a subset of glycosyl-phosphatidylinositol-anchored ectoproteins in yeast.

Previously, we have studied the lipolytic cleavage of a glycosyl-phosphatidylinositol (GPI)-anchored plasma membrane protein in yeast in response to a physiologically relevant external signal, i.e., transfer of spehroplasts from lactate to glucose medium (cf. Müller and Bandlow (1993) J. Cell. Biol. 122, 325-336). In the present study the glucose-induced lipolytic processing of myo-[14C]inositol-labeled total GPI proteins of the plasma membrane and in particular of two such proteins, Gas1p and Gce1p, was examined in yeast spheroplasts. It was found that a small number of GPI proteins, among them Gce1p, are readily cleaved, whereas Gas1p and the majority of the GPI proteins are relatively little affected. Glucose-induced processing of Gce1pcould be demonstrated also in intact cells. Increased GPI cleavage after exposure of cells or spheroplasts to glucose is not due to stimulation of cell surface expression of Gce1p, as the amount of total GPI-anchored Gce1p bound to plasma membranes is comparable in cells grown in glucose or lactate. In agreement with this, Brefeldin A added together with the label blocks transport of newly made Gce1p to the cell surface and, in the consequence, cleavage of labeled Gce1p in spheroplasted yeast cells. (The drug is ineffective in intact cells). On the other hand, Brefeldin A does not significantly affect glucose-induced processing of inositol-labeled Gce1p at the plasma membrane when present during the period of nutritional upshift. We discuss that addition of glucose to the cells leads to the activation of a GPI-specific phospholipase which accepts only a subset of GPI proteins as substrates. This interpretation is additionally corroborated by the finding that purified [14C]inositol-labeled Gcep1p is lipolytically cleaved when incubated with Triton X-100-insoluble membrane complexes isolated from glucose-induced but not from uninduced spheroplasts. It is concluded that the phospholipase is present in these complexes and its state of activity is preserved during the preparation. GPI anchor cleavage in yeast appears to resemble strikingly the situation in insulin-responsive adipocytes subsequently to stimulation by insulin of glucose transport into these cells.

Biological Transport↗
PubMed1995

IL-12 as mediator and adjuvant for the induction of contact sensitivity in vivo.

To determine whether IL-12 serves as a regulator of contact sensitivity reactions, mice were painted with either 1.0% trinitrochlorobenzene or 0.5% dinitrofluorobenzene on abdominal skin. At various time points thereafter, regional lymph nodes or spleens were prepared for RNA extraction, and the signals for IL-12 p35 and p40 chain were sought by quantitative reverse transcriptase-PCR. Time course analysis showed a constitutive expression of p35 chain mRNA signals throughout the experiment (0 to 72 h), whereas the signal for the p40 chain was transiently induced in lymph node and spleen cells after 12 to 14 h. Cellular depletion experiments and double label in situ hybridization studies showed that dendritic cells were sources for a major part of the p40 chain message. The presence of functional IL-12 in culture supernatants was indirectly assessed by addition of anti-IL-12 antiserum and analysis of IFN-gamma production. Significant amounts of IFN-gamma could only be detected in supernatants of allergen-treated animals. Addition of anti-IL-12 antiserum inhibited IFN-gamma production by about 55%. In a further attempt to assess the role of IL-12 in contact sensitivity, anti-IL-12 antiserum was injected i.p. into mice, and ear swelling responses were assessed following challenge. Injection of anti-IL-12 antiserum significantly reduced ear swelling responses by 85%. Thus anti-IL-12 treatment almost completely prevented sensitization. To assess whether IL-12 would be able to overcome in vivo tolerance, UV-tolerized animals were treated with i.p. IL-12 in a contact allergy system. Treatment of mice with IL-12 not only prevented tolerance induction, but was able to reverse UV-induced tolerance. In aggregate, our data point to an important role for IL-12 as a mediator and adjuvant for the induction of contact sensitivity in vivo.

Adjuvants, Immunologic↗