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Biomedical subjects

G Müller

Publications and source records attributed to G Müller.

At least 127 records · Page 7Linked to original sources
PubMed2000

[Diagnosis and therapy of non-occlusive mesenteric ischemia (NOMI)].

Pathophysiologically, the non-occlusive mesenteric ischemia (NOMI) results from reduced blood supply to the intestine, caused by "low cardiac output syndrome", or the use of certain drugs leading to intestinal vasoconstriction and stasis of the microcirculation. Regardless of the aetiopathogenesis, the patient's prognosis crucially depends on rapid diagnosis and initiation of adequate medical or surgical intervention. In a 10-year retrospective chart analysis (1989 to 1998) we identified a total of 62 patients that demonstrated classical features of NOMI. The investigation focused on patients' history, risk factors, clinical symptoms, diagnostic procedures and patient's clinical outcome. The most important associated risk factors and concomitant diseases were reduced cardiac output (caused by preexisting heart failure), renal diseases, diabetes and the use of some specific drugs (digitalis, furosemide, ergotamine). Except for leucocytosis, elevated serum lactate and an increased CK/CK-MB level, all laboratory findings were unspecific. Using abdominal ultrasound and plain abdominal x-ray, 80% of the cases showed positive signs of ileus, subileus and free intraabdominal fluid. The angiographic diagnostics (mesentericography) of non-occlusive mesenteric ischemia showed the typical signs of peripheral vasoconstriction in 90% of the cases. Fifty three patients (86%) presenting with peritoneal signs underwent operative bowel exploration. Necrotic bowel had to be resected in 37 cases (60%). The overall letality was 58%. The progress made in better understanding the pathophysiology of NOMI has led to differential treatment of the disease. Close cooperation between surgeons and radiologists, coupled with early diagnosis and prompt treatment are necessary to optimize the clinical outcome.

Aged↗
PubMed2000

Epstein-Barr virus infection in peripheral blood mononuclear cells, synovial fluid cells, and synovial membranes of patients with rheumatoid arthritis.

OBJECTIVE: Different infectious agents have been proposed to be involved in the pathogenesis of rheumatoid arthritis (RA). We investigated the role of latent Epstein-Barr virus (EBV) infection in patients with RA. METHODS: Sera of 55 patients with RA and 60 age and sex matched healthy controls were examined for antibodies against EBV encoded antigens (EBNA-1, VCA, and EA) by ELISA. The presence of viral DNA was analyzed by polymerase chain amplification of DNA isolated from peripheral blood mononuclear cells (PBMC) of these samples and from cells of synovial fluid (SF) specimens. Paraffin sections of synovial membranes from 25 patients were subjected to in situ hybridization analysis for the EBV encoded small RNA EBER1 and EBER2. RESULTS: Two-fold increased values of IgG antibodies against EBNA-1 were found in patients with RA in comparison to healthy controls (p = 0.029). No statistically significant difference could be observed for antibody levels against EBV-VCA. Fourteen (24.1%) of 55 patients with RA had serological evidence of reactivated EBV infection in comparison to none of the control group (p = 0.028). In PBMC, EBV DNA was detected in a significantly higher proportion in the patient group (50.9 vs. 30%; p = 0.02). In addition, SF cells harbored the viral DNA in 30% of RA cases compared to 16.6% of control cases (p = 0.02). However, EBER1/2 transcripts could only be found within synovial membranes of 2 (8%) of 25 patients with RA. CONCLUSION: These findings support the hypothesis that EBV infection may be involved in the pathogenesis of RA. Further studies may define the precise pathogenetic mechanisms of viral infection for the development of inflammatory arthritis.

Adolescent↗
PubMed2000

The molecular mechanism of the insulin-mimetic/sensitizing activity of the antidiabetic sulfonylurea drug Amaryl.

The hypoglycemic sulfonylurea drugs cause reduction of blood glucose predominantly via stimulation of insulin release from pancreatic beta cells. In addition, during long-term treatment, an insulin-independent blood glucose-decreasing mechanism is assumed to operate. This may include insulin-sensitizing and insulin-mimetic activity in muscle and adipose tissue. This review summarizes our current knowledge about the putative modes of action of the sulfonylurea compound, Amaryl, in pancreatic beta cells and, in particular, peripheral target cells that form the molecular basis for its characteristic pharmacological and clinical profile. The analysis was performed in comparison with the conventional and the "golden standard" sulfonylurea, glibenclamide. I conclude: (I) The blood glucose decrease provoked by Amaryl can be explained by a combination of stimulation of insulin release from the pancreas and direct enhancement, as well as potentiation of the insulin response of glucose utilization in peripheral tissues only. (II) The underlying molecular mechanisms seemed to rely on beta cells on a sulfonylurea receptor protein, SURX, associated with the ATP-sensitive potassium channel (K(ATP)) and different from SUR1 for glibenclamide, and in muscle and adipose cells on: (a) the increased production of diacylglycerol and activation of protein kinase C; (b) the enhanced expression of glucose transporter isoforms; and (c) the insulin receptor-independent activation of the insulin receptor substrate/phosphatidylinositol-3-kinase pathway. (III) The latter mechanism involved a nonreceptor tyrosine kinase and a number of components, such as caveolin and glycosylphosphatidylinositol structures, which are assembled in caveolae/detergent-insoluble glycolipid-enriched rafts of the target cell plasma membrane. Since hyperinsulinism and permanent K(ATP) closure are supposed to negatively affect the pathogenesis and therapy of non-insulin-dependent diabetes mellitus, the demonstrated higher insulin-independent blood glucose-lowering activity of Amaryl may be therapeutically relevant.

Amino Acid Sequence↗
PubMed1999

Insulin selectively activates STAT5b, but not STAT5a, via a JAK2-independent signalling pathway in Kym-1 rhabdomyosarcoma cells.

The STAT multigene family of transcriptional regulators conveys signals from several cytokines and growth factors upon phosphorylation by janus kinases (JAK). Activation of STAT5 is typically mediated by JAK2, but more recent data indicate a direct activation by the insulin receptor kinase. STAT5 exists in two closely homologous isoforms, STAT5a and b. We here describe the selective tyrosine phosphorylation of STAT5b in Kym-1 cells in response to insulin. Blocking insulin signalling by HNMPA-(AM)(3), an insulin receptor kinase inhibitor, resulted in the loss of insulin-induced STAT5b tyrosine phosphorylation, whereas the inhibition of JAK2 by the JAK selective inhibitor tyrphostin AG490 had no effect. By contrast, in the same cells, IFNgamma-induced STAT5b activation was JAK2-dependent, indicating that this signal pathway is functional in Kym-1 cells. We conclude from this rhabdomyosarcoma model that STAT5b, but not STAT5a is a direct target of the insulin receptor kinase.

DNA-Binding Proteins↗
PubMed1999

A cellular reporter assay to monitor insulin receptor kinase activity based on STAT 5-dependent luciferase gene expression.

A highly sensitive method for determination of insulin receptor (IR) kinase activity in whole cells, which is based on a STAT5 (signal transducer and activator of transcription 5)-dependent reporter gene assay, has been developed. We show in Rat1 fibroblasts stably overexpressing the human IR (Rat1-HIR-cl5) an insulin-dependent direct association and phosphorylation of STAT5b by IR kinase. Rat1-HIR cells transfected with a luciferase gene reporter construct under control of a STAT5-inducible promoter showed insulin-mediated induction of STAT5-dependent luciferase activity, with peak activities around 8 h of insulin treatment over a wide dose range. Transient STAT5b but not STAT5a cotransfection significantly enhanced reporter gene activity, yielding up to a fivefold induction. Addition of the IR kinase inhibitor tyrphostin AG1024 down-regulated luciferase induction in a dose-dependent manner. This is the first assay allowing determination of IR kinase activity in intact cells in a 24-well culture and a microtiter format. Kinetics of this cellular response, sensitivity range, and signal amplitude make it well suited for automation and offer the potential for establishing high-throughput screening systems for both insulin mimetic substances and IR kinase antagonists in a simple nonradioactive assay.

Animals↗
PubMed1999

Hodgkin/Reed-Sternberg cells induce fibroblasts to secrete eotaxin, a potent chemoattractant for T cells and eosinophils.

Hodgkin's disease is histopathologically characterized by the relative scarcity of neoplastic Hodgkin and Reed-Sternberg cells and for yet unknown reasons by an abundant reactive background of T lymphocytes and often eosinophils. Eotaxin is a CC-chemokine attracting eosinophils and T helper 2 (Th2) cells in allergic inflammation. We now report that eotaxin is strongly expressed in fibroblasts of Hodgkin's disease tissues, whereas Hodgkin/Reed-Sternberg cells do not express this chemokine. In tissue culture, Hodgkin's disease tumor cells induce eotaxin expression in cocultured dermal fibroblasts in a concentration leading to a specific chemotactic response of a Th2 cell clone. Production of tumor necrosis factor-alpha (TNF-alpha) by Hodgkin/Reed-Sternberg cells appears to be responsible for this induction, because blocking of TNF-alpha by neutralizing antibodies prevented fibroblast eotaxin expression. Our data suggest that eotaxin is involved in the pathobiology of Hodgkin's disease by contributing to eosinophil and T-lymphocyte recruitment.

Cells, Cultured↗
PubMed1999

[Sentinel node biopsy in breast cancer--a minimally invasive procedure for staging of the axilla].

Clinical examinations and imaging methods are not sufficiently reliable for an exact staging of axillary nodes in breast cancer. The sentinel node biopsy concept is a minimally invasive procedure to locate and remove the first and important nodes responsible for draining a tumor. Histologic examinations using immunohistochemical methods permit more accurate staging than hematoxylin and eosin staining alone. Between 4/1997 and 9/1998 a total of 62 patients with 65 breast cancers underwent surgery. The sentinel node procedure with radio tracers and/or blue dye was performed in patients with clinically negative or unclear positive findings in the axilla, with a primary tumor size less than 5 cm; 11 patients had received preoperative chemotherapy. The sentinel node biopsy was followed by axillary dissection in 44 cases. In 58 (89%) cases we found one or more (on an average 1.4) sentinel nodes with radio tracers (in 73%) and/or the blue dye method (in 85%). Axillary nodal status was correctly predicted in 43 of 44 (97.7%) cases; only in one patient was the sentinel node false negative. After preoperative chemotherapy sentinel nodes were found in 9 cases; all of these were predictive. Micrometastases were found in two patients only after cytokeratine staining. Our results concur with the experience of other study groups in regard of sentinel node biopsy. The sentinel node concept is a fascinating method; its importance in breast cancer treatment appears to be comparable with introduction of breast saving surgery in the 1980's.

Adult↗
PubMed1999

Interleukin-10-treated human dendritic cells induce a melanoma-antigen-specific anergy in CD8(+) T cells resulting in a failure to lyse tumor cells.

Dendritic cells (DC) are critically involved in the initiation of primary immune processes, including tumor rejection. In our study, we investigated the effect of interleukin-10 (IL-10)-treated human DC on the properties of CD8(+) T cells that are known to be essential for the destruction of tumor cells. We show that IL-10-pretreatment of DC not only reduces their allostimulatory capacity, but also induces a state of alloantigen-specific anergy in both primed and naive (CD45RA+) CD8(+) T cells. To investigate the influence of IL-10-treated DC on melanoma-associated antigen-specific T cells, we generated a tyrosinase-specific CD8(+) T-cell line by several rounds of stimulation with the specific antigen. After coculture with IL-10-treated DC, restimulation of the T-cell line with untreated, antigen-pulsed DC demonstrated peptide-specific anergy in the tyrosinase-specific T cells. Addition of IL-2 to the anergic T cells reversed the state of both alloantigen- or peptide-specific anergy. In contrast to optimally stimulated CD8(+) T cells, anergic tyrosinase-specific CD8(+) T cells, after coculture with peptide-pulsed IL-10-treated DC, failed to lyse an HLA-A2-positive and tyrosinase-expressing melanoma cell line. Thus, our data demonstrate that IL-10-treated DC induce an antigen-specific anergy in cytotoxic CD8(+) T cells, a process that might be a mechanism of tumors to inhibit immune surveillance by converting DC into tolerogenic antigen-presenting cells.

Antigen Presentation↗
PubMed1999

Risk assessment of a former military base contaminated with organoarsenic-based warfare agents: uptake of arsenic by terrestrial plants.

Organoarsenic-based chemical warfare agents (CWAs) such as the sternutators diphenylchloroarsine (CLARK I), diphenylcyanoarsine (CLARK II) or phenyldichloroarsine (PFIFFIKUS) still pose a notable risk in countries where former military bases that have stored these weapons have not yet been reclaimed. In fact, this is the case for many countries of Eastern Europe and the CIS. One of the most important military bases of the former Third Reich, the Heeresmunitionsanstalt I and II, is situated close to the German-Polish border at Loecknitz (Fig. 1). The German army stored and decanted different compounds of CWAs at this military base until 1945. When the Soviet Army destroyed the base in 1946, large amounts of CWAs and other organoarsenic compounds polluted the soil. Today up to 250 g (!) of arsenic may be found in 1 kg of soil at some places in this area. Since 1991, a Government Working Group has been working on the risk assessment in order to define the scope of reclamation measures. This study investigates the contamination and the uptake of arsenic by plants because little is known about the bioavailability and metabolism of sternutators and their constituents. The total arsenic concentration of nine different species of terrestrial plants with at least six samples per species is presented. In spite of the considerable arsenic contamination of the soil (mean value 923 mg arsenic/kg soil) the plant contamination remained comparably low. The median value of arsenic contamination of the above-ground organs of velvet grass, Holcus lanatus, was 0.7 mg/kg dry wt. and the mean value was 4.3 mg/kg dry wt. due to some highly contaminated samples. The highest arsenic concentration registered was 26 mg/kg dry wt. in a sample of H. lanatus, which was most probably caused by soil particles adhering to the plant. The chemical structure of the arsenic compounds carried by the above-ground plant organs has been determined by gas chromatographic investigations and showed an uptake of triphenyl arsine by the plants.

Arsenic↗
PubMed1999

The murine chemokine receptor CXCR4 is tightly regulated during T cell development and activation.

We have characterized the murine homolog of the HIV-co-receptor CXCR4 during T cell development and activation. Our data demonstrate that this chemokine receptor, although highly conserved between human and mouse, is differently expressed and regulated in both species. Mitogenic activation resulted in an increase of surface CXCR4 on murine T cells within 2 days, whereas the receptor was strongly down-regulated on human T cells during this period. Furthermore, intraperitoneal immunization of mice resulted in a strong increase of splenic and mesenteric cytotoxic T cells co-expressing CXCR4. It is interesting that, on thymocytes, expression of CXCR4 is restricted to CD4+CD8+ cells. Stromal cell-derived factor-1alpha, a natural ligand of CXCR4, induced chemotaxis of thymocytes and was found to counteract dexamethasone-induced apoptosis to a certain extent in these cells. Thus, our data show that expression of CXCR4 is tightly controlled on murine T cells and indicate that this highly conserved chemokine receptor might serve different functions in humans and mice.

Animals↗
PubMed1999

CombiTool--a new computer program for analyzing combination experiments with biologically active agents.

CombiTool is a new computer program for the analysis of combination effects of biologically active agents. It performs model calculations and an analysis of experimental combination effects for two or three agents according to both the Bliss independence and the Loewe additivity criteria. Zero interaction response surfaces are calculated from single-agent dose-response relations and compared to experimental combination data. The calculation of response surfaces for Loewe additivity is based on a new approach which combines the implicit definition equation in terms of doses alone with single-agent dose-response relations. The simultaneous analysis of experimental data according to both Loewe additivity and Bliss independence within one program can hopefully contribute to a better understanding of the meaning and limits of the two criteria. CombiTool has a built-in graphics facility which allows the direct visualization of the response surfaces or the corresponding contour plots and the experimental data.

Algorithms↗
PubMed1999

Signalling via caveolin: involvement in the cross-talk between phosphoinositolglycans and insulin.

In recent years, a number of cross-talk systems have been identified which feed into the insulin signalling cascade at the level of insulin receptor substrate (IRS) tyrosine phosphorylation, e.g., receptor and non-receptor tyrosine kinases and G-protein-coupled receptors. At the molecular level, a number of negative modulator and feedback systems somehow interacting with the beta-subunit (catecholamine-, phorbolester-, or tumor necrosis factor-alpha-induced serine/threonine phosphorylation, carboxy-terminal trimming by a thiol-dependent protease, association of inhibitory/regulatory proteins such as RAD, PC1, PED, alpha2-HS-glycoprotein) have been identified as candidate mechanisms for the impairment of insulin receptor function by elevations in the activity and/or amount of the corresponding modification enzymes/inhibitors. Both decreased responsiveness and sensitivity of the insulin receptor beta-subunit for insulin-induced tyrosine autophosphorylation have been demonstrated in several cellular and animal models of metabolic insulin resistance as well as in the adipose tissue and skeletal muscle of diabetic patients and obese Pima Indians compared to non-obese subjects. Therefore, induction of the insulin signalling cascade by bypassing the defective insulin receptor kinase may be useful for the therapy of non-insulin dependent diabetes mellitus. During the past two decades, phosphoinositolglycans (PIGs) of various origin have been demonstrated to exert potent insulin-mimetic metabolic effects upon incubation with cultured or isolated muscle and adipose cells. However, it remained to be elucidated whether these compounds actually manage to trigger insulin signalling and if so at which level of hierarchy within the signalling cascade the site of interference is located. Recent studies using isolated rat adipocytes and chemically synthesized PIG compounds point to IRS1/3 tyrosine phosphorylation by p59Lyn kinase as the site of cross-talk, the negative regulation of which by interaction with caveolin is apparently abrogated by PIG. This putative mechanism is thus compatible with the recently formulated caveolin signalling hypothesis, the supporting data for which are reviewed here. Though we have not obtained experimental evidence for the involvement of PIG in physiological insulin action, the potential cross-talk between insulin and PIG signalling, including the caveolae/detergent-insoluble glycolipid-enriched rafts as the compartments where the corresponding signalling components are concentrated, thus represent novel targets for signal transduction therapy.

Amino Acid Sequence↗
PubMed1999

Constraint-induced movement therapy for motor recovery in chronic stroke patients.

OBJECTIVE: Assessment of the effectiveness of constraint-induced (CI) movement therapy and quantitative evaluation of the effects of CI therapy. DESIGN: Intervention study; case series; pretreatment to posttreatment measures and follow-up 3 months after intervention. SETTING: An outpatient department. PATIENTS: Five chronic stroke patients with moderate motor deficit; convenience sample. INTERVENTIONS: CI therapy consisting of restraint of the unaffected upper extremity in a sling for 14 days combined with 6 hours of training per weekday of the affected upper extremity. MAIN OUTCOME MEASURES: Actual Amount of Use Test (AAUT), Motor Activity Log (MAL), Wolf Motor Function Test (WMFT), and Arm Motor Ability Test (AMAT) RESULTS: There was a substantial improvement in the performance times of the laboratory tests (AMAT, WMFT, p < or = .039) and in the quality of movement (AMAT, WMFT, p < or = .049; MAL, p = .049), particularly in the use of the extremity in "real world" environments (AAUT, p = .020), supported by results of quantitative evaluation. The effect sizes were large and comparable to those found in previous studies of CI therapy. CONCLUSIONS: CI therapy is an efficacious treatment for chronic stroke patients, especially in terms of real world outcome.

Aged↗
PubMed1999

Nitrile hydratase from Rhodococcus erythropolis: metabolization of steroidal compounds with a nitrile group.

The progestin dienogest (17alpha-cyanomethyl-17beta-hydroxy-estra-4,9-dien-3-one) was metabolized by the nitrile hydratase-containing microorganism Rhodococcus erythropolis. An enzymatic hydrolysis of the nitrile group at the 17alpha-side chain was intended to obtain novel derivatives and to test them for progesterone receptor affinity. In contrast to the rapid enzymatic hydrolysis of nonsteroidal nitriles, the nitrile group of dienogest was cleaved very slowly. The dominant reaction was an aromatization of ring A. After prolonged fermentation, the 17alpha-acetamido derivatives of estradiol and of 9(11)-dehydroestradiol were formed. Three of the metabolites were also prepared synthetically. They were tested for hormonal activity by assessing their binding to progesterone and estrogen receptors in vitro. Neither the aromatized 17alpha-acetamido derivatives nor the dienogest derivative 17alpha-acetamido-17beta-hydroxy-estra-4,9-dien-3-one, which was prepared synthetically only, exhibited affinity for the progesterone receptor.

Animals↗
PubMed1999

Hepatosplenomegalic lipidosis: what unless Gaucher? Adult cholesteryl ester storage disease (CESD) with anemia, mesenteric lipodystrophy, increased plasma chitotriosidase activity and a homozygous lysosomal acid lipase -1 exon 8 splice junction mutation.

A 36-year-old woman was admitted for hepatosplenomegaly and anemia. Bone marrow cytology showed "sea-blue histiocytes", vacuolated macrophages and plasma cells. As primary liver disease, malignancy or hematologic disorders were excluded, and plasma chitotriosidase activity was increased 27-fold over control, the presence of a lysosomal storage disease was suspected. Biochemical analysis of skin fibroblasts revealed normal glucocerebrosidase and sphingomyelinase activity, but lipid analysis showed a more than 15-fold accumulation of cholesterol esters within the cells. The activity of lysosomal acid lipase (LAL) in fibroblast homogenates was decreased to 12% of control subjects. Mutational analysis of the patient's blood showed the homozygous G-->A mutation at position -1 of the exon 8 splice donor site (E8SJM-allele) known for adult cholesteryl ester storage disease (CESD); the polymorphic background was that of the complex haplotype -6Thr, 2Gly, 894 G-->A. Based on clinical, laboratory, cytological and and biochemical findings, CESD can clearly be separated from other more frequent inherited lysosomal storage diseases, e.g. atypical forms of Gaucher disease.

Adult↗