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Biomedical subjects

G Müller

Publications and source records attributed to G Müller.

At least 145 records · Page 8Linked to original sources
PubMed1999

Cross-talk mechanisms in the development of insulin resistance of skeletal muscle cells palmitate rather than tumour necrosis factor inhibits insulin-dependent protein kinase B (PKB)/Akt stimulation and glucose uptake.

Insulin resistance in skeletal muscle is one of the earliest symptoms associated with non-insulin-dependent diabetes mellitus (NIDDM). Tumour necrosis factor (TNF) and nonesterified fatty acids have been proposed to be crucial factors in the development of the insulin-resistant state. We here show that, although TNF downregulated insulin-induced insulin receptor (IR) and IR substrate (IRS)-1 phosphorylation as well as phosphoinositide 3-kinase (PI3-kinase) activity in pmi28 myotubes, this was, unlike in adipocytes, not sufficient to affect insulin-induced glucose transport. Rather, TNF increased membrane expression of GLUT1 and glucose transport in these muscle cells. In contrast, the nonesterified fatty acid palmitate inhibited insulin-induced signalling cascades not only at the level of IR and IRS-1 phosphorylation, but also at the level protein kinase B (PKB/Akt), which is thought to be directly involved in the insulin-induced translocation of GLUT4, and inhibited insulin-induced glucose uptake. Palmitate also abrogated TNF-dependent enhancement of basal glucose uptake, suggesting that palmitate has the capacity to render muscle cells resistant not only to insulin but also to TNF with respect to glucose transport by GLUT4 and GLUT1, respectively. Our data illustrate the complexity of the mechanisms governing insulin resistance of skeletal muscle, questioning the role of TNF as a direct inhibitor of glucose homoeostasis in this tissue and shedding new light on an as yet unrecognized multifunctional role for the predominant nonesterified fatty acid palmitate in this process.

Animals↗
PubMed1999

Studies on the influence of combined administration of ochratoxin A, fumonisin B1, deoxynivalenol and T2 toxin on immune and defence reactions in weaner pigs.

In weaners, combined administration of fumonisin, deoxynivalenol and T2 together with ochratoxin A in quantities expected to be present in feeds of central European origin resulted, as a rule, in changes identical to those observed after single administration of ochratoxin A. Such reactions were partly compensated. Synergistic amplification of immunosuppressive changes due to the simultaneous intake of these mycotoxins in low concentrations is not to be expected.

Animals↗
PubMed1999

Studies of the influence of ochratoxin A on immune and defence reactions in weaners.

Even in subtoxic amounts, the mycotoxin, ochratoxin A, produced immunomodulation in weaner pigs in a dose-dependent mode. In addition to increased counts of total leukocytes and neutrophils in the blood, reduced lymphocyte levels were observed. There was a striking increase in the counts of eosinophils and of apoptotic phagocytes. Functionally, there was a predominance of the production of reactive oxygen radicals in whole blood, reduced phagocytosis performance and reduced expression of a swine-specific surface marker (SWC1) on lymphocytes. In a few single experiments, clinical manifestations could be demonstrated. Lung clearance and the degree of severity of experimental pneumonia as well as cutaneous hypersensitization may be influenced by ochratoxin A.

Animals↗
PubMed1999

The role of laser in cardiac surgery.

With lasers tissue can be removed or coagulated. Laser coagulation has the same effect as radiofrequency or microwave applications. So far lasers are barely used in atrial fibrillation but it has been shown that a total block of the AV-node or a change of the PQ-time are possible with a percutaneous laser-catheter. Also the myocard can be coagulated if the laser radiation is delivered through the mitral valve without any damage to it. Short pulsed lasers produce shockwaves and thus mechanical injury to tissue. This mechanical damage to the myocard along with a controlled coagulation may lead to an interpretation of the effectiveness of TMLR.

Animals↗
PubMed1999

A new system for a combined laser and ultrasound application in neurosurgery.

A new combined Laser and Ultrasound Surgical Therapy (LUST) device suitable for endoscopical coagulation and tissue fragmentation has been developed at the LMTB. The new feature is the simultaneous transmission of laser radiation and ultrasound via flexible silica glass fibers. The ultrasound tissue interaction is based on the well-known CUSA-technology which enables the surgeon to cut various types of tissue with different degrees of effectiveness. Application fields are in oncology, neurosurgery and angioplasty. The laser radiation can be used, for example, for tissue coagulation purposes. With a fiber based LUST-system working at a frequency of 30 kHz, a displacement of 100 microns could be attained at the distal end. (The usual standard CUSA displacement is 10-350 microns.) During in vitro experiments the following tissue fragmentation rates could be achieved: brain tissue 50 mg sec-1, liver 4.5 mg sec-1 and kidney 4 mg sec-1 (displacement of the tip 60 microns; phi 1.3 mm; suction setting: 5 W). Laser radiation up to 25 W was sufficient to coagulate soft tissue. This technology offers new possibilities in minimal invasive surgery. The flexible opto-acoustic waveguide (phi 400-1700 microns) can be bent making areas accessible that were previously inaccessible. Without changing the instrumentation the surgeon can use the laser radiation for tissue coagulation or cutting and the ultrasound for tissue fragmentation and tissue reduction.

Animals↗
PubMed1999

Laser-induced thermotherapy combined with hepatic arterial embolization in the treatment of liver tumors in a rat tumor model.

OBJECTIVE: To assess the effect of combined laser-induced thermotherapy (LITT) and hepatic arterial embolization with degradable starch microspheres (DSM) on tumor response and intrahepatic temperature distribution in rats with liver tumors. SUMMARY BACKGROUND DATA: Laser-induced thermotherapy is a promising in situ ablation technique for malignant liver tumors. However, clinical use is still limited, mainly because of the small size of the inducible coagulation necroses. This results in insufficient tumor destruction. METHODS: Colon carcinoma CC531 was implanted in 60 WAG rat livers. Fourteen days later, a silicon catheter was implanted in the hepatic artery for DSM administration. Tumors were exposed to 1064 nm Nd:YAG laser light at 2 watts for 10 minutes from a diffuser tip applicator placed in the tumor. The animals were randomized into a sham-operated control (group I) and three test groups. Group II received DSM alone, group III received LITT alone, and group IV received DSM + LITT. Tumor control was examined 1, 7, and 14 days after treatment. RESULTS: A complete tumor remission was achieved in all rats treated with LITT + DSM (group IV). In contrast, tumor progression was seen in animals treated with LITT alone (group III) or DSM alone (group II), as well as in the sham-operated controls (group I). CONCLUSIONS: The authors' results suggest that the combination of LITT and DSM considerably increases the efficacy of LITT in the treatment of liver metastases in the rat.

Animals↗
PubMed1999

A role for leptin in sexual maturation and puberty?

Leptin, the ob gene product, is involved in the regulation of body weight in rodents, primates and humans. It provides a molecular basis for the lipostatic theory of the regulation of energy balance. White adipose tissue and placenta are the main sites of leptin synthesis. There is also evidence of ob gene expression in brown fat. Leptin seems to play a key role in the control of body fat stores by coordinated regulation of feeding behaviour, metabolic rate, autonomic nervous system regulation and body energy balance. Apart from the function of leptin in the central nervous system on the regulation of energy balance, it may well be one of the hormonal factors that signal to the brain the body's readiness for sexual maturation and reproduction. During late pregnancy and at birth when maternal fat stores have been developed, leptin levels are high. During these developmental stages leptin could be a messenger molecule signalling the adequacy of the fat stores for reproduction and maintenance of pregnancy. At later stages of gestation leptin could signal the expansion of fat stores in order to prepare the expectant mother for the energy requirements of full-term gestation, labour and lactation. Leptin serum concentrations change during pubertal development in rodents, primates and humans. In girls, leptin serum concentrations increase dramatically as pubertal development proceeds. The pubertal rise in leptin levels parallels the increase in body fat mass. In contrast, leptin levels increase shortly before and during the early stages of puberty in boys and decline thereafter. Testosterone has been found to suppress leptin synthesis by adipocytes both in vivo and in vitro. The decline of leptin levels in late puberty in boys accompanies increased androgen production during that time and most likely reflects suppression of leptin by testosterone and a decrease in fat mass and relative increase in muscle mass during late puberty in males. This overview focuses on those topics of leptin research which are of particular interest in reproductive and adolescent medicine.

Animals↗
PubMed1999

[Thrombosed temporary vena cava filter].

The application of temporary vena cava filters for the treatment of deep venous thrombosis of the lower extremity has become increasingly important in recent years. The filters are supposed to guarantee temporary protection from more extensive pulmonary embolism. Occlusion of the filter system by a larger embolus as well as vena cava thrombosis including the filter struts present major therapeutic problems. We report on one patient in whom the temporarily inserted filter was trapped in a large vena cava thrombus and had to be removed surgically by caval thrombectomy. Because of possible complications such as the above, the indication for insertion of temporary vena cava filters requires thorough consideration. Their duration of stay should be as short as possible and should be limited to the high risk phase, not exceeding ten days.

Equipment Failure↗
PubMed1999

Adenoviruses and enteroviruses as pathogens in myocarditis and dilated cardiomyopathy.

BACKGROUND: Enteroviruses were detected in up to 50% in myocardium of patients with myocarditis and dilated cardiomyopathy, the latter being considered as a result of a prior subclinical myocarditis. A wide range of other infectious agents are being discussed as pathogens, often only based on reports of single cases. Adenovirus genome was recently identified in a significant number in the myocardium of paediatric patients with myocarditis. However, data on the role of adenoviruses for the aetiopathogenesis of myocarditis in adult patients is missing so far. Therefore, we studied the prevalence of adenoviral and enteroviral genome in myocardium of adults with myocarditis and dilated cardiomyopathy. METHODS: 15 patients were diagnosed at baseline with myocarditis, 16 patients with dilated cardiomyopathy according to clinical and histological criteria. Endomyocardial biopsies of these patients and 8 control patients with non-infectious heart diseases were evaluated by polymerase chain reactions for enterovirus and adenovirus genome. RESULTS: Enteroviral genome was detected in 27.3% patients with myocarditis or dilated cardiomyopathy, whereas adenoviral genome was not identified in any patient. Samples from control subjects systematically yielded negative results. CONCLUSIONS: From our data, it seems doubtful that adenoviruses are major pathogens of myocarditis or DCM, whereas enterovirus genome was identified in a significant number of patients with both diseases.

Adenovirus Infections, Human↗
PubMed1999

Telepathology and imaging spectroscopy as a new modality in histopathology.

Telemedicine started in the late 1950's by transmitting data on patients' pulse and heart rates. In the 1980's it expanded to radiology and orthopedics. The technology is now expanding to other specialties that can digitally gather patient data. Telepathology comprises the transmission of microscopic images via telecommunication network. Image compression and multiplexing technologies enabled high-resolution telepathology as well as real-time video consultations over international telephone lines. Organ transplantation has become a viable treatment and offers new life to an increasing number of patients suffering from chronic end stage diseases and from irreversible organ failure. Rejection is still a major problem in kidney, liver, and heart transplantation. To gain further insight into the complex interactions within the components of the immune system, it has become increasingly necessary to develop rapid and simple methods to monitor the status of the immune system in patients. Clinical signs suggest organ rejection and abnormal laboratory test results, but only histological signs on biopsy specimens are adequately specific. The financial cost of organ transplant makes it imperative to develop tools for the early identification and treatment of organ rejection. An increasingly sensitive and accurate way of localizing key structures and abnormalities is through spectroscopy of either H&E stained samples or with a fluorescent tag (fluorophore) or by relying on natural fluorescence. The system is based on a unique Prism and Mirror Imaging Spectroscopy System ("PARISS), spectrometer originally designed and implemented for remote Earth monitoring from space and aircraft and astronomical imaging spectroscopy. Compact and lightweight both the mirror and prism are presently constructed in inexpensive glass but can also be injection molded in plastic. Any number of vendors anywhere in the world can produce all parts of the assembly. This greatly enhances the chances of future commercial viability. The Interactive Histopathology Consultation Network INTERPATH (PL961121) project integrated of remote control imaging microscopy system, imaging spectroscopy, and communication networks called SPECTROMIC. This telepethology unit will be a useful tool in the Regional and International Integrated Telemedicine Network for Medical Assistance in End Stage Diseases and Organ Transplant, RETRANSPLANT HC 4028 (HC) & IN 4028 (HC).

Computer Systems↗
PubMed1998

Recombination of nonreplicative RNA precursors of Sindbis virus in infected cells overexpressing murine-inducible nitric oxide synthase.

The Sindbis virus-based SINrep5 expression system is one of the most efficient vectors for gene transfer leading to fast and high expression of the gene of interest. This system was used to transfect vascular endothelial and smooth muscle cells using murine inducible nitric oxide synthase (miNOS) as a reporter gene. Infection of both cell types leads to high expression levels of miNOS. In addition, the harvested supernatant of these infected cells was used for further rounds of infections, demonstrating that recombination of the parental RNA with the helper RNA takes place and results in the production of infectious particles. As shown by RT-PCR, after recombination the miNOS gene is located in between the nonstructural and structural viral genes. This study demonstrates that despite claims in other publications, the Sindbis virus-based SINrep5 expression system leads to recombination and is thus not a safe system for in vitro and in vivo applications.

Animals↗
PubMed1998

TNF inhibits insulin induced STAT5 activation in differentiated mouse muscle cells pmi28.

Tumor necrosis factor (TNF) plays a central role in the state of insulin resistance leading to type II diabetes. We here describe the crosstalk of TNF with insulin signaling cascades in the mouse muscle cell line pmi28. TNF downregulated insulin induced insulin receptor kinase activity and insulin induced activation of the transcription factor STAT5. Our results provide evidence that the inhibitory crosstalk between TNF and insulin in skeletal muscle cells comprises an interference with the expression of STAT5 regulated genes which may play an important role in the manifestation and/or progression of insulin resistance in muscle cells.

Animals↗
PubMed1998

Tumor necrosis factor induces ceramide oscillations and negatively controls sphingolipid synthases by caspases in apoptotic Kym-1 cells.

The role, origin, and mode of action of the lipid messenger ceramide in programmed cell death and its linkage to receptor-associated apoptotic signal proteins is still unresolved. We show here in Kym-1 rhabdomyosarcoma cells that tumor necrosis factor (TNF)-induced apoptosis is preceded by a multiphasic increase in intracellular ceramide levels. Distinct enzymes were found to contribute to three waves of ceramide, neutral sphingomyelinase, ceramide synthase, and acid sphingomyelinase, with peak activities at 1-2, 40, and around 200 min, respectively, the latter coinciding with progression to irreversible damage. In parallel with ceramide generation, TNF-mediated inhibition of glucosylceramide and sphingomyelin (SM) synthase prevents the immediate metabolization of this lipid mediator. In the presence of benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-fmk) or benzyloxycarbonyl-Asp-Glu-Val-Asp-chloromethyl ketone (Z-DEVD-cmk), a broad spectrum and a caspase 3-selective inhibitor, respectively, glucosylceramide and SM synthase activity remains unaffected by TNF, and intracellular ceramide accumulation is not observed. Our results show that several lipid enzymes contribute to generation of ceramide in response to TNF and identify glucosylceramide and SM synthase as important regulators of the kinetics and magnitude of intracellular ceramide accumulation. As glucosylceramide and SM synthase activity is caspase-sensitive, our data suggest a novel functional link between caspase(s) and ceramide during apoptotic processes.

4-Chloro-7-nitrobenzofurazan↗
PubMed1998

Insulin-mimetic signalling of synthetic phosphoinositolglycans in isolated rat adipocytes.

A set of synthetic phosphoinositolglycan (PIG) compounds has been demonstrated to exert insulin-mimetic activity on glucose and lipid metabolism in rat adipocytes differing considerably in potency [compound 41>37>45>>7>1; W. Frick, A. Bauer, J. Bauer, S. Wied and G. Müller, G. (1998) Biochemistry 37, 13421-13436]. In the present study we examine whether these differences are based on the capability of the PIG compounds to stimulate signalling components which are thought to mediate metabolic insulin action. Studies using a tyrosine kinase inhibitor and introduction into adipocytes of anti-phosphotyrosine or inhibitory anti-insulin receptor beta-subunit antibodies demonstrated dependence on tyrosine phosphorylation but independence of insulin receptor kinase activation of the insulin-mimetic signalling and metabolic activity of the PIG compounds. The five compounds elicited in rat adipocytes a significant increase in tyrosine phosphorylation of both insulin receptor substrate 1 (IRS-1) and IRS-3 and, to a minor degree, IRS-2, in IRS-1/3-associated phosphatidylinositol 3-kinase (PI 3-K) protein as well as activity, and in protein kinase B (PKB) activity as well as phosphorylation. This was most pronounced for compound 41, approaching 65-95% of the maximal insulin response (MIR) at 20 microM, and declined in the order of compounds 37, 45, 7 and 1. The same ranking was true for the maximal inhibition of glycogen synthase kinase 3 activity (GSK-3) (41, 75% of MIR; compound 37, 65%; compound 7, 25%; compound 1, 10%) and GSK-3 autophosphorylation. The half-maximal concentrations effective for signalling (compound 41, 2-5 microM; compound 37, 10-20 microM) corresponded well to those stimulating glucose and lipid metabolism. Interestingly, compounds 37 and 41 stimulated mitogen-activated protein kinase (MAPK) and protein synthesis in rat adipocytes to only about 20-30% (at 50 microM) of MIR. We conclude that in rat adipocytes: (i) the potency of PIG compounds to regulate glucose/lipid metabolism depends on the activation of PI 3-K and PKB and inhibition of GSK-3; (ii) initiation of tyrosine phosphorylation of IRS-1/3 is sufficient and activation of the PI 3-K cascade is required for insulin-mimetic metabolic signalling; and (iii) PIG compounds are quite selective for the PI 3-K compared to the MAPK cascade, (iv) PIG compounds seem to use the same signalling components downstream of PI 3-K (including Rab4) for stimulation of glucose transport as does insulin. Thus the early signalling step(s) used by PIG, but not by insulin, may represent a target for the treatment of insulin-resistant states.

Adipocytes↗
PubMed1998

Structure-activity relationship of synthetic phosphoinositolglycans mimicking metabolic insulin action.

Phosphoinositolglycan (PIG) molecules have been implicated to stimulate glucose and lipid metabolism in insulin-sensitive cells and tissues in vitro and in vivo. The structural requirements for this partial insulin-mimetic activity remained unclear so far. For establishment of a first structure-activity relationship, a number of PIG compounds were synthesized consisting of the complete or shortened/mutated glycan moiety derived from the structure of the glycosylphosphatidylinositol (GPI) anchor of the GPI-anchored protein, Gce1p, from yeast. The PIG compounds were divided into four classes according to their insulin-mimetic activity in vitro with the typical representatives: compound 41, HO-SO2-O-6Manalpha1(Manalpha1-2)-2Manalpha1 (6-HSO3)- -6Manalpha1-4GluNb eta1-6(D)inositol-1,2-(cyclic)-phosphate; compound 37, HO-PO(H)O-6Manalpha1(Manalpha1-2)-2Manalpha1-6Manal pha1-4GluNbeta1-6( D)inositol-1,2-(cyclic)-phosphate; compound 7, HO-PO(H)O-6Manalpha1-4GluN(1-6(L)inositol-1,2-(cyclic)-ph osp hate; and compound 1, HO-PO(H)O-6Manalpha1-4GluN(1-6(L)inositol. Compounds 41 and 37 stimulated lipogenesis up to 90% (at 20 microM) of the maximal insulin response but with differing concentrations required for 50% activation (EC50 values 2.5 +/- 0.9 vs 4.9 +/- 1.7 microM) as well as glycogen synthase (4.7 +/- 1 vs 9.5 +/- 1.5 microM) and glycerol-3-phosphate acyltransferase (3.5 +/- 0.8 vs 8.0 +/- 1.1 microM). Compound 7 was clearly less potent (20% of the maximal insulin response at 100 microM), whereas compound 1 was almost inactive. This relative ranking in the insulin-mimetic potency between members of the PIG classes (e.g., 41 > 37 >> 7 > 1) was also observed for the (i) activation of glucose transport and glucose transporter isoform 4 translocation in isolated normal and insulin-resistant adipocytes, (ii) inhibition of lipolysis in adipocytes, (iii) stimulation of glucose transport and glycogen synthesis in isolated normal and insulin-resistant diaphragms, and (iv) induction of tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) in diaphragms. The complete glycan core structure (Man3-GluN) of typical GPI anchors including a mannose side chain and the inositolphosphate moiety was required for maximal insulin-mimetic activity of the PIG compounds with some variations possible with respect to the type of residues coupled to the terminal mannose/inositol as well as the type of linkages involved. These data argue for the potency and specificity of the interaction of PIG molecules with putative signaling component(s) (presumably at the level of the IRS proteins) in adipose and muscle cells which finally lead to insulin-mimetic metabolic activity even in insulin-resistant states.

Adipocytes↗
PubMed1998

Insulin signaling in the yeast Saccharomyces cerevisiae. 1. Stimulation of glucose metabolism and Snf1 kinase by human insulin.

Effects of human insulin on glucose metabolism in the yeast Saccharomyces cerevisiae were studied in this report. Under two conditions of growth limitation (glucose-grown cells during transition to stationary phase or spheroplasts during incubation in synthetic glucose medium), human insulin (10 and 1 microM, respectively) enhanced glycogen accumulation and glycogen synthase activity by 40-60% compared to control cells. Glycogen phosphorylase activity was also increased under the same conditions, but this stimulation was diminished by 35-45% in insulin-treated compared to control cells. Thus, under growth limitation, insulin causes glycogen phosphorylase and glycogen synthase to become more sensitive to inactivation and activation, respectively. In glucose-induced spheroplasts, insulin (1 microM), in addition to glycogen accumulation, led to about 2-fold increases of the rates of ethanol production and glucose oxidation compared to control cells, and the maximal concentration of hexose 6-phosphate was increased by 30-40%. In contrast, glucose transport as well as the levels of the allosteric regulators, fructose 2,6-bisphosphate and cAMP, were not altered at all. Snf1 kinase is assumed to be involved in the regulation of glycogen metabolism in yeast, although it does not seem to be modulated directly by the glucose concentration. Snf1 kinase activity was elevated 5-10-fold in response to insulin both during glucose induction of yeast spheroplasts and during transition to stationary phase of glucose-grown cells. We conclude that Saccharomyces cerevisiae and insulin-sensitive mammalian cells share some parts of the signaling cascades regulating oxidative and nonoxidative glucose metabolism in response to glucose and insulin.

Biological Transport↗
PubMed1998

Insulin signaling in the yeast Saccharomyces cerevisiae. 2. Interaction of human insulin with a putative binding protein.

A putative insulin-binding protein (Kd = 0.5 +/- 0.2 microM for human insulin) was partially purified from solubilized plasma membranes of Saccharomyces cerevisiaeby wheat germ agglutinin and insulin affinity chromatographies. The binding affinities of various mutant insulin analogues correlated well with their capacities to activate glycogen synthase and SNF1 kinase in glucose-induced yeast spheroplasts, the ranking of their relative efficacies in yeast and in isolated rat adipocytes being similar. Using a bifunctional cross-linker and two different experimental protocols, a 53-kDa polypeptide contained in the insulin-binding protein preparation was specifically affinity cross-linked to [125I]monoiodo[B26]insulin. The relative rankings of the insulin analogues with respect to inhibition of cross-linking and binding to the partially purified insulin-binding protein were identical. Incubation of intact yeast spheroplasts with [125I]monoiodo[AI4]insulin led to specific and time-dependent association of the radiolabeled insulin with the cell surface followed by its internalization and degradation. These processes were considerably delayed by low temperature and energy depletion of the spheroplasts, suggesting involvement of the ATP-dependent endosomal apparatus. These data provide evidence for the existence of a low-affinity insulin-binding protein in the plasma membrane of Saccharomyces cerevisiae.

Animals↗