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Biomedical subjects

M Elsner

Publications and source records attributed to M Elsner.

At least 19 recordsLinked to original sources
PubMed2006

Nephrotoxicity of iso-osmolar versus low-osmolar contrast media is equal in low risk patients.

BACKGROUND: Contrast media-induced nephropathy (CIN) is an increasing cause of hospital-acquired acute kidney injury and leads to a significant increase in mortality. There is uncertainty whether the use of iso-osmolar contrast media as opposed to the use of low-osmolar contrast media would be associated with a lower incidence of CIN. Therefore, we compared the nephrotoxicity of isoosmotic contrast media iodixanol with the low-osmotic contrast media iopromid in patients receiving contrast media during coronary angiography. METHODS: In this prospective double-blind study we examined 221 patients with normal renal function who received up to 1,000 ml of contrast media during coronary angiography, and compared the effect of iodixanol and iopromid on inducing contrast media nephropathy. Patients received 800 ml fluid orally before contrast media administration and 1,000 ml saline i.v. thereafter. Creatinine clearance, serum creatinine and urine-N-acetyl-beta-D-glucosaminidase (NAG) concentration was obtained 24 h before and 48 h after contrast media administration. Decrease of 20% of the creatinine clearance, increase of 25% of serum creatinine and increase of 20% of the urine concentration of NAG was defined as CIN. RESULTS: Incidence of CIN assessed by decreased creatinine clearance was 22.2% in the iopromid group and 19.7% in the iodixanol group. CIN defined by increased serum creatinine was 6.9% in the iopromid group and 8.6% in the iodixanol group. The difference between these two groups was not significant. Subgroup analysis of the diabetic patients or the patients that received high dose of contrast media revealed no significant difference in the incidence of CIN between the two contrast media. CONCLUSION: The iso-osmolar and the low-osmolar contrast media exhibited the same incidence of CIN in our study population. If fluid administration is sufficient, the selection of either iopromid or iodixanol has no impact on the risk of developing CIN in patients with normal renal function, even when they are diabetic or receive a high dose of more than 500 ml contrast media.

Acetylglucosaminidase↗
PubMed2004

Cytokines activate genes of the endocytotic pathway in insulin-producing RINm5F cells.

AIMS/HYPOTHESIS: Cytokines are important humoral mediators of beta cell destruction in autoimmune diabetes. The aim of this study was to identify novel cytokine-induced genes in insulin-producing RINm5F cells, which may contribute to beta cell death or survival. METHODS: A global gene expression profile in cytokine-exposed insulin-producing RINm5F cells was achieved by automated restriction fragment differential display PCR. The expression of selected candidate genes was confirmed by real-time RT-PCR analysis. RESULTS: Exposure of RINm5F cells to IL-1beta or to a cytokine mixture (IL-1beta, TNF-alpha, IFN-gamma) for 6 h resulted in the differential expression of a functional gene cluster. Apart from the well-known up-regulation of the cytokine-responsive genes iNOS, NF-kappaB, MnSOD and Hsp70, several genes that belong to the functional cluster of the endocytotic pathway were identified. These endocytotic genes comprised: clathrin, megalin, synaptotagmin and calcineurin, which were up-regulated by IL-1beta or the cytokine mixture. In contrast, the expression of the calcineurin inhibitor CAIN and of the GDP/GTP exchange protein Rab3 was down-regulated by cytokines. Other up-regulated cytokine-responsive genes were: agrin, murine adherent macrophage protein mRNA ( MAMA) and transport-associated protein ( TAP1/MTP), whereas the plasma membrane calcium ATPase ( PMCA) 2 and PMCA 3 genes were down-regulated by cytokines. CONCLUSIONS/INTERPRETATION: Our results indicate that genes of the endocytotic pathway are regulated by pro-inflammatory cytokines. This might affect the density of cytokine receptors at the beta cell surface and concomitantly the sensitivity of the cells to cytokine toxicity. A better understanding of the functional cross-talk between endocytotic and cytokine signalling pathways could further the development of novel strategies to protect pancreatic beta cells against toxic effects of pro-inflammatory cytokines.

Agrin↗
PubMed2002

Importance of the GLUT2 glucose transporter for pancreatic beta cell toxicity of alloxan.

AIMS/HYPOTHESIS: We investigated the importance of the low affinity GLUT2 glucose transporter in the diabetogenic action of alloxan in bioengineered RINm5F insulin-producing cells with different expressions of the transporter. METHODS: GLUT2 glucose transporter expressing RINm5F cells were generated through stable transfection of the rat GLUT2 cDNA under the control of the cytomegalovirus promoter in the pcDNA3 vector. Viability of the cells was determined using a microtitre plate-based 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. RESULTS: Cells expressing the GLUT2 transporter were susceptible to alloxan toxicity due to the uptake of alloxan by this specific glucose transporter isoform. The extent of the toxicity of alloxan was dependent upon the GLUT2 protein expression in the cells. The lipophilic alloxan derivative, butylalloxan, was toxic also to non-transfected control cells. Expression of the GLUT2 glucose transporter caused only a marginal increase in the toxicity of this substance. Butylalloxan, unlike alloxan itself, is not diabetogenic in vivo although, like the latter substance, it is beta-cell toxic in vitro through its ability to generate free radicals during redox cycling with glutathione. CONCLUSION/INTERPRETATION: Our results are consistent with the central importance of selective uptake of alloxan through the low affinity GLUT2 glucose transporter for the pancreatic beta-cell toxicity and diabetogenicity of this substance. Redox cycling and the subsequent generation of oxygen free radicals leads to necrosis of pancreatic beta cells and thus to a state of insulin-dependent diabetes mellitus, well-known as alloxan diabetes in experimental diabetes research.

3-O-Methylglucose↗
PubMed2001

The LEW.1AR1/Ztm-iddm rat: a new model of spontaneous insulin-dependent diabetes mellitus.

AIMS/HYPOTHESIS: We describe a new Type I (insulin-dependent) diabetes mellitus rat model (LEW.1AR1/Ztm-iddm) which arose through a spontaneous mutation in a congenic Lewis rat strain with a defined MHC haplotype (RT1.Aa B/Du Cu). METHODS: The development of diabetes was characterised using biochemical, immunological and morphological methods. RESULTS: Diabetes appeared in the rats with an incidence of 20 % without major sex preference at 58+/-2 days. The disease was characterised by hyperglycaemia, glycosuria, ketonuria and polyuria. In peripheral blood, the proportion of T lymphocytes was in the normal range expressing the RT6.1 differentiation antigen. Islets were heavily infiltrated with B and T lymphocytes, macrophages and NK cells with beta cells rapidly destroyed through apoptosis in areas of insulitis. CONCLUSION/INTERPRETATION: This Type I diabetic rat develops a spontaneous insulin-dependent autoimmune diabetes through beta cell apoptosis. It could prove to be a valuable new animal model for clarifying the mechanisms involved in the development of autoimmune diabetes.

Animals↗
PubMed2001

Platelet CD62 expression and PDGFAB secretion in patients undergoing PTCA and treatment with abciximab.

AIMS: To investigate a correlation of the platelet activation marker CD62 and secretion of the growth factor PDGF from platelets in coronary patients under therapy with the GPIIb/IIIa-inhibitor abciximab. METHODS: Flow cytometric assessment of fibrinogen binding (GPIIb/IIIa-binding site) and CD62 expression, as well as PDGF release of human platelets (immunoassay) and platelet aggregation with 20 microM ADP and 2 microg ml(-1) collagen were evaluated in nine patients with stable coronary artery disease. Patients were undergoing elective balloon angioplasty and were treated with aspirin (100 mg day(-1)), heparin (ACT < 220 s) and abciximab (bolus and infusion over 12 h). Blood samples were obtained before initiation of abciximab therapy (under aspirin and heparin) (I), 3 h after angioplasty under abciximab (II) and 12 h after termination of abciximab infusion (III). RESULTS: Compared with sample I before abciximab therapy, fibrinogen binding was reduced to 37% (+/- 34 s.d., P < 0.05) (II) and 55% (+/- 40 s.d., P < 0.05) (III). Reduced fibrinogen binding also led to a significant reduction of the aggregation response to ADP (down to 37% +/- 20) and collagen (down to 0%). Mean fluorescence intensity of CD62-expression was 78 units (+/- 20 s.d.) (I), 72 units (+/- 14 s.d.) (II) and 64 units (+/- 12 s.d., P < 0.05) (III). PDGF release from isolated, washed platelets was 99 (+/- 33 s.d.) ng/10(9) platelets at (I), 82 (+/- 31 s.d.) ng/10(9) platelets and 96 (+/- 30 s.d.) ng/10(9) platelets. CONCLUSIONS: The results indicate that despite a strong reduction of GPIIb/IIIa-binding and platelet aggregation, CD62 as a marker of platelet secretion and the secretion product PDGF were only slightly reduced under abciximab treatment. No direct correlation between CD62 expression and PDGF release could be demonstrated.

Abciximab↗
PubMed2001

Statin therapy is associated with reduced restenosis rates after coronary stent implantation in carriers of the Pl(A2)allele of the platelet glycoprotein IIIa gene.

Aims Platelets play a central role in the restenosis process by inducing neointimal proliferation after coronary interventions. Glycoprotein IIb/IIIa Pl(A2)polymorphism has been associated with the occurrence of acute coronary syndromes and increased restenosis rates. Statins have been shown to exert potent antiproliferative, antiinflammatory and antithrombotic properties, thereby potentially interfering with the major processes of in-stent restenosis. Therefore, we sought to find out whether statin therapy interferes with restenosis and clinical outcome at 6 months following successful coronary stent implantation in the presence or absence of the Pl(A2)allele. Methods and Results Six hundred and fifty consecutive patients were followed for 6 months after coronary stent insertion. Carriers of the Pl(A2)allele demonstrated a significantly increased restenosis rate, which was abrogated by statin therapy (50.9% vs 28.6%, P=0.01). Moreover, statin therapy was associated with a significant reduction (28.2% vs 49.3%, P<0.01) in the occurrence of major adverse coronary events (myocardial infarction, cardiac death, target vessel revascularization) in the 6 months after the intervention in patients with the Pl(A2)allele. Conclusion Statin therapy reduces increased stent restenosis rates and improves clinical outcome following coronary stent implantation in patients bearing the Pl(A2)allele, suggesting that statins interfere with the functional consequence of a genetically determined platelet-mediated risk factor associated with Pl(A2)polymorphism.

Adult↗
PubMed2000

Treatment of aortocoronary vein graft lesions with membrane-covered stents: A multicenter surveillance trial.

BACKGROUND: Stent implantation in lesions of degenerated aortocoronary vein grafts is associated with a high risk of periprocedural thrombus embolization and in-stent restenosis. METHODS AND RESULTS: In a multicenter study, we followed up 109 consecutive patients (mean age 66+/-8 years, 12% female) who received polytetrafluoroethylene (PTFE) membrane-covered stents for 125 de novo stenoses in vein grafts 11+/-5 years after bypass surgery. Stent deployment was successful in all but 1 patient; 1 patient suffered from subacute stent thrombosis. Six-month cardiac mortality was 7% (8 patients), 3 patients (3%) underwent repeat bypass surgery, and 9 patients (8%) required target-lesion PTCA. Repeat angiography revealed vessel occlusions in 9% and in-stent restenosis in 8% of patients by the end of follow-up. CONCLUSIONS: Membrane-covered stents appear to be a safe and efficient treatment strategy associated with a low incidence of restenosis and target-vessel revascularization. Compared with previous studies, the investigated device is not associated with an increase in mortality or late vessel occlusions.

Aged↗
PubMed2000

Effect of statin therapy on restenosis after coronary stent implantation.

The effect of statins on the development of restenosis and clinical outcome after coronary stent implantation was assessed in a retrospective analysis of 525 consecutive patients. Baseline clinical, angiographic, and procedural characteristics did not differ between 258 patients with and 267 patients without statin therapy. Statin therapy was associated with a significantly (p<0.04) improved survival free of myocardial infarction and a significant reduction in repeat target vessel revascularization procedures (27.9% vs. 36.7%, p<0.05) during 6-month follow-up. Minimal lumen diameter was significantly larger (1.98+/-0.88 vs. 1.78+/-0.88 mm, p = 0.01), late lumen loss was significantly less (0.64+/-0.8 vs. 0.8+/-0.8 mm, p = 0.032), and net gain significantly increased (1.2+/-0.88 vs. 0.98+/- 0.92 mm, p = 0. 009) in patients receiving statin therapy. Dichotomous angiographic restenosis (> or =50%) rates were significantly lower, with 25.4% in the statin group compared with 38% in the no-statin group (p<0.005). Multivariate analysis identified statin therapy (p = 0.005), minimal lumen diameter immediately after stenting (p = 0.02), and stent length (p = 0.02) as independent predictors for subsequent restenosis development. Thus, statin therapy is associated with reduced recurrence rates and improved clinical outcome after coronary stent implantation.

Anticholesteremic Agents↗
PubMed2000

Engineering of a glucose-responsive surrogate cell for insulin replacement therapy of experimental insulin-dependent diabetes.

Glucose responsiveness in the millimolar concentration range is a crucial requirement of a surrogate pancreatic beta cell for insulin replacement therapy of insulin-dependent diabetes. Novel insulin-secreting GK cell clones with millimolar glucose responsiveness were generated from an early-passage glucose-unresponsive RINm5F cell line. This line expressed constitutively both the K(ATP) channel and the GLUT2 glucose transporter; but it had a relative lack of glucokinase. Through overexpression of glucokinase, however, it was possible to generate glucose-responsive clones with a glucokinase-to-hexokinase ratio comparable to that of a normal pancreatic beta cell. This aim, on the other hand, was not achieved through overexpression of the GLUT2 glucose transporter. Raising the expression level of this glucose transporter into the range of rat liver, without correcting the glucokinase-to-hexokinase enzyme ratio, did not render the cells glucose responsive. These glucokinase-overexpressing RINm5F cells also stably maintained their molecular and insulin secretory characteristics in vivo. After implantation into streptozotocin diabetic immunodeficient rats, glucokinase-overexpressing cells retained their insulin responsiveness to physiological glucose stimulation under in vivo conditions. These cells represent a notable step toward the future bioengineering of a surrogate beta cell for insulin replacement therapy in insulin-dependent diabetes mellitus.

Animals↗
PubMed2000

Relative importance of transport and alkylation for pancreatic beta-cell toxicity of streptozotocin.

AIMS/HYPOTHESIS: The role of selective uptake and alkylation in the diabetogenic action of streptozotocin was investigated in bioengineered RINm5F insulin-producing cells, with different expression levels of the glucose transporter GLUT2, by comparing the toxicity of streptozotocin with that of four chemically related alkylating compounds, N-methyl-N-nitrosourea (MNU), N-ethyl-N nitrosourea (ENU), methyl methanesulphonate (MMS) and ethyl methanesulphonate (EMS). METHODS: GLUT2 expressing RINm5F cells were generated through stable transfection of the rat glucose transporter GLUT2 cDNA under the control of the cytomegalovirus promoter in the pcDNA3 vector. Viability of the cells was determined using a microtitre plate-based 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. RESULTS: Cells expressing the glucose transporter GLUT2 were much more susceptible to streptozotocin toxicity than control cells due to the uptake of streptozotocin by this specific glucose transporter. In contrast, the GLUT2 expression had no effect upon the toxicity of MNU, ENU, MMS or EMS. Although the latter substances are, like streptozotocin, cytotoxic through their ability to cause DNA alkylation, they are not diabetogenic because they are not taken up through the glucose transporter GLUT2. CONCLUSION/INTERPRETATION: Our results are consistent with the central importance of selective uptake and alkylating activity in the mechanism of streptozotocin diabetogenicity. Alkylation of DNA leads to necrosis of pancreatic beta cells and thus to a state of insulin-dependent diabetes mellitus, well-known as streptozotocin diabetes in experimental diabetes research.

3-O-Methylglucose↗
PubMed2000

Coronary artery bypass grafting in adult coronary artery disease due to suspected Kawasaki disease in childhood.

Development of coronary artery aneurysms is one typical complication of Kawasaki disease and can cause coronary artery disease even in early childhood. Information about course and outcome in adults is rare. Here, we present a 49-year-old man with serious three-vessel coronary artery disease and giant coronary artery aneurysms following suspected Kawasaki disease.

Coronary Aneurysm↗
PubMed1999

A positive family history of premature coronary artery disease is associated with impaired endothelium-dependent coronary blood flow regulation.

BACKGROUND: The aim of the study was to determine whether a positive family history of coronary artery disease is related to impaired coronary blood flow regulation. METHODS AND RESULTS: In 150 patients with angiographically normal or minimally diseased coronary vessels, risk factors for coronary artery disease, the extent of atherosclerosis and endothelium-dependent vasomotor responses to acetylcholine, and endothelium-independent blood flow regulation by papaverine or adenosine were assessed. Coronary blood flow responses to acetylcholine were reduced in a dose-dependent manner in patients with a positive family history (P=0.030). By multivariate analysis, hypercholesterolemia (P=0.001), age (P=0.002), and a positive family history (P=0.008) remained predictors of coronary blood flow increase to acetylcholine. The extent of atherosclerotic coronary artery disease was, by multivariate analysis, an additional independent predictor of acetylcholine-induced blood flow (P=0.014), but also of endothelium-independent blood flow regulation (P=0.001). A positive family history had additive effects in addition to the other risk factors, such as hypercholesterolemia or increased age. Angiotensin-converting-enzyme genotype polymorphism had no influence either on endothelium-dependent or endothelium-independent coronary blood flow responses. However, in a subset of 28 patients, homocysteine (which is, in part, genetically determined) was inversely related to maximal acetylcholine-induced blood flow regulation (r=-0.47, P=0.012). CONCLUSIONS: The results of this study demonstrate, for the first time, that a positive family history of coronary artery disease is an important predictor of impaired endothelium-dependent coronary blood flow regulation in humans. The influence of a positive family history is independent of other well known risk factors but instead aggravates endothelial vasodilator dysfunction associated with hypercholesterolemia and increased age, suggesting important interacting effects between genetic and environmental risk factors.

Adult↗
PubMed1999

Coronary stent grafts covered by a polytetrafluoroethylene membrane.

In a prospective observational study, 40 patients were treated with coronary stent grafts covered by a polytetrafluoroethylene membrane. These devices may be regarded as therapy of choice for acute coronary rupture; treatment of conventional in-stent restenosis was not associated with a favorable outcome, whereas the promising results in degenerated vein grafts warrant a randomized, controlled trial.

Aged↗
PubMed1999

Metabolic regulation, activity state, and intracellular binding of glucokinase in insulin-secreting cells.

Regulation of glucose-induced insulin secretion is crucially dependent on glucokinase function in pancreatic beta-cells. Glucokinase mRNA expression was metabolically regulated allowing continuous translation into enzyme protein. Glucokinase enzyme activity in the beta-cell was exclusively regulated by glucose. Using a selective permeabilization technique, different intracellular activity states of the glucokinase enzyme in bioengineered glucokinase-overexpressing RINm5F tissue culture cells were observed. These results could be confirmed in analogous experiments with dispersed islet cells. A diffusible glucokinase fraction with high enzyme activity could be distinguished from an intracellularly bound fraction with low activity. Glucose induced a significant long-term increase of the active glucokinase fraction. This effect was accomplished through the release of glucokinase enzyme protein from an intracellular binding site of protein character. The inhibitory function of this protein factor was abolished through proteolytic digestion or heat inactivation. Northern blot analyses revealed that this binding protein was not identical to the well-known liver glucokinase regulatory protein. This hitherto unknown new protein factor may have the function of a glucokinase regulatory protein in the pancreatic beta-cell, which may regulate glucokinase enzyme activity in a glucose-dependent manner.

Animals↗
PubMed1998

Clinical outcome at six months of coronary stenting followed by ticlopidine monotherapy.

Antiplatelet therapy has been shown to be superior to oral anticoagulation after coronary stent implantation. Different regimens for postinterventional antiplatelet therapy have been proposed. A combination of ticlopidine and aspirin has gained the most widespread use. The relative merit of the different compounds in this combination remains unclear. There are several, partly conflicting, reports on coronary stent implantation followed by aspirin alone, but data on ticlopidine monotherapy are scarce. We conducted a prospective trial of elective coronary stenting followed by ticlopidine monotherapy in 263 consecutive, unselected patients. One-, 2-, and 3-vessel disease was present in 42.9%, 42.6%, and 14.5% of patients, respectively. We deployed a total of 322 stents. All patients received 250 mg of ticlopidine twice daily for up to 6 months. The clinical end points encountered during the hospital stay and at 5.9+/-2.9 months, respectively, were: death (2 [0.8%] and 2 [0.8%]); myocardial infarction (5 [1.9%] and 4 [1.5%]); target vessel occlusion (2 [0.8%] and 4 [1.5%]); bypass surgery (0 and 2 [0.8%]); and repeat angioplasty (2 [0.8%] and 52 [19.8%]). There was 1 vascular surgery (0.4%) and 4 (1.5%) non-procedure-related ischemic cerebrovascular events at follow-up. We conclude that coronary stent deployment followed by ticlopidine monotherapy is safe and effective in an unselected population. The overall clinical outcome at 6 months is good and comparable to that of patients treated with combined antiplatelet therapy. Ticlopidine monotherapy may be a safe alternative for patients with contraindications to aspirin.

Adult↗
PubMed1998

Molecular characterization of the glucose-sensing mechanism in the clonal insulin-secreting BRIN-BD11 cell line.

BRIN-BD11 cells represent a novel insulin-secreting cell line generated by electrofusion. Molecular characterization of these cells demonstrated the presence of mRNA and protein for the two key elements of the beta cell glucose-sensing system, GLUT2 and glucokinase. While levels of GLUT2 expression and 3-O-methyl-D-glucose equilibration were similar for both the BRIN-BD11 cell line and the parental control RINm5F cells, glucokinase expression was substantially higher in BRIN-BD11 cells. Expression of the two-component KATP channel complex, KIR6.2 and SUR1, was similar in both cells. However, while control RINm5F cells were completely unresponsive to glucose, BRIN-BD11 cells responded to physiological millimolar concentrations of this hexose sugar. These studies strongly suggest that the glucose-sensing ability of insulin-secreting cells is largely dictated by the level of glucokinase, as opposed to GLUT2, expression. Thus, BRIN-BD11 cells expressing the key attributes of the normal beta cell provide an interesting model for elucidation of regulatory principles of beta cell function.

3-O-Methylglucose↗
PubMed1998

[Perforation and rupture of coronary arteries].

Spontaneous rupture of coronary arteries as well as coronary perforation during percutaneous interventions are rare but potentially life-threatening incidents often resulting in emergency surgery. Frequency of acute perforation due to therapeutic catheterization varies according to the devices employed. With conventional balloon angioplasty it is estimated to be 0.1 to 0.2% whereas substantially higher rates of up to 3% have been reported with the use of so-called "new devices" (i.e. directional atherectomy, rotablation, excimer laser angioplasty or extractional atherectomy). Interventional strategies for nonsurgical treatment of acute coronary perforations during catheterization procedures have been developed. In recent times, availability of coronary stent-grafts allows for a percutaneous resolution of acute perforations while maintaining vessel patency. Whereas iatrogenic perforations in the catheterization laboratory may thus be treated immediately at the site of their occurrence, rupture of pre-existing but potentially unknown coronary pathology frequently is associated with a diagnostic interval, giving rise to serious clinical events (i.e. myocardial infarction, cardiac tamponade, malign arrhythmias or sudden death). It may be warranted to advocate prophylactic treatment of rupture-prone coronary conditions even on incidental diagnosis. This can either be performed by cardiothoracic surgery or, in suitable cases, by interventional therapy. Implantation of coronary stent-grafts could prove to become the therapy of choice due to its technical facility, safety and the short length of hospital stay associated with it. Before general recommendations can be made, however, as to the extension of indication for these novel coronary devices, further clinical studies encompassing long-term clinical and angiographic follow-up are needed.

Angioplasty, Balloon, Coronary↗