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Biomedical subjects

M Winkler

Publications and source records attributed to M Winkler.

At least 37 records · Page 2Linked to original sources
PubMed2001

Desensitization of insulin secretory response to imidazolines, tolbutamide, and quinine. I. Secretory and morphological studies.

The desensitization of pancreatic B-cells against stimulation by insulin secretagogues that inhibit ATP-dependent K(+) channels (K(ATP) channels) was investigated by measuring insulin secretion of perifused pancreatic islets. Additionally, the islet insulin content and the number of secretory granules per B-cell were determined. Prior to the measurement of secretion, islets were cultured for 18 h in the presence or absence of the test agents in a cell-culture medium containing 5 mM glucose. The effects of three imidazolines, phentolamine, alinidine, and idazoxan (100 microM each) were compared with those of the well-characterized sulfonylurea, tolbutamide (500 microM), and those of the ion channel-blocking alkaloid, quinine (100 microM). Insulin secretion was strongly reduced upon re-exposure to phentolamine, alinidine, tolbutamide, and quinine, whereas idazoxan, which stimulated secretion only weakly, had no significant effect. The imidazoline secretagogues phentolamine and alinidine induced a cross-desensitization against the stimulatory effect of tolbutamide and quinine. A long-term depolarization with 40 mM KCl was also able to induce a significant reduction of the secretory response to all of the above secretagogues. The insulin content of cultured islets was moderately, but significantly reduced by alinidine, whereas the reduction by phentolamine, tolbutamide, and quinine was not significant. In contrast to these observations, the ultrastructural examination revealed that tolbutamide-treated B-cells had a high degree of degranulation, whereas the other test agents and 40 mM KCl produced only a partial degranulation, except for phentolamine, which produced no significant degranulation at all. These results suggest that the desensitization of insulin secretion is a common property of all agents that stimulate insulin secretion by depolarisation of the plasma membrane. Depending on the specific secretagogue, additional mechanisms, proximal and distal to Ca(2+) influx, appear to contribute to the desensitization (see Rustenbeck et al., pages 1695-1703, this issue).

Animals↗
PubMed2001

Hemodynamic consequences of porcine kidney xenograft reperfusion in cynomolgus monkeys.

BACKGROUND: After xenograft reperfusion, complement activation may lead to generation of anaphylatoxins and cardiocirculatory instability of the recipient. METHODS: In 13 cynomolgus recipients of either unmodified or human decay accelerating factor transgenic porcine kidneys cardiocirculatory parameters were measured by single indicator transpulmonary thermodilution. RESULTS: After graft reperfusion, recipient cardiac output decreased by 25.4% (P<0.05), intrathoracic blood volume by 22.8% (P<0.05), extravascular lung water increased slightly (P=n.s.). The impairment in cardiac output was neither influenced by the graft's weight or human decay accelerating factor transgenicity. sC3a and sC5b-9 complement levels in the recipient monkeys showed a sharp peak upon reperfusion. CONCLUSIONS: After reperfusion a marked and significant cardiodepression accompanied by relative volume depletion were observed. Analysis of volume status ruled out a mere volume shift as the underlying reason for the observed drop in cardiac output. These data may be relevant for the perioperative management of human recipients of discordant xenografts in the future.

Animals↗
PubMed2001

RAD in de novo renal transplantation: comparison of three doses on the incidence and severity of acute rejection.

BACKGROUND: The effects of three doses of RAD (40-O-[2-hydroxyethyl]-rapamycin), a novel macrolide with potent immunosuppressive and antiproliferative properties, on the incidence and severity of acute rejection episodes as well as its tolerability were evaluated in a dose-ranging study in de novo renal transplant recipients. METHODS: In this double-blind, parallel group, multicenter study, recipients were randomized to receive 1 mg, 2 mg, or 4 mg/day of RAD in combination with Neoral (cyclosporine, USP MODIFIED) and corticosteroids. The incidence and severity of biopsy-proven acute rejection episodes, graft survival, patient survival, infection rates, laboratory measurements, and adverse events were compared across groups after 6 months of therapy. RESULTS: Among the 103 recipients, patients receiving 1, 2, or 4 mg/day experienced a 32.4%, 14.7%, or 25.7% incidence of biopsy-proven acute rejection episodes within the first 6 months posttransplantation, respectively. Even though the study was not powered to demonstrate efficacy, the incidence of moderate and severe acute rejection episodes was found to be significantly lower among patients in the 2 mg and 4 mg/day groups than in the 1 mg/day group (P=0.002 and P=0.006, respectively). Overall graft and patient survival rates were excellent. RAD was generally well tolerated. Although blood lipid levels increased in all groups, changes were manageable with lipid-lowering agents and did not warrant discontinuation of study medication. The incidence of viral and fungal infections was low; however, it was higher among recipients treated with 4 mg/day. CONCLUSIONS: In combination with Neoral and corticosteroids, RAD doses of 2 mg and 4 mg/day resulted in lower rates of acute rejection episodes and efficacy failure than the 1 mg/day dose and were significantly more effective in reducing the severity of rejection. Large-scale, controlled, follow-up studies are currently in progress to confirm these initial findings.

Acute Disease↗
PubMed2001

[Vascular complications in thoracic outlet syndrome: combined transaxillary revascularization and rib resection].

Based on two patients with vascular complications in thoracic outlet-syndrome, the anatomic and pathophysiologic principles prior to surgery are discussed. Causative therapy including rib resection and elimination of the embolic source in the subclavian artery is often supplemented by peripheral revascularization with bypass, lysis and/or sympathectomy. The transaxillary approach seems to be optimal, combining minimally invasive principles with a long exposure of the subclavian artery from segment 3 to the proximal axillary artery.

Adult↗
PubMed2001

Selective degradation of ibuprofen and clofibric acid in two model river biofilm systems.

A field survey indicated that the Elbe and Saale Rivers were contaminated with both clofibric acid and ibuprofen. In Elbe River water we could detect the metabolite hydroxy-ibuprofen. Analyses of the city of Saskatoon sewage effluent discharged to the South Saskatchewan river detected clofibric acid but neither ibuprofen nor any metabolite. Laboratory studies indicated that the pharmaceutical ibuprofen was readily degraded in a river biofilm reactor. Two metabolites were detected and identified as hydroxy- and carboxy-ibuprofen. Both metabolites were observed to degrade in the biofilm reactors. However, in human metabolism the metabolite carboxy-ibuprofen appears and degrades second whereas the opposite occurs in biofilm systems. In biofilms the pharmacologically inactive stereoisomere of ibuprofen is degraded predominantly. In contrast, clofibric acid was not biologically degraded during the experimental period of 21 days. Similar results were obtained using biofilms developed using waters from either the South Saskatchewan or Elbe River. In a sterile reactor no losses of ibuprofen were observed. These results suggested that abiotic losses and adsorption played only a minimal role in the fate of the pharmaceuticals in the river biofilm reactors.

Biodegradation, Environmental↗
PubMed2001

Udder disease etiology, milk somatic cell counts and NAGase activity in Israeli Assaf sheep throughout lactation.

Bacterial pathogens causing udder infections in Israeli Assaf dairy sheep were identified and changes occurring throughout lactation were monitored to study the correlation between the contaminant and the severity of the infection, as measured by somatic cell count (SCC) and NAGase tests. A total of 159 Israeli Assaf dairy sheep on one farm, in their first (69), second (13) or third and more (77) lactations were included in this study. Udder halves were tested for bacterial condition, SCC and NAGase activity 2-3 weeks post lambing and every 4 weeks after until drying-off. At first sampling, in 60.7% (193/318 quarters) of the halves no bacterial growth (NBG) was detected. Different species of coagulase negative staphylococci (CNS) were the main pathogen group in infected udders. Streptococci were isolated from 14 halves, most of them in the two udder halves. The percent of udder infection in sheep in their third or further lactations was 2.8 greater (P<0.05) than in that of sheep in their first lactation. During the lactation, 90.6% of the halves did not change their classification status, suggesting that most infections occur before lambing and/or during the following first few days. The arithmetic mean of SCC and NAGase of total half udder milk and samplings (during the lactation) were 1144+/-48x10(3)cells/ml and 49.4+/-2.5, respectively. The average SCC in the milk of halves classified as NBG was 321+/-35x10(3)cells/ml and was not significantly changed during the lactation period. In halves infected with CNS, average SCC was 1371+/-150x10(3)cells/ml at the first testing and increased to 2129+/-347x10(3)cells/ml at drying-off. No significant differences were found in SCC and NAGase activity between the different species of the CNS. The mean SCC over the types of bacteria isolated, lactation number and days in lactation was significantly different (P<0.0001). In 4% of the halves, from all samples, SCC was above 5000x10(3)cells/ml although no bacteria were detected in their milk. The higher SCC in the CNS infected halves contrasted with the more moderate SCC found in dairy cows similarly infected, suggesting that the sheep udder has a lower resistance and an augmented immunological response against this group of bacteria. Thus, this should be considered accordingly in schemes for sheep's milk quality payment.

Journal Article↗
PubMed2001

An automatic camera-holding system for gynecologic laparoscopy.

Ergonomic analysis of conditions prevailing during laparoscopy show that static holding work causes considerable problems. The surgeon's assistant is particularly affected, for example, by holding the endoscope optical system. To minimize strain for the entire operating team and to increase the range of activities that can be performed by the assistant, an automatic surgical camera-holding system was developed. Its value in clinical practice was tested in gynecologic laparoscopy, where it enabled the surgical team to work more comfortably.

Equipment Design↗
PubMed2001

[Monstrous, retroperitoneal liposarcoma--a case report].

Liposarcomas comprise about 20% of soft tissue sarcomas and occur in 14% in the retroperitoneal space originating in one third from the perirenal fat. The case of a patient with an extraordinary huge, resectable, well-differentiated retroperitoneal liposarcoma is reported. The presenting symptoms were abdominal pain and distension as well as weight gain. Magneticresonance imaging revealed a huge retroperitoneal tumor suspected of well-differentiated liposarcoma. Curative resection of the tumor could be obtained. Only 50% of all tumors are excised without residual tumor and recurrence, occurring in 90% after 10 years, is the main therapeutic challenge. Since neoadjuvant and adjuvant therapy as well as intraoperative radiotherapy failed to prove prognostic value, curative resection remains the main treatment for primary and recurrent liposarcomas.

Adipose Tissue↗
PubMed2001

C1-Inhibitor for treatment of acute vascular xenograft rejection in cynomolgus recipients of h-DAF transgenic porcine kidneys.

At present, the major barrier to successful discordant xenotransplantation of unmodified or complement regulator transgenic porcine xenografts is acute vascular xenograft rejection (AVR). AVR is associated with the intragraft deposition of induced recipient xenoreactive antibodies and subsequent complement activation. In a life-supporting pig to primate kidney xenotransplantation setting using h-DAF transgenic donor organs and postoperative immunosuppression, episodes of AVR were either treated with boluses of cyclophosphamide and steroids or with the same regimen supplemented by a three-day course of C1-Inhibitor, a multifunctional complement regulator. In 8 out of 10 animals stable initial graft function was achieved; in all animals one or more episodes of AVR were observed. When, in 4 animals, C1-Inhibitor was added to the standard anti-rejection treatment regimen, AVR was successfully reversed in 6 out of 7 episodes, while in another group of 4 animals receiving the standard anti-rejection treatment 0 out of 4 episodes of AVR responded to treatment. Response to anti-rejection treatment was associated with a significant increase in recipient survival time. We conclude that AVR of h-DAF transgenic porcine kidneys can be successfully treated by additional short-term fluid phase complement inhibition.

Animals↗
PubMed2001

Dacron vs. polytetrafluoroethylene grafts for femoropopliteal bypass: a prospective randomised multicentre trial.

OBJECTIVES: To compare the patency of PTFE (Polytetrafluoroethylene) and unsealed knitted Dacron femoro-popliteal bypasses. DESIGN: Multi-centre prospective randomised trial. MATERIALS AND METHODS: Of 203 patients randomised, 194 were included in the final analysis (103 Dacron grafts and 91 PTFE grafts). The median follow-up was 36 months (range: 6-72 months); the distal anastomosis was above-knee in 141 and below-knee in 53 cases. Univariate comparisons of patency were made by the Kaplan-Meier method, multivariate calculations on the effects of covariables by a Cox regression analysis. RESULTS: There was no difference regarding primary and secondary patency or limb salvage between Dacron and PTFE. The primary 3-year patency for Dacron grafts was 64% (95% confidence interval [C.I.] 55-74%) and for PTFE grafts 61% (C.I. 49-72%). The corresponding 3-year secondary patency was 81% (C.I. 73-89%) and 75% (C.I. 65-86%) respectively, the limb salvage rate 90% (C.I. 84-96%) and 91% (C.I. 84-97%). Upon multivariate analysis below-knee anastomosis was the principal independent predictor of primary graft failure (risk ratio 1.7 [C.I. 1.05-2.8]), impaired secondary patency was associated with infragenicular bypass (risk ratio 3.3 [C.I. 1.8-6.3]) and distal gangrene (risk ratio [C.I. 1.01-3.8]p=0.048), major amputation was independently predicted by below-knee bypass, tissue necrosis, and poor run-off index. CONCLUSIONS: PTFE and Dacron are equally suitable for femoro-popliteal bypass.

Adult↗
PubMed2001

Longitudinal assessment of everolimus in de novo renal transplant recipients over the first post-transplant year: pharmacokinetics, exposure-response relationships, and influence on cyclosporine.

OBJECTIVE: Our objective was to characterize the steady-state pharmacokinetics of everolimus and cyclosporine (INN, ciclosporin) when coadministered in de novo kidney allograft recipients during the first year after transplantation. METHOD: This study was a multicenter randomized double-blind study of 101 patients who were randomly assigned 1:1:1 to receive everolimus tablets at doses of 0.5 mg, 1 mg, or 2 mg twice daily with cyclosporine and prednisone. Blood sampling for the pharmacokinetics of everolimus and cyclosporine was performed on day 1, on weeks 1, 2, 3, and 4, and on months 2, 3, 6, 9, and 12. Everolimus dose-proportionality and stability over time were assessed in the context of linear regression and ANOVA models. Everolimus exposure-response relationships between area under the blood concentration-time curve (AUC) and changes in platelets, leukocytes, and lipids were explored with the median-effect model. Potential differences in cyclosporine dosing and pharmacokinetics at different levels of everolimus exposure were assessed in the context of ANOVA. RESULTS: Everolimus steady state was reached on or before day 7, with a median 3-fold accumulation of drug exposure compared with that after the first postoperative dose. Both steady-state maximum concentration and AUC were dose proportional over the full dose range when assessed on day 1, as well as for the full duration of the study at steady state. There was evidence for longitudinal stability in AUC of everolimus during the course of the study. The interindividual pharmacokinetic variability for AUC was 85.4% and intraindividual, interoccasion variability was 40.8%. Age (range, 17-69 years), weight (range, 49-106 kg), and sex (65 men and 36 women) were not significant contributors to variability. There was an increasing incidence of transient thrombocytopenia (< or =100 x 10(9)/L) with increasing everolimus AUC (P = .03). Cyclosporine doses, trough concentrations, and AUC exhibited similar temporal patterns during the course of the study regardless of the co-administered everolimus dose level (P = .13, .82, and .76, respectively). CONCLUSIONS: Everolimus exhibited dose-proportional, stable exposure during the first post-transplant year. For a 4-fold range of everolimus doses there were no differential effects on cyclosporine dosing or pharmacokinetics.

Administration, Oral↗
PubMed2001

Analysis of potential porcine endogenous retrovirus (PERV) transmission in a whole-organ xenotransplantation model without interfering microchimerism.

The question whether porcine xenografts can lead to porcine endogenous retrovirus (PERV) infection of recipients is critical for the evaluation of the safety of pig-to-man xenotransplantation. Unfortunately, polymerase chain reaction (PCR)-based analysis of potential PERV infections in nonhuman-primate whole-organ xenotransplantation models is hampered by false positive results due to chimeric porcine cells. To avoid the inherent analytical problem of xenomicrochimerism, we developed a non-life-supporting pig-to-primate kidney xenotransplantation model: porcine kidneys were transplanted, whereas the functioning recipient kidneys remained in situ. Subsequent to rejection (after 2 hours to 15 days), xenografts were removed, and recipients remained alive for up to 287 days. Immunosuppressive therapy based on cyclophosphamide, cyclosporine, and steroids was maintained for 28 days after transplantation. Using appropriate PCR assays, xenochimerism was found in tissue samples and partly even in peripheral blood leukocytes (PBLs) while the porcine kidneys were in situ. After graft removal, xenochimerism was no longer detectable, thus allowing analysis for possible PERV transmission.

Animals↗
PubMed2001

Matrix attachment region-dependent function of the immunoglobulin mu enhancer involves histone acetylation at a distance without changes in enhancer occupancy.

Nuclear matrix attachment regions (MARs), which flank the immunoglobulin mu heavy-chain enhancer on either side, are required for the activation of the distal variable-region (V(H)) promoter in transgenic mice. Previously, we have shown that the MARs extend a local domain of chromatin accessibility at the mu enhancer to more distal sites. In this report, we examine the influence of MARs on the formation of a nucleoprotein complex at the enhancer and on the acetylation of histones, which have both been implicated in contributing to chromatin accessibility. By in vivo footprint analysis of transgenic mu gene constructs, we show that the occupancy of factor-binding sites at the mu enhancer is similar in transcriptionally active wild-type and transcriptionally inactive DeltaMAR genes. Chromatin immunoprecipitation experiments indicate, however, that the acetylation of histones at enhancer-distal nucleosomes is enhanced 10-fold in the presence of MARs, whereas the levels of histone acetylation at enhancer-proximal nucleosomes are similar for wild-type and DeltaMAR genes. Taken together, these data indicate that the function of MARs in mediating long-range chromatin accessibility and transcriptional activation of the V(H) promoter involves the generation of an extended domain of histone acetylation, independent of changes in the occupancy of the mu enhancer.

Acetylation↗
PubMed2001

Localization and quantification of adhesion molecule expression in the lower uterine segment during premature labor.

AIMS: To investigate localization and concentration of adhesion molecules in the human lower uterine segment during preterm parturition. METHODS: In a prospective study biopsy specimens from the lower uterine segment of 43 patients undergoing cesarean section at 24 + 0 to 36 + 4 weeks' gestation were immunostained for intercellular adhesion molecule-1, endothelial leukocyte adhesion molecule-1, vascular cell adhesion molecule-1, and platelet endothelial cell adhesion molecule-1, and the concentrations measured by enzyme immunoassay. The results were analyzed in relation to the degree of cervical dilatation (< 2 cm, 2- < 4 cm, > or = 4 cm) and duration of labor (< or = 6 h, > 6-12 h; > 12 h). RESULTS: Intercellular adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 were strongly expressed by capillary endothelium, endothelial leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1 to only a minor degree. Intercellular adhesion molecule-1 concentration was greater at > or = 4 cm dilatation than at 2- < 4 cm and after > 12 h labor than after < or = 6 h. Endothelial leukocyte adhesion molecule-1 concentration was greater after > 12 h than after < or = 6 h. CONCLUSIONS: Premature labor is associated with up-regulation of adhesion molecules in the lower uterine segment.

Adult↗
PubMed2001

Tissue concentrations of cytokines in the lower uterine segment during preterm parturition.

AIMS: To determine the concentrations of tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, and interleukin-8 in the lower uterine segment during preterm parturition. METHODS: In 71 patients who delivered prematurely by non-elective cesarean tissue specimens were obtained from the lower uterine segment. The patients were grouped in relation to the stage of cervical dilatation (< 2 cm, 2- < 4 cm, > or = 4 cm), duration of labor (< or = 6 h, > 6-12 h; > 12 h), and parity (1 versus > 1). Cytokine concentrations in protein extracts of the tissue samples were measured using enzyme-linked immunosorbent assays. RESULTS: Median concentration of tumor necrosis factor alpha did not change, but that of interleukin-1 beta, interleukin-6, and interleukin-8 were significantly higher at 2- < 4 cm than at < 2 cm cervical dilatation (6.6, 67.7, and 125.8 versus 1.1, 17.6, and 22.2 pg/mg protein, respectively). The concentrations of interleukin-6 and interleukin-8 showed a further increase at > or = 4 cm (297.2 and 468.6 pg/mg, respectively), but for interleukin-1 beta a decrease was observed (0.6 pg/mg). Cytokine concentrations were not related to duration of labor or parity. CONCLUSIONS: Local inflammation-associated changes that are mainly related to the stage of cervical dilatation and to only a minor degree to uterine activity may play a crucial role in preterm parturition.

Adult↗
PubMed2001

Cutaneous reactions to anticoagulants. Recognition and management.

Anticoagulant-induced skin reactions appear as allergic or necrotic responses to vitamin K antagonists or heparins. Cutaneous allergy has been reported with danaparoid sodium and flush reactions have been seen with hirudins. The pathogenesis of the reactions differs between drugs. Generally, they occur between days 3 to 10 after the start of treatment, but may also occur later. In patients experiencing necrosis with a vitamin K antagonist, concomitant protein C deficiency, protein S deficiency or lupus anticoagulant has been described, whereas the precise mechanism of the other reactions is unknown. In patients with allergic reactions to heparins, cutaneous tests may help to identify alternative anticoagulants. Such a test cannot be performed in patients with skin necrosis. In patients with heparin-induced skin reactions danaparoid sodium may be used after negative intracutaneous testing in some patients and a hirudin may be used without testing in all patients. Heparin-induced skin necrosis has been reported to be mediated by immunologic mechanisms and to be associated with a high frequency of heparin-induced thrombocytopenia type II. Surgical excision of the necrosis may be required. If further anticoagulation is indicated in any patient, extreme caution has to be taken when restarting oral anticoagulants. Because a large number of anticoagulants available today, safe treatment of all patients experiencing anticoagulant-induced skin reactions is feasible.

Anticoagulants↗