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Klaus Fink

Publications and source records attributed to Klaus Fink.

12 recordsLinked to original sources
PubMed2006

Toll-like receptor 4, nitric oxide, and myocardial depression in endotoxemia.

The molecular mechanisms that mediate gram-negative sepsis-associated myocardial dysfunction remain elusive. Myocardial expression of inflammatory mediators is Toll-like receptor 4 (TLR4) dependent. However, it remains to be elucidated whether TLR4, expressed on cardiac myocytes, mediates impairment of cardiac contractility after lipopolysaccharide (LPS) application. Cardiac myocyte contractility, measured as sarcomere shortening of isolated cardiac myocytes from C3H/HeJ (with nonfunctional TLR4) and C3H/HeN (control), were recorded at stimulation frequencies between 0.5 and 10 Hz and after incubation with 1 and 10 mug/mL LPS for up to 8 h. Control cells treated with LPS were investigated with and without a competitive LPS inhibitor (E5564) and a specific inducible nitric oxide synthase (iNOS) inhibitor S-methylisothiourea. In control mice, LPS reduced sarcomere shortening amplitude and prolonged duration of relaxation, whereas sarcomere shortening of C3H/HeJ cells was insensitive to LPS. NFkappaB and iNOS were upregulated after LPS application in control mice compared with C3H/HeJ. Inhibition of TLR4 by E5564 as well as inhibition of iNOS prevented the influence of LPS on contractile activity in control myocytes. LPS-dependent suppression of cardiac myocyte contractility was significantly blunted in C3H/HeJ mice. Competitive inhibition of functional TLR4 with E5564 protects cardiac myocyte contractility against LPS. These findings suggest that TLR4, expressed on cardiac myocytes, contributes to sepsis-induced myocardial dysfunction. E5564, currently under investigation in two clinical phase II trials, seems to be a new therapeutic option for the treatment of myocardial dysfunction in sepsis associated with endotoxemia.

Animals↗
PubMed2006

Prostatic phyto-oestrogen tissue levels in different Austrian regions.

INTRODUCTION: A number of studies suggest that the low incidence of prostate cancer as well as benign prostatic enlargement in Asia depends on the extended consumption of phyto-oestrogens in these parts of the world. In most Asian men, phyto-oestrogen levels are multiple higher compared to Austrian (European) men. The aim of our study was to evaluate, according to the East-West decline, whether there were significant differences within the Austrian population. We compared prostate phyto-oestrogen tissue levels of men living in three different geographical regions of Austria. We further compared men living in rural and urban environments. MATERIAL AND METHODS: Prostatic tissue samples of 103 men undergoing surgery for benign prostatic hyperplasia or prostate cancer were collected and frozen at -40 degrees C. In tissue samples, enterolactone (representative for lignans) and genistein levels (representative for isoflavones) were determined in duplicate by monoclonal antibody-based immunoassays. We subsequently compared tissue levels of men living in rural and urban environments and different geographical regions of Austria. RESULTS: Prostatic enterolactone tissue levels were similar in men living in an urban (median 19.1 ng/g dry weight, range 1.5-76.4) or rural environment (median 15.7 range 0.6-140.6) p = 0.99. The respective values for genistein were 20.5 ng/g dry weight (range 4.6-47.4) and 9.3 (range 0.1-156.7) p = 0.77. Furthermore, enterolactone (p = 0.1) and genistein (p = 0.65) levels were similar in three different geographic regions in Austria. CONCLUSION: No significant differences regarding genistein and enterolactone were found between our study populations. However, we found a wide variation between individual patients.

Austria↗
PubMed2006

Anti-apoptotic function of gelsolin in fas antibody-induced liver failure in vivo.

Apoptosis is a key mechanism underlying fulminant hepatic failure. The role of gelsolin in such apoptotic pathways is not well understood because both pro-apoptotic and anti-apoptotic effects have been reported in vitro, depending on the cell type and in vitro expression model used. Therefore, we studied an in vivo model of hepatic failure by analyzing expression of gelsolin; intrahepatic activation of caspase-3, -8, and -9; and the extent of apoptosis in gelsolin knockout (gsn(-/-)) versus wild-type mice (gsn(+/+)) after exposure to stimulatory Fas antibody Jo-2. Gelsolin was expressed exclusively in sinusoidal lining cells, including sinusoidal endothelial cells and Kupffer cells, of gsn(+/+) mice. Compared with wild-type mice, Jo2-exposed gsn(-/-) mice showed significantly higher numbers of apoptotic cells in the liver (22 +/- 9 versus 5 +/- 4% terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells, P = 0.002); shorter survival (P = 0.037); and enhanced activation of caspase-3 (P = 0.009), -8 (P = 0.004), and -9 (P = 0.004). Furthermore, inhibition of caspase-3 with z-DEVD-fmk blocked Jo2-induced liver failure in all mice. Thus, our data on Jo2-induced hepatic failure suggest that gelsolin exerts an overall anti-apoptotic effect in vivo. Moreover, selective expression of gelsolin in sinusoidal endothelial cells indicates a pivotal role for interactions between sinusoidal endothelial cells and liver parenchymal cells in Fas ligand-mediated liver failure.

Animals↗
PubMed2005

Female mice lacking estrogen receptor beta display prolonged ventricular repolarization and reduced ventricular automaticity after myocardial infarction.

BACKGROUND: Major gender-based differences in the incidence of ventricular tachyarrhythmia after myocardial infarction have been shown in humans. Although the underlying mechanisms are unclear, earlier studies suggest that estrogen receptor-mediated effects play a major role in this process. METHODS AND RESULTS: We examined the effect of estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) on the electrophysiological phenotype in female mice with and without chronic anterior myocardial infarction. There was no significant difference in overall mortality, infarct size, and parameters of left ventricular remodeling when we compared infarcted ERalpha-deficient and ERbeta-deficient mice with infarcted wild-type animals. In the 12-hour telemetric ECG recording 6 weeks after myocardial infarction, surface ECG parameters did not show significant differences in comparisons of ERalpha-deficient mice versus wild-type controls, infarcted versus noninfarcted ERalpha-deficient mice, and infarcted ERalpha-deficient versus infarcted wild-type mice. However, infarcted ERbeta-deficient versus noninfarcted ERbeta-deficient mice showed a significant prolongation of the QT (61+/-6 versus 48+/-8 ms; P<0.05) and QTc intervals (61+/-7 versus 51+/-9 ms; P<0.05) and the JT (42+/-6 versus 31+/-4 ms; P<0.05) and JTc intervals (42+/-7 versus 33+/-4 ms; P<0.05). Furthermore, infarcted ERbeta-deficient versus infarcted wild-type mice showed a significant prolongation of the QT (61+/-6 versus 53+/-8 ms; P<0.05) and QTc intervals (61+/-7 versus 53+/-7 ms; P<0.05) and the JT (42+/-6 versus 31+/-5 ms; P<0.05) and JTc intervals (42+/-7 versus 31+/-5 ms; P<0.05), accompanied by a significant decrease of ventricular premature beats (7+/-21/h versus 71+/-110/h; P<0.05). Finally, real-time polymerase chain reaction-based quantitative analysis of mRNA levels showed a significantly lower expression of Kv4.3 (coding for I(to)) in ERbeta-deficient mice (P<0.05). CONCLUSIONS: Estrogen receptor beta deficiency results in prolonged ventricular repolarization and decreased ventricular automaticity in female mice with chronic myocardial infarction.

Animals↗
PubMed2004

Decrease of mitochondrial DNA content and energy metabolism in renal cell carcinoma.

To elucidate the relationship between tumor genesis and the mitochondrial energy metabolism in renal neoplasms, we studied three individual enzyme activities of the oxidative phosphorylation, two components of the Krebs cycle and the mitochondrial DNA content of renal carcinomas including 29 conventional, five papillary, two unclassified carcinomas with sarcomatoid features and one collecting duct carcinoma. A significant reduction of all mitochondrial enzyme activities including complex V, as well as of the mitochondrial DNA content was detected in 34 of 37 renal carcinoma tissues as compared with control kidney. Mitochondrial enzyme activities and mitochondrial DNA levels were not statistically different between the conventional, papillary and unclassified sarcomatoid type of renal carcinoma and did not correlate with tumour grade, metastasis, ploidy and proliferative activity as determined by Ki-67 staining. Taken together, our data indicate that a co-ordinated down-regulation of all components necessary for mitochondrial energy metabolism occurs in most renal carcinomas as an early event in carcinoma formation, which does not change with progression of the disease.

Adult↗
PubMed2004

Neuronal gelsolin prevents apoptosis by enhancing actin depolymerization.

Gelsolin (gsn), an actin-severing protein, protects neurons from excitotoxic cell death via inactivation of membranous Ca(2+) channels. Its role during apoptotic cell death, however, has remained unclear. Using several models of neuronal cell death, we demonstrate that endogenous gelsolin has anti-apoptotic properties that correlate to its dynamic actions on the cytoskeleton. We show that neurons lacking gelsolin (gsn(-/-)) have enhanced apoptosis following exposure to staurosporine, thapsigargin, or the cholinergic toxin ethylcholine aziridinium (AF64A). AF64A-induced loss of mitochondrial membrane potential and activation of caspase-3 was specifically enhanced in gsn(-/-) neurons and could be reversed by pharmacological inhibition of mitochondrial permeability transition. Moreover, increased caspase-3 activation and cell death in AF64A-treated gsn(-/-) neurons were completely reversed by pharmacological depolymerization of actin filaments and further enhanced by their stabilization. In conclusion, actin remodeling by endogenous gelsolin or analogues protects neurons from apoptosis mediated by mitochondria and caspase-3.

Actin Cytoskeleton↗
PubMed2004

Phytoestrogen tissue levels in benign prostatic hyperplasia and prostate cancer and their association with prostatic diseases.

OBJECTIVES: To compare phytoestrogen tissue levels in men with small-volume benign prostatic hyperplasia (BPH), large-volume BPH, and prostate cancer (PCa). METHODS: Prostatic tissue samples of men consuming a Western diet who underwent surgery for BPH (n = 63) or PCa (n = 31) were collected and frozen at -40 degrees C. In the tissue samples, the enterolactone and genistein levels were determined in duplicate by monoclonal antibody-based immunoassays. We subsequently compared the tissue levels in patients with BPH and PCa and studied the impact of enterolactone and genistein on prostate volume. RESULTS: The enterolactone tissue levels were comparable in patients with BPH and PCa and revealed no correlation to prostate volume. The genistein tissue levels tended to be lower in patients with PCa (median 8.4 ng/g dry weight) compared with the entire BPH group (11.0 ng/g dry weight; P = 0.072). In addition, the genistein tissue levels were significantly greater in men with small-volume BPH (median 20.9 ng/g dry weight) compared with those with large-volume BPH (8.8 ng/g dry weight; P = 0.023). CONCLUSIONS: Our data suggest an involvement of genistein in the pathogenesis of BPH and, possibly, of PCa. The impact of enterolactone is currently unknown.

4-Butyrolactone↗
PubMed2003

Magnitude of trauma and personality change.

In this paper the author postulates that, in post-traumatic personality structures caused by overwhelming traumatic experiences, pre-traumatic personality features and childhood experiences are of little or no relevance. Sixty-four survivors of Nazi concentration camps are examined, their concentration camp experiences detailed and pre-persecution histories and post-persecution psychopathology studied. The significance of a concentration camp experience is analytically discussed and evaluated. This study shows that 52 cases (81.2%) of the 64 survivors of concentration camps presented an almost identical depressive personality structure irrespective of their prepersecution life history. The 64 survivors of concentration camps are psychologically compared to 78 cases of people who, in view of the menacing circumstances, decided to emigrate and in this way were spared from becoming victims of the Nazi 'final solution'. Finally, the author discusses the value of psychoanalytical treatment.

Adult↗
PubMed2002

Ca2+ entry via P/Q-type Ca2+ channels and the Na+/Ca2+ exchanger in rat and human neocortical synaptosomes.

Rat or human neocortical synaptosomes were used to study the role of voltage-gated Ca(2+) channels and the Na(+)/Ca(2+) exchanger in (45)Ca(2+) influx into nerve terminals. K(+) depolarization-induced (45)Ca(2+) influx through voltage-gated Ca(2+) channels into rat or human synaptosomes was completely blocked by mibefradil 30 microM or Cd(2+) 100 microM but was not affected by tetrodotoxin 1 microM. It was reduced by omega-agatoxin IVA 0.2 microM by 68% in synaptosomes of either species, whereas omega-conotoxin GVIA 0.1 microM and nifedipine 1 microM had no effect. Veratridine-induced (45)Ca(2+) entry into rat neocortical synaptosomes was completely blocked by mibefradil 30 microM, reduced by 80% by Cd(2+) 100 microM, by 90% by tetrodotoxin 1 microM and by 53% by omega-agatoxin IVA 0.2 microM but not by omega-conotoxin GVIA 0.1 microM or nifedipine 1 microM. Na(+)/Ca(2+) exchanger-mediated (45)Ca(2+) uptake into rat neocortical synaptosomes evoked by replacement of Na(+) by choline(+) in the incubation buffer was reduced by KB-R7943 (3-50 microM), an inhibitor of the Na(+)/Ca(2+) exchanger, in a concentration-dependent manner (maximal inhibition by 46% at 50 microM; IC(23%)=7.1 microM). Mibefradil also inhibited the Na(+)/Ca(2+) exchanger-mediated Ca(2+) uptake, although at 3.7 times lower potency (IC(23%)=26 microM). It is concluded that in rat and human neocortical nerve terminals Ca(2+) entry is mediated under physiological conditions by P/Q-type, but not by N- or L-type Ca(2+) channels or the Na(+)/Ca(2+) exchanger. If the cytosolic Na(+) concentration is increased, Ca(2+) is also taken up via the Na(+)/Ca(2+) exchanger. In addition to the ability of mibefradil to block all voltage-operated Ca(2+) channels, this drug is a low potency inhibitor of the Na(+)/Ca(2+) exchanger.

Adult↗
PubMed2002

Induction of atrial fibrillation in mice by rapid transesophageal atrial pacing.

OBJECTIVE: Atrial fibrillation (AF) as an "indicator arrhythmia" for enhanced atrial vulnerability in mouse hearts has not yet been systematically examined. We therefore evaluated a transesophageal rapid atrial stimulation protocol for the induction of AF in C57Bl/6 mice. METHODS: 40 C57Bl/6 mice (19 female and 21 male; 5.2 +/- 2.1 months; 18 - 27 g) were examined by closed chest transesophageal atrial stimulation. Baseline ECG and electrophysiological parameters, AF-inducing stimulation cycle length (CL) and AF duration were analyzed. RESULTS: The surface ECG demonstrated a significantly faster heart rate in female mice (R-R: 138.7 +/- 19.9 ms versus 150.5 +/- 15.7 ms, P < 0.05). AF was inducible in 90 % of the population and not inducible in 4 mice, all female (21 % in this subgroup). Mean induction CL was 27.4 +/- 7.3 ms. Mean AF duration was 26.9 +/- 42.6 s before spontaneous termination. In a subgroup of 4 female and 4 male mice (mean age 7.5 months), successive testing of AF induction showed a range of higher susceptibility to AF at stimulus amplitudes of 3.0 - 4.0 mA and stimulation CLs between 15 - 25 ms. AF induction was observed to be constantly reproducible in the individual animals. No correlation to pacing stimulus length and amplitude was found. CONCLUSIONS: This study demonstrates that it is possible to reproducibly induce self-terminating AF and supraventricular arrhythmias in mice by transesophageal atrial burst stimulation. The presented method allowing serial testings of the same animal can be a useful tool in further investigations with transgenic mice and might be helpful in the characterization of underlying genetic or molecular mechanisms of AF.

Animals↗
PubMed2002

Inhibition of neuronal Ca(2+) influx by gabapentin and pregabalin in the human neocortex.

Gabapentin and pregabalin (S-(+)-3-isobutylgaba) produced concentration-dependent inhibitions of the K(+)-induced [Ca(2+)](i) increase in fura-2-loaded human neocortical synaptosomes (IC(50)=17 microM for both compounds; respective maximal inhibitions of 37 and 35%). The weaker enantiomer of pregabalin, R-(-)-3-isobutylgaba, was inactive. These findings were consistent with the potency of these drugs to inhibit [(3)H]-gabapentin binding to human neocortical membranes. The inhibitory effect of gabapentin on the K(+)-induced [Ca(2+)](i) increase was prevented by the P/Q-type voltage-gated Ca(2+) channel blocker omega-agatoxin IVA. The alpha 2 delta-1, alpha 2 delta-2, and alpha 2 delta-3 subunits of voltage-gated Ca(2+) channels, presumed sites of gabapentin and pregabalin action, were detected with immunoblots of human neocortical synaptosomes. The K(+)-evoked release of [(3)H]-noradrenaline from human neocortical slices was inhibited by gabapentin (maximal inhibition of 31%); this effect was prevented by the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide). Gabapentin and pregabalin may bind to the Ca(2+) channel alpha 2 delta subunit to selectively attenuate depolarization-induced Ca(2+) influx of presynaptic P/Q-type Ca(2+) channels; this results in decreased glutamate/aspartate release from excitatory amino acid nerve terminals leading to a reduced activation of AMPA heteroreceptors on noradrenergic nerve terminals.

Acetates↗