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Biomedical subjects

G Stark

Publications and source records attributed to G Stark.

At least 91 records · Page 5Linked to original sources
PubMed1994

The transcription factor MTF-1 is essential for basal and heavy metal-induced metallothionein gene expression.

We have described and cloned previously a factor (MTF-1) that binds specifically to heavy metal-responsive DNA sequence elements in the enhancer/promoter region of metallothionein genes. MTF-1 is a protein of 72.5 kDa that contains six zinc fingers and multiple domains for transcriptional activation. Here we report the disruption of both alleles of the MTF-1 gene in mouse embryonic stem cells by homologous recombination. The resulting null mutant cell line fails to produce detectable amounts of MTF-1. Moreover, due to the loss of MTF-1, the endogenous metallothionein I and II genes are silent, indicating that MTF-1 is required for both their basal and zinc-induced transcription. In addition to zinc, other heavy metals, including cadmium, copper, nickel and lead, also fail to activate metal-responsive promoters in null mutant cells. However, cotransfection of an MTF-1 expression vector and metal-responsive reporter genes yields strong basal transcription that can be further boosted by zinc treatment of cells. These results demonstrate that MTF-1 is essential for metallothionein gene regulation. Finally, we present evidence that MTF-1 itself is a zinc sensor, which exhibits increased DNA binding activity upon zinc treatment.

Animals↗
PubMed1994

A novel member of the interferon receptor family complements functionality of the murine interferon gamma receptor in human cells.

Expression of the human interferon gamma receptor (IFN-gamma R) in mouse cells is not sufficient to confer biological responsiveness to human IFN-gamma and vice versa. An additional species-specific component is required for signal transduction. We identified this cofactor by expression cloning in simian COS cells stably transfected with the nonfunctional murine IFN-gamma R and a IFN-gamma-inducible reporter construct encoding the human Tac antigen (interleukin-2 receptor alpha chain, CD25). A cDNA clone was obtained that, upon stable transfection, rendered human HEp-2 cells expressing the murine IFN-gamma R fully responsive to murine IFN-gamma. This cDNA encodes a novel 332 amino acid type I transmembrane protein that belongs to the IFN receptor family and that we designate IFN-gamma R beta chain.

Amino Acid Sequence↗
PubMed1994

Frequency-dependent effects of propafenone decrease with duration of ventricular tachycardia in isolated guinea pig hearts.

Na+ channel blockers terminate tachyarrhythmias primarily by rate-dependent effects. The purpose of this study was to investigate the use-dependent effects of propafenone in isolated guinea pig and rabbit hearts perfused by the method of Langendorff. In the presence of propafenone (0.3 microM) during ventricular pacing, an abrupt decrease of the pacing cycle length (220 ms to 120 ms) slowed the intraventricular conduction with a transient peak QRS prolongation of 33.8 +/- 2.0% after 5.7 +/- 0.5 s (P < 0.01) which subsequently decreased to a steady state of 14.0 +/- 2.5% after 38.0 +/- 5.5 s (mean +/- S.E.M.; n = 10; P < 0.01). The ventricular effective refractory period was significantly prolonged if evaluated by a train of 10 basic stimuli (S1) (interstimulus interval: 120 ms) followed by a premature stimulus (S2). However, when the train of basic stimuli was increased the effective refractory period diminished progressively. An initial increase in total activation time vanished with continued rapid ventricular stimulation. These effects may be explained by a shortening of the action potential during high rates resulting in a decreased binding of propafenone to Na+ channels.

Action Potentials↗
PubMed1994

Thrombolytic treatment and balloon angioplasty in chronic occlusion of the aortic bifurcation.

OBJECTIVE: To evaluate nonsurgical alternatives in reopening chronically occluded aortic bifurcation. DESIGN: Uncontrolled randomized study. SETTING: University-affiliated referral center for vascular diseases. PATIENTS: Twenty-five of 39 consecutive patients with chronic aortoiliac disease including a totally occluded aortic bifurcation were found to be acceptable candidates for an aortobifemoral prosthetic graft. INTERVENTION: Patients were randomly assigned to receive either streptokinase or urokinase or recombinant tissue-type plasminogen activator (rt-PA). In cases of successful thrombolysis and residual obstructions, subsequent balloon angioplasty was attempted. Prosthetic bypass grafting was done if thrombolytic treatment and balloon angioplasty failed. RESULTS: Complete lysis was achieved in 5 of 25 patients (20%). In 10 (40%) patients, lysis showed residual obstructions, which were reopened mechanically in 8 patients; 2 patients had extra-anatomical bypass grafts. Ten patients (40%) without thrombolysis had surgical aortobifemoral bypass grafts. Overall, recanalization and clinical improvement were achieved in 13 of 25 patients (52%) by thrombolytic therapy and subsequent balloon angioplasty. The recanalization rate did not differ among the different thrombolytic drugs. However, rt-PA therapy resulted in reopening after 4 days of treatment; streptokinase, after 6 days; and urokinase, after 9 days (P < 0.005). No major complications or deaths occurred. CONCLUSION: Thrombolytic treatment followed by balloon angioplasty may help avoid the need for aorto-bifemoral prosthetic bypass grafting in more than 50% of patients with chronic aortoiliac disease.

Adult↗
PubMed1994

A prospective evaluation of sensitivity and specificity of the ankle/brachial index in the follow-up of superficial femoral artery occlusions treated by angioplasty.

The aim of this study was to provide estimates of sensitivity and specificity of clinical history, pulses, and ankle/brachial index (ABI) in the follow-up of atherosclerotic occlusions of the superficial femoral artery treated by peripheral transluminal angioplasty (PTA). A total of 116 patients were followed prospectively for 1 year after angioplasty with follow-up visits immediately after angioplasty, and at 3, 6, and 12 months. All patients underwent digital subtraction angiography after 1 year of if they reported a deterioration of their symptoms. Reobstruction was defined as reocclusion or as restenosis exceeding 70%. Patency rates were calculated separately by clinical and ankle/brachial criteria; sensitivity and specificity were derived using angiography as standard. The presence or absence of pulses distal to the treated vessel segment had a sensitivity of 78% and a specificity of 66% for a reocclusion or significant restenosis; subjective complaints evaluated by history had a sensitivity of 83% and a specificity of 51%. The sensitivity of the ABI was 72% and 66%, with a specificity of 82% and 100% for cutoff values of 0.10 and 0.15, respectively. One year after PTA the angiographic patency rate was 39% +/- 5%; the patency rate based on ABI criteria 34% +/- 5%. A deterioration in the ABI by 0.15 indicated with reasonable certainty a reocclusion or significant restenosis whereas the sensitivity of the ABI was poor in detecting significant restenosis after PTA of occlusions of the superficial femoral artery. When only clinical criteria were used, the true patency rate was significantly overestimated as more than half of all reobstructions remained asymptomatic.

Angiography, Digital Subtraction↗
PubMed1994

Adenosine for the management of patients with tachycardias--a new protocol.

We developed a new protocol for diagnosis and treatment of patients with sustained tachycardias (heart rate > 150 beats.min-1). The patients first underwent vagal manoeuvres; if those remained unsuccessful, i.v. adenosine in increasing doses of 6, 12, and 18 mg was administered until sinus rhythm (SR) or transient atrioventricular (AV) block, unmasking the underlying rhythm, was recorded. In the latter and in the non-responding cases other antiarrhythmics were applied. Ninety-three episodes of tachycardia in 46 patients were treated according to this protocol. Six episodes (6%) were terminated by carotid massage, 64 of the remaining 87 episodes (74%) responded to adenosine with return to SR. Conversion to SR occurred more often in episodes with narrow- than in wide-complex tachycardia (81 vs. 59%, P < 0.05). To achieve SR, the mean adenosine dose was lower in narrow- than in wide-complex tachycardia (13 +/- 8 vs 21 +/- 10 mg; P < 0.01). The duration of asystole after adenosine did not differ between these two groups, whereas the duration of arrhythmia after adenosine differed significantly (8.5 +/- 5.8 vs 18.6 +/- 22.9 s; P < 0.05). Side effects of adenosine such as flush, dyspnoea, and chest pain did not seem to be dose dependent and occurred in about 20%. According to our protocol, in more than 75% SR was achieved in patients with sustained tachycardias after vagal manoeuvres and adenosine.

Adenosine↗
PubMed1994

Action of ATP on ventricular automaticity.

ATP is an effective treatment of supraventricular tachycardia when the atrioventricular (AV) node is part of the reentrant circuit. However, the lower a pace-maker in the pacemaker hierarchy, the more sensitive it is to adenosine. Therefore, we investigated the effects of ATP on ventricular automaticity in in vivo and in vitro conditions. Wide and narrow QRS complex tachycardia in 46 patients was treated with 6, 12, and 18 mg ATP as sequential intravenous (i.v.) bolus. ATP terminated tachycardias in 67%. Bolus infusion ATP caused < or = 6.4-s asystole that was self-limited. Perfusion of isolated spontaneously beating guinea pig heart with 100 microM ATP completely suppressed ventricular automaticity. After ATP-infusion was discontinued, the first ventricular beat was evident after 3.1 +/- 0.9 s and sinus node activity recovered with a time constant of 3.0 +/- 1.1 s. Because sinus node and ventricular automaticity recovered within seconds after ATP infusion was discontinued in vitro, recovery in vivo is also likely to be determined by the short half-life (+1/2) of ATP.

Adenosine Triphosphate↗
PubMed1994

Stability of dantrolene oral suspension prepared from capsules.

The chemical stability of an extemporaneously compounded dantrolene oral suspension (5 mg/ml dantrolene sodium) in Syrup BP containing citric acid with and without methyl hydroxybenzoate preservative was studied on storage at 5, 25 and 40 degrees C for 150 days in high density polyethylene dispensing bottles. The amount of dantrolene free acid in suspension was monitored by a stability indicating HPLC assay. There was no significant decomposition of dantrolene under all storage conditions irrespective of the presence of preservative. The results show that the formulation of dantrolene oral suspension provides a convenient and stable dosage form for use in pediatric patients and in those unable to swallow capsules. It is recommended that the formulation be stored at room temperature and in the absence of microbiological testing a shelf-life of 30 days is proposed for the product prepared with preserved syrup.

Capsules↗
PubMed1993

A comparison of the effects of adenosine and verapamil on the conduction and pacemaker system of isolated guinea pig hearts.

Adenosine and verapamil are effective in the treatment of supraventricular arrhythmias. Also, both substances can provoke sinus node arrest or a third-degree atrioventricular (AV) block with a ventricular escape rhythm. The aim of this study was to compare the effects of adenosine and verapamil on sinus rate and on the rate of the ventricular escape rhythm while a third-degree AV block was induced by both drugs. Experiments were performed on isolated spontaneously beating guinea pig hearts perfused by the method of Langendorff. A third-degree AV block was induced by adenosine at a concentration of 30 microns and by verapamil at a concentration of 1 micron. Adenosine (30 microns) reduced sinus rate only moderately whereas it nearly halved the rate of the ventricular escape rhythm compared with that produced by cutting the AV node. In contrast, verapamil left the rate of the ventricular escape rhythm unchanged but nearly halved the spontaneous sinus rate compared with control conditions. In conclusion, adenosine and verapamil given at dosages with comparable effect on the AV node have markedly different effects on different pacemakers in the same heart. In the treatment of supraventricular arrhythmias, adenosine probably should be used with great caution since it can cause a very slow ventricular escape rhythm.

Adenosine↗
PubMed1993

Endothelium-dependent contractions to NG-nitro-L-arginine methyl ester in the porcine isolated splenic artery are sensitive to cyclooxygenase and lipoxygenase inhibitors.

The nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), produced large endothelium-dependent contractions in isolated segments of the porcine splenic artery, equivalent to approximately 30% of the maximum responses to 5-hydroxytryptamine (5-HT). These responses were inhibited by 1mM L-arginine, but not by either 1mM D-arginine or the superoxide anion scavenger, superoxide dismutase. However, L-NAME-induced contractions were markedly inhibited by the cyclooxygenase inhibitor, flurbiprofen, and the lipoxygenase inhibitor, 2,3,5-tri-methyl-6-(12-hydroxy-5,10-dodecadiynyl)1,4-benzoquinone (AA-861). The combined cyclooxygenase and lipoxygenase inhibitor 3-amino-1-[m-(trifluoromethyl)phenyl]-2-pyrazoline (BW-755C) abolished L-NAME-induced contractions. These findings suggest that suppression of endothelial nitric oxide synthase in the porcine isolated splenic artery results in activation of arachidonic metabolism and production of vasoconstrictor eicosanoids.

Amino Acid Oxidoreductases↗
PubMed1993

Inactivation by ionizing radiation of ion channels formed by polyene antibiotics amphotericin B and nystatin in lipid membranes: an inverse dose-rate behavior.

The phenomena reported are part of a study about the effects of ionizing radiation on membrane transport. We found that the conductance of lipid membranes in the presence of the polyene-antibiotics nystatin or amphotericin B is reduced to virtually zero following irradiation. Ion channels formed by these substances seem to represent extremely sensitive structures being inactivated by radiation doses in the range of a few Centigray (1 cGy = 1 rad) at sufficiently small dose rates. Inactivation shows a so-called inverse dose-rate behavior, i.e., at constant radiation dose the effect increases with decreasing dose rate. Similar to radiation-induced lipid peroxidation the phenomenon may be understood on the basis of a radical chain mechanism initiated by free radicals of water radiolysis. The process--via peroxidation of the polyene part of the molecules--is suggested to modify the hydrophobic exterior and to destabilize the barrel-like structure of the ion channels.

Amphotericin B↗
PubMed1993

A simplified procedure for intra-arterial thrombolysis with tissue-type plasminogen activator in peripheral arterial occlusive disease: primary and long-term results.

One-hundred and fifty patients with thrombotic and 60 patients with embolic occlusions of the superficial femoral and/or popliteal artery underwent a simplified IAT (intra-arterial thrombolysis) procedure. Ten mg rt-PA combined with 3000 IU Heparin were infused over 6 h, thereafter the extent of thrombolysis was checked fluoroscopically and the above mentioned treatment course repeated up to four times if necessary. The IAT regimen employed did not involve mechanical recanalization attempts; if complete thrombolysis revealed an underlying stenosis, a PTA (percutaneous transluminal angioplasty) was subsequently performed. IAT resulted in complete recanalization of 88 thrombotic occlusions (59%; 95% confidence interval: 50.8%-66.8%) and of 53 embolic occlusions (88%; 95% confidence interval: 77.1%-94.8% P < 0.001). In a further 33 (22%) thrombotic and four (7%) embolic occlusions IAT reduced the length of the occluded segment. At discharge, 102 (67%) patients with thrombotic and 55 (92%) patients with embolic occlusions were clinically improved. Overall, untoward effects occurred in 60 patients (29%): 47 (22%) were minor. Four patients (2%) suffered a systemic haemorrhage (three gastrointestinal, one macrohaematuria). The cumulative potency rate was significantly higher in patients with embolic occlusions throughout follow-up (82% vs 49% for thrombotic occlusions at 2 years, P < 0.001). Although all amputations were carried out in patients with thrombotic occlusions, follow-up mortality did not differ significantly between patients with embolic and thrombotic occlusions.

Adult↗
PubMed1993

Frequency-dependent effects of adenosine and verapamil on atrioventricular conduction of isolated guinea pig hearts.

Frequency-dependent depressant effects of a drug on slow channels in the atrioventricular (AV) node are important in its efficacy against supraventricular tachycardias. Verapamil terminates reentrant supraventricular arrhythmias by depressing conduction through the AV node. Similar effects have been described for adenosine. We compared the use-dependent effects of both drugs on AV nodal conduction in isolated guinea pig hearts perfused by the method of Langendorff. Adenosine 3 microM and verapamil 0.01 microM caused a comparable prolongation of AV conduction time (AVCT) and reduction in sinus rate (SR). The time dependence of drug-induced changes in AV conduction was characterized after the atrial pacing rate was changed abruptly. The basic cycle length was shortened abruptly from 240 to 180 ms. The resulting time constant for adenosine (tau = 467 +/- 187 beats, mean +/- SD) was significantly (p < 0.05) longer than that for verapamil (tau = 264 +/- 121 beats). At a pacing cycle length of 180 ms, the rate-dependent conduction slowing tended to be more pronounced in the presence of adenosine than of verapamil. Adenosine had more pronounced frequency-dependent effects on AV conduction than did the calcium channel blocker verapamil. This may explain the higher clinical efficacy of adenosine in supraventricular tachycardias in which the AV node forms a part of the reentrant circuit.

Adenosine↗
PubMed1992

Pulsed excimer laser versus continuous-wave Nd:YAG laser versus conventional angioplasty of peripheral arterial occlusions: prospective, controlled, randomised trial.

Early clinical studies of coronary and peripheral laser angioplasty showed that arterial occlusions could be recanalised by continuous-wave lasers delivered with contact probes and by pulsed lasers applied with multifibre catheters. However, whether laser-assisted angioplasty improves success rates in reopening occlusions and in long-term patency rates is unclear. We have compared the primary recanalisation and long-term patency rates after laser-assisted and conventional percutaneous transluminal angioplasty (PTA) of femoropopliteal artery occlusions in 116 consecutive symptomatic patients (excimer laser 37, Nd:YAG laser 40, PTA 39). Primary recanalisation was achieved in 81 patients (70%). The primary recanalisation rate achieved with the excimer laser was significantly lower than that with the Nd:YAG laser (49% vs 78%, p < 0.01) or with PTA (82%, p < 0.003). The overall angiographic recanalisation rate (primary and secondary recanalisation) after laser and PTA was 89%. After 3 months, clinical improvement was recorded in 76% of patients. Clinical long-term results were available in 94 (91%), and angiographic long-term results in 77 (75%), of 103 successfully recanalised patients. Life-table analysis of the long-term results revealed no significant difference of the restenosis rate between the three treatment groups. The 12-month patency rate was 60% as assessed clinically and 39% as judged by angiography. Primary and secondary recanalisation rates and long-term patency rates were significantly correlated with length of the occlusion. Our results suggest that PTA of femoropopliteal artery occlusions is only indicated if the occlusion is short (< 8 cm) and that laser-assisted angioplasty should only be used after failure of conventional PTA.

Aged↗
PubMed1992

Membrane actions of calcitonin gene-related peptide in cardiac and smooth muscle myocytes.

Calcitonin gene-related peptide is a 37-amino acid neuropeptide acting as a transmitter of nonadrenergic, noncholinergic nerves in the heart. Binding sites of high affinity have been reported in coronary arteries, in atria, and, of minor density, in ventricular myocardium. These sites are likely linked to G-proteins mediating modifications of ion channel opening probability and duration and to stimulation of adenylate cyclase activity and cAMP-mediated alterations of ion channel activities. In isolated and perfused guinea pig hearts, low concentrations of CGRP (1-3 nM) exerted no chronotropic effect, but increased coronary flow slightly. Atrioventricular conduction duration and effective refractory period of atrioventricular conduction were prolonged by 3 nM of CGRP. The higher concentration of 10 nM increased the sinus rate, and the effects on the atrioventricular node were counterbalanced. HV and QRS duration of the ECG remained essentially unchanged, but persistent ventricular fibrillation was inducible by burst stimulation in all CGRP-treated hearts. Results in human myometrial myocytes indicate that CGRP exerted direct G protein-mediated activation of potassium channels, leading to hyperpolarization and smooth muscle relaxation. Activation of potassium channels, most prominent in smooth muscle relaxation, is likely an additional factor in the cardiostimulatory profile of CGRP.

Action Potentials↗
PubMed1992

Photodynamic inactivation of an ion channel: gramicidin A.

The ion channel formed by the peptide gramicidin A in planar lipid membranes is inactivated by visible light in the presence of the photosensitizer Rose Bengal. This is concluded from the strong decrease of the membrane conductance by more than two orders of magnitude. Experiments performed at different oxygen concentrations, in the presence of the singlet oxygen quenchers beta-carotene or alpha-tocopherol indicate, that presumably a type I process between the dye Rose Bengal and the tryptophan residues of the gramicidin channel with a subsequent oxidation of the tryptophans is responsible for the loss of the conductance properties of the channel.

Amino Acid Sequence↗