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The current generation of ground-based imaging atmospheric Cherenkov telescopes (IACTs) operate in the very-high-energy (VHE) domain from ~100 GeV to ~100 TeV. They use electronic digital trigger systems to discern the Cherenkov light flashes emitted by extensive air showers (EASs), from the overwhelming light of the night sky (LoNS) background. Near the telescope energy threshold, the number of emitted Cherenkov photons by gamma-ray-induced EASs is comparable to the fluctuations of the LoNS and the photon distribution at the Cherenkov-imaging camera plane becomes patchy. This results in a severe loss of effectiveness of the digital triggers based on combinatorial logic of thresholded signals. A stereoscopic analog trigger system has been developed for improving the detection capabilities of the Major Atmospheric Gamma-ray Imaging Cherenkov (MAGIC) telescopes at the lowest energies. It is based on the analog sum of the photosensor electrical signals. In this article, the architectural design, technical performances, and configuration of this stereoscopic analog trigger, dubbed “Sum-Trigger-II,” are described. [ABSTRACT FROM AUTHOR]

Empiric initial antibiotic therapy of bacterial infections is based primarily upon the susceptibility of the most common causative pathogens. The purpose of this study was to provide susceptibility data on six bacterial species known to cause ear, nose and throat (ENT) infections. A total of 1066 isolates collected during a nationwide laboratory-based surveillance study were analysed. All Streptococcus pyogenes isolates were penicillin (PEN)-susceptible, indicating that natural penicillins can still be recommended as the first-line treatment for group A streptococcal tonsillopharyngitis. Of the S. pneumoniae isolates, 92.9% were PEN-susceptible and of the Haemophilus influenzae isolates, 89.7% were amoxicillin-susceptible, retaining aminopenicillins as the first-line treatment for acute otitis media (AOM) and acute rhinosinusitis (ARS), in case antibiotic therapy is considered. In contrast, cefuroxime axetil seems less likely to be suitable for the treatment of AOM or ARS, as all Moraxella catarrhalis and >99% of the H. influenzae isolates were categorised as intermediate or resistant. The susceptibility rates of Pseudomonas aeruginosa were 97-100% for the drugs tested, except for the fluoroquinolones (87.6%). Overall, bacterial isolates from outpatients presenting with ENT infections showed low frequencies of resistance in Germany. However, given the emergence of multidrug resistance to standard antibiotics in Escherichia coli and other pathogens, inappropriate use of broad-spectrum antibiotics for the treatment of ENT infections has to be avoided. [ABSTRACT FROM AUTHOR]

We show asymptotic completeness for a class of superradiant Klein--Gordon equations. Our results are applied to the Klein--Gordon equation on the De Sitter--Kerr metric with small angular momentum of the black hole. For this equation we obtain asymptotic completeness for fixed angular momentum of the field. [ABSTRACT FROM AUTHOR]

Körber-Irrgang, B., Wetzstein, H.-G., Bagel-Trah, S., Hafner, D., Kresken, M. Comparative activity of pradofloxacin and marbofloxacin against coagulase-positive staphylococci in a pharmacokinetic-pharmacodynamic model based on canine pharmacokinetics. J. vet. Pharmacol. Therap. 35, 571-579. Pradofloxacin (PRA), a novel veterinary 8-cyano-fluoroquinolone (FQ), is active against Staphylococcus pseudintermedius, the primary cause of canine pyoderma. An in vitro pharmacokinetic-pharmacodynamic model was used to compare the activities of PRA and marbofloxacin (MAR) against three clinical isolates of S. pseudintermedius and reference strain Staphylococcus aureus ATCC 6538. Experiments were performed involving populations of 1010 CFU corresponding to an inoculum density of approximately 5 × 107 CFU/mL. The time course of free drug concentrations in canine serum was modelled, resulting from once daily standard oral dosing of 3 mg of PRA/kg and 2 mg of MAR/kg. In addition, experimentally high doses of 6 mg of PRA/kg and 16 mg of MAR/kg were tested against the least susceptible strain. Viable counts were monitored over 24 h. At concentrations associated with standard doses, PRA caused a faster and more sustained killing than MAR of all strains. The ratios of free drug under the concentration-time curve for 24 h over MIC and the maximum concentration of free drug over MIC were at least 90 and 26, and 8.5 and 2.1 for PRA and MAR, respectively. At experimentally high doses, PRA was superior to MAR in terms of immediate killing. Subpopulations with reduced susceptibility to either FQ did not emerge. We conclude that PRA is likely to be an efficacious therapy of canine staphylococcal infections. [ABSTRACT FROM AUTHOR]

PTEN (phosphatase and tensin homologue deleted from chromosome 10) is a well established tumor suppressor gene, which was cloned to chromosome 10q23. PTEN plays an important role in controlling cell growth, apoptosis, cell adhesion, and cell migration. In various studies, a genetic change as well as loss of PTEN expression by different carcinomas has been described. To date, the role of PTEN as a differentiation marker for neuroendocrine tumors (NET) and for the loss of PTEN expression is still unknown. It is assumed that loss of PTEN expression is important for tumor progression of NETs. We hypothesize that PTEN might be used as a new prognostic marker. We report 38 patients with a NET of the pancreas. Tumor tissues were surgically resected, fixed in formalin, and embedded in paraffin. PTEN expression was evaluated by immunohistochemistry and was correlated with several clinical and pathological parameters of each individual tumor. After evaluation of our immunohistochemistry data using a modified Remmele Score, a widely accepted method for categorizing staining results for reports and statistical evaluation, staining results of PTEN expression were correlated with the clinical and pathological parameters of each individual tumor. Our data demonstrates a significant difference in survival with existence of lymph node or distant metastases. Negative patients show a significant better survival compared with positive patients. Furthermore, we show a significant difference between PTEN expression and WHO or TNM classification. Taken together, our data shows a positive correlation between WHO classification and the new TNM classification of NETs, and loss of PTEN expression as well as survival. These results strongly implicate that PTEN might be helpful as a new prognostic factor. [ABSTRACT FROM AUTHOR]

Here we tested whether global histone modifications predict survival in organic hyperinsulinism and whether global histone modification pattern can be used to distinguish benign from malignant primary insulinoma. A tissue microarray (TMA) was built, using samples from 63 patients with organic hyperinsulinism. The TMA was classified according to the WHO classification of 2004 [WHO 1A: benign insulinoma (wdPET); WHO 1B: unknown behavior (wdPETub); WHO 2/3: malignant insulinoma (wdPEC/pdPEC)]. The TMA consisted of tissue cores from islands of Langerhans, primary insulinomas, lymph node metastases, and hepatic metastases. Immunohistochemistry was performed on consecutive TMA slides with antibodies against H3K9Ac, H3K18Ac, H4K12Ac, H3K4diMe, and H4R3diMe. The Remmele immunoreactive scoring system was used to classify the staining. The IHC staining results were correlated to the WHO-classification of 2004 as well as to clinical follow-up data (mean: 107 months; range: 1-312 months). A nuclear staining pattern was observed for all antibodies directed against histone H3 and H4 acetylation/methylation sites. We observed significant differences in the distribution of the medians across all investigated tissue types (H3K9Ac, p = 0.004; H3K18Ac, p = 0.001; H4K12Ac, p = 0.006; H4R3diMe, p = 0.002) except for H3K4diMe (p = 0.183). Correlation of the histone modification with the WHO-classification and clinical follow-up data, showed in the dichotomized groups ["low" (score 0-3), "moderate" (4-7) vs. "high" ( ⩾ 8)] that patients with lower H3K18Ac levels ("low + moderate") had a significantly decreased relapse-free survival vs. patients with high H3K18Ac levels (p = 0.038). The WHO classification and age were also of significant prognostic impact upon univariate analysis. A backwards Cox proportional hazards model revealed the independent prognostic effekt of H3K18Ac levels. Our data revealed low K18 acetylation levels of histone H3 as independent prognostic factor in organic hyperinsulinism. This result warrants validation with independent data sets of organic hyperinsulinism, but is in line with several previous studies in different cancer entities. The broad applicability of this potential biomarker might lead to standardized diagnostic tests in near future and may help to manage insulinoma patients more effectively. [ABSTRACT FROM AUTHOR]

The article criticizes a study conducted by R. R. Ramey II et al., designed to synonymize the threatened Preble's meadow jumping mouse Zapus hudsonius preblei with two currently unlisted subspecies, the prairies jumping mouse Zapus hudsonius intermedius and the Bear Lodge meadow jumping mouse Zapus hudsonius campestris. According to the authors, Ramey et al., dismissed the geographic isolation of the population as unimportant and ignored the diagnostic characteristics cited in the taxon's original description by Krutzsch.

Copyright of Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A multicenter study for monitoring antimicrobial drug resistance in clinical isolates of the family Enterobacteriaceae, Pseudomonas aeruginosa, Staphylococcus and Enterococcus species in central Europa conducted by the Study Group Bacterial Resistance of the Paul-Ehrlich-Society for Chemotherapy has been ongoing since 1975. Between 1975 and 1995 susceptibility data on almost 60,000 bacteria, which were isolated and sampled under a common protocol by laboratories from Austria, Germany and Switzerland, were collected. These bacterial isolates were known by the respective investigators to have caused infections. From 1975 to the mid-80s none of the bacterial species examined showed an increase in resistance. The frequency of resistance in klebsiellae and Staphylococcus aureus to some antibiotics even declined. In 1990 and particularly in 1995, a clear increase in resistance for a number of antibiotic-organism pairs was observed. Resistance rates of fluoroquinolones increased in all species under investigation. In Escherichia coli the increase of resistance to ampicillin, co-trimoxazole and gentamicin was remarkable. Resistance to imipenem increased in P. aeruginosa. Resistance to cephalosporins, on the other hand, remained largely unchanged in gram-negative bacilli. Between 1990 and 1995, the prevalence of oxacillin resistance increased from 1.7 to 12.9% in S. aureus and from 15.8 to 55.8% in coagulase-negative staphylococci, whereas staphylococcal and enterococcal resistance to glycopeptides was still rare. [ABSTRACT FROM AUTHOR]

Copyright of Herz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

A great number of antiarrhythmic drugs is available for the treatment of tachyarrhythmias. The classiffication of these drugs according to their action on different ionic channels of cardiac cells is discussed and summarized. Furthermore, drugs are characterized with respect to their mechanism of action on membrane currents and their action in different cardiac tissues. From the results, strategies may be developed which represent the basis for clinical application of antiarrhythmic drugs. [ABSTRACT FROM PUBLISHER]

A patient with chronic relapsing inflammatory demyelinating polyneuropathy was successfully treated with plasma exchanges and cyclosporin A (CsA). Dynamometric measurements of hand force during the time of CsA treatment showed a highly significant correlation between hand force and CsA blood levels. The largest influence of CsA on hand force occurred 11-13 days after CsA uptake. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of a 25:1 combination of ticarcillin and clavulanate were studied in nine pre-term and seven full-term neonates. Pre-term neonates with a gestational age ranging from 30 to 36 weeks received 83.3 mg of ticarcillin and 3.3 mg of clavulanate per kg bw and full-term neonates with a gestational age from 39 to 43 weeks received 100 mg of ticarcillin and 4 mg of clavulanate per kg bw 8-hourly, each by a slow infusion over 10 min. Serum was sampled 15, 30, 60, 120, 240 and 480 min after the first dose and trough samples were additionally obtained on the fourth day of treatment The patients were allocated to Groups 1–3 on the basis of the pharmacokinetic characteristics obtained. Group 1 comprised seven full-term babies. Group 2 contained seven pre-term neonates with a birth weight between 1915 and 2650 g and Group 3 consisted of two pre-term neonates of low birth weight (1400 g and 1640 g). Mean (± s.e.) pharmacokinetic characteristics of Group 1 patients for ticarcillin were: Cmax = 404.9 mg/1 (36.0); T½= 2.68 h (0.23); AUC = 1287 h.mg/1 (69); Vd =266 ml/kg (28) and for clavulanate: Cmax = 15.0 mg/1 (1.2); T½=1.39 h (0.12); AUC= 30.1 h.mg/1 (1.7); Vd = 263 ml/kg (22). Corresponding parameters for Group 2 patients for ticarcillin were: Cmax 278.7 mg/1 (304); T½ = 4.20 h (0.49); AUC = 1107 h.mg/1 (57); Vd = 338 ml/kg (35) and for clavulanate: Cmax = 8.4 mg/1 (0.56); T½ = 2.56 h (0.18); AUC = 271 h.mg/1 (20); Vd = 414 ml/kg (29). Drug accumulation was not observed in patients of Groups 1 and 2. Each of the two patients of Group 3 presented a pharmacokinetic profile which was considerably different from those observed in Groups 1 and 2. While in patients of the latter group the peak serum concentrations were achieved at 15–30 min after the end of infusion, these concentrations occurred between 120 and 240 min in one of the Group 3 patients. In the other Group 3 patient a remarkable drug accumulation was noted but was not associated with clinical or laboratory evidence of toxicity. These data show that ticarcillin and clavulanic acid in these dose ranges achieved adequate peak and trough concentrations in pre-term and full-term neonates. [ABSTRACT FROM PUBLISHER]

The influence of several factors on cadmium (Cd) concentrations in the hair of 474 pre-school children was examined. The study was performed in an industrial (Duisburg) and rural area (Westfalen) of the (FRG). Season, sex, hair color, and place of residence were found to be the main factors influencing Cd levels in hair. Concentrations of Cd in samples obtained during summer were on the average nearly twice as high as those sampled during winter (geometric means: 116.1 vs. 63.7ng/g). Boys had more Cd in their hair than girls (111.5 vs.74.0 ng/g). Cd levels in hair decreased from red to blond, to brown, and black hair. Children living in Duisburg had more Cd in their hair than those from rural areas (103.9 vs.77.Ong/g). Cd content in hair was inversely related to age. [ABSTRACT FROM AUTHOR]

Tedisamil has been described as a selective inhibitor of a fast inactivating transient outward current (ito,f) in rat ventricular myocytes. Because recent reports demonstrated the existence of a second slowly inactivating transient component (ito,s) we investigated ito,s and differentiated the effects of tedisamil on both transient outward current components and their influence on action potential duration. Standard electrophysiological techniques were used for whole cell recordings at 24–26° C from enzymatically isolated myocytes. Inhibition of ito,f by tedisamil was the result of an acceleration of inactivation at positive test potentials with a concentration for halfmaximal inhibition (EC50) of 4–7 μmol/l, which is confirmatory to reports from other investigators. Our new results show that ito,s is more sensitive to tedisamil with an EC50 of 0.5 μmol/l. Furthermore the pattern of ito,s inhibition is different compared with ito,f, because inactivation of ito,s is not accelerated by tedisamil. Instead the amplitude of the steady state inactivation curve of ito,s is attenuated which indicates a reduction of maximally available current. Ito,s was evaluated by three different methods as time-dependently inactivating current (7.5 s test pulse duration), voltage-dependently inactivated current and tedisamil-sensitive current. All approaches yield similar inactivation curves. The potential for halfmaximal inactivation of ito,s lies about 35 mV more negative than that for ito,f and the slope factor (K = –23 mV) is different to that of ito,f (K = –3 mV). Effectiveness of tedisamil-induced modulation of ito,f and ito,s on action potential repolarization was tested. Action potentials stimulated at 0.5 Hz were not prolonged by 1 μmol/l tedisamil (dominant ito,s block) at a repolarization level of 0 mV but prolonged to about 120% of control at –70 mV. This indicates that ito,f was sufficient to guarantee a regular early repolarization whereas decrease of ito,s delayed the final repolarization. In conclusion, the observation that tedisamil inhibits ito,f and ito,s differently supports the hypothesis that the two ito-components are related to two different channel populations expressed in rat ventricular myocytes. [ABSTRACT FROM AUTHOR]

This study describes electrophysiological effects of estrogens in isolated male rat ventricular myocytes. According to the literature these cells do not express the nuclear estrogen receptor. Action potentials or membrane currents were recorded in the whole-cell configuration with standard techniques. Action potential durations (APD) measured at a level of 0 mV (APD 0) and –70 mV (APD –70) were prolonged by 17β-estradiol (0.5 Hz stimulation frequency, 24–26° C). Threshold concentration was 1 μmol/l. At the highest concentration used (30 μmol/l) no saturation of the response was reached and APD 0 was 162% and APD –70 was 230% of the respective control. The resting potential remained unaffected in most cells. The prolongation induced by 17β-estradiol developed rapidly and reached a steady state 10 min after start of hormone superfusion. Effects of estrogen were completely reversible during 10–15 min wash-out with hormone-free solution. The extent of prolongation (10 μmol/l 17β-estradiol) was frequency dependent. Expressed as percentage of the respective control APD 0 (or APD –70) was 115% (188%) at 0.05 Hz, 118% (163%) at 0.5 Hz and 99% (129%) at 5 Hz stimulation frequency. The response was stereoselective, because 30 μmol/l 17α-estradiol did not prolong action potentials (APD 0: 101%, APD –70: 104% of the respective control, 0.5 Hz stimulation frequency). The endogenous estrogens estrone and estriol were less effective than 17β-estradiol. With 30 μmol/l estrone (0.5 Hz stimulation frequency) APD 0 was 103% and ADP-70 148% of control and with 30 μmol/l estriol APD 0 was 135% and APD –70 137% of control. The prolongation of action potentials can be explained by inhibition of transient outward current which, in rat ventricle, is composed of fast ( i to,f) and slowly ( i to,s) inactivating components. At 30 μmol/l 17β-estradiol i to,f was reduced to 50% and i to,s to 43% of their maximal amplitudes. The voltage sensor of i to,f or i to,s was hardly affected. Additionally, 17β-estradiol decreased the calcium current ( i Ca,L) to 76% (10 μmol/l) and 38% at 30 μmol/l. The inwardly rectifying potassium current ( i K1) was reduced partly with 30 μmol/l 17β-estradiol and its amplitude was 72% of control at –90 mV (inward current flow) and 65% at –40 mV (outward current flow). These results show that 17β-estradiol is active in cardiac cells which do not express the nuclear estrogen receptor. The hormone exerts class III activity and reduces calcium inward current. These effects, however, occur in vitro with concentrations above the physiological level and therefore may be without significance in vivo. [ABSTRACT FROM AUTHOR]

The inhibition of the pacemaker current ( i) in sheep cardiac Purkinje fibres by ZD 7288 [4-( N-ethyl- N-phenylamino)-1,2-dimethyl-6-(methylamino)pyrimidinium chloride] is lost use-dependently. This disinhibition of i was investigated by using the two-microelectrode voltage-clamp technique. The pulse protocol consisted of a rest period (holding potential of about -50 mV, 1-10 μmol/l ZD 7288) followed by a train of test pulses (potential negative to -100 mV, stimulation frequency 0.05 Hz). At the beginning of the first test pulse there was an immediate reduction of i but inhibition was lost during continued stimulation. Activation of i is sigmoidal and the early delay in current activation was prolonged from 33 ms (no ZD 7288) to 424 ms (10 μmol/l ZD 7288). Therefore hardly any disinhibition occurred during short test pulses (0.5 s). During longer test pulses (5 s, -120 mV, 10 μmol/l) disinhibition developed with a time constant of about 2 s. The inhibition of i by ZD 7288 was lost voltage-dependently. With 10 μmol/l ZD 7288 the half-maximal disinhibition occurred at -92 mV and the slope factor of the disinhibition/voltage curve (Boltzmann relation) was 4.8 mV. The voltage-dependent disinhibition could be abolished largely by extracellular application of protease (0.5 mg/ml, 7 min). After prior disinhibition, reinhibition at the holding potential (about -50 mV) followed a bi-exponential time course indicating that inhibition may be produced by a fast (τ=0.7 min) and a slow component (τ=20-30 min). Increasing ZD 7288 concentration from 1 to 10 μmol/l accelerated reinhibition, mainly by an increase of the amplitude ( A) of the fast component. The ratio A/ A was 0.399 at 1 μmol/l and 2.65 at 10 μmol/1 ZD 7288. The reinhibition of i was unchanged by shifting the holding potential from -50 mV to -20 mV Trials to wash out the effects of 10 μmol/l ZD 7288 gave two results. The inhibition of i was slightly reversed after a wash-out of 1.5 h with drug-free solution. A second effect of the drug, the fast reinhibition, could be completely removed by washout. In summary i is inhibited by ZD 7288 at membrane potentials at which the virtual i gate is closed. Disinhibition occurs during long-lasting hyperpolarization but will hardly be operative in unclamped fibres under physiological conditions. [ABSTRACT FROM AUTHOR]

The bradycardic mechanism of ZD 7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)pyrimidinium chloride) was investigated in sheep cardiac Purkinje fibres. The pacemaker i-current measured with the two-microelectrode voltage-clamp technique, as well as the diastolic depolarization rate and the frequency of spontaneously active fibres were evaluated. ZD 7288 did inhibit i-current. The i-amplitude recorded with a 0.8s-lasting test pulse from about −50 mV to −100 mV was reduced to 50% of control at 0.85 μmol/l and to 5% of control at 10 μmol/l. The threshold potential of i-activation was unaffected at a concentration of 1 μmol/l ZD 7288. The time constant of i-activation at different test potentials was not changed by 1 μmol/l ZD 7288. The drug was equally effective during i-activation with a 0.5 s-lasting test pulse applied at 0.05 Hz or 0.5 Hz. During long lasting (5 s) hyperpolarizing test pulses (−120 mV) the inhibition of i-current was removed. In constantly stimulated Purkinje fibres (0.5 Hz) the slope of the early diastolic depolarization was decreased by ZD 7288. The half-maximal effect occurred at 0.92 μmol/l. There was strong correlation over the concentration range of 0.01 to 10 μmol/l ZD 7288 between the decrease of the slope of early diastolic depolarization and inhibition of i-amplitude recorded with 0.8s-lasting test pulses to −100 mV. The correlation coefficient was r = 0.97. These results will explain the decrease in frequency of spontaneously active (about 0.6 Hz) Purkinje fibres. At 0.3 μmol/l ZD 7288 spontaneous activity had stopped in 8 of 11 preparations. Complete recovery of drug-induced effects on the frequency was gained after 3 h of wash-out with drug-free solution. [ABSTRACT FROM AUTHOR]

The effects of zymosan and human serum opsonized zymosan on membrane currents of adherent mouse peritoneal macrophages which had been cultured for 5 to 20 days were investigated with the whole-cell voltage-clamp technique. Both stimuli activated an outward current. The outward current activation was transient and lasted about 5 min. In solutions with 10 or 50 mmol/l extracellular potassium concentration the activation of an outwardly directed current occurred at test potentials positive to the respective potassium equilibrium potential. This particle-induced current resembled a calciu-mactivated potassium current which could be activated with the calcium ionophore A 23187 and with platelet activating factor. The order of maximal responses (test potential +55 mV, amplitude given as percentage of the respective control) was: 0.1 μmol/l platelet activating factor (222±36%, n=8, P<0.01) > 1 μmol/l A 23187 (190±24%, n=11, P<0.01) >900 μg/ml opsonized zymosan (134±7%, n=22, P<0.01) >900 μg/ml zymosan (116±5%, n = 21, P<0.01) The lower efficiency of zymosan as compared to opsonized zymosan is explained in part by a lower percentage of responding cells which was 48% for zymosan and 73% for opsonized zymosan. Macrophages which were pretreated with particles showed a greater reactivity to calcium as compared to untreated cells. Elevation of extracellular calcium from 0.9 to 4.5 mmol/l activated the outward current to 145±12% ( n = 11, P< 0.01) after preincubation with opsonized zymosan and to 144±21% ( n = 12, P< 0.01) under the influence of zymosan while in untreated cells current increase by elevation of extracellular calcium was not significant (120±10%, n = 9, n.s.). [ABSTRACT FROM AUTHOR]

The aim of the present study was to search for electrophysiological effects of human lipoproteins on membrane currents in mouse peritoneal macrophages which had been cultured for 5 to 20 days. Whole-cell currents were recorded by using a voltage-clamp technique. Low density lipoprotein (LDL, 100 μg/ml) increased a slowly activating nonspecific cation current (i) in the positive potential range to 244 ± 23% of the reference (test potential + 55 mV, n = 13, P < 0.005). Augmentation of current resulted out of a negative shift of the activation curve along the voltage axis (−22 mV) and an increase of maximally available current. Furthermore, LDL increased a rapidly activating outward current (i) at test potentials positive to the potassium equilibrium potential. At +55 mV i-amplitude increasedto 165 ± 14% ofreference ( n = 16, P < 0.005). LDL-induced effects on i-current could be mimicked by application of the calcium ionophore A 23187 (1 μmol/l) which led to an increase of i-current to 161 ± 25% of the reference (test potential + 55 mV, n = 11, P < 0.005). Acetylated-LDL (100 μg/ml, 5-15 min) produced no significant effect on the membrane currents under investigation. [ABSTRACT FROM AUTHOR]

The electrophysiologic mode of action and potency of the verapamil derivative YS 035 (N,N-bis-(3,4-dimethoxyphenethyl)-N-methyl amine) were investigated in sheep cardiac Purkinje fibres. Action potential duration measured at a repolarization level of −60 mV (APD-60) and membrane currents recorded with the two-microelectrode voltage-clamp technique were evaluated. At 10 μmol/l YS 035 APD-60 was increased to about 115% of reference. Prolongation measured as percentage of the respective control exhibited on the average no dependence on stimulation frequency (0.17-2 Hz). At 100 μmol/l membrane became depolarized to about −50 mV and action potentials could no longer be elicited. Further study was focussed on effects on outward currents, mostly activated at a frequency of 0.05 Hz. Transient outward current (i) was completely blocked at 100 μmol/l and half-maximal inhibition occurred at about 14 μmol/l. Inwardly rectifying potassium current (i) was reduced to 47% of reference at 100 μmol/l. An initially activating outward current at positive membrane potentials (i) was reduced to 73% at 100 μmol/l. Time-dependent (delayed) outward current (i) was on the average not affected up to 100 μol/l. Besides inhibition of repolarizing outward currents YS 035 completely blocked pacemaker current (i) at 100 μmol/l and half-maximal reduction was achieved at 5 μmol/l. YS 035 (1-100 μmol/l) did not clearly affect time constants of activation at selected test potentials (I: +35 mV; i: −90 mV) or inactivation (i: 0 mV). Voltage-dependent control mechanisms of currents (it, i) were not influenced by YS 035 but the amount of available current was reduced. In conclusion, the verapamil derivative YS 035 inhibited pacemaker current and potassium outward currents which correlated to a prolongation of cardiac action po tentials. Electrophysiological actions of the compound favour it to be tested in vivo as an antiarrhythmic drug candidate. [ABSTRACT FROM AUTHOR]

This study was aimed to differentiate the action of (+)- and (±)-sotalol (10-1000 μmol/l) on membrane currents which are active during the repolarization of cardiac action potentials Effects where studied in shortened sheep cardiac Purkinje fibres with the two-microelectrode voltage-clamp technique Action potentials were activated at a frequency of 0.25 Hz and membrane currents at 0.03 Hz or 0.05 Hz in most experiments. Out of the currents investigated the transient outward current (i) reacted most sensitively to (+)- and (±)-sotalol. I-amplitude was decreased on the average to 77% of reference at 10 μmol/l and to 53% at 1000 μmol/l (+)- or (±)-sotalol. The maximally available ito-current was decreased but the voltage-dependent control of inactivation was left nearly unchanged. The initial inwardly rectifying current (i), which propels the last repolarization phase of the action potential and controls resting potential to a large extent was reduced on the average to 93% of reference at 10 μmol/l and to 62% at 1000 μmol/l (+)- or (±)-sotalol. Time-dependent (delayed) outward current (i) was on the average not affected by (+)- or (±)-sotalol up to 100 μmol/l and was decreased to 84% of reference current under the influence of 1000 μmol/l. An initial outward current, which is activated at positive membrane potentials (i) was not clearly affected by (+)- or (±)-sotalol at concentrations up to 1000 μmol/l Pacemaker current (i) was not influenced by the drugs up to 100 μmol/l. Only at 1000 μmol/l was the amount of available i-current decreased to 79% of reference. (The potential-dependent control of activation was not affected) Time constants of time-dependent currents i, i and i did not change in concentrations up to 1000 μmol/l of the drug. Action potential duration increased at (+)- or (±)-sotalol concentrations ≥ 10 μmol/l and maximal prolongation was achieved at concentrations of 100-300 μmol/l Resting potential remained nearly unchanged at these concentrations, but the membranes depolarized at 1000 μmol/l. According to our data action potential prolongation in sheep Purkinje fibres under the influence of (+)- and (±)-sotalol correlates to the drug-induced block to i-current and inwardly rectifying i-current. [ABSTRACT FROM AUTHOR]

(1) Effects of bepridil (0.3-100 μmol/l) on transmembrane currents which are active during the repolarization of the cardiac action potential were studied in sheep cardiac Purkinje fibres with the two-microelectrode voltage-clamp technique. Transmembrane currents were activated at a frequency of 0.03 Hz. (2) The initial inwardly rectifying current ( i) was reduced by 1.8 μmol/l bepridil to 70% of the reference i-current in the absence of the drug. (3) An initial outward current, which is activated at positive membrane potentials ( i) was depressed to 70% of reference by 14 μmol/l bepridil. (4) The time-dependent outward current ( i) was decreased by 1.8 μmol/l bepridil to 70% of its amplitude in the absence of bepridil. The biexponential time course of i-current activation changed to be monoexponential with 100 μmol/l bepridil. The effect of bepridil on i-current resulted in a shift of the activation curve of i-current to more positive membrane potentials (10 μmol/l bepridil) and an additional decrease of driving force and/or conductance of the i-channels with higher bepridil concentrations (100 μmol/l). (5) The transient outward current ( i) was completely blocked by 30 μmol/l bepridil. Inhibition to 70% of reference occurred with 1 μmol/l bepridil. The voltage-dependent inactivation of i-current was affected by bepridil: the amplitude of the steady-state inactivation curve was reduced and i-current was inactivated faster after application of bepridil. Bepridil caused no pronounced shift of the steady-state inactivation curve along the voltage axis. (6) The pacemaker current ( i) was slightly increased under the influence of low bepridil concentrations (0.3, 1 μmol/l) while it was reduced to 70% of reference by 100 μmol/l bepridil. (7) The blocking action of bepridil on outward currents in sheep cardiac Purkinje fibres will explain the action potential prolongation, which is observed in different mammalian cardiac tissues under the influence of bepridil. [ABSTRACT FROM AUTHOR]

Histamine-induced electrophysiological effects have been investigated in guinea-pig left atria, papillary muscles and rabbit AV-nodal preparations by means of intracellular recording of action potentials, slow responses in the presence of 27 mmol/l (K) and voltage clamp experiments. Differentiation of the H-receptor subtypes was performed by the use of the H-selective agonists dimaprit and impromidine and the H- and H-selective antagonists dimetindene and cimetidine, respectively. The following results were obtained: [ABSTRACT FROM AUTHOR]

The electrophysiological effects mediated by β1- and β2- in spontaneously active sheep cardiac Purkinje fibers were investigated using the non-selective agonist (−)-isoproterenol (IPN) and the selective agonists (−)-noradrenaline (β1) and procaterol (β2) in the absence and presence of the selective antagonists bisoprolol (β1) and ICI 118,551 (β2). IPN (0.01 μmol/l) increased the spontaneous rate by 54% and the slope of diastolic depolarization by 68% of the respective control values. Further, IPN increased the action potential duration at −20 mV (APD −20 mV) from 96 to 154 ms, reduced the APD −70 mV by 17% and the duration of the diastole by 39% and slightly hyperpolarized the maximum diastolic potential. These effects were partially inhibited by ICI 118,551 (0.03 μmol/l), diminished by bisoprolol (0.1 μmol/l) and almost completely blocked by the combination of both antagonists. Concentration response curves of IPN were influenced by the selective antagonists as follows: ICI 118,551 (0.03 μmol/l) shifted the curves to the right by 0.2–0.4 log units and increased the slope factor. Bisoprolol (0.1 μmol/l) induced a greater shift to the right by 1.1–1.5 log units. Combination of bisoprolol with ICI 118,551 shifted the curves to the right by 1.5–1.7 log units. Noradrenaline (0.3 μmol/l) elicited similar actions as IPN. Bisoprolol (0.1 μmol/l) shifted the concentration response curves of noradrenaline to the right by 1.1–1.9 log units. Actions of procaterol (0.1 μmol/l) were weak, attained only 15–35% of the maximal effects of IPN and could be blocked by ICI 118,551 (0.03 μmol/l). These results show that the increase of pacemaker activity induced by catecholamines in sheep cardiac Purkinje fibers is predominantly mediated by stimulation of β1. However, contribution of β2 mediated effects could be demonstrated. [ABSTRACT FROM AUTHOR]

In sheep cardiac Purkinje fibers concentration-dependent inhibition of transient outward current (i) by 4-aminopyridine (4-AP, 3-1000 μmol/l) was recorded with the two-microelectrode voltage-clamp technique, and correlated effects on action potential duration measured at - 70 mV (APD-70) were investigatigated. Half-maximal inhibition of i-amplitude occurred at 15 μmol/l 4-AP. The drug exhibited no major effect on voltage-dependent control of inactivation but reduced the maximally available i-current. At different activation frequencies (0.05 Hz, 0.25 Hz, 1 Hz) an equal amount of i-current, measured as percentage of the respective control, was inhibited by 4-AP. The APD-70 was on the average increased by 4-AP (3-500 μmol/l) in a concentration-dependont manner up to 151 % of control. The drug-induced prolongation, measured as percentage of the respective control, was independent of stimulation frequency (0.05 Hz, 0.25 Hz, 1 Hz). Prolongation of APD-70 was on the average more pronounced for short action potentials (APD-70<150 ms: 169 % of reference) than for longer ones (APD-70 150-300 ms: prolongation to 117 % of reference; 500 μmol/l 4-AP; 0.25 Hz stimulation rate). Few long control signals (APD-70 >300 ms) were shortened by 4-AP. These results indicate that inhibition of i-current by appropriate drugs will result in a reduction of inhomogeneity of action potential duration. [ABSTRACT FROM AUTHOR]

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Hair zinc levels were estimated by atomic absorption spectrophotometry in 474 children, aged 3-7 years, from 11 kindergartens in a highly industrialized and polluted area (Duisburg) and 8 kindergartens in a rural area of North Rhine-Westphalia. The mean hair zinc level amounted to 118 micrograms/g, increasing between the 4th and 7th year of life. At all ages the values from the urban toddlers were lower than from rural toddlers, and in both regions they were higher in winter than in summer. Children with frequent upper respiratory tract infections (greater than 6 infections/year) showed significantly lower zinc hair values, independent of their age. Low hair zinc values (below 70 micrograms/g) were frequently found, raising the question as to whether this is a normal, age-related phenomenon, or whether it indicates a suboptimal zinc status of young children from North Rhine-Westphalia. [ABSTRACT FROM AUTHOR]

The toxicokinetics of aluminum (Al) in male Wistar rats was studied after single intragastric (IG) doses of 1000 and 12000 μg Al/kg and intravenous (IV) doses of 10, 100, 1000, and 12000 μg Al/kg. Serial blood samples, daily samples of urine and feces as well as brain, liver, kidney, spleen, quadriceps muscle, and femur samples were collected. Al was measured by atomic absorption spectrometry. Al blood profiles after IV doses were adequately described by a two-compartment open model. Al toxicokinetics was dose dependent and appeared to plateau at 12000 μg/kg. At IV doses between 10 and 1000 μg/kg the terminal half-life of elimination from whole blood (t) increased from 29.9±7.8 to 209.3±32.6 min, and the total body clearance (CL) decreased from 2.45±0.64 to 0.28±0.03 ml min kg. Following an IV bolus of 10 and 100 μg/kg the administered Al was recovered completely from urine (94.4%±9.9% and 98.5%±3.2%). Twenty-nine days after the IV dose of 1000 μg/kg daily renal excretion decreased to baseline values while only 55.1%±8.0% of the dose was excreted. Nineteen days after the single IV dose of 1000 μg/kg Al accumulated in liver (28.1±7.7 versus 1.7±0.5 μg/g of control rats) and spleen (72.5±21.1 versus <0.4 μg/g). After the single 1000 μg/kg IG dose no absorption of Al was detectable. The IG dose of 12000 μg/kg resulted in a maximum blood Al level of 47.9±12.4 μg/l after 50 min. The blood concentration time curve fitted a one-compartment open model with a half-life of absorption of 28.2±3.6 min and a t of 81.2±20.2 min. Cumulative renal Al excretion was 0.18%±0.10% of the dose and oral bioavailability was 0.02%. Seventeen days after the 12000 μg/kg IG dose the Al content in femur samples was increased (2.7±1.3 versus 0.6±0.4 μg/g). In no case was fecal elimination of incorporated Al observed. [ABSTRACT FROM AUTHOR]

The histamine-receptor-subtype-mediated effects on action potentials of electrically driven and spontaneously active isolated sheep cardiac Purkinje fibers were investigated using H-and H-selective agonists and antagonists. In electrically stimulated Purkinje fibers, histamine (3 μmol/l) increased the action potential plateau height, decreased the action potential duration measured at a repolarization level of −60 mV and enhanced the pacemaker activity. These effects were abolished by the H-selective antagonist cimetidine (30 μmol/l), but were not impaired by the H-selective antagonist dimetindene (0.3 μmol/l). In spontaneously active Purkinje fibers, histamine (10 μmol/l) increased the spontaneous rate by 24%, the slope of diastolic depolarization by 45% and shortened the duration of the diastole by 32% of the respective control measurements. These effects were blocked by 30 μmol/l cimetidine, but remained unchanged in the presence of 0.3 μmol/l dimetindene. Concentration-response curves of histamine were shifted to the right by approximately 2 logarithmic units in the presence of 30 μmol/l cimetidine, but were not influenced in the presence of 0.3 μmol/l dimetindene. The H-selective agonist impromidine (0.001-0.3 μmol/l) had similar actions as histamine on spontaneously active Purkinje fibers, while the H-selective agonist 2-(2-pyridyl-)ethylamine was ineffective. It is concluded that the pronounced stimulatory action of histamine on spontaneous activity in sheep cardiac Purkinje fibers is exclusively mediated by H receptors. [ABSTRACT FROM AUTHOR]

H-receptor reserves in guinea-pig left atria, trachea and pig coronary arteries were calculated by the use of phenoxybenzamine (Pba), a β-haloalkylamine that irreversibly blocks the H-receptor response to histamine or 2-(2-pyridyl)-ethylamine (PEA). Equieffective concentrations of the H-agonist in the absence (A) and presence (A′) of Pba were evaluated from concentration-response curves. By plotting the reciprocal values 1/A versus 1/A′ the amount of H-receptors not occupied by the agonist was calculated. The size of the H-receptor reserve could be estimated by comparison of the receptor occupation with the corresponding effect. Furthermore, the dissociation constants for histamine, PEA, Pba and the pD′-values for Pba were determined for the different tissues. 5% and 6% H-receptor occupation is necessary to achieve a half maximal contraction of the trachea with the agonists histamine and PEA, respectively. Only 0.5% H-receptor occupation is needed for the half maximal positiv inotropic effect of histamine in left atria, while 5.5% of the H-receptors have to be accupied using PEA as an agonist in this tissue. In the coronary artery of the pig 50% of the maximal contraction can be achieved by stimulation of 15.1% of the H-receptors with histamine. [ABSTRACT FROM AUTHOR]

Electrophysiological investigations of histamine in different cardiac tissues have led to the following results: [ABSTRACT FROM AUTHOR]

Copyright of Infection is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The histamine-receptor subtype mediated effects on action potentials of electrically driven and spontaneously active isolated sheep cardiac Purkinje fibres were investigated using H-and H-selective agonists and antagonists. In electrically stimulated Purkinje fibres histamine (3 μmol/l) increased action potential plateau height, decreased action potential duration at −60mV, and enhanced pacemaker activity. These effects were abolished by 30 μmol/l cimetidine (H-selective antagonist), but not impaired by 0.3 μmol/l dimethindene (H-selective antagonist). In spontaneously active Purkinje fibres, histamine (10 μmol/l) increased the spontaneous rate by 24%, the slope of diastolic depolarization by 45% and shortened the duration of the diastole at −60mV by 32% of the respective control measurements. These effects were blocked by 30 μmol/l cimetidine, but not by 0.3 μmol/l dimethindene. The concentration-response relationship of histamine was shifted to higher histamine concentrations by approximately 2 logarithmic units in the presence of 30 μmol/l cimetidine, but no displacement was found in the presence of 0.3 μmol/l dimetindene. The H-selective agonist impromidine (0.001-0.3 μmol/l) has similar actions to histamine on spontaneously active Purkinje fibres, while the H-selective agonist 2-(2-pyridyl-)ethylamine was ineffective. It is concluded that the pronounced stimulatory action of histamine on spontaneous activity in sheep cardiac Purkinje fibres is exclusively mediated by H-receptors. [ABSTRACT FROM AUTHOR]