Cardioprotective effects of 5-hydroxymethylfurfural mediated by inhibition of L-type Ca2+ currents.

BACKGROUND AND PURPOSE: The antioxidant 5-hydroxymethylfurfural (5-HMF) exerts documented beneficial effects in several experimental pathologies and is currently tested as an antisickling drug in clinical trials. In the present study, we examined the cardiovascular effects of 5-HMF and elucidated the mode of action of the drug. EXPERIMENTAL APPROACH: The cardiovascular effects of 5-HMF were studied with pre-contracted porcine coronary arteries and rat isolated normoxic-perfused hearts. Isolated hearts subjected to ischaemia/reperfusion (I/R) injury were used to test for potential cardioprotective effects of the drug. The effects of 5-HMF on action potential and L-type Ca2+ current (ICa,L ) were studied by patch-clamping guinea pig isolated ventricular cardiomyocytes. KEY RESULTS: 5-HMF relaxed coronary arteries in a concentration-dependent manner and exerted negative inotropic, lusitropic and chronotropic effects in rat isolated perfused hearts. On the other hand, 5-HMF improved recovery of inotropic and lusitropic parameters in isolated hearts subjected to I/R. Patch clamp experiments revealed that 5-HMF inhibits L-type Ca2+ channels. Reduced ICa,L density, shift of ICa,L steady-state inactivation curves toward negative membrane potentials and slower recovery of ICa,L from inactivation in response to 5-HMF accounted for the observed cardiovascular effects. CONCLUSIONS AND IMPLICATIONS: Our data revealed a cardioprotective effect of 5-HMF in I/R that is mediated by inhibition of L-type Ca2+ channels. Thus, 5-HMF is suggested as a beneficial additive to cardioplegic solutions, but adverse effects and contraindications of Ca2+ channel blockers have to be considered in therapeutic application of the drug.

Experimental discrimination of ion stopping models near the Bragg peak in highly ionized matter.

The energy deposition of ions in dense plasmas is a key process in inertial confinement fusion that determines the α-particle heating expected to trigger a burn wave in the hydrogen pellet and resulting in high thermonuclear gain. However, measurements of ion stopping in plasmas are scarce and mostly restricted to high ion velocities where theory agrees with the data. Here, we report experimental data at low projectile velocities near the Bragg peak, where the stopping force reaches its maximum. This parameter range features the largest theoretical uncertainties and conclusive data are missing until today. The precision of our measurements, combined with a reliable knowledge of the plasma parameters, allows to disprove several standard models for the stopping power for beam velocities typically encountered in inertial fusion. On the other hand, our data support theories that include a detailed treatment of strong ion-electron collisions.

Temperature measurement of hohlraum radiation for energy loss experiments in indirectly laser heated carbon plasma.

For ion energy loss measurements in plasmas with near solid densities, an indirect laser heating scheme for carbon foils has been developed at GSI Helmholtzzentrum für Schwerionenforschung GmbH (Darmstadt, Germany). To achieve an electron density of 10^{22}cm^{3} and an electron temperature of 10-30eV, two carbon foils with an areal density of 100µg/cm^{2} heated in a double-hohlraum configuration have been chosen. In this paper we present the results of temperature measurements of both primary and secondary hohlraums for two different hohlraum designs. They were heated by the PHELIX laser with a wavelength of 527nm and an energy of 150J in 1.5ns. For this purpose the temperature has been investigated by an x-ray streak camera with a transmission grating as the dispersive element.

Predictions for the energy loss of light ions in laser-generated plasmas at low and medium velocities.

The energy loss of light ions in dense plasmas is investigated with special focus on low to medium projectile energies, i.e., at velocities where the maximum of the stopping power occurs. In this region, exceptionally large theoretical uncertainties remain and no conclusive experimental data are available. We perform simulations of beam-plasma configurations well suited for an experimental test of ion energy loss in highly ionized, laser-generated carbon plasmas. The plasma parameters are extracted from two-dimensional hydrodynamic simulations, and a Monte Carlo calculation of the charge-state distribution of the projectile ion beam determines the dynamics of the ion charge state over the whole plasma profile. We show that the discrepancies in the energy loss predicted by different theoretical models are as high as 20-30%, making these theories well distinguishable in suitable experiments.

Role of charge transfer in heavy-ion-beam-plasma interactions at intermediate energies.

In this paper we investigate the influence of the plasma properties on the charge state distribution of a swift heavy ion beam interacting with a plasma. The main finding is that the charge state in plasma can be lower than in cold matter. The charge state distribution is determined by the ionization and recombination rates which are balancing each other out. Both, ionization and recombination rates, as well as atomic excitation and decay rates, depend on the plasma parameters in different ways. These effects have been theoretically studied by Monte Carlo simulations on the example of an argon ion beam at an energy of 4MeV/u in a carbon plasma. This study covers a plasma parameter space ranging from ion densities from 10(18) to 10(23) cm(-3) and electron temperatures from 10 to 200 eV.

Probing the complex ion structure in liquid carbon at 100 GPa.

We present the first direct experimental test of the complex ion structure in liquid carbon at pressures around 100 GPa, using spectrally resolved x-ray scattering from shock-compressed graphite samples. Our results confirm the structure predicted by ab initio quantum simulations and demonstrate the importance of chemical bonds at extreme conditions similar to those found in the interiors of giant planets. The evidence presented here thus provides a firmer ground for modeling the evolution and current structure of carbon-bearing icy giants like Neptune, Uranus, and a number of extrasolar planets.

Energy loss and charge transfer of argon in a laser-generated carbon plasma.

This Letter reports on the measurement of the energy loss and the projectile charge states of argon ions at an energy of 4 MeV/u penetrating a fully ionized carbon plasma. The plasma of n(e)≈10(20) cm(-3) and T(e)≈180 eV is created by two laser beams at λ(Las)=532 nm incident from opposite sides on a thin carbon foil. The resulting plasma is spatially homogenous and allows us to record precise experimental data. The data show an increase of a factor of 2 in the stopping power which is in very good agreement with a specifically developed Monte Carlo code, that allows the calculation of the heavy ion beam's charge state distribution and its energy loss in the plasma.

The effect of nimodipine, fentanyl and remifentanil intravenous products on the stability of propofol emulsions.

Nimodipine is used parenterally to treat ischemic neurological deficits caused by subarachnoid haemorraghe. Infusion of nimodipine should be continued during anaesthesia, surgery or angiography. In this context a simultaneous administration of nimodipine, propofol and fentanyl or remifentanil could be of great advantage. So the aim of this study was to evaluate the physical stability (droplet size) of propofol emulsions in combination with nimodipine and fentanyl/remifentanil. Droplet size of intravenous emulsions is of particular relevance as the administration of larger droplets to patients may cause pulmonary embolism. So the number of oil droplets > 10 microm was determined in combinations of propofol emulsion with nimodipine and fentanyl/remifentanil immediately after mixing and after 20 hours by using microscopy. The experiments showed that all combinations of propofol (1 and 2%) with nimodipine infusion solution resulted in coalescence of oil droplets, which finally caused a visible phase separation. Macrogol (polyethylene glycol 400) was identified as the component in nimodipine infusion solution which induced the physicochemical incompatibility with propofol lipid emulsions.

Genotoxic properties of 4-hydroxyalkenals and analogous aldehydes.

4-Hydroxynonenal (HNE), one of the major products of lipid peroxidation, has been demonstrated to induce genotoxic effects in the micromolar range. HNE has too structural domains, a lipophilic tail and a polar head with three functional groups: the aldehyde and hydroxy groups and the trans CC double bond. To evaluate their relative importance, the genotoxic effects of HNE were compared with those of the homologous aldehydes 4-hydroxyhexenal and 4-hydroxyundecenal (different lengths of the lipophilic tail), and the analogous aldehydes 2-trans-nonenal (lacking the OH group) and nonanal (lacking the OH group and the trans CC double bond). This investigation was carried out on primary cultures of adult rat hepatocytes in order to further determine the influence of biotransformation- and/or detoxification reactions. A 3-h treatment with HNE induces statistically significant levels of SCE at concentrations > or = 0.1 microM, micronuclei at concentrations > or = 1 microM and chromosomal aberrations at a concentration of 10 microM. Compared to HNE the homologous aldehydes induced a significant genotoxic effect at higher concentrations. Statistically significant increases in SCE frequency were obtained at concentrations > or = 1 microM for 4-hydroxyundecenal and at a concentration of 10 microM for 4-hydroxyhexenal. The induction of chromosomal aberrations was significantly elevated at concentrations of > or = 10 microM and 10 microM for 4-hydroxyhexenal and 4-hydroxyundecenal, respectively. Except for a 4-hydroxyhexenal concentration of 1 microM, both aldehydes did not induce statistically significant levels of micronuclei. The HNE analogous aldehydes 2-trans-nonenal and nonanal induced statistically significant frequencies of SCE at concentrations of > or = 1 microM (nonanal) and > or = 10 microM (2-trans-nonenal). No significant induction of chromosomal aberrations or micronuclei could be demonstrated. The structure of the aldehydes investigated appears to influence the cyto- and genotoxic potential in the following ways. (1) The length of the lipophilic tail has no influence on chromosomal aberration induction, but appears to determine the yield of SCE and micronuclei, and the cytotoxic potential. (2) The lack of the OH group (2-trans-nonenal) reduces the SCE-inducing potential of the aldehyde shifting the dose-effect curve to higher concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)

Possible mutagens derived from lipids and lipid precursors.

Free radicals can initiate the oxidative decomposition of cellular membranes by lipid peroxidation. In this process a great variety of reactive aldehydes are produced intracellularly. Some of them, such as 4-hydroxynonenal or malonaldehyde, are biologically very active and might be involved in free radical-mediated DNA damage. A short review of the effects of aldehydic lipid peroxidation products on isolated DNA, their genotoxic effect in prokaryotes and eukaryotes and their in vivo carcinogenicity is given. Additionally own experiments on cytotoxic and genotoxic effects of 4-hydroxynonenal, 2-nonenal and nonanal in primary cultures of rat hepatocytes are reported. 4-Hydroxynonenal was highly cytotoxic at 100 microM, at subcytotoxic concentrations of 0.1-10 microM 4-hydroxynonenal increased the frequency of micronuclei, chromosomal aberrations and sister-chromatid exchange. 2-Nonenal and nonanal were not cytotoxic at 100 microM, the maximum dose tested. At 100 microM 2-nonenal led to a slight increase in micronuclei; chromosomal aberrations were not significantly altered. Nonanal had no detectable genotoxic effects. The level of endogenous 4-hydroxynonenal in tissues is in the range of 0.1-3.0 microM and can increase to 10 microM in conditions of oxidative stress; such levels appear to be sufficiently high to produce DNA damages, whether such damages are transient or irreversible is not known.

[Effect of body posture and venous congestion on blood fat picture]. / Einfluss der Körperlage und der venösen Stauung auf die Blutfettspiegel.

The effects on the concentrations of total cholesterol, high-density lipids (HDL), triglycerides and glycerol of temporary venous occlusion during blood sampling and changing body posture (lying and standing) were measured on 20 healthy male volunteers (mean age 25 [21-27] years) with normal blood-lipid levels. Venous occlusion in the upper arm increased the concentration of lipids in the antecubital vein, by 8% after five min and 37% after 15 min. Initial levels were restored 10 and 15 min after the occlusion. Blood-lipid levels were similarly raised on standing up again. After 5 min they had risen by about 9%, after 15 min by 16%. After renewed recumbency the levels were up from the initial values by 5% after 10 min and by 3% after 15 min (P less than 0.01). The concentration of free glycerol on the whole varied randomly, but there was a statistically significant rise after 10 and 15 min standing. These results indicate that different techniques of blood sampling can influence the lipid concentrations in venous blood.

Clinical and endocrinologic study of precocious puberty in girls.

We describe 30 girls with precocious puberty whom we have seen during the last ten years. Modern procedures such as cerebral computer tomography and abdominal sonography increase diagnostic accuracy so that the incidence of idiopathic precocious puberty is likely to diminish. Abdominal sonography is of value in detecting and monitoring the growth of ovarian cysts and thus exploratory laparotomy can be avoided in those cases in which cysts regress rapidly. A modified classification of precocious is proposed.

[Effectiveness of rubella vaccination in the puerperium]. / Effektivität der Rötelnimpfung im Wochenbett.

This study investigates the degree of effectiveness of post partum rubella vaccination, measured as percentage of true seroconversions. The vaccine used was RA 27/3. In the years 1983/84 the seronegative rate was 7% of the total number of births. The 270 seronegative women who had given birth during these two years had all been vaccinated post partum. 128 of them were controlled, and a seroconversion rate of 91.4% was obtained.

[Morphologic changes in cervix smears by intrauterine pessary]. / Morphologische Veränderungen von Zervixabstrichen bei Intrauterinpessar.

656 cervical smears and 74 endocervical biopsies were studied for morphological alterations associated with the presence of an intrauterine device. 12,085 cervical smears served as a control for inflammatory and metaplastic cellular changes. Slight to moderate cellular alterations were found in 202 (31%) out of 656 cases. Metaplastic and inflammatory lesions were identified in 26 (35%) out of 74 endocervical biopsies. We found no increased incidence of dysplastic lesions in women wearing an intrauterine device. Inflammatory and metaplastic cellular alterations have been seen more frequently in women with IUD than in the controls. The duration of time the IUD were in situ, did not have an effect on the cellular alterations. "Actinomyces-like" organisms were described in 38 (6%) out of 656 cases. The cytopathologist may be able to identify an "IUD-related" specimen in about one third of PAP-smears from women with an IUD, when he is aware that cervical smears from women having IUD may present with cellular alterations.

Histiocytosis-X in gynecology.

(1) Histiocytosis-X can manifest itself in virtually every organ, but in gynecology it is an absolute curiosity. (2) Differential diagnosis must exclude specific and nonspecific ulcerations and granulations such as syphilis, tuberculosis, Boeck's disease, and also neoplastic processes like lymphomas, sarcomas, carcinomas, and malignant diseases of the hemopoietic system. (3) The diagnosis by light microscopy alone, as in our case, may be insufficient; therefore, electron microscopy should be used. As soon as the diagnosis is confirmed histologically, an extensive examination of all organs is necessary in order to establish an exact prognosis and an optimal plan of therapy. (4) Because of the unknown etiology of histiocytosis-X, a causal treatment is not yet possible. In spite of this, with a symptomatic, individualized therapy by means of excision, low-dose irradiation and cytotoxic agents a 5-year survival of 90% was obtained for the patients. (5) Because of its rarity and multidisciplinary character, histiocytosis-X is a challenge to interdisciplinary and interregional cooperation. Though not being a malignoma in the strict sense, diagnosis, therapy, and in part prognosis are not essentially different from a malignant disease.

Epithelial compartment volume density: a proposal of a prognosis score in endometrial adenocarcinoma.

The point count method was used to calculate the relative volume density of the epithelial, stromal, and luminal compartments of endometrial adenocarcinoma, according to stereological principles. All three compartments could be correlated with survival in a significant way. The relative volume density of the epithelial compartment further correlated with the histologic grade of the tumor, but not with the clinical stage of disease or age of the patient. Providing the pathologist with a 40% relative volume density of the epithelial compartment as a decision line, this parameter may be useful as a prognostic factor. A prognosis scoring system on a pretherapeutic and postsurgical-pathologic level is proposed and its utility applied to the study group.

Selective incorporation of fluorescein-labeled steroids in the vaginal epithelium of women of childbearing age.

The incorporation of fluorescein-labeled estradiol and desoxycorticosterone in human vaginal epithelial cells during the menstrual cycle was studied. The uptake of these steroids changes during the menstrual cycle and can be related to data on nuclear binding sites in the human endometrium during the menstrual cycle. Further studies must be done to prove the effectiveness of this method as a test for the hormone sensitivity of tissue or cells, especially the sensitivity of neoplastic tissue to hormonal therapy.