Effect of insulin versus sulfonylurea therapy on cardiovascular risk factors and fibrinolysis in type II diabetes

1. The synthesis and release of nitric oxide may play a role in the pathogenesis of peripheral vasodilatation and hyperdynamic circulation observed in liver cirrhosis. In this work, we analysed the synthesis of nitric oxide by the lympho-mononuclear cells of peripheral blood from patients with chronic alcoholic and non-alcoholic liver disease and we identified the isoform of nitric oxide synthase involved in the increased nitric oxide synthesis. 2. Patients were classified following clinical and histological criteria in non-alcoholic cirrhotic, alcoholic cirrhotic and non-cirrhotic chronic liver disease. We studied clinical and analytical characteristics, haemodynamic parameters and endotoxin levels in these patients. 3. Cirrhotic patients showed an increase of cardiac output and a decrease of peripheral vascular resistance. These patients had higher levels of plasma endotoxin than those observed in the control group. N omega-Nitro-L-arginine methyl ester (L-NAME)-inhibitable nitrite production from mononuclear lymphocyte cells was higher in patients than in the control group, the highest levels being in non-alcoholic cirrhotic patients, and the lowest levels in patients with non-cirrhotic alcoholic liver disease. 4. Immunocytochemistry studies revealed a positive immunoreactivity for the inducible isoform of nitric oxide synthase in lympho-mononuclear cells that was more evident in non-alcoholic than in alcoholic cirrhotic patients. By Northern blot, inducible nitric oxide synthase mRNA expression was observed only in lymphomononuclear cells from non-alcoholic cirrhotic patients. 5. Our patients show a correlation between nitric oxide synthesis, endotoxin levels and haemodynamic parameters. 6. These findings indicate that lympho-mononuclear cell stimulation may play a role in elevated nitric oxide production in hepatic cirrhosis. Thus, this increased nitric oxide synthesis could be implicated in the pathogenesis of the haemodynamic disturbances frequently found in cirrhotic patients. This increase seems to be induced, at least in part, by activation of an inducible isoform of nitric oxide synthase.     

Increase of striatal dopamine release by cadmium in nursing rats and its prevention by dexamethasone-induced metallothionein

Repeated daily intraperitoneal (i.p.) administrations of cadmium (CdCl2, 1 mg/kg per day for 5 days) increased striatal dopamine (DA) release (180% of controls) and turnover (150% of controls) in 13-day-old rats. Cd treatment also increased striatal metallothionein (MT) content (161%), Cd (127%) and lipid peroxidation (LPO, 190%). In addition, Cd treatment decreased striatal tyrosine hydroxylase (TH) activity (-28%), and such an effect may result from D-2 receptor blockade as a consequence of excessive dopamine release, since sulpiride (a specific D-2 receptor antagonist) administration to Cd-treated rats abolished the effect of Cd on TH. No effect was observed on striatal monoamine oxidase (MAO) activity. Dexamethasone (Dx) treatment increased striatal MT content and caused no effect on either DA release or turnover. However, Dx administration prevented the effects caused by Cd, including the increased DA release and enhanced striatal lipid peroxidation. These results indicate that toxic effects on the brain are to be expected as a result of Cd exposure and that Dx administration can attenuate them.     

Cardiovascular effects of conventional sulfonylureas and glimepiride

Sulfonylureas have, in the past, been reported to have adverse cardiovascular effects. Glimepiride is a new sulfonylurea. In spite of stimulating less insulin secretion, it has, depending on the species, equal or higher blood glucose decreasing activity and according to preliminary studies less cardiovascular activity than glibenclamide. Further studies were performed to confirm the lower cardiovascular activity of glimepiride. The IC50 for inhibition of rilmakalim-activated KATP channel currents in isolated ventricular myocytes was 31.6 nM for glimepiride and 6.8 nM for glibenclamide. In endotoxin shock-rats at a dose of 1 x 2 mg/kg i.v., glibenclamide induced a significantly higher blood pressure increase than glimepiride. At two i.v. doses of 20 mg/kg 4 min apart, in normal rats, glibenclamide produced signs of ischemia in the ECG in nearly all animals, glimepiride almost none, in diabetic rats, glibenclamide produced in all animals a lethal cardiogenic shock preceeded by serious ECG changes, glimepiride only in one fifth of the animals. In open-chest dogs, on intracoronary infusion of equieffective blood glucose-lowering doses, glibenclamide, gliclazide and glimepiride all reduced coronary blood flow, increased coronary resistance, depressed the mechanical activity of the heart, enhanced myocardial O2-extraction, reduced the serum potassium level and induced a moderate endocardial ST-segment elevation, but glimepiride to a significantly less extent than glibenclamide and gliclazide. The presented data confirm that glimepiride at equivalent blood glucose decreasing doses has less cardiovascular activity than conventional sulfonylureas.     

Alumina scale growth at zirconia-MCrAlY interface: a microstructural study

High-temperature oxide scale growth at the ceramic-metal interface is a major contributor to the thermomechanical resistance of thermal barrier coatings for hot stages of gas turbines. In order to better understand this phenomenon, microstructural observations of the alumina scales formed at 1100 and 1200 °C under air, between low-pressure plasma-sprayed NiCrAlY and air plasma-sprayed ZrO₂-8.5 wt % Y₂O₃, have been performed by classical and analytical transmission electron microscopy on transverse thin foil specimens. The evolution of the oxide grain morphology from the metal-oxide to the oxide-oxide interface suggests that the scale growth principally takes place at the metal-oxide interface. Segregation of yttrium at oxide grain boundaries has been detected as well as significant quantities of zirconium inside the alumina grains. The oxide growth seems to be dominated by a classical grain-boundary oxygen diffusion mechanism. The presence of zirconium inside the alumina grains also suggests that Al₂O₃ partially forms by chemical reduction of ZrO₂ by AI. The comparison between the microstructures observed and that of alumina scales grown under similar conditions on bare MCrAlY alloys gives some insight into how the ceramic top-coat modifies NiCrAlY high-temperature oxidation mechanisms.     

A method for dynamic measurement of the resistance to dry heat exchange by footwear

Five different types of cold protective footwear have been tested with regard to their resistance to dry heat loss (i.e. the insulation) with a new electrically heated foot model. The model is able to simulate 'walking' movements in order to provide a more realistic simulation of wear conditions. Thermal insulation of shoes with and without a steel toe cap was the same. The insulating properties during simulated walking movements were 10-25% lower compared with static conditions. For two of the shoe models a significantly lower insulation value for the sole area was obtained when adding a weight of 30 kg. A significant difference could also be found between the insulation values of two different sizes of one of the models. Measurements with the standard method (EN 344) correlated well with the local insulation value of the sole part of the thermal foot. Correlation with the insulation value for the whole shoe was much less, variation was bigger and ranking in terms of cold protection differed between methods. The electrically heated foot model appears to provide a reproducible, accurate and more realistic method for measuring the insulation properties of shoes than EN 344.     

Memory complaints in epilepsy: correlations with cognitive performance and neuroticism

Experimental results are presented to show that the adhesion force is the single most important limiting factor in high-resolution atomic force microscopy of DNA in air, prepared by the cytochrome-C-assisted spreading method. It is also shown that humidity plays a minor role in the control of probe force. Using a pure carbon film as the substrate to clean the AFM tip prior to imaging, it is demonstrated that 4-6 nm resolution on DNA can be routinely obtained by the atomic force microscope with commercial Si3N4 pyramid cantilevers. We also show that in organic solvents a resolution of up to 3 nm can be obtained under optimal conditions.     

Surgical management of congenital high vaginal atresia

In the past 15 years five neonates and children have been treated for high vaginal atresia at the Surgical Unit of Department of Pediatrics, University Medical School, Pécs, Hungary. In three of the six patients distal atresia of the vagina was found (Type III). Two of the three were neonates and had a large hydrometrocolpos and the third, a 13-year-old girl, hematometrocolpos. In the fourth patient the vaginal atresia was associated with cloacal and anorectal malformation (Type V). In the fifth there was a duplication of uterus and vagina; however, only one of the two vaginas was atretic. In three patients a pull-through of the vagina was carried out, in one of them according to Pena, in another a transvesical approach, as suggested by Monfort, was used. Following repeated surgeries in the patient with cloacal malformation the vagina was replaced with large intestine. In the case of duplication of vagina and uterus one half of the duplication was removed.     

A one-site, two-state model for the binding of anions in photosystem II

Photosystem II membranes, dialyzed against a Cl(-)-free buffer to remove bound Cl-, lost about 65% of the control activity. A light-intensity study of the Cl(-)-free membranes showed that all PS II centers were able to evolve oxygen at about 35% of the control rate when measured in Cl(-)-free medium. The Cl(-)-depleted membranes were immediately (< 15 s) reactivated to 85-90% of the original activity by the addition of fairly high concentrations of Cl- (Kd = 0.5 mM), but both Cl- and the activity were promptly lost when the membranes immediately after reactivation were diluted in a Cl(-)-free medium. However, stabilization of Cl(-)-binding could be accomplished by prolonged incubation in the presence of Cl-. The transition to stable binding, followed using 36Cl-, occurred over several minutes. The stable binding was further characterized by a Kd of 20 microM and a t1/2 for dissociation of about 1h [Lindberg et al. (1993) Photosynth. Res. 38, 401-408]. The effects on S2 signals of removal of Cl- were studied using EPR. The depletion of Cl- was accompanied by a shift in intensity toward the g = 4.1 signal at the expense of the multiline signal. When Cl- or Br- but not F- was added to the depleted PS II membranes, the original distribution of the signals was immediately (< 30 s) restored. We propose that Cl(-)-binding responsible for high oxygen-evolution activity and normal EPR properties of the S2 state may occur either as high affinity (Kd = 20 microM) and slowly exchanging (t1/2 = 1 h), or as low affinity (Kd = 0.5 mM) and rapidly exchanging (t1/2 < 15 s). Our results suggest that Br- but not F- has a mode of binding similar to that of Cl-. The high-affinity state is the normal state of binding, but once Cl- has been removed, it will first rebind as low-affinity, rapidly exchanging followed by conversion into a high-affinity, slowly exchanging mode of binding.     

Expression of a mannose/fucose membrane lectin on human dendritic cells

Dendritic cells (CD) are the most efficient antigen presenting cells for T lymphocytes. CD1a+ CD14- CD with high antigen-presenting capacities can now be obtained easily from adherent peripheral blood monocytes by culture in the presence of granulocyte/macrophage colony-stimulating factor and interleukin-4 (Sallusto et al., J. Exp. Med. 1994. 179: 1109). Human macrophages express a membrane lectin, or sugar-specific receptor, which specifically mediates the binding and endocytosis of mannose- and fucose-terminated glycoproteins and is involved in the phagocytosis of pathogens. A similar lectin activity was sought on cultured human DC using flow cytometry and confocal microscopy to detect binding and internalization of fluoresceinated neoglycoproteins [bovine serum albumin (BSA) substituted with sugar residues]. Several neoglycoproteins, especially alpha-L-fucosyl-, alpha-D-mannosyl-, N,N'-di-acetyl-beta-chitobiosyl- and beta-D-glucosyl-BSA, were endocytosed by cultured human CD1a+ DC as well as by CD1a- CD14- cells which were also obtained in the culture. Fuc-BSA and Man-BSA had the same number of binding sites (1.7 x 10(6)/cell) on CD1a+ DC, and bound with an affinity constant close to 10(7) 1/mol. Inhibition experiments indicated that these two neoglycoproteins bound to the same membrane lectin. CD1a+ and CD1a- cells were both labeled by an antiserum specific for the human macrophage mannose receptor. The membrane lectin specific for mannose and fucose that is evidenced in these experiments on cultured DC may be similar to the macrophage membrane lectin or may share functional and structural properties with it.