bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of transdermal nitroglycerin on glucose‐stimulated insulin release in healthy male volunteers
Authors: Kovacs  , Szilvassy  , Hegyi  , Nemeth  , Ferdinandy  , Tosaki  
Published: March 2003

BackgroundMorpholinosydnonimine, a nitric oxide (NO) donor, has been reported to inhibit insulin release in isolated pancreatic islets. We studied whether transdermal application of nitroglycerin, another NO donor widely used for angina prophylaxis, influenced glucose‐stimulated insulin release in healthy, young, male volunteers.Methods and resultsOral glucose tolerance tests [(OGTT) 75 g glucose in 200 mL of water) were performed in the presence of placebo patches or nitroglycerin‐releasing ‘active’ patches (approx. 0.4 mg hour−1 nitroglycerin) in the same patients with a 2‐week intertest interval. Venous blood samples were taken before and 15, 30, 60, 90, 120 and 180 min after the glucose load and evaluated for plasma glucose level and immunoreactive insulin responses (radioimmunoassay). Glucose‐stimulated maximum increase in plasma insulin immunoreactivity were 36.3 ± 5 and 78.8 ± 6.1 mU mL−1 (P < 0.05) in the presence of active and placebo patches, respectively. Nevertheless, both fasting and postload blood glucose levels were the same at either patch. Active patches significantly decreased blood pressure with a marginal increase in heart rate.ConclusionWe conclude that inhibition of glucose‐stimulated insulin release by transdermal nitroglycerin without causing hyperglycaemia may serve as a novel component of the antianginal mechanism of action of nitrates.
Assessment of bilirubin toxicity to erythrocytes. Implication in neonatal jaundice management
Authors: Brito  , Silva  , Tiribelli  , Brites  
Published: March 2003

BackgroundNeonatal hyperbilirubinaemia remains one of the most common clinical conditions requiring therapeutic intervention. Nevertheless, reliable indicators of bilirubin toxicity are still missing. This prompted us to investigate (a) the progression of cytotoxic events produced by increasing concentrations of bilirubin; (b) the relevance of the membrane lipid package on bilirubin binding to erythrocytes; and (c) the reliability of chloroform extraction compared with albumin extraction to evaluate erythrocyte‐bound bilirubin and cytotoxicity.Materials and methodsMorphological alterations, free bilirubin, erythrocyte‐bound bilirubin (albumin‐ and chloroform‐extractable), haemolysis and membrane‐released lipids, were determined in human erythrocytes at 4 °C or 37 °C, after 4 h incubation at pH 7.4, with increasing molar ratios of bilirubin to albumin (0.5–5). The reversibility of cytotoxicity by albumin washing was assessed by morphological analysis.ResultsDecreased free bilirubin, lower erythrocyte‐bound bilirubin concentration by albumin extraction (superficial/non‐aggregated bilirubin) and higher values by chloroform extraction (deep/aggregated bilirubin) were observed for 37 °C vs. 4 °C, at molar ratios > 1. Echinocytosis increased with bilirubin concentration and temperature and was not fully reversed by albumin washing. Haemolysis was already significant at a molar ratio of 1, and was enhanced by temperature at molar ratios 3 and 5 (P < 0.01). The loss of membrane lipids was remarkable at molar ratios ≥ 0.5, both at 4 °C and 37 °C (P < 0.01), although correlation with bilirubin concentration was only significant at 37 °C (r = 0.971; P < 0.01).ConclusionsThese results suggest that increased lipid fluidity and high bilirubin concentrations promote membrane bilirubin translocation and toxicity. They also show that albumin is not able to displace the bilirubin located deeply or aggregated within the membrane, which in turn is removed by chloroform. Accordingly, chloroform‐extractable rather than albumin‐extractable bilirubin is a more accurate parameter to assess erythrocyte‐bound bilirubin during severe hyperbilirubinaemia.
Iron supplementation affects the production of pro‐inflammatory cytokines in IL‐10 deficient mice
Authors: Oldenburg  , Van Berge Henegouwen  , Rennick  , Van Asbeck  , Koningsberger  
Published: March 2003

BackgroundIron supplements may increase disease activity in inflammatory bowel disease through the production of the hydroxyl radical because of its catalytic activity in the Fenton reaction. The purpose of this study was to assess the effect of dietary and locally administered iron in the IL‐10 knock‐out (−/−) mouse, a model of chronic inflammatory bowel disease.Materials and methodsIL10−/− and wild‐type mice received a standard or a high‐iron diet (35 mg kg−1 ferrosulphate vs. 500 mg kg−1 ferrosulphate) after weaning. After 4 weeks the mice were sacrificed. Furthermore, a group of adult IL‐10 knock‐out mice was given three iron‐containing enema's (0.2 mL of 1 m
m ferrous‐ammonium sulphate) or phosphate buffered saline. These mice were sacrificed after 1 week. Production of pro‐inflammatory cytokines by colon tissue cultures, haematological parameters and histology was determined to assess inflammatory activity.ResultsOral as well as rectal administration of iron resulted in increased pro‐inflammatory cytokine production in IL‐10−/− mice. Neutrophil counts in IL10−/− on a high iron diet increased as well. No enhanced colonic inflammation was noted on histology after iron supplementation.ConclusionWe conclude that dietary or topical administered iron increases pro‐inflammatory cytokine production in the colon of IL10−/− mice. No significant increase of histological intestinal inflammation was observed.
Immortalisation of human bone marrow endothelial cells: characterisation of new cell lines
Authors: Rood  , Calafat  , Kr. Von dem Borne  , Gerritsen  , Van Der Schoot  
Published: March 2003

BackgroundAdhesion of haematopoietic progenitor cells (HPC) to human bone marrow endothelial cells (HBMEC) plays a key role in homing of HPC to bone marrow. Here we describe four new HBMEC cell lines that can be used to study the (specific) adhesion of HPC to HBMEC.DesignHBMEC were immortalised with a retroviral construct containing the human papilloma virus 16 E6/E7 genes. Four cell lines were characterised.ResultsThe cell lines showed their endothelial nature by the expression of von Willebrand Factor and VE‐cadherin (CD144). Electron microscopic analysis revealed normal endothelial‐cell characteristics, including the presence of Weibel‐Palade bodies and intercellular junction structures. An extensive phenotypic analysis of the cell‐lines was performed, they were found to resemble primary HBMEC. The only difference found was the absence of expression of E‐selectin (CD62e) and VCAM‐1 (CD106) on resting HBMEC cell lines. Upon stimulation with IL‐1β the expression of E‐selectin, VCAM‐1 and ICAM‐1 (CD54) was upregulated. All resting cell lines bound CD34+ HPC. Adhesion was increased by addition of the phorbol ester PMA. Two cell lines showed increased binding upon IL‐1β prestimulation. Highest adhesion was observed after the combination of IL‐1β prestimulation of the endothelial cells and addition of PMA. Binding of CD34+ HPC to HBMEC was compared with the binding to human umbilical vein endothelial cell lines and to a human dermal microvascular endothelial cell line (HMEC‐1). So far, we have only found relatively less binding of HPC to IL‐1β prestimulated HMEC‐1 cells, which could be explained by a reduced induction of E‐selectin and VCAM‐1 upon IL‐1β stimulation of these cells.ConclusionThe immortalised HBMEC cell lines have maintained their normal phenotype for the majority of characteristics examined. The expression of E‐selectin and VCAM‐1, which are not constitutively expressed on the cell lines, can be induced by stimulation of the endothelial cells with IL‐1β. The cell lines have furthermore maintained their capability to bind HPC. They will therefore be useful to investigate the interactions between HPC and HBMEC involved in homing of HPC.
Amelioration of hyperglycemic and hyperosmotic induced vascular dysfunction by in vivo inhibition of protein kinase C and p38 MAP kinase pathway in the rat mesenteric microcirculation
Authors: Schäffler  , Arndt  , Schölmerich  , Palitzsch  
Published: March 2003

BackgroundRecently, we demonstrated in vivo effects of acutely induced hyperglycemia, diabetes and mannitol infusions on rat mesenteric microcirculation concerning leukocyte–endothelial‐cell interaction (Schäffler et al. EJCI 28: 886–893, 1998).DesignIn this study we have investigated the possible involvement of the protein kinase C (PKC) and p38 MAP kinase cascade as signal transducing elements during hyperglycemic and osmotic stress in an in vivo rat model.ResultsAcutely induced hyperglycemia resulted in a significant increase in leukocyte adhesion. This effect could be mimicked by mannitol. Both PKC and p38 MAP kinase were involved in the effects mediated by glucose and mannitol. Acutely induced hyperglycemia resulted in a significant increase in leukocyte emigration. This effect could be imitated by mannitol. However, PKC and p38 MAP kinase were only involved under osmotic stimulation. The hyperglycemia‐induced reduction in leukocyte rolling velocity seemed to be a glucose‐specific effect, since mannitol did not influence leukocyte rolling velocity. This glucose effect on leukocyte rolling velocity was mediated by an activation of the PKC/p38 MAP kinase cascade. Both hyperglycemia and osmotic stimuli alone were able to reduce venular shear rate without recruitment of the p38 MAP kinase cascade. The observed reduction of shear rate seems to be mediated only by the osmotic effects of glucose via activation of the PKC system.ConclusionThe observed effects of glucose on adhesion, emigration and shear rate are due to osmotic effects. The PKC/MAP kinase cascade is involved as a signal transducing component. The reduction of leukocyte rolling velocity is a glucose‐specific effect, mediated by the activation of both the PKC and the p38 MAP kinase cascade. Venular shear rate and leukocyte emigration can be influenced by glucose and mannitol due to different regulation mechanisms. It is concluded, that isoform‐specific inhibitors of PKC and specific MAP kinase inhibitors represent a potential drug target for preventing microvascular dysfunction in diabetes.
A β‐turn rich oats peptide as an antigen in an ELISA method for the screening of coeliac disease in a paediatric population
Authors: Ribes‐Koninckx  , Alfonso  , Ortigosa  , Escobar  , Suárez  , Arranz  , Méndez  
Published: March 2003

BackgroundELISA methods for the measurement of IgA antigliadin antibodies (AGA), both home‐made and commercial systems, routinely employ wheat gliadin fractions as coating antigens. We investigate the sensitivity and specificity for CD diagnosis of a new ELISA method using a highly immunoreactive β‐turn rich γ3‐avenin peptide as an alternative coating antigen.MethodsThe assay was standardized with antihuman IgA peroxidase‐conjugated as the second antibody. Alternatively, an ELISA based on the use of protein A‐peroxidase was assayed to measure both IgG plus IgA antibodies. Sixty‐three sera from healthy controls were analized to establish the system's cut‐off point. Sera from 103 coeliac and from 65 noncoeliac children were tested; for diagnosis purposes, a small intestinal biopsy had been performed in all of them.ResultsFor the IgA class antibodies assay a high sensitivity and specificity of 90.3% and 98.5%, respectively, was obtained, comparable to those achieved for IgA antiendomysium antibodies (EmA) with the same sera.ConclusionsIn view of the high sensitivity and specificity obtained together with water solubility of the peptide and easiness for large‐scale reproducible synthesis, the new AGA IgA avenin peptide ELISA represents a significant improvement in CD diagnosis in comparison with conventional established AGA IgA ELISA using crude gliadins as coating antigens.
The noradrenaline plasma concentration and its gradient across the lung
Authors: Marenzi  , Agostoni  , Guazzi  , Lauri  , Assanelli  , Guazzi  
Published: March 2003

BackgroundWe investigated the lung contribution to circulating noradrenaline (NA) homeostasis. Evaluation of the transpulmonary NA gradient, related to the NA amount entering the lungs, is potentially important, mainly regarding clinical conditions, such as congestive heart failure (CHF), that are associated with excessive circulating NA.Materials and methods15 moderate (group 1) and 15 severe (group 2) CHF patients, and 10 normal individuals had determination of NA transpulmonary gradient in the baseline and during rise (exercise, in normals and group 1) or fall (withdrawal from plasma by ultrafiltration, in group 2) of plasma NA.ResultsNA gradient (pg mL−1) at rest was 30 ± 3 in normals, 21 ± 6 in group 1 and 5 ± 8 in group 2. Increase of NA concentration in the mixed venous blood with exercise was paralleled by depression of the transpulmonary gradient. Pulmonary arteriovenous difference disappeared when NA entering the lungs averaged 1300 pg mL−1. In group 2, ultrafiltration lowered NA in the mixed venous blood from 1225 ± 213 to 718 ± 182, which caused transpulmonary gradient to increase from 5 ± 8 to 22 ± 9.ConclusionsTranspulmonary gradient of NA diminishes when NA entering the lungs increases, and 1300 pg mL−1 in the pulmonary artery is, both in patients and normal subjects, the level at which gradient disappears; which likely reflects cessation of NA uptake or achievement of a balance between lung uptake and production. This may have physiological and pathological implications.
Elevated serum dipeptidyl peptidase IV (CD26, EC 3.4.14.5) activity in experimental liver cirrhosis
Authors: Lakatos  , Firneisz  , Borcsiczky  , Zalatnai  , Selmeci  , Szalay  
Published: March 2003

BackgroundDipeptidyl peptidase IV (DPP IV) is a cell surface ectoenzyme widely distributed in the rat body, present on the epithelial cells of the brush border membranes (e.g. bile canaliculi) and on the surface of reactive lymphocytes and fibroblasts. DPP IV has been implicated in hepatocyte–extracellular matrix interactions, fibroblast activation and proliferation and in T‐cell activation. Aberrant DPP IV expression was found in human liver cirrhosis, and elevated serum DPP IV activity was reported in patients with primary biliary cirrhosis and chronic hepatitis C virus infection. The aim of the study was to examine serum DPP IV activity in experimental liver cirrhosis.MethodsLiver cirrhosis was induced by administering diethyl‐nitrosamine, phenobarbital and CCl4 in Fischer‐344 male rats (n = 22). Phenobarbital‐treated (n = 9) and nontreated (n = 9) male rats were used as controls. Serum DPP IV activity was measured using a microplate‐based continuous‐monitoring assay. Recombinant rat DPP IV was used as standard and Gly‐Pro‐PNA was used as substrate. Enzyme activity was given in nmol mL−1 min−1 (U L−1).ResultsSignificantly higher DPP IV activity was found in the sera of rats with experimental liver cirrhosis (39.2 ± 3.7; mean ± SD) compared to phenobarbital‐treated (11 ± 4, P < 0.000002) and nontreated (10.9 ± 0.9, P < 0.000002) rats. There was a positive correlation between DPP IV activity and concentrations of aspartate aminotransferase (r = 0.73, P = 0.0001) and alanine aminotransferase (r = 0.69, P = 0.0004).ConclusionsThe significantly higher serum DPP IV activity found in experimental liver cirrhosis is in concordance with human observations. The elevation was probably not due to the enzyme induction effect of phenobarbital. In this experimental model, serum DPP IV seems to be an indicator for chronic liver injury.
Biliary lipid composition in patients with cholesterol and pigment gallstones and gallstone‐free subjects: deoxycholic acid does not contribute to formation of cholesterol gallstones
Authors: Gustafsson U. , Sahlin S. , Einarsson C. 
Published: March 2003

Four main disturbances have been attributed to cholesterol gallstone disease: hypersecretion of cholesterol from the liver with cholesterol supersaturation in bile; disturbed motility with defective absorption and secretion by the gallbladder; increased crystallisation of cholesterol in the gallbladder bile; and slow intestinal transit with increased amount of deoxycholic acid in the bile acid pool. We aimed to evaluate the biliary lipid composition in a large series of gallstone patients, with emphasis on the amount of deoxycholic acid and with respect to number of stones, compared to gallstone free subjects. Materials and methods Bile was sampled during operations through puncture of the gallbladder from 145 cholesterol gallstone patients, 23 patients with pigment stones and 87 gallstone free patients undergoing cholecystectomy. Biliary lipid composition, cholesterol saturation, bile acid composition, nucleation time and cholesterol crystals were analysed.The patients with cholesterol gallstones showed higher molar percentage of cholesterol, lower total biliary lipid concentration, higher cholesterol saturation, shorter nucleation time and higher proportion of crystals in bile than the other groups. The nucleation time was significantly shorter in multiple cholesterol gallstone patients, but this was not due to higher cholesterol saturation. Male cholesterol gallstone patients showed higher cholesterol levels, lower total biliary lipid concentration, and higher cholesterol saturation in bile than female patients. There was no difference in biliary content of deoxycholic acid, but significantly lower content of cholic acid in gallstone patients compared to gallstone free patients.We conclude that deoxycholic acid does not contribute to gallstone formation in cholesterol gallstone patients. The short nucleation time in patients with multiple cholesterol stones is not due to higher cholesterol saturation.
Insulin‐mediated increases in renal plasma flow are impaired in insulin‐resistant normal subjects
Authors: Ter Maaten J. C. , Bakker S. J. L. , Serné E. H. , Moshage H. J. , Donker A. J. M. , Gans R. O. B. 
Published: March 2003

Impaired vasodilatation in skeletal muscle is a possible mechanism linking insulin resistance to blood pressure regulation. Increased renal vascular resistance has been demonstrated in the offspring of essential hypertensives. We assessed whether insulin‐mediated renal vasodilatation is impaired in insulin‐resistant normal subjects.In two groups of 10 insulin‐resistant and 10 insulin‐sensitive normal subjects, we compared the effects of sequential physiological and supraphysiological insulin dosages (50 and 150 mU kg−1 h−1) on renal plasma flow (RPF) and leg blood flow using the euglycaemic clamp technique, 131I‐labelled Hippuran clearances and venous occlusion plethysmography. Time‐control experiments were performed in the same subjects.Whole‐body glucose uptake amounted to 4·9 ± 2·1 and 11·0 ± 2·4 mg kg −1min−1 in the insulin‐resistant and to 12·7 ± 2·3 and 17·4 ± 2·6 mg kg −1min−1 in the insulin‐sensitive subjects during physiological and supraphysiological hyperinsulinaemia, respectively. RPF increased more in insulin‐sensitive compared to insulin‐resistant subjects during physiological hyperinsulinaemia (13·7 vs. 6·8%, P < 0·05). RPF increased to comparable levels during supraphysiological hyperinsulinaemia. Insulin‐mediated changes in leg blood flow did not differ between groups. In the combined group, we found a positive correlation between insulin‐mediated glucose uptake and changes in RPF during physiological hyperinsulinaemia (r = 0·57, P = 0·009), whereas insulin‐mediated glucose uptake correlated with changes in leg blood flow during supraphysiological hyperinsulinaemia (r = 0·54. P = 0·017).Our results suggest that the sensitivities of the skeletal muscle and renal vascular bed differ for insulin's vasodilatory action. Insulin‐mediated increases in RPF are impaired in insulin‐resistant but otherwise normal subjects during physiological hyperinsulinaemia.
The role of the insulin‐like growth factor system in adrenocortical tumourigenesis
Authors: Weber M. M. , Fottner C. , Wolf E. 
Published: March 2003

BackgroundThe insulin‐like growth factor (IGF) system plays a central role in the mechanism of transformation and tumourigenesis. Elevated levels of IGF‐II and IGF‐I have been found in adrenocortical carcinomas.Material and methodsWe examined binding characteristics and concentrations of both IGF‐receptors in normal adult human adrenocortical glands, and compared them with the IGF‐I receptor binding in adrenocortical tumours of various origins. The human IGF‐I receptor was overexpressed in the mouse adrenocortical tumour cell line Y1, and growth studied in response to IGF stimulation. The influence of IGF‐II on adrenal morphology and function was assessed in transgenic mice that postnatally overexpress IGF‐II.ResultsWhile the abundance of the IGF‐I receptor in adrenocortical hyperplasias and adenomas was similar to normal tissue, a strong overexpression of the intact IGF‐I receptor was found in three out of four adrenocortical carcinomas. Y1 cells overexpressing the human IGF‐I receptor respond to IGF‐I with an increase in thymidine incorporation by 140%. Furthermore, the antiproliferative effect of ACTH is blunted. In transgenic mice postnatally overexpressing IGF‐II, adrenal weight is increased, mainly due to a 50% increase in the number of zona fasciculata cells. Plasma corticosterone levels in these mice are twofold higher than in controls, in contrast to similar plasma ACTH levels, thus indicating a direct effect of IGF‐II on adrenal cell hyperplasia and function.ConclusionThere is substantial evidence that the IGF‐system is involved in adrenal growth and tumourigenesis. High local levels of IGF‐II in combination with elevated IGF‐I receptor concentrations would represent a significant growth advantage of the adrenocortical carcinoma cell and could contribute to a highly malignant phenotype. IGF‐II overexpression alone seems not to be sufficient for malignant transformation.
Cardiovascular effects of beta 3‐adrenoceptor stimulation in perinephritic hypertension
Authors: Donckier J. E. , Massart P.‐E. , Van Mechelen H. , Heyndrickx G. R. , Gauthier C. , Balligand J.‐L. 
Published: March 2003

Background A new beta 3‐adrenoceptor (β3‐AR) has been shown to mediate peripheral vasodilation. This study was conducted to evaluate effects of the β3‐AR agonist, SR58611 in normal and hypertensive dogs.Materials and Methods In protocol 1, SR58611 was infused in normal dogs after placebo, after β1/β2 blockade with nadolol, after β1/β2/β3 blockade with bupranolol and after combined autonomic blockade (CAB). In protocol 2, perinephritic hypertension was produced in dogs, which received SR58611 at 3 and 6 weeks of hypertension. Effects of SR58611 were evaluated at 7 weeks of hypertension after CAB.Results In normal dogs, SR58611 produced a dose‐dependent decrease in mean aortic pressure (AOP) (from 116 ± 19 to 100 ± 19 mmHg, − 14%; P < 0·05) that was accompanied by baroreflex activation (heart rate increased by 70%; P < 0·01). This hypotensive effect resulting from peripheral vasodilation persisted after nadolol or CAB while baroreflex activation was blunted or abolished. A biphasic response of cardiac output, characterized by a rise and a decline (P < 0·05) reflected a reduction in after‐ and pre‐load. After CAB, SR58611 did not modify cardiac contractility. SR58611 stimulated lipolysis as reflected by a 4‐fold increase in blood free fatty acids (FFA) (P < 0·0005). Under CAB, the rise of FFA was reduced (P < 0·01). In hypertensive dogs, SR58611 produced a dose‐dependent decrease in mean AOP (from 168 ± 32 to 125 ± 35 mmHg; − 26%, P < 0·0001), that was greater than in normal dogs (P < 0·05). Reflex‐mediated tachycardia also occurred but at higher blood pressure values. Blood FFA rose similarly (P < 0·0001). Under CAB, heart rate remained unchanged but SR58611 still induced a decrease (P < 0·0001) in mean AOP concomitantly with a rise of (dP/dt)/DP40 (P < 0·005), an effect not observed in normal dogs.Conclusions β3‐AR stimulation exerts hypotensive effects, increases cardiac contractility and stimulates lipolysis in hypertensive dogs.