bluuebunny/crossref_metadata_2025_split huggingface dataset:
A 4‐trifluoromethyl derivative of salicylate, triflusal, stimulates nitric oxide production by human neutrophils: role in platelet function
Authors: De Miguel  , Jiménez  , Montón  , Farré  , Del Mar Arriero  , Rodríguez‐Feo  , García‐Cañete  , Rico  , Gómez  , Núñez  , Casado  , Farré  
Published: March 2003

BackgroundThe thrombotic process is a multicellular phenomenon in which not only platelets but also neutrophils are involved. Recent in vitro studies performed in our laboratory have demonstrated that triflusal, a 4‐trifluoromethyl derivative of salicylate, reduced platelet aggregation not only by inhibiting thromboxane A2 production but also by stimulating nitric oxide (NO) generation by neutrophils. The aim of the present study was to evaluate whether oral treatment of healthy volunteers with triflusal could modify the ability of their neutrophils to produce NO and to test the role of the NO released by neutrophils in the modulation of ADP‐induced platelet aggregation and α‐granule secretion.MethodsThe study was performed in 12 healthy volunteers who were orally treated with triflusal (600 mg day−1) for 5 days. Flow cytometric detection of platelet surface expression of P‐selectin was used as a measure of the ability of platelets to release the contents of their α‐granules.ResultsAfter treatment with triflusal, there was an increase in NO production by neutrophils and an increase in endothelial nitric oxide synthase (eNOS) protein expression in neutrophils. A potentiation of the inhibition of platelet aggregation by neutrophils was reversed by incubating neutrophils with both an l‐arginine antagonist, NG‐nitro‐
l‐arginine methyl ester (
l‐NAME) and an NO scavenger, 2‐(4‐carboxyphenyl)‐4,4,5,5 tetramethylimidazoline 1‐oxyl 3‐oxide (C‐PTIO). A slight decrease in P‐selectin surface expression on platelets was found which was not modified by the presence of neutrophils and therefore by the neutrophil‐derived NO. Exogenous NO released by sodium nitroprusside dose‐dependently inhibited both ADP‐stimulated α‐granule secretion and platelet aggregation. Therefore, platelet aggregation showed a greater sensitivity to be inhibited by exogenous NO than P‐selectin expression.ConclusionOral treatment of healthy volunteers with triflusal stimulated NO production and eNOS protein expression in their neutrophils. After triflusal treatment, the neutrophils demonstrated a higher ability to prevent ADP‐induced platelet aggregation. However, the neutrophils and the endogenous NO generated by them failed to modify P‐selectin expression in ADP‐activated platelets.
Disordered calcium homeostasis of sepsis: association with calcitonin precursors
Authors: Müller  , Becker  , Kränzlin  , Schächinger  , Huber  , Nylèn  , Snider  , White  , Schmidt‐Gayk  , Zimmerli  , Ritz  
Published: March 2003

BackgroundHypocalcemia and increased serum levels of calcitonin precursors are common in critically ill patients, especially in those with sepsis. We investigated calcium homeostasis in such patients.Patients and methodsSerum concentrations of total and ionized calcium and known factors influencing or reflecting calcium homeostasis were measured in 101 consecutive patients of a medical intensive care unit. Calcitonin precursor levels were determined using a highly sensitive radioimmunoassay.ResultsCritical illness per se was associated with decreased serum total and ionized calcium levels, which correlated with the severity of the underlying disease as measured by the APACHE II score. In addition, total and ionized hypocalcemia was more pronounced with increasing severity of infection (P < 0.02), and occurred in parallel with a marked increase of calcitonin precursors (P < 0.001). Mature calcitonin levels, however, remained normal. Changes of serum ionized calcium concentrations from admission to discharge correlated significantly with changes in the serum calcitonin precursor concentration (r2 = − 0.14, P < 0.001). Circulating vitamin D levels, parathyroid hormone levels and other markers reflecting calcium homeostasis did not correlate with the severity of infection.ConclusionsIn critically ill patients with sepsis, markedly elevated circulating calcitonin precursors might play a role in the development of the pronounced hypocalcemia. The specific calcitonin precursor(s) responsible for this effect and the pathophysiological mechanism remain to be elucidated.
Oxidative stress in symptom‐free HCV carriers: relation with ALT flare‐up
Authors: Vendemiale G. , Grattagliano I. , Portincasa P. , Serviddio G. , Palasciamo G. , Altomare E. 
Published: March 2003

BackgroundThe reason why some hepatitis C virus carriers with normal aminotransferase activity present, during time, an activation of the disease, is unknown. The aim of this study was to assess the oxidative balance in such patients and to evaluate its possible role on the severity of disease.Materials and methodsHistology, glutathione and malondialdehyde were determined in the liver of 30 HCV‐RNA positive patients with persistently normal aminotransferase. Patients were followed‐up for 18 months with plasmatic determinations of aminotransferase, ferritin, glutathione, malondialdehyde, carbonyl and sulphydryl protein levels (every 2 months) and serum HCV‐RNA (every 3 months).ResultsFour subjects had normal histology, whereas the remaining 26 showed mild/moderate chronic hepatitis. Hepatic glutathione and malondialdehyde concentrations were normal in 16 patients and clearly altered in the other 14. The hepatic redox state did not correlate with histology whereas it correlated with plasmatic oxidative markers. During the study, aminotransferase flared up in 11 patients, 9 of these (82%) having at enrolment an altered hepatic oxidative balance. Patients with aminotransferase elevation showed increased blood indices of oxidative stress, which occurred earlier than aminotransferase flare‐ups. No oxidative stress was observed in the remaining subjects.DiscussionThis study suggests that symptom‐free HCV carriers with impaired redox state have a higher risk of aminotransferase flare‐up; therefore the impaired oxidative balance may have a prognostic significance on disease activity.
Molecular analysis of estrogen receptor alpha and beta in lupus patients
Authors: Kassi E. N. , Vlachoyiannopoulos P. G. , Moutsopoulos H. M. , Sekeris C. E. , Moutsatsou P. 
Published: March 2003

Background In female patients with systemic lupus erythematosus (SLE), we identified estrogen receptor ERα, ERβ and ERα variant transcripts in peripheral blood mononuclear cells (PBMC). Exon 1 and 2 of ERα gene was subjected to mutation analysis to assess whether possible nucleotide alterations are linked to the disease. Methods The whole coding sequence of ERα was analysed by reverse transcription polymerase chain reaction (RT‐PCR) and cDNA sequencing in PBMC prepared from 19 SLE patients and 12 healthy females. ERα exon 1 and exon 2 were subjected to mutation analysis using DNA isolated from whole blood of 21 SLE patients and 29 healthy females. The aminoterminal coding sequence of ERβ was also analysed by RT‐PCR. Results Wild type ERα and ERα splicing variants with deletions in exons 2, 5 and 7 were detected both in healthy individuals and in SLE patients, with no qualitative difference in their expression among the two populations. In ERα exon 1, the polymorphisms identified codon 10 and codon 87, both in patients and in healthy individuals who were not associated with the disease. No other mutations were present in ERα exon 1 or ERα exon 2 in all subjects studied. ERβ was expressed in both populations. Conclusion: PBMC of SLE patients express wild type ERα, ERβ and the same ERα variants as do healthy individuals. Genetic alterations in exon 1 and exon 2 of the ERα gene are not linked with SLE disease.
Effect of vitamin C on neutrophil function after high‐intensity exercise
Authors: Krause R. , Patruta S. , Daxböck F. , Fladerer P. , Biegelmayer C. , Wenisch C. 
Published: March 2003

High‐intensity exercise leads to an increased risk of upper respiratory tract infections in athletes, which had been related to an exercise‐induced impairment of neutrophil function. In this study, several indices of neutrophil function were analysed before and after a biathlon and the effect of oral vitamin C on neutrophil function was determined.Six athletes took 2 g vitamin C daily for 1 week prior to a biathlon and four athletes did not take any supplementation. Neutrophil phagocytosis was analysed by fluorescence microscopy and flow cytometry. Cytosolic calcium kinetics were assessed fluorometrically and neutrophil bactericidal ability was assessed by fluorescence microscopy. Reactive oxygen production was analysed by flow cytometry. Catecholamines were analysed by high‐performance liquid chromatography.After high‐intensity exercise there were significant reductions in the number of phagocytosed Escherichia coli per neutrophil and in neutrophil bactericidal ability. There was a significant exercise‐dependent increase of catecholamines. There was no difference between the two groups of athletes.These results do not support the concept that vitamin C supplementation corrects neutrophil dysfunction after strenuous exercise.
Idiopathic chronic constipation: tachykinins as cotransmitters in colonic contraction
Authors: Mitolo‐Chieppa D. , Mansi G. , Nacci C. , De Salvia M. A. , Montagnani M. , Potenza M. A. , Rinaldi R. , Lerro G. , Siro‐Brigiani G. , Mitolo C. I. , Rinaldi M. , Altomare D. F. , Memeo V. 
Published: March 2003

Background Tachykinins (TKs) have been shown to be involved in the excitatory enteric motor pathway. This study aimed to examine the direct and nerve‐mediated effect of specific NK1, NK2 and NK3 receptor agonists and antagonists in colonic preparations from control subjects and patients with idiopathic chronic constipation (ICC).Materials and methods Cumulative concentrations of Sar9Met(O2)11 substance P (selective NK1 receptor agonist), [Ala5,β‐Ala8]‐neurokinin A (4–10) (selective NK2 receptor agonist) and [MePhe7]‐neurokinin B (selective NK3 receptor agonist) were tested on colonic circular muscle strips to evaluate the direct drug effects. In addition, in the presence of atropine, the role of TKs in the off‐contraction that follows the typical inhibitory response evoked by low frequencies of electrical field stimulation (0·5–10 Hz, 20 V, 1 ms pulse trains lasting 1 min) was investigated.Results In control preparations, the rank order of potency was: NK2 receptor‐selective agonist > NK3 receptor‐selective agonist > NK1 receptor‐selective agonist. The off‐contraction was found to be reduced by about 30–40% in colonic circular muscle from ICC patients with respect to controls. Incubation with the NK1 receptor agonist did not modify the off‐contraction measurements in either control or ICC preparations. Conversely, both NK2 and NK3 receptor agonists significantly (P < 0·01) increased the off‐contraction in ICC preparations only. This increased response was fully antagonized by MEN‐10627, a NK2 and NK3 receptor antagonist depending on the dose.Conclusions We may conclude that ICC is hyporesponsive to TKs and that the contractile reflex to distension is greatly reduced in ICC disease, but can be restored by incubation with NK2 and NK3 receptor agonists.
Interferon‐γ in healthy subjects: selective modulation of inflammatory mediators
Authors: De Metz J. , Hack C. E. , Romijn J. A. , Levi M. , Out T. A. , Ten Berge I. J. M. , Sauerwein H. P. 
Published: March 2003

Background It is suggested that interferon‐γ (IFN‐γ), like other cytokines, is a mediator in the host inflammatory response, which could be of importance in the pathophysiology of sepsis. The role of IFN‐γ in human host inflammatory responses, however, has not been studied.Design In a placebo‐controlled trial we studied the acute effects of IFN‐γ administration on host inflammatory mediators in healthy men: i.e. the cytokine/chemokine cascade system, acute‐phase proteins, activation markers of the innate cellular immunity and coagulation/fibrinolysis parameters.Results IFN‐γ increased plasma levels of interleukin‐6 (IL‐6), IL‐8 and IFN‐γ‐inducible protein‐10 (IP‐10) (P < 0·05), but did not affect plasma levels of other cytokines (IL‐4, IL‐10, tumour necrosis factor‐α, IL‐12p40/p70). Plasma concentrations of C‐reactive protein and secretory phospholipase A2 both increased (P < 0·05). Plasma levels of the leucocyte activation marker elastase‐α1–antitrypsin complexes increased after IFN‐γ administration (P < 0·05), IFN‐γ increased the percentage of high‐affinity Fcγ‐receptor (FcγRI) ‐positive neutrophils (P < 0·05), but did not affect the mean fluorescence intensity of FcγRI on neutrophils. Procoagulant and profibrinolytic effects of IFN‐γ were evidenced by increased plasma levels of prothrombin fragment F1 + F2, tissue‐plasminogen activator and plasmin‐α2–antiplasmin complexes (P < 0·05).Conclusion We conclude that IFN‐γ selectively affects host inflammatory mediators in humans.
Effects of smoking on activation markers, Fas expression and apoptosis of peripheral blood lymphocytes
Authors: Bijl M. , Horst G. , Limburg P. C. , Kallenberg C. G. M. 
Published: March 2003

Background Smoking influences numbers and function of peripheral blood lymphocytes (PBL) by a process that is badly understood. We conducted this study to evaluate whether the immune impairment of smoking might be related to changes in the expression or functionality of Fas, a cell surface molecule that plays a central role in immune homeostasis and cytotoxic activity. Methods PBL from 10 smoking and 10 nonsmoking healthy volunteers were isolated. Flow cytometry was performed to measure the state of activation, Fas expression and apoptosis of PBL. Functionality of Fas was tested by assessing apoptosis after incubation of isolated lymphocytes with agonistic anti‐Fas antibodies in four smoking and four nonsmoking individuals. Results Smoking was associated with an increase in the percentage of Fas‐expressing CD4+ T and B lymphocytes. A decrease in the percentage of activated (CD38+) B cells was observed. In vitro Fas‐induced apoptosis did not appear different between smokers and nonsmokers. No differences in the percentages of circulating apoptotic lymphocytes could be demonstrated between smoking and nonsmoking individuals. Conclusion Smoking is associated with increased Fas expression on PBL in general, and on B cells in particular. This might render these cells more susceptible for apoptosis. As Fas is functionally intact this may also explain the reduced percentage of activated (CD38+) B cells found in smoking individuals. The latter may contribute to the reduced humoral immune response observed in smokers.
Peripheral blood T‐cell responses to pyruvate dehydrogenase complex in primary biliary cirrhosis: role of antigen‐presenting dendritic cells
Authors: Akbar S. M. F. , Yamamoto K. , Miyakawa H. , Ninomiya T. , Abe M. , Hiasa Y. , Masumoto T. , Horiike N. , Onji M. 
Published: March 2003

Patients with primary biliary cirrhosis (PBC) are usually characterized by the presence of antibody to pyruvate dehydrogenase complex (PDC) in the sera and PDC‐specific T cells in the liver. However, most of the patients with PBC do not show peripheral blood T cells response to PDC. In this study, we re‐evaluated the peripheral blood T cell responses to PDC in PBC using antigen‐presenting dendritic cells (DCs).Twenty‐four patients with PBC (AMA‐positive: 16; AMA‐negative: 8) and 13 normal controls were enrolled in the study. Peripheral blood mononuclear cells (PBMC) and highly enriched populations of T cells were stimulated with either only PDC or DCs plus PDC or PDC‐pulsed DC plus PDC. Antibodies to different components of PDC were estimated by an immunoblotting technique.PBMC from only one out of ten AMA‐positive PBC patients proliferated when cultured with only PDC. However, peripheral blood T cells from ten out of ten AMA‐positive PBC patients and three out of ten AMA‐negative PBC patients, but none of the five normal controls showed PDC‐specific proliferation when cultured with PDC‐pulsed DCs. Two of these three AMA‐negative PBC patients, although negative for AMA, were positive for antibodies to other components of PDC.PDC‐specific T cells are present in the peripheral blood from most of the patients with PBC. This is the first report on the effectiveness of antigen‐pulsed DCs for the elucidation of autoantigen‐specific immune response in human autoimmune diseases.
Lack of association between apolipoprotein E genoype and ischaemic stroke in a Scottish population
Authors: MacLeod M. J. , De Lange R. P. , Breen G. , Meiklejohn D. , Lemmon H. , St Clair D. 
Published: March 2003

Background Apolipoprotein E ε4 allele has been associated with increased risk of coronary heart disease, and is also a major genetic susceptibility locus for Alzheimer's disease. Some studies have shown an association between apoE genotype and ischaemic stroke or outcome following stroke, while other studies have failed to do so. Materials and methods Using PCR and the Taqman fluorescence system to detect polymorphisms we examined apoE genotype in 266 ischaemic stroke cases and in a control population. Results We found no association between apoeE ε 4 allele distribution and ischaemic stroke, or with outcome following stroke as measured using the Rankin score. Conclusion This study disagrees with a recent meta‐analysis, and suggests that further studies are required to clarify the exact relationship between apoE genotype and ischaemic stroke.
Gemfibrozil improves insulin sensitivity and flow‐mediated vasodilatation in type 2 diabetic patients
Authors: Avogaro A. , Miola M. , Favaro A. , Gottardo L. , Pacini G. , Manzato E. , Zambon S. , Sacerdoti D. , De Kreutzenberg S. , Piliego T. , Tiengo A. , Del Prato S. 
Published: March 2003

Background Endothelial dysfunction is an early feature of atherosclerosis. The relationship between insulin action and hypertriglyceridaemia on endothelial function is still debated.Materials and Methods This study was designed to determine the effect of a 3 month treatment with Gemfibrozil (GF) on flow‐mediated vasodilatation and insulin sensitivity. Ten type 2 diabetic patients were randomised in crossover, double blind fashion, either to GF, 600 mg b.i.d. or placebo, for 12 weeks. Lipid profile, low‐density lipoprotein (LDL) distribution and flotation properties, insulin action and flow‐mediated vasodilatation (FMD) by brachial artery ultrasound, were assessed.Results GF decreased serum triglyceride (TG) concentration with an absolute difference of 1·79 ± 1·28 mmol L−1 (P < 0·0016) between active treatment and placebo, and significantly increased serum high‐density lipoprotein (HDL) cholesterol (P = 0·0233). No differences were observed in total, intermediate‐density lipoproteins (IDL), LDL cholesterol concentration and LDL peak buoyancy between treatments. GF also improved SI, an index of insulin action (P = 0·005). The FMD was 7 ± 3% in the baseline condition, 7 ± 2% during placebo and 14 ± 3% after GF (P < 0·006).Conclusions GF treatment improves both insulin action and flow‐mediated vasodilatation in type 2 diabetic patients. The reduction of TG concentration allows the simultaneous correction of two important components of the metabolic syndrome.
Genetic polymorphisms and lipid response to dietary changes in humans
Authors: Weggemans R. M. , Zock P. L. , Ordovas J. M. , Ramos‐Galluzzi J. , Katan M. B. 
Published: March 2003

Previous studies on the effects of genetic polymorphisms on the serum cholesterol response to dietary treatments were often inconsistent and frequently involved small numbers of subjects.We studied the effect of 10 genetic polymorphisms on the responses of serum cholesterol to saturated and trans fat, cholesterol and the coffee diterpene, cafestol, as measured in 26 dietary trials performed over 20 years in 405 mostly normolipidaemic subjects.Apoprotein A4 360‐2 allele attenuated the response of low‐density lipoprotein cholesterol to dietary cholesterol, but not in women. Subjects with the cholesteryl ester transfer protein TaqIb‐1 allele had −0·02 to −0·05 mmol L−1 smaller responses of high‐density lipoprotein cholesterol to diet than those with the 2/2 genotype. The effects of the other eight polymorphisms on cholesterol response were either inconsistent with results in previous studies or need to be replicated in other studies.Apoprotein A4360 and cholesteryl ester transfer protein TaqIb polymorphisms may affect dietary responses. However, no one single genotype was a major determinant of a subject's lipid response to diet. Therefore, knowledge of these genotypes by themselves is of little use in the identification of subjects who may or may not benefit from dietary treatment.
Saturated triglycerides and fatty acids activate neutrophils depending on carbon chain‐length
Authors: Wanten G. J. A. , Janssen F. P. , Naber A. H. J. 
Published: March 2003

AbstractBackground Unsaturated fatty acids are known as neutrophil activators. In the present study we investigated whether saturated triglycerides and fatty acids may also contribute to the previously observed activation of neutrophils by nutritional lipid emulsions. Furthermore we tested the hypothesis that carbon‐chain length is of importance in this respect.Materials and methods Neutrophils (1 × 106 mL−1) were isolated from the blood of nine volunteers. Chemiluminescence was used to evaluate neutrophil activation, characterized by the production of oxygen radicals by neutrophils during incubation with 1 mmol L−1 saturated fatty acid (6–20 carbon) or triglycerides (6–12 carbon fatty acid), dissolved in aqueous medium by preparing micelles with dipalmitoyl phosphatidylcholine (DPPC). Results were expressed as means ± SEMs of the overall luminescence signal relative to the signal of cells incubated in medium.Results Similar to a positive control, the polyunsaturated fatty acid arachidonic acid (C20 : 4), the triglycerides tricaproin (TC6 : 0), tricaprylin (TC8 : 0) and trilaurin (TC12 : 0) as well as the fatty acids lauric acid (C12 : 0), palmitic acid (C16 : 0), stearic acid (C18 : 0) and arachidic acid (C20 : 0) all induced oxygen radical production in neutrophils, while the medium‐chain triglyceride tricaprin (TC10 : 0) and fatty acids caproic acid (C6 : 0), caprylic acid (C8 : 0) and capric acid (C10 : 0) exerted no clear effects, similar to negative controls (DPPC and glycerol).Conclusions Besides their (poly)‐unsaturated counterparts, saturated triglycerides and fatty acids also activate neutrophils. Carbon chain‐length is pivotal in the interaction of fatty acids and triglycerides and cells of the immune system.