bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of melatonin in pathogenesis of aspirin‐sensitive asthma
Authors: Evsyukova H. V. 
Published: March 2003

BackgroundPlatelets are involved in the pathogenesis of bronchial asthma, including aspirin‐sensitive asthma (ASA). The pineal hormone melatonin (MT) has been described as inhibiting several physiological processes in platelets. The MT metabolite −N‐acetyl‐5‐methoxy‐kynurenamine − has a chemical structure similar to that of acetylsalicylic acid. Because ASA patients usually suffer from an active disease, despite the avoidance of aspirin and cross‐reactive drugs, it has been suggested that the MT synthesis may be lower and sensitivity of platelet reception to MT may be higher in aspirin‐sensitive asthmatic subjects than in aspirin‐tolerant ones. The objective of this study was to investigate this hypothesis.Materials and methodsWe studied the urinary excretion of 6‐sulphatoxymelatonin, the major metabolite of melatonin, and the effect of different MT doses on ADP‐induced platelet aggregation in vitro in 17 ASA patients, 17 patients with aspirin‐tolerant asthma (ATA) and 16 healthy subjects.ResultsThe results of the study have revealed a lower level of daytime aMT6s excretion in ASA patients (12.7 ± 2.7 ng mL−1) than in ATA patients (32.7 ± 9.9 ng mL−1, P < 0.05) and control subjects (19.9 ± 5.8 ng mL−1, P < 0.05). The preincubation of platelet‐rich plasma with the MT in a dose of 0.01 pg mL−1 plasma results in an increase in the intensity and the rate of the first platelet aggregation phase only in the ASA patients compared with the ATA patients and control subjects.ConclusionWe conclude that the reduction in MT production in ASA patients defines the character of ADP‐induced platelet aggregation and the change in its first phase after the further addition of MT in vitro. The latter is associated with the opening of some receptor‐operated channels for Ca2+ or/and its mobilization from the intracellular stores. The higher sensitivity of platelet reception and a distorted reaction not only to MT but also to its metabolite may be prerequisites for aspirin intolerance in ASA patients.
Acute‐phase response patterns in isolated hepatic perfusion with tumour necrosis factor α (TNF‐α) and melphalan in patients with colorectal liver metastases
Authors: De Vries M. R. , Borel Rinkes I. H. M. , Swaak A. J. G. , Hack C. E. , Van de Velde C. J. H. , Wiggers T. , Tollenaar R. A. E. M. , Kuppen P. J. K. , Eggermont A. M. M. 
Published: March 2003

BackgroundIn this study, we have evaluated hepatotoxicity, secondary cytokine production and hepatic acute‐phase response (APR) in patients who underwent isolated hepatic perfusion (IHP) with tumour necrosis factor (TNF) α and melphalan for irresectable colorectal liver metastases.DesignAn extracorporeal veno‐venous bypass was used to shunt blood from the lower body and intestines to the heart. Inflow catheters were placed in the hepatic artery and portal vein, and an outflow catheter in the inferior caval vein. The liver was perfused for 60 min with 0.4 mg of TNF‐α plus 1 mg kg−1 melphalan (IHPTM group, n = 6) or 1 mg kg−1 melphalan (IHPM group, n = 3). The liver was washed with macrodex before restoring vascular continuity.ResultsAfter the washout procedure, a TNF‐α peak (169 ± 38 pg mL−1) was demonstrated in the IHPTM group only. Both groups demonstrated peak levels of interleukin 6 (IL‐6) in the perfusate as well as systemically. These were significantly higher in the IHPTM group. Acute‐phase protein (APP) levels followed a similar pattern as has been demonstrated after major surgery, with no significant differences between both groups. The addition of TNF‐α to the perfusate did not lead to a significant difference in APP levels and the time course between groups.ConclusionsIHP with TNF and melphalan is followed by a transient systemic peak of TNF directly after liver washout. Secondary IL‐6 induction was seen in the present study after IHP with and without TNF, which was highest when TNF was added. This phenomenon cannot be extrapolated to APP induction, which appeared unaffected by the addition of TNF, presumably because the surgical procedure itself already causes maximal stimulation of APP production.
Occurrence of sialic acids in healthy humans and different disorders
Authors: Sillanaukee  , Pönniö  , Jääskeläinen  
Published: March 2003

Sialic acid (SA), N‐acetylated derivatives of neuraminic acid, play a central role in the biomedical functioning of humans. The normal range of total sialic acid (TSA) level in serum/plasma is 1.58–2.22 mmol L−1, the free form of SA only constituting 0.5–3 μmol L−1 and the lipid‐associated (LSA) forms 10–50 μmol L−1. Notably, considerably higher amounts of free SA are found in urine than in serum/plasma (approximately 50% of the total SA).In inherited SA storage diseases such as Salla's disease, SA levels are elevated many times over, and their determination during clinical investigation is well established. Furthermore, a number of reports describe elevated SA levels in various other diseases, tentatively suggesting broader clinical utility for SA markers. Increased SA concentrations have been reported during inflammatory processes, probably resulting from increased levels of richly sialylated acute‐phase glycoproteins. A connection between increased SA levels and elevated stroke and cardiovascular mortality risk has also been reported. In addition, SA levels are slightly increased in cancer, positively correlating with the degree of metastasis, as well as in alcohol abuse, diabetes, chronic renal failure and chronic glomerulonephritis. Several different mechanisms are assumed to underlie the elevated SA concentrations in these disorders.The apparent non‐specificity of SA to a given disease limits the potential clinical usefulness of SA determination. In addition, some non‐pathological factors, such as aging, pregnancy and smoking, may cause changes in SA concentrations. The absolute increases in SA levels are also rather small (save those in inherited SA storage disorders); this further limits the clinical potential of SA as a marker.Tentatively, SA markers might serve as adjuncts, when combined with other markers, in disease screening, disease progression follow‐up, and in the monitoring of treatment response. To become clinically useful, however, the existing SA determination assays need to be considerably refined to reduce interferences, to be specific for certain SA forms, and to be more easy to use.
Inhaled nitric oxide does not influence bleeding time or platelet function in healthy volunteers
Authors: Albert  , Norman  , Wallén  , Frostell  , Hjemdahl  
Published: March 2003

BackgroundBleeding time has been reported to increase during gaseous nitric oxide (NO) inhalation in healthy volunteers and patients, and it has been speculated that inhaled NO inhibits platelet function. However, results have not been unanimous, and we have been unable to document any effects of inhaled NO on circulating platelets.Materials and methodsWe performed a double‐blind, placebo controlled cross‐over study in which healthy volunteers (n = 15) inhaled NO (30 ppm, 30 min) or control gas. Aspirin (640 mg × 1 orally) was used as positive control on the third occasion (n = 14). Bleeding time was measured, and platelet function was determined flow cytometrically by measuring the expression of P‐selectin on circulating platelets and locally activated platelets in wound blood. Skin perfusion close to the site for bleeding time incisions was assessed by laser Doppler flowmetry.ResultsBleeding time was unaffected by NO, as there were slight increases during both NO and control inhalation (+20% and +14% respectively, P = 0.9). Similarly, NO inhalation had no effect on platelet P‐selectin expression in either systemic or wound blood, or on skin perfusion. Aspirin pretreatment, on the other hand, prolonged bleeding time (P < 0.001) and decreased P‐selectin expression of platelets in wound blood (P = 0.03).ConclusionsThis first placebo‐controlled study indicates that inhaled NO does not influence either bleeding time, platelet activity or skin perfusion. Thus, it is unlikely that treatment of critically ill patients with inhaled NO will aggravate haemostatic disturbances, which has previously been feared, by influencing platelet function.
A metabolic syndrome of hypertension, hyperinsulinaemia and hypercholesterolaemia in the New Zealand obese mouse
Authors: Ortlepp  , Kluge  , Giesen  , Plum  , Radke  , Hanrath  , Joost  
Published: March 2003

BackgroundNew Zealand obese (NZO) mice exhibit a polygenic obesity associated with hyperinsulinaemia and hyperglycaemia. Here we show that the strain presents additional features of a metabolic syndrome, i.e. elevated blood pressure, serum cholesterol and serum triglyceride levels.Materials and methodsA back‐cross model of NZO mice with the lean Swiss Jackson Laboratory (SJL) strain was established in order to investigate further the correlation between hypertension, obesity, serum insulin and hyperglycaemia.ResultsSystolic blood pressure was significantly elevated at 6 weeks of age and appeared to parallel the weight gain of the animals. Serum insulin levels, presumably reflecting insulin resistance, and systolic blood pressure values were significantly correlated with the body mass index (r2 = 0.707 and 0.486, respectively) in the back‐cross mice. In contrast, blood pressure was only weakly correlated with serum insulin (r2 = 0.288) in non‐diabetic mice, and was independent of serum insulin levels in diabetic animals.ConclusionThe data are consistent with the concept that hypertension and insulin resistance are a characteristic consequence of the genetic constellation leading to obesity in the NZO strain, and that these traits reflect related mechanisms. It appears unlikely, however, that hypertension is a direct consequence of hyperinsulinaemia.
Potential aetiological factors concerning the development of osteonecrosis of the femoral head
Authors: Zalavras CH. , Dailiana  , Elisaf  , Bairaktari  , Vlachogiannopoulos  , Katsaraki  , Malizos  
Published: March 2003

BackgroundThe aetiology and pathogenesis of non‐traumatic osteonecrosis (ON) of the femoral head have not been fully elucidated. The present study was conducted to evaluate the possible correlation of relevant haematological and biochemical factors with the development of ON.Patients and methodsOur investigation consisted of measurement of haematological indices and assessment of the biochemical and lipid profile of a study population of 68 patients with non‐traumatic ON of the femoral head and 36 healthy controls. The disease was considered idiopathic in 17 and secondary in 51 patients.ResultsThere were no statistically significant differences in the parameters measured among the idiopathic ON, secondary ON and control groups, except for globulins α1, α2 and β, which were significantly increased in both patient groups, and apolipoprotein B (Apo B), which was increased in patients with idiopathic disease compared with the control group. Both patient groups presented increased von Willebrand factor (VWF) and lipoprotein (a) [Lp(a)] levels and decreased protein C and S concentrations, but without statistical significance. However, both patient groups exhibited a greater proportion of abnormal values of any of these parameters, in 58.9% of the idiopathic and in 62.7% of the secondary ON patients, compared with 8.3% of the controls.ConclusionOur study underlines the potential association of abnormal values of protein C, protein S, VWF and Lp(a) with ON. To our knowledge this is the first reported association of VWF with the disease. The majority of both idiopathic and secondary ON patients in our series exhibits a thrombotic potential that adds further support to the postulation that intravascular coagulation is a major pathogenetic mechanism leading to the disease.
Localization and characterization of antigen‐presenting dendritic cells in the gastric mucosa of murine and human autoimmune gastritis
Authors: Ninomiya  , Matsui  , Akbar  , Murakami  , Onji  
Published: March 2003

BackgroundActivated CD4+ T cells and inflammatory cytokines are implicated in the pathogenesis of experimental autoimmune gastritis. However, there is a paucity of information about the cells that induce them. Antigen‐presenting dendritic cells (DCs) play a cardinal role in the formation and survival of activated lymphocytes.Materials and methodsAutoimmune gastritis was induced in neonatal BALB/c mice by thymectomy. DCs were detected in situ in the gastric mucosa from thymectomized mice and in patients with autoimmune gastritis, by immunohistochemistry and immunoelectron microscopy. The expression of MHC class II and CD86 antigens on DCs in the gastric mucosa and spleen was evaluated in dual‐colour flow cytometry.ResultsDCs were detected in the gastric mucosa of mice with autoimmune gastritis, and the number of DCs increased as the levels of gastritis became more severe as time passed following thymectomy. Flow cytometric analyses revealed that more than 60% of the DCs in the gastric mucosa had a mature phenotype (expressed MHC class II and/or CD86 antigens) both at 4 and 16 weeks after thymectomy. Activated and mature DCs were localized in the gastric mucosa from patients with autoimmune gastritis.ConclusionsThis is the first report on the localization and phenotypes of DCs in the gastric mucosa of autoimmune gastritis. The presence of mature DCs in the gastric mucosa of murine and human autoimmune gastritis, in spite of their absence in the gastric mucosa of normal mice, suggests that mature DCs play a role in the pathogenesis of autoimmune gastritis.
Late diagnosis of Kawasaki disease is associated with haptoglobin phenotype
Authors: Lee  , Hwang  , King  , Chen  , Chiou  , Yang  , Huang  
Published: March 2003

BackgroundKawasaki disease (KD) is an acute febrile illness characterized by multiple clinical and biochemical features of inflammation and the most common complications of coronary artery abnormality (CAA). Haptoglobin (Hp) is an acute‐phase protein whose phenotype is known to be involved in coronary artery diseases. In this paper, we report the investigation of the association of Hp phenotype with the formation of CAA in KD.Patients and methodsForty‐seven consecutive patients with clinically diagnosed KD were admitted. Sera were taken before therapy of intravenous immunoglobulins (IVIG) plus aspirin, and levels of serum proteins were measured by a rate immunonephelometer. The echocardiographic criteria for coronary artery abnormality were evaluated during acute or subacute stages. Hp phenotyping was performed by Western immunoblotting.ResultsDuration of fever at diagnosis of KD was significantly different between patients with Hp 2–2 (6.4 ± 1.2 days, n = 25) and with Hp1 allele (Hp 2–1 plus Hp 1–1; 8.8 ± 3.5 days, n = 22). In contrast, serum levels of Hp between KD patients with Hp2–2 and with Hp1 allele (297 ± 121 mg dL−1 vs. 330 ± 101 mg dL−1, respectively) was not significantly different. On the other hand, no patients with Hp 2–2 (0/25) were recognized as having KD in subacute stage. However, 5 out of 20 patients with Hp 2–1 were recognized in subacute stage, and their incidence of CAA was 80.0% (4/5).ConclusionsPatients with Hp 2–1 have patterns of delayed or incomplete presentation of clinical symptoms. Therefore, the late diagnosis of KD is associated with haptoglobin phenotype.
Pre‐eclampsia‐induced alterations in IGF‐I of human umbilical cord
Authors: Bańkowski  , Pałka  , Jaworski  
Published: March 2003

BackgroundExtracellular matrix (ECM)‐components serve as a storage site to concentrate and stabilise growth factors in the vicinity of cells. Human umbilical cord (UC) tissues contain significant amounts of IGF‐I and IGF‐binding proteins (BPs). IGF‐I is known as a stimulator of collagen and sulphated glycosaminoglycans (GAGs) biosynthesis. Pre‐eclampsia, the most common pregnancy associated syndrome, is accompanied by an accumulation of collagen and sulphated glycosaminoglycans in the UC. One may expect that IGF‐I and BPs play an important role in such a remodelling of the UC tissue. For this reason it was decided to evaluate the alterations in amounts of IGF‐I and BPs in UC serum and in the UC arterial wall of newborns delivered by mothers with pre‐eclampsia.Materials and methodsStudies were performed on the UCs of 12 control and 12 investigated newborns, delivered by mothers with pre‐eclampsia (edema, proteinuria > 500 mg l−1, arterial pressure: systolic > 140 mmHg, diastolic > 100 mmHg). Radioimmunological techniques were employed to determine IGF‐I and IGF‐BPs (BP‐1 and BP‐3).ResultsIt was found that pre‐eclampsia is associated with an increase of IGF‐I concentration in the UC serum and with simultaneous decrease of its content in the umbilical cord artery (UCA). The decrease of IGF‐I content in the UCA wall was accompanied by an increase of BP‐3 and BP‐1 in this tissue. The increase in BPs content in the UCA wall was not associated with an enhancement of IGF binding by extracts from the homogenates of arterial wall. Heparin drastically decreased the binding of IGF‐I by BP‐3.ConclusionsPre‐eclampsia is associated with an increase of IGF‐I‐concentration in the umbilical cord blood and an elevation of BPs contents in the UCA wall. Despite a high concentration of binding proteins, IGF‐I is not accumulated in this tissue. High amounts of sulphated GAGs in the UCA wall may be a factor that prevents the binding of IGF‐I by BPs. Free IGF‐I can easily bind to cell receptors and stimulate the cells to produce collagen and sulphated GAGs in the arterial wall.
Insulin activates p38 mitogen‐activated protein (MAP) kinase via a MAP kinase kinase (MKK) 3/MKK 6 pathway in vascular smooth muscle cells
Authors: Igarashi  , Yamaguchi  , Hirata  , Daimon  , Tominaga  , Kato  
Published: March 2003

BackgroundInduction of stress‐activated mitogen‐activated protein (MAP) kinases such as p38 could be important for the development of cardiovascular diseases since p38 MAP kinase activation stimulates apoptosis, cell growth, prostanoid formation and other cellular dysfunctions when induced by oxidants, hyperosmolarity, or pro‐inflammatory cytokines. On the other hand, insulin resistance is one of the most important factors promoting atherogenesis, including cardiovascular diseases, but it is not clear how these different factors transmit their signals intracellularly at the cytosolic and nuclear levels. In this study, we investigated the effect of insulin on p38 mitogen‐activated protein (MAP) kinase activation in cultured rat vascular smooth muscle cells (VSMC).Materials and methodsVSMC were obtained from the aortas of male Wistar rats by the media explant technique. After being stimulated by insulin with SB‐203580, PD‐98059, or GF109203X, the cells were solubilized and the expressions of MAP kinases, MAP kinase kinases and p70 S6 kinase were examined by immunoblot analysis. The amount of DNA synthesis was measured by [3H]thymidine incorporation.ResultsInsulin activated p38 MAP kinase phosphorylation in a dose‐dependent manner, and the phosphorylation was specifically inhibited by SB‐203580, a p38 MAP kinase‐specific inhibitor, but not by PD‐98059, a specific inhibitor of upstream kinase (MEK), of extracellular signal‐regulated kinase (ERK), or GF209203X, a protein kinase C‐specific inhibitor. Insulin also activated MAP kinase kinase (MKK) 3/MKK 6 phosphorylation, the upstream kinase of p38 MAP kinase, but neither stress‐activated protein kinase (SAPK)/ERK kinase (SEK1/MKK4) nor SAPK/c‐jun NH2‐terminal protein kinase. Surprisingly, phosphorylation of p70 S6 kinase and an increase of DNA synthesis by insulin were suppressed dose dependently by SB‐203580.ConclusionThese results have established that insulin activates the p38 MAP kinase cascade via an MKK 3/6 pathway in rat VSMC, independently of a MEK–ERK cascade, and partly regulates cell growth.
Differential expression of human α‐ and β‐defensins mRNA in gastrointestinal epithelia
Authors: Frye  , Bargon  , Lembcke  , F. Wagner  , Gropp  
Published: March 2003

BackgroundWhile defensins have received great attention for their role in bronchial innate immune defence, little is known about the expression levels of the four human epithelial defensins (HD5, HD6, hBD1 and hBD2) in the digestive tract. In this study we quantified the α‐ and β‐defensins mRNA in biopsies obtained from the gastrointestinal mucosa and identified the cells expressing the β‐defensin hBD1 mRNA in ileal mucosa.Material and methodsBiopsies from human stomach (corpus and antrum), duodenum, jejunum, ileum and colon were analysed for their expression of α‐ and β‐defensins. The mRNA of defensins was quantified by semiquantitative reverse transcription–polymerase chain reaction. Cells expressing β‐defensin hBD1 mRNA were identified by in situ hybridization with 35S‐labelled RNA probes in tissue sections of human ileum.ResultsThe hBD1 mRNA was expressed at low levels with little variability throughout the gastrointestinal tract and was detected in all epithelial cells of ileal mucosa. HD5 and HD6 mRNA expression was restricted to the intestine and displayed high interindividual variability. The highest expression levels were observed in jejunum and ileum. Biopsies obtained from duodenum displayed low levels or no expression of HD5 and HD6. The expression level increased considerably in a biopsy obtained from a patient with acute coeliac sprue. In contrast, low levels were observed in a biopsy from a patient with coeliac sprue in remission.ConclusionsThe expression levels of hBD1, HD5 and HD6 throughout the gastrointestinal tract are tissue and peptide specific and these defensins are expressed with high interindividual variability.
Effects of phospholipase A2, free fatty acids and 2‐lysolecithin on the crystallization of cholesterol in gallbladder bile
Authors: Schöne  , Jüngst  , Meyer  , Hernandez‐Richter  , Fischer  
Published: March 2003

BackgroundPhospholipase A2 (PLA2) and its enzymatic products free fatty acids (FFAs) and 2‐lysolecithin are physiological constituents of bile. Their role in the crystallization of cholesterol in gallbladder bile of patients with cholesterol gallstones is still controversial.DesignTo clarify this issue we evaluated the activity of PLA2 and the concentration and pattern of FFAs in the gallbladder bile of cholesterol stone patients. We furthermore added PLA2, FFAs and 2‐lysolecithin to isotropic gallbladder bile, determined the crystal observation time (COT) and counted the cholesterol crystals in a crystal growth assay for up to 21 days.ResultsA PLA2 activity of 1.8 ± 1.2 U L−1 and total FFA concentrations of 1.32 ± 0.71 mmol L−1 were determined. After incubation of bile for 24 h at 37 °C total FFAs increased to 2.72 ± 1.29 mmol L−1 (P < 0.005). Biliary saturated and unsaturated FFAs were found in equal proportions before and after incubation, pointing to an additional presence of lipases other than PLA2. A COT of 1 day was observed in all gallbladder biles and increased to 1.7 ± 0.5 days after addition of 5 U L−1 of PLA2 (P < 0.01). An even higher COT of 2.5 ± 0.8 days was seen after addition of 5 mmol L−1 of a ‘biliary’ mixture of FFAs (P < 0.005) but the COT remained unchanged after addition of 5 mmol L−1 of 2‐lysolecithin. However, in the crystal growth assay in gallbladder bile addition of 5 U L−1 of PLA2, of 5 mmol L−1 of ‘biliary’ FFAs and of 5 mmol L−1 of 2‐lysolecithin decreased significantly the number of cholesterol crystals formed during follow‐up.ConclusionAn elevated activity of PLA2 in gallbladder bile may counteract the formation of cholesterol crystals through increased formation of FFAs and 2‐lysolecithin. However, regarding the comparatively low activity of PLA2 in gallbladder bile PLA2 seems to be of only minor pathophysiological importance in the formation of cholesterol gallstones.