bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microcirculatory effects of KATP channel blockade by sulphonylurea derivatives in humans
Authors: Abbink E. J. , Wollersheim H. , Netten P. M. , Russel F. G. M. , Lutterman J. A. , Smits P. 
Published: March 2003

AbstractBackground Recent investigations have shown that glibenclamide inhibits the opening of vascular ATP‐sensitive potassium channels during ischemia. This observation may implicate cardiovascular effects of sulphonylurea derivatives when used under conditions of ischemia in patients with Type 2 diabetes mellitus. In addition to resistance arteries, the (pre) capillary vessels also contain ATP‐dependent potassium channels. Closure of these channels by sulphonylurea derivatives might affect the development of microvascular disease in Type 2 diabetes mellitus. Therefore, we investigated the microcirculatory effects of sulphonylurea derivatives in Type 2 diabetic patients as compared with healthy volunteers.Materials and methods Arteriovenous blood flow (skin temperature and laser Doppler flux) and capillary blood cell velocity were measured before and during infusion of four doses of glibenclamide (0·1, 0·3, 1·0 and 3·0 µg min−1 dL−1) into the brachial artery of 14 Type 2 diabetic patients and 13 healthy controls. The experiments included appropriate time control studies.Results Both skin temperature and laser Doppler flux decreased in response to glibenclamide in healthy volunteers (−7 ± 2%, P < 0·0005 and −31 ± 11%, P = 0·001, respectively), but did not change in Type 2 diabetic patients (1 ± 3%, P = 0·29 and 4 ± 14%, P = 0·97). However, capillary blood cell velocity decreased in Type 2 diabetic patients (−38 ± 18%, P = 0·04), but did not change in healthy volunteers (−1 ± 11%, P = 0·28).Conclusions The results of the present study indicate that glibenclamide indeed affects microvascular blood flow. Glibenclamide may induce redistribution of the microvascular skin flow from nutritive flow to arteriovenous shunt flow in Type 2 diabetic patients. Therefore, closure of ATP‐dependent potassium channels by glibenclamide possibly plays a role in the development of microangiopathy in Type 2 diabetic patients.
Depletion of non specific esterase activity in the colonic mucosa of patients with ulcerative colitis
Authors: Kolios G. , Valatas V. , Psilopoulos D. , Petraki K. , Kouroumalis E. 
Published: March 2003

AbstractBackground Non specific esterases (NSE) are a group of cellular carboxylesterases, enzyme markers of monocytes/macrophages, whose tissue distribution in the human body and changes in various disease states have not been adequately studied. We investigate the presence and localization of NSE, in the normal and inflamed human colonic mucosa.Design NSE were studied histochemically and biochemically using α‐naphthyl acetate as the substrate, in the colonic mucosa from 67 patients with colitis of various aetiologies and 10 normal controls. In addition, esterase activity was studied biochemically in serum from colitic patients and normal controls.Results Histochemical study of the colonic tissue demonstrated that NSE were localised in the epithelial brush border, the goblet cells of the glands and a macrophage population of the lamina propria in the colonic mucosa of normal controls and patients with non specific colitis. In active ulcerative colitis, esterase depletion and esterase negative macrophages were identified in parallel with goblet cell disappearance. Gradual reappearance of esterase activity was found after successful treatment. Biochemical study of NSE activity showed that serum and colonic tissue esterase levels were greatly (P < 0·001) reduced in active ulcerative colitis compared to the normal controls or non specific colitis patients and they were increased after successful treatment. Despite this increase, the esterase activity in the colonic tissue from ulcerative colitis patients after treatment was significantly reduced compared to the normal controls. Interestingly, the enzyme levels from non‐inflamed areas of the bowel of patients with ulcerative colitis were also significantly (P < 0·01) decreased compared to the normal controls.Conclusions These data suggest that esterase reduction in ulcerative colitis is not a simple result of the inflammatory process but rather it precedes its development. This enzyme depletion might have an important pathogenetic implication in the inflammatory process.
Relationship of genetic variation in genes encoding apolipoprotein A‐IV, scavenger receptor BI, HMG‐CoA reductase, CETP and apolipoprotein E with cholesterol metabolism and the response to plant stanol ester consumption
Authors: Plat J. , Mensink R. P. 
Published: March 2003

AbstractBackground Differences in genetic constitution may affect cholesterol metabolism and responses to diet. Identification of common variations in genes related to dietary responsiveness is therefore an attractive goal to be able to prescribe individually tailored diets for the treatment of dyslipidaemia.Materials and methods We have examined relationships between serum lipids and lipoproteins, cholesterol‐standardized campesterol and lathosterol concentrations with genetic variation, and the presence of a gene–diet interaction between plant stanol ester consumption. Candidate genes were apolipoprotein A‐IV (apoA‐IV), scavenger receptor‐BI (SR‐BI), cholesterol ester transfer protein (CETP), 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase, and apolipoprotein E (apoE). These relations were examined in 112 nonhypercholesterolaemic subjects, of whom 70 consumed 3·8–4·0 g plant stanol esters a day for 8 weeks.Results At baseline, high‐density lipoprotein (HDL) concentrations of 1·56 ± 0·36 mmol L−1 in SR‐BI‐2 allele carriers tended to be lower compared to the 1·72 ± 0·42 mmol L−1 in SR‐BI‐1/1 subjects (P = 0·069). Cholesterol standardized lathosterol concentrations were also lower in the SR‐BI‐2 allele carriers (P = 0·002). Furthermore, low‐density lipoprotein (LDL) cholesterol concentrations in apoE2 subjects, were lower compared to the LDL cholesterol concentration in apoE3 group (P = 0·002) and apoE4 subjects (P < 0·001). No significant differences between the polymorphisms and dietary responsiveness to plant stanol ester consumption could be found, which indicates that it is unlikely that one of the single polymorphisms analysed in this study is a major factor in explaining the variation in serum LDL cholesterol responses.Conclusion These findings suggest that all subjects who want to lower their cholesterol concentration, will benefit from plant stanol ester consumption, irrespective of their apoA‐IV, SR‐BI, HMG‐CoA reductase, CETP, or apoE genotype.
Molecular causes of colon cancer
Authors: Oving Irma M. , Clevers Hans C. 
Published: March 2003

AbstractCells in a developing embryo communicate with each other through a limited number of intercellular signalling pathways, of which the Wnt signalling pathway is one. Little is known about the function of Wnt signalling beyond that in embryogenesis. However, recent insights into the molecular etiology of colon cancer have implied a central role for the Wnt signalling pathway. The malignant transformation of colorectal epithelium is well defined, leading to adenoma and sequentially carcinoma formation. Several genes that regulate the Wnt pathway are mutated in cancer of the human colon and other organs. All of these mutations lead to the inappropriate activation of the pathway, which instructs the cell to divide unrestrictedly. These insights now allow the Wnt pathway to be exploited as a new target for drug development in colon cancer.
Interactions of human immunodeficiency virus‐1 proteins with neurons: possible role in the development of human immunodeficiency virus‐1‐associated dementia
Authors: Van De Bovenkamp M. , Nottet H. S. L. M. , Pereira C. F. 
Published: March 2003

AbstractHuman immunodeficiency virus‐1 (HIV‐1)‐associated dementia is a severe neurological complication of HIV‐1 infection that affects 15–20% of the patients in the late stages of acquired immunodeficiency syndrome. HIV‐1‐associated dementia is most probably a consequence of HIV‐1 infection of the brain rather than of an opportunistic pathogen. The exact mechanism by which the virus causes this disorder, however, is not completely understood. A number of HIV‐1 proteins have been shown to be released from HIV‐1‐infected cells and/or to be present in the extracellular milieu in the HIV‐1‐infected brain. Moreover, these proteins have been shown to posses neurotoxic and/or neuromodulatory features in vitro. This review describes the possible direct interactions of the HIV‐1 proteins gp120, gp41, vpr, tat, rev, vpu and nef with neurons, which might play a role in the development of HIV‐1‐associated dementia in vivo.
Effect of fluticasone on the elastase:antielastase profile of the normal lung
Authors: Kamal A. M. , Corrigan C. J. , Tetley T. D. , Alaghband‐Zadeh J. , Smith S. F. 
Published: March 2003

AbstractBackground Excessive elastolytic activity contributes to the pathogenesis of several inflammatory respiratory diseases. The effect of glucocorticoids, which are potent anti‐inflammatory agents, on the elastase:antielastase balance of the human respiratory tract is unclear, as studies on patients and in vitro have yielded inconsistent results.Design To clarify this, bronchoalveolar lavage and lavage fluids from the upper and central airways were collected from 10 healthy, nonsmoking volunteers before and after a 2‐week course of inhaled fluticasone propionate (2 × 500 µg day−1). Concentrations of two neutrophil elastase inhibitors, α‐1‐proteinase inhibitor (PI) and secretory leukoproteinase inhibitor (SLPI), as well as neutrophil elastase (NE) activity and NE inhibitory capacity (NEIC) were quantified in all lavage fluids.Results Concentrations of SLPI were highest in the proximal airways and decreased distally. Neutrophil elastase inhibitory capacity activity followed the same gradient and correlated positively and consistently with SLPI, suggesting that this inhibitor makes an important contribution to the regulation of elastolytic activity in the healthy human respiratory tract. Inhaled fluticasone propionate had no effect on any component of the elastase:antielastase balance at any level of the respiratory tract, even though circulating cortisol levels were reduced in all subjects, confirming subject compliance and adequate pulmonary delivery of the drug.Conclusion This lack of action in the respiratory tract may contribute to the ineffectiveness of inhaled glucocorticoids in respiratory conditions characterised by excessive elastolytic activity.
Inflammatory imbalance between IL‐10 and TNFα in unstable angina potential plaque stabilizing effects of IL‐10
Authors: Wæhre T. , Halvorsen B. , Damås J. K. , Yndestad A. , Brosstad F. , Gullestad L. , Kjekshus J. , Frøland S. S. , Aukrust P. 
Published: March 2003

AbstractBackground The pathogenesis of atherosclerosis and acute coronary syndromes involves inflammation and immunological mechanisms. We hypothesized that patients with unstable angina may have an imbalance between inflammatory and anti‐inflammatory cytokines.Design Plasma levels of tumour necrosis factor (TNF)α and interleukin (IL)‐10 were analyzed in 44 patients with stable angina, 29 patients with unstable angina and 20 controls. mRNA levels of these cytokines were analyzed in peripheral blood mononuclear cells (PBMC). We also studied the in vitro effects of IL‐10 in PBMC from unstable angina patients.Results Our main findings were: (1) the angina patients and particularly those with unstable disease had significantly raised TNFα in comparison with the controls, both at the protein and mRNA level; (2) in contrast, the levels of IL‐10 were not different in the angina patients in comparison with the healthy controls, resulting in a markedly enhanced TNFα:IL‐10 ratio, particularly in the unstable angina patients; (3) while exogenously added IL‐10 markedly inhibited the release of TNFα, IL‐8 and tissue factor as well as impairing the gelatinolytic activity and mRNA production of matrix metalloproteinase‐9, it enhanced the tissue inhibitor of this metalloproteinase (i.e. TIMP‐1) in PBMC from the unstable angina patients.Conclusion Patients with unstable angina appear to have an imbalance between TNFα and IL‐10, possibly favouring inflammatory net effects. IL‐10 may have beneficial effects on mechanisms that are important in plaque rupture and thrombus formation.
Airway surface liquid recovered by lavage with perfluorocarbon liquid in cats
Authors: Southern K. W. , Funkhouser W. K. , Kazachkova I. , Godfrey V. L. , Fordham L. A. , Gatzy J. T. , Barker P. M. 
Published: March 2003

AbstractBackground Airway surface liquid (ASL) is difficult to sample. Lavage with an immiscible perfluorocarbon (PFC) liquid to recover ASL was evaluated in cats.Materials and Methods Six wild‐type cats underwent bronchoscopic lavage with a PFC (perfluorohexane), with the bronchoscope wedged in the feline equivalent of the right lower lobe. Two cats (control animals) were lavaged with a saline vehicle only. Four procedures were performed on each animal at 2–3‐week intervals. Ionic composition of ASL was determined by flame photometry.Results Cats lavaged with PFC showed significantly more acute respiratory distress than those lavaged with saline (respiratory rate following procedure: PFC, 47 ± 5 min−1 vs. saline, 27 ± 2 min−1, P < 0·05; O2 saturation: PFC 80 ± 1% vs. saline, 91 ± 1%, P < 0·01). The PFC group also had clinical evidence of chronic respiratory compromise (mean respiratory rate before next anaesthetic; PFC, 37 ± 2 min−1 vs. saline, 20 ± 3 min−1, P < 0·01). The PFC‐lavaged lungs demonstrated persistent radiographic changes and histological evidence of small airways obstruction with distal alveolar damage. Six PFC lavages yielded ASL samples (> 100 µL) which were sufficient for analysis. Mean (± SEM) ionic concentrations in these samples were Na+ 157·4 ± 14·5 mmol L−1, Cl− 150·5 ± 16·8 mmol L−1 and K+ 10·1 ± 1·7 mmol L−1.Conclusions Perfluorocarbon lavage can be used to collect unmodified ASL from the distal lung. However, repeated lavage with perfluorohexane was associated with significant pathological changes in this study.
The effect of lipoproteins on endothelial nitric oxide synthase is modulated by lipoperoxides
Authors: Lubrano V. , Vassalle C. , Blandizzi C. , Del Tacca M. , Palombo C. , L’Abbate A. , Baldi S. , Natali A. 
Published: March 2003

AbstractBackground and aim The effect of low‐density lipoproteins (LDLs) on endothelial nitric oxide synthase (eNOS) is debated. By coupling in vivo and in vitro experiments we evaluated the role of oxidized lipid substrates in the modulation of eNOS activity by LDLs.Materials and methods Plasma lipids, nitrite/nitrates (NO2/NO3), and malondialdehyde (MDA) were measured in 14 controls, and in 13 patients with familial hypercholesterolemia (FH) before and after 12 weeks of treatment with atorvastatin (20 mg u.i.d.). Nitric oxide synthase in cell lysate and NO2/NO3 into the medium were measured in human microvascular (HMEC‐1) and umbilical vein (HUVEC) endothelial cells after 24 h of incubation with increasing concentrations of mildly oxidized LDLs with and without atorvastatin and in HMEC‐1 with and without vitamin C. In HMEC‐1, NO2/NO3 was also determined after exposure to more intensively oxidized LDLs.Results At baseline, plasma NO2/NO3 (56 ± 7 vs. 35 ± 3 µM) and MDA (5·6 ± 0·7 vs. 2·9 ± 0·3 µM), were significantly (P < 0·02 for both) higher in the FH patients. In the whole study group, NO2/NO3 was more strongly correlated with plasma MDA (Rho = 0·70) than LDL‐cholesterol (Rho = 0·57). In the FH patients, atorvastatin induced a significant decline in plasma total and LDL‐cholesterol (−3·1 ± 0·5 and −2·9 ± 0·5 mM, respectively), NO2/NO3 (−35 ± 8 µM) and MDA (−3·4 ± 0·7 µM) (P < 0·001 for all). Changes in plasma NO2/NO3 were related to the concomitant changes in plasma MDA (Rho = 0·79, P < 0·006) and not to changes in LDL‐cholesterol. In HMEC‐1 and in HUVEC, mildly oxidized LDLs stimulated both e‐NOS and NO2/NO3 accumulation; the effect on e‐NOS was potentiated by vitamin C in HMEC‐1. Atorvastatin had no effect in HMEC‐1 while it stimulated eNOS but not NO2/NO3 in HUVEC. The accumulation of NO2/NO3 in HMEC exposed to increasing concentrations of more intensively oxidized‐LDLs showed a nonlinear dose–response curve.Conclusions In uncomplicated patients with FH, plasma NO2/NO3 concentrations are elevated; the cross‐sectional data, intervention study and in vitro experiments indicate that oxidized lipids exert a tonic stimulatory action on e‐NOS and NO2/NO3 generation not mediated through superoxide anion formation. Atorvastatin amplify this eNOS response in HUVEC, but not in HMEC, and this effect is not associated with a parallel increased NO2/NO3 generation.
Early endothelial dysfunction following renal mass reduction in rats
Authors: Benchetrit S. , Green J. , Katz D. , Bernheim J. , Rathaus M. 
Published: March 2003

AbstractBackground Endothelial dysfunction has been previously described in severely hypertensive rats with renal mass reduction (RMR) receiving large dietary Na loads. Because hypertension and Na loading reduce endothelium‐dependent vasodilation, the effect of renal failure per se is unclear.Methods Responses to acetylcholine in noradrenaline‐contracted isolated perfused mesenteric arteries were studied. Vessels were obtained from RMR rats kept on a normal diet, 3 and 10 days after surgery, and the results were compared with those from sham‐operated rats (SN). The role of three putative mediators of endothelium‐dependent vasodilation was assessed using: L‐NAME (10−4 mol L−1); indomethacin (INDO, 10−5 mol L−1); and a mixture of charybdotoxin and apamin (C/A, both 10−7 mol L−1), inhibitors of Ca‐activated K‐channels to mediate the effects of endothelium‐derived hyperpolarizing factor (EDHF).Results Response to acetylcholine but not that to nitroprusside (endothelium‐ independent) was decreased in RMR. L‐NAME reduced further acetylcholine relaxations in SN but not in RMR. By contrary, INDO decreased acetylcholine vasodilation in RMR but had no effect in SN. C/A had similar effects in the SN and RMR rats. The levels of 6‐keto prostaglandin F1α were elevated in the urine of the RMR rats and were perfusate from the RMR vessels.Conclusion Endothelial dysfunction occurs early after RMR, even when systolic blood pressure is only minimally elevated and Na intake is normal. This alteration may be because of decreased availability of nitric oxide, partially compensated by increased prostacyclin production.
Effects of adrenaline and potassium on QTc interval and QT dispersion in man
Authors: Lee S. , Harris N. D. , Robinson R. T. , Yeoh L. , Macdonald I. A. , Heller S. R. 
Published: March 2003

AbstractBackground Hypoglycaemia alters cardiac repolarization acutely, with increases in rate‐corrected QT (QTc) interval and QT dispersion (QTd) on the electrocardiogram (ECG); such changes are related to the counterregulatory sympatho‐adrenal response. Adrenaline produces both QTc lengthening and a fall in plasma potassium (K+) when infused into healthy volunteers. Hypokalaemia prolongs cardiac repolarization independently however, and therefore our aim was to determine whether adrenaline‐induced repolarization changes are mediated directly or through lowered plasma K+.Materials and methods Ten healthy males were studied on two occasions. At both visits they received similar l‐adrenaline infusions but on one occasion potassium was also administered; infusion rates were adjusted to maintain circulating K+ at baseline. The QTc interval, QTd, peripheral physiological responses and plasma adrenaline and potassium concentrations were measured during both visits.Results The QTc interval and QTd increased both with and without potassium clamping. Without K+ replacement, mean (SE) QTc lengthened from 378 (5) ms to a final maximum value of 433 (10) ms, and QTd increased from 36 (5) ms to 69 (8) ms (both P < 0·001). During K+ replacement, QTc duration at baseline and study end was 385 (7) ms and 423 (11) ms, respectively (P < 0·001), and QTd 38 was (4) ms and 63 (5) ms (P = 0·001).Conclusions These data suggest that disturbed cardiac repolarization as a result of increases in circulating adrenaline occurs independently of extracellular potassium. A direct effect of adrenaline upon the myocardium appears the most likely mechanism.
Polymorphism of HLA‐A, ‐B, ‐DRB1, ‐DQA1 and ‐DQB1 haplotypes in a Croatian population
Authors: Grubic Z. , Z unec R. , C ec uk‐Jelic ic E. , Kerhin‐Brkljac ic V. , Kas telan A. 
Published: March 2003

AbstractWe describe for the first time extended haplotypes in a Croatian population. The present study gives the HLA‐A, ‐B, ‐DRB1, ‐DQA1 and ‐DQB1 allele and haplotype frequencies in 105 families with at least two offspring. All individuals were studied by conventional serology for HLA class I antigens (A and B), while class II alleles (DRB1, DQA1, DQB1) were typed using the PCR–SSOP method. HLA genotyping was performed by segregation in all 105 families. For extended haplotype analysis, 420 independent parental haplotypes were included. Fourteen HLA‐A, 18 HLA‐B, 28 DRB1, 9 DQA1 and 11 DQB1 alleles were found in the studied population. Most of the DRB1 alleles in our population had an exclusive association with one specific DQA1‐DQB1 combination. This strong linkage disequilibrium within the HLA class II region is often extended to the HLA‐B locus. A total of 10 HLA‐A, ‐B, ‐DRB1, ‐DQA1, ‐DQB1 haplotypes were observed with a frequency ≤ 1.0%. The three most frequent haplotypes were HLA‐A1, B8, DRB1*0301, DQA1*0501, DQB1*0201; HLA‐A3, B7, DRB1*1501, DQA1*0102, DQB1*0602 and HLA‐A24, B44, DRB1*0701, DQA1*0201, DQB1*02. These results should provide a useful reference for further anthropological studies, transplantation studies, and studies of associations between HLA and diseases.
The effect of geographic origin on the frequency of HLA antigens and their association with ageing
Authors: Izaks G. J. , Remarque E. J. , Schreuder G. M. T. , Westendorp R. G. J. , Ligthart G. J. 
Published: March 2003

AbstractThe association between HLA antigens and ageing is not clear. Ageing in women was associated with B40 and DR5 in a recent study, but other studies yielded conflicting results. In none of the studies, however, did the young and elderly samples originate from the same homogeneous population. Homogeneity is dependent on geographic origin. The aim of this study was to investigate whether differences in geographic origin between age groups could explain the age‐associated differences in the frequencies of B40 and DR5. The authors used the new design of a ‘birth‐place‐restricted comparison’ in which the origin of all subjects was ascertained. The total study population comprised 1010 young women aged 25–40 years and 660 elderly women aged 85 years and older. The ‘birth‐place‐restricted comparison’ included 66 young and 285 elderly women from one geographic area (Leiden, the Netherlands). Men were not included because ageing in men was not associated with HLA antigens in a recent study. In the total population, the frequency of B40 in young women of different origin varied between 16 and 28%, and the frequency of DR5 between 11 and 23%. Similar differences were observed in the elderly women. In the ‘birth‐place‐restricted comparison’, the frequency of B40 was 15% in the young women and 11% in the elderly women (difference 4%, 95% confidence interval, −5 to 13%). The frequency of DR5 was 20% in the young women, and 28% in the elderly women (difference 8%, 95% confidence interval, −4 to 19%). Thus, marked differences in HLA antigen frequency were found between populations of various geographic origins. Definition and ascertainment of the target population are therefore necessary in genetic studies of ageing. In such a ‘birth‐place‐restricted comparison’, the authors confirmed that ageing in women was negatively associated with HLA‐B40 and positively associated with HLA‐DR5.