bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reassignment of the EPB4·1 gene to 1p36 and assessment of its involvement in neuroblastomas
Authors: Huang S. , Lichtenauer U. D. , Pack S. , Wang C. , Kim A. C. , Lutchman M. , Koch C. A. , Torres‐Cruz J. , Huang S.‐C. , Benz E. J. , Christiansen H. , Dockhorn‐Dworniczak B. , Poremba C. , Vortmeyer A. O. , Chishti A. H. , Zhuang Z. 
Published: March 2003

Objectives EPB4·1 has been previously mapped to human chromosome 1p33‐p34.2. In contradiction to this chromosomal location, we have mapped EPB4·1–1p36 by using fluorescence in situ hybridization and radiation hybrid mapping. In neuroblastomas, deletions of the telomeric end of chromosome 1 (1p36) are the most common genetic aberration.Methods We investigated whether genetic aberrations of EPB4·1 can be detected in some neuroblastomas by analyzing 72 tumours for EPB4·1 mutation, expression, and alternative splicing pattern. Furthermore, EPB4·1 protein from a neuroblastoma cell line was studied for its subcellular localization.Results Sequence changes could be detected in 14 out of 72 neuroblastomas, including missense, silent, and intronic changes. Duplex RT‐PCR analysis revealed a subset of 11 tumours expressing significantly low levels of EPB4·1. Significant EPB4·1 sequence changes that were detected included an exon 4 G/A missense mutation (amino acid: V/I) that was shown to be associated with absence of wild‐type EPB4·1 expression (3 tumours), an exon 8 G/A missense mutation (V/M) (1 tumour), and an intronic sequence change that was shown to be associated with the presence of an aberrant transcript (1 tumour). Splicing pattern analysis revealed that all EPB4·1 transcripts from tumours exclude exon 3, a splicing pattern for generating the 135 kDa isoform. EPB4·1 cDNA cloned from a neuroblastoma cell line produced a 135‐kDa protein with a cytoplasm/membrane localization.Conclusions Out of 72 neuroblastomas we have identified 11 tumours with impaired EPB4·1 expression and 5 tumours with significant sequence changes. We also found that the 135 kDa isoform is the main EPB4·1 product in neuroblastoma. EPB4·1 cDNA from a neuroblastoma cell line produced a 135‐kDa protein and displayed a cytoplasm/membrane localization in transfected cells.
Food deprivation increases post‐heparin lipoprotein lipase activity in humans
Authors: Ruge T. , Svensson A. , Eriksson J. W. , Olivecrona T. , Olivecrona G. 
Published: March 2003

Objective To study the effect of fasting on lipoprotein lipase (LPL) activity in human post‐heparin plasma, representing the functional pool of LPL.Design Fourteen healthy volunteers were recruited for the study. The subjects were fasted for 30 h. Activities of LPL and hepatic lipase (HL), and LPL mass, were measured in pre‐ and post‐heparin plasma in the fed and in the fasted states, respectively. For comparison, LPL and HL activities were measured in pre‐ and post‐heparin plasma from fed and 24‐h‐fasted guinea pigs.Results Fasting caused a significant drop in the levels of serum insulin, triglycerides and glucose in the human subjects. Post‐heparin LPL activity increased from 79 ± 6·4 mU mL−1 in the fed state to 112 ± 10 mU mL−1 in the fasted state (P < 0·01), while LPL mass was 361 ± 29 in the fed state and 383 ± 28 in the fasted state, respectively (P = 0·6). In contrast, fasting of guinea pigs caused an 80% drop in post‐heparin LPL activity. The effect of fasting on human and guinea pig post‐heparin HL activity were moderate and statistically not significant.Conclusions In animal models such as rats and guinea pigs, post‐heparin LPL activity decreases on fasting, presumably due to down‐regulation of adipose tissue LPL. In humans, fasting caused increased post‐heparin LPL activity.
Hyperprolactinaemia in patients with heart failure: clinical and immunogenetic correlations
Authors: Limas C. J. , Kroupis C. , Haidaroglou A. , Cokkinos D. V. 
Published: March 2003

Background Prolactin represents a stimulatory link between the neuroendocrine and immune systems, but its involvement in the neurohumoral adaptations to heart failure (HF) has not been explored.Methods We prospectively studied 55 patients (45 males, 10 females, age 48 ± 7 years) with NYHA Class II/III HF due either to dilated cardiomyopathy (CMP) (n = 33) or ischemic heart disease (IHD) (n = 22). Serum prolactin levels were determined by radioimmunoassay, soluble interleukin‐2 receptor (sIL‐2R) levels by enzyme‐linked immunoassay and HLA‐DQ genotyping with PCR. Left ventricular ejection fraction (LVEF) and end‐diastolic diameter (LVEDd) were assessed echocardiographically.Results Hyperprolactinaemia (17·3 ± 4 ng mL−1[Group I] vs. 4·64 ± 2 ng mL−1[Group II], P < 0·01) was found in 14 patients (8 with IHD, 6 with CMP). The distribution of HLA‐DQB1 alleles was compared in the two groups and showed a significant increase in the frequency of *0301 (86% in Group I vs. 45% in Group II, P < 0·05). Histidine at position 30 of the HLA‐DQB1 gene was found in 22% of Group II but in none of Group I patients. Furthermore, there was an inverse correlation between the presence of histidine at position 30 and the levels of serum prolactin. Both sIL‐2R levels, a marker of T‐cell activation, and concanavalin A‐stimulated lymphocyte proliferation were lower in Group I patients (561 ± 106 vs. 804 ± 109 pg mL−1 and 20·8 ± 4 vs. 37·3 ± 5 cpmX103[3H] thymidine, respectively). LVEF was significantly higher (32 ± 5%) and LVEDd smaller (62·0 ± 6 mm) in Group I compared to Group II (25 ± 4% and 68·0 ± 5 mm, respectively, P < 0·01) patients.Conclusion Hyperprolactinaemia presents in 25% of patients with HF and may reflect decreased activation of T‐lymphocytes associated with relatively preserved LV systolic function which is under immune‐genetic control at the HLA‐DQ locus.
Oxysterols induce interleukin‐1β production in human macrophages
Authors: Rosklint T. , Ohlsson B. G. , Wiklund O. , Norén K. , Hultén L. M. 
Published: March 2003

Abstract Background  Oxysterols are biologically active molecules generated during the oxidation of low‐density lipoprotein or formed enzymatically in vivo. In the atherosclerotic plaque newly recruited macrophages may be exposed to oxysterols present in the plaque. How these oxysterols affect the expression and secretion of inflammatory cytokines such as interleukin‐1β (IL‐1β) in macrophages is not known. Therefore the aim of the present study was to investigate how oxysterols regulate the expression and secretion of IL‐1β in human monocyte‐derived macrophages.Methods  The IL‐1β messenger RNA (mRNA) expression was analysed by reverse transcription‐polymerase chain reaction, and the IL‐1β protein secretion was measured by enzyme‐linked immunosorbent assay.Results  A significant, dose‐dependent increase in the secretion of IL‐1β was given by 25‐hydroxycholesterol without the addition of lipopolysaccharide (LPS). At a concentration of 2·5 µg mL−1 this increase was similar to that obtained by endotoxin (LPS, 1 µg mL−1). A transient increase in IL‐1β mRNA expression was found in macrophages incubated with 25‐hydroxycholesterol compared with untreated controls. In addition, 25‐hydroxycholesterol dramatically increased the IL‐1β secretion induced by LPS. At a concentration of 5 µg mL−1 of 25‐hydroxycholesterol the LPS‐induced IL‐1β secretion was increased by about 25‐fold. A similar tendency, but not so consistent, was found for 27‐hydroxycholesterol.Conclusions  Our results show that oxysterols, and 25‐hydroxycholesterol in particular, may modulate the inflammatory response in human macrophages. Consequently the presence of oxysterols in atherosclerotic tissue may dramatically influence the effect of inflammation.
Antitumour and toxic effects on Wistar rats of two new platinum complexes
Authors: Charalabopoulos K. , Karkabounas S. , Ioachim E. , Papalimneou V. , Syrigos K. , Evangelou A. , Agnantis N. , Hadjiliadis N. 
Published: March 2003

AbstractBackground Cancer chemotherapy in humans based on metal complexes started at the clinical level in the late 1970s with the use of cisplatin, which forms intra‐strand cross‐links with DNA.Methods Two new platinum complexes of cis‐geometry with the amino acids inosine (ino) and l‐alanine (ala), Pt(ino)2Cl2 and cis‐[Pt(NH3)2(ala)](NO3), respectively, were synthesized and pure samples were obtained by means of flash chromatography. These complexes were tested on benzo(a)pyrene‐induced tumours in Wistar rats to detect their antitumour and toxic effects.Results There was a statistically significant prolongation of the mean survival time of the animals in the two groups tested (272 ± 18 days and 246 ± 26 days, respectively) compared to the control group (195 ± 22 days) (P < 0·001). Toxic effects included a decrease in leucocyte cell count, mild haemolysis, mild haematuria, mild hepatotoxicity, elevated body temperature and hair loss. All of these effects were reversible after drug discontinuation.Conclusions The two new platinum complexes described here appear to have an effective antitumour activity without severe toxicity when tested on Wistar rats.
Endothelin ETA receptor‐subtype specific antagonism does not mitigate the acute systemic or renal effects of exogenous angiotensin II in humans
Authors: Bayerle‐Eder M. , Langenberger H. , Pleiner J. , Polska E. , Mensik C. , Eichler H.‐G. , Wolzt M. , Schmetterer L. 
Published: March 2003

AbstractBackground Angiotensin II (Ang II) is assumed to play a pathophysiological role in a variety of vascular diseases. Animal studies indicate that these effects are partly attributed to stimulation of endothelin‐1 (ET‐1) release. The aim of the present study was to investigate whether the acute effects of Ang II on systemic and renal haemodynamics in healthy subjects can be influenced by endothelin ETA‐receptor blockade.Design The study design was balanced, randomized, placebo‐controlled, double blind, two‐way cross‐over, in 10 healthy male subjects.Methods Subjects received stepwise increasing intravenous doses of Ang II (0·65, 1·25, 2·5, 5 ng kg−1 min−1 for 15 min per dose level) in the presence or absence of BQ‐123 (60 µg min−1), a specific ETA‐receptor antagonist. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by the para‐aminohippurate and inulin plasma clearance method, respectively. Renal vascular resistance (RVR) was calculated from mean arterial pressure (MAP) and renal plasma flow.Results Ang II decreased RPF by 34% and GFR by 9% and increased RVR by 94% and MAP by 27% (ANOVA, P < 0·001 vs. baseline, for all parameters). BQ‐123 did not alter these renal and systemic haemodynamic responses to a significant degree. In addition, BQ‐123 had no significant haemodynamic effect under baseline conditions.Conclusions Short‐term increase of circulating Ang II levels causes systemic and renal pressor effects, which are not mitigated by endothelin ETA‐receptor blockade. This suggests that the pressor response to Ang II cannot be accounted for by the acute release of vasoactive ET‐1.
Higher antioxidant defences in plasma and low density lipoproteins from rugby players
Authors: Evelson P. , Gambino G. , Travacio M. , Jaita G. , Verona J. , Maroncelli C. , Wikinski R. , Llesuy S. , Brites F. 
Published: March 2003

AbstractBackground Even if physical activity constitutes a well‐known antiatherogenic factor, the precise mechanisms underlying this protective effect are not completely clear.Materials and methods Lipid and antioxidant profiles were evaluated in 15 well‐trained rugby players and 15 sedentary controls. Lipoprotein fractions were separated by sequential ultracentrifugation and α‐tocopherol content was determined in each fraction by high‐performance liquid chromatography. Susceptibility to in vitro oxidation was also measured in intermediate and low density lipoproteins isolated from both groups of subjects as the production of conjugated dienes.Results Although the sportsmen were not receiving any special diet or vitamin supplementation they showed a slightly improved lipoprotein profile, mainly represented by increased high density lipoprotein‐cholesterol levels (P < 0·05), and an enhanced antioxidant status. The latter was evidenced by an increment in total radical antioxidant potential (P < 0·001), higher ascorbic acid (P < 0·005) and α‐tocopherol (P < 0·05) plasma concentrations, and elevated activities of superoxide dismutase (P < 0·001) and arylesterase (P < 0·01). Moreover, only the fraction of intermediate and low density lipoproteins from rugby players presented higher α‐tocopherol content in comparison with sedentary controls (484 ± 67 vs. 377 ± 123 µg dL−1, respectively; P < 0·01). Nevertheless, the susceptibility to in vitro oxidation of this lipoprotein fraction was not different between both groups.Conclusions Given that intermediate density and low density lipoproteins represent the most atherogenic fraction, this finding, in combination with the improved lipid and antioxidant status, would add to the link between regular physical activity and protection against cardiovascular disease.
No increase in mortality and morbidity among carriers of the C282Y mutation of the hereditary haemochromatosis gene in the oldest old: the Leiden 85‐plus Study
Authors: Van Aken M. O. , De Craen A. J. M. , Gussekloo J. , Moghaddam P. Hanifi , Vandenbroucke J. P. , Heijmans B. T. , Slagboom P. E. , Westendorp R. G. J. 
Published: March 2003

AbstractBackground The C282Y mutation in the gene for haemochromatosis (HFE) has been associated with various diseases at middle age. However, recent studies indicate that penetrance of the C282Y mutation is low. We explored the association between the C282Y mutation, iron metabolism, and morbidity and mortality in participants of the Leiden 85‐plus.Study design A cross‐sectional comparison and prospective follow‐up was conducted in two unselected cohorts of 661 and 552 subjects. All subjects were aged 85 years and over. We determined the prevalence of C282Y homozygous and heterozygous subjects, and the association between the C282Y mutation and iron metabolism, all‐cause and specific causes of death.Results Prevalence of C282Y homozygosity in both cohorts was 0·2% (1/661 and 1/552, respectively) and of C282Y heterozygosity was 12·4% (82/661) and 11·4% (63/552), respectively. These estimates coincide exactly with reported estimates in younger age groups. Median ferritin level was 97 µg L−1 (IQR 39–162) for heterozygous carriers and 89 µg L−1 (IQR 41–157) for noncarriers (P = 0·66). The serum ferritin concentration for one C282Y homozygous subject, a woman aged 86 years at the time of enrollment in 1986, was 392 µg L−1. Cardiovascular morbidity was comparable between the C282Y heterozygous subjects and the noncarriers in both study cohorts. All‐cause and cardiovascular mortality of carriers of the C282Y mutation was similar to that in noncarriers.Conclusions We found two C282Y homozygous subjects, illustrating that homozygosity can be compatible with survival in very old ages. C282Y heterozygosity was not associated with history of cardiovascular disease morbidity, all cause mortality, cardiovascular mortality, or biochemical phenotype of haemochromatosis at old age.
Captopril and quinapril reduce reactive oxygen species
Authors: Van Der Giet M. , Erinola M. , Zidek W. , Tepel M. 
Published: March 2003

AbstractBackground Angiotensin‐converting enzyme inhibitors may affect reactive oxygen species in humans in vitro and in vivo. In the present study we evaluated whether angiotensin‐converting enzyme inhibitors may affect NAD(P)H oxidase activity.Materials and methods The production of reactive oxygen species was measured spectrophotometrically in mononuclear leukocytes using the fluorescent dye, dichlorofluorescein diacetate. The effects of quinaprilat, captopril, enalaprilat and lisinopril on phorbol myristate acetate‐induced reactive oxygen species generation were investigated in vitro. The effects of quinaprilat, captopril, enalaprilat and lisinopril on the NAD(P)H oxidase activity of the mononuclear leukocytes were measured photometrically. In addition, reactive oxygen species were measured before and 4 h after oral administration of quinapril.Results In vitro, the addition of quinaprilat (72 ± 6% of control; mean ± SEM; n= 19; P < 0·001) and captopril (48 ± 2% of control; n= 19; P < 0·001) significantly reduced the phorbol‐12‐myristate‐13‐acetate‐induced reactive oxygen species generation by the mononuclear leukocytes, whereas enalaprilat and lisinopril showed no effect. The effect of captopril on phorbol‐12‐myristate‐13‐acetate‐induced reactive oxygen species generation in vitro was concentration‐dependent. Quinaprilat and captopril significantly inhibited the NAD(P)H oxidase activity. After the oral administration of 10 mg of quinapril the phorbol‐12‐myristate‐13‐acetate‐induced reactive oxygen species generation by the mononuclear leukocytes was significantly decreased from 1981 ± 292% to 988 ± 141% (n = 14; P < 0·01).Conclusion Quinapril and captopril decrease the production of reactive oxygen species.
Regulation of ferritin: a specific role for interferon‐alpha (IFN‐α)? The acute phase response in patients treated with IFN‐α‐2b
Authors: Stam T. C. , Swaak A. J. G. , Kruit W. H. J. , Eggermont A. M. M. 
Published: March 2003

AbstractBackground Adult onset of Still’s disease is characterized by very high serum ferritin levels, in disproportion with other acute phase proteins (APPs). Because interferon‐alpha (IFN‐α) was observed to cause hyperferritinaemia in three healthy people without increase of other APPs, we hypothesized that IFN‐α stimulates specifically the synthesis of ferritin. To test this hypothesis, we studied ferritin and other APP levels in patients treated with IFN‐α.Patients and methods Fifteen patients treated with IFN‐α‐2b 3–5 times a week, as adjuvant treatment after excision of a high‐risk melanoma, were compared with six patients without adjuvant treatment (controls). Serum levels of C‐reactive protein (CRP) and secretory phospholipase A2 (sPLA2) were measured using ELISA. Levels of ferritin, alpha1‐acid glycoprotein (AAG) and albumin were determined by nephelometry.Results CRP was decreased significantly after 4 weeks (P < 0·01) in the patients treated with IFN‐α compared with the nontreated patients, after 6 months of treatment it was still decreased although not significantly. Ferritin increased significantly in the IFN‐α‐treated patients: 187% of pretreatment value after 4 weeks and 217% after 6 months (P < 0·01), while ferritin levels decreased in the nontreated patients. AAG increased significantly in IFN‐α‐treated patients (107, 114%) compared with the control‐patients (91, 76%) but differences were less compared with CRP and ferritin. sPLA2 had a variable course, while albumin remained constant within the normal range in both patient groups.Conclusions IFN‐α induced a significant increase in ferritin, with a significant decrease in CRP, little increase in AAG, varying response of sPLA2 and no change in albumin. This finding suggests a specific role for IFN‐α in the synthesis or secretion of ferritin. This mechanism may also be involved in the marked hyperferritinaemia in adult onset of Still’s disease.
Functional approach to investigate Lp(a) in ischaemic heart and cerebral diseases
Authors: De La Peña‐Díaz A. , Cardoso‐Saldaña G. , Zamora‐González J. , Barinagarrementeria F. , Izaguirre R. , Loyau S. , Anglés‐Cano E. 
Published: March 2003

AbstractBackground Lp(a), a major cardiovascular risk factor, contains a specific apolipoprotein, apo(a), which by virtue of structural homology with plasminogen inhibits the formation of plasmin, the fibrinolytic enzyme. A number of clinical reports support the role of Lp(a) as a cardiovascular or cerebral risk factor, and experimental data suggest that it may contribute to atherothrombosis by inhibiting fibrinolysis.Design A well‐characterized model of a fibrin surface and an apo(a)‐specific monoclonal antibody were used to develop a functional approach to detect pathogenic Lp(a). The assay is based on the competitive binding of Lp(a) and plasminogen for fibrin, and quantifies fibrin‐bound Lp(a). High Lp(a) binding to fibrin is correlated with decreased plasmin formation. In a transversal case–control study we studied 248 individuals: 105 had a history of ischaemic cardiopathy (IC), 52 had cerebro‐vascular disease (CVD) of thrombotic origin, and 91 were controls.Results The remarkably high apo(a) fibrin‐binding in CVD (0·268 ± 0·15 nmol L−1) compared with IC (0·155 ± 0·12 nmol L−1) suggests the existence of peculiar and poorly understood differences in pro‐ or anti‐thrombotic mechanisms in either cerebral and/or coronary arteries.Conclusions Our results demonstrated that Lp(a) fibrin‐binding and small Apo(a) isoforms are associated with athero‐thrombotic disease.
Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and β‐cell dysfunction
Authors: Boden G. , Shulman G. I. 
Published: March 2003

AbstractPlasma free fatty acids (FFA) play important physiological roles in skeletal muscle, heart, liver and pancreas. However, chronically elevated plasma FFA appear to have pathophysiological consequences. Elevated FFA concentrations are linked with the onset of peripheral and hepatic insulin resistance and, while the precise action in the liver remains unclear, a model to explain the role of raised FFA in the development of skeletal muscle insulin resistance has recently been put forward. Over 30 years ago, Randle proposed that FFA compete with glucose as the major energy substrate in cardiac muscle, leading to decreased glucose oxidation when FFA are elevated. Recent data indicate that high plasma FFA also have a significant role in contributing to insulin resistance. Elevated FFA and intracellular lipid appear to inhibit insulin signalling, leading to a reduction in insulin‐stimulated muscle glucose transport that may be mediated by a decrease in GLUT‐4 translocation. The resulting suppression of muscle glucose transport leads to reduced muscle glycogen synthesis and glycolysis. In the liver, elevated FFA may contribute to hyperglycaemia by antagonizing the effects of insulin on endogenous glucose production. FFA also affect insulin secretion, although the nature of this relationship remains a subject for debate. Finally, evidence is discussed that FFA represent a crucial link between insulin resistance and β‐cell dysfunction and, as such, a reduction in elevated plasma FFA should be an important therapeutic target in obesity and type 2 diabetes.
Redefining the clinical management of type 2 diabetes: matching therapy to pathophysiology
Authors: Gerich J. E. 
Published: March 2003

AbstractConventional treatments for type 2 diabetes do not provide adequate glycaemic control to prevent the long‐term progression of the disease. The introduction of increasingly intensive therapeutic regimens in stepwise management strategies aims to maintain glycaemic control in the face of progressive deterioration in β‐cell function. However, such an approach does not entirely address the underlying disease mechanisms. Although much remains unclear about the aetiology of type 2 diabetes, both β‐cell dysfunction and insulin resistance play important roles, and there is a complex, dynamic interaction between these two abnormalities. Growing evidence suggests that treatments that can reverse insulin resistance and improve β‐cell function may be able to slow or prevent the progression of the disease. The clinical management of type 2 diabetes therefore needs to be re‐examined and redefined to reflect new insights into the underlying pathogenetic mechanisms, including consideration of the potential benefits of early, aggressive intervention to counter both β‐cell dysfunction and insulin resistance.