bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non‐transferrin‐bound iron is present in serum of hereditary haemochromatosis heterozygotes
Authors: De Valk  , Addicks  , Gosriwatana  , Lu  , Hider  , M. Marx  
Published: March 2003

BackgroundHereditary haemochromatosis (HH) is a common autosomal recessive disease. Recently, HH heterozygosity has been identified as an independent risk factor for myocardial infarction and cardiovascular mortality. Iron may play an important role in atherogenesis by catalyzing peroxidation of low‐density‐lipoprotein (LDL), an essential step in atherogenesis. In iron overload conditions, non‐transferrin‐bound iron (NTBI) is found in serum, which can catalyze lipid peroxidation. We investigated whether sera of HH heterozygotes contain more NTBI than sera of normal controls.MethodsIn 27 treated HH homozygotes, 22 HH heterozygotes and 17 healthy control subjects, conventional parameters of iron status (serum iron, transferrin saturation, serum ferritin) were measured. NTBI was detected using HPLC after addition of nitrilotriacetic acid and pretreatment with cobalt.ResultsThe conventional parameters of iron status were similar in the HH heterozygous group and the control group. NTBI was significantly higher in homozygotes compared to heterozygotes (1.79 μmol L−1 vs. 0.51 μmol L−1, 95% CI of the difference = 0.6–1.95, P < 0.001), and controls (1.79 μmol L−1 vs. − 0.3 μmol L−1, 95% CI of the difference = 1.36–2.81, P < 0.001). The difference in NTBI between the heterozygous subjects and control subjects was also significant (0.51 μmol L−1 vs. − 0.3 μmol L−1, 95% CI of the difference = 0.05–1.57, P < 0.05).ConclusionPhlebotomy treated HH homozygotes maintain a high and potentially harmful serum NTBI. HH heterozygotes have a higher serum NTBI than normal controls. The reported increased risk of cardiovascular events in heterozygous haemochromatosis may be explained by NTBI‐catalyzed LDL peroxidation.
Cytochrome P450 2D6 and glutathione S‐transferase M1 genotypes and migraine
Authors: Mattsson  , Bjelfman  , Lundberg  , Rane  
Published: March 2003

BackgroundMigraine is thought to be a disease of the brain and trigeminovascular system. Migraine patients often claim that stress, food, and beverages trigger their attacks. Chemical substances in these foodstuffs with the property of triggering migraine attacks have not yet been characterised. Cytochrome P450 2D6 (CYP2D6) and glutathione S‐transferase M1 (GSTM1) are thought to be present in the brain. They metabolise numerous environmental compounds. The genes exhibit genetic polymorphism that is associated with altered enzyme activity. The aim of this study was to determine if the genotypes of these two enzymes are associated with migraine.Materials and methodsThe study included 100 female patients and 245 female controls from the general population. Genomic DNA was isolated from whole blood. Allele specific PCR methods were used to identify the normal CYP2D6*1 allele and the mutated CYP2D6*3 and CYP2D6*4 alleles. Initially all samples were genotyped only for GSTM1 plus (+) and GSTM1 null (−) variants. All samples positive for GSTM1 were further analysed for the presence of allelic variants GSTM1*A and GSTM1*B.ResultsNone of the CYP2D6 and GSTM1 genotypes was associated with migraine. We observed an odds ratio (OR) for the poor metaboliser genotype of CYP2D6 of 1.4 (95% CI = 0.5–3.6) and for the GSTM1 null genotype of 1.0 (95% CI = 0.6–1.5).ConclusionThe results of this study indicate that deficient metabolism because of mutated CYP2D6 alleles or GSTM1 allele variants is not important in the aetiology of migraine.
Low levels of colonic glutathione S‐transferase in patients with X‐linked agammaglobulinaemia
Authors: Grubben  , Van Den Braak  , Peters  , Van Der Meer  , Nagengast  
Published: March 2003

BackgroundPatients with X‐linked agammaglobulinaemia, a primary immunodeficiency disorder, suffer from recurrent infections of the respiratory and intestinal tract. Rapidly progressive colorectal cancer was diagnosed in three unrelated young adults with X‐linked agammaglobulinaemia. This finding implies a 30‐fold increase of risk for this cancer in this patient group. Glutathione S‐transferases are a family of biotransformation enzymes involved in the detoxification of cytotoxic and carcinogenic compounds, that may function in the prevention of carcinogenesis. We investigated the possible role of the glutathione S‐transferase enzyme system in the apparently increased colorectal cancer risk in X‐linked agammaglobulinaemia patients.Materials and methodsWe analysed the glutathione levels and the glutathione S‐transferase enzyme activity and iso‐enzyme composition in normal colonic biopsies of eight X‐linked agammaglobulinaemia patients, 25 patients with a recent history of colonic adenomas and 10 healthy volunteers.ResultsX‐linked agammaglobulinaemia patients had significantly lower glutathione S‐transferase enzyme activities at all sites in the normal colonic mucosa as compared to adenoma patients. In X‐linked agammaglobulinaemia patients the rectal glutathione S‐transferase enzyme activity was lower than in the proximal colon and significantly lower as compared to controls.ConclusionThis lower glutathione S‐transferase enzyme activity might play a role in the apparently increased colorectal cancer risk in X‐linked agammaglobulinaemia patients, assuming that detoxification of carcinogenic compounds plays a role in the aetiology of colon cancer of these patients.
Postprandial response to a fat tolerance test in young adults with a paternal history of premature coronary heart disease — the EARS II study
Authors: Tiret  , Gerdes  , Murphy  , Dallongeville  , Nicaud  , J. O'Reilly  , Beisiegel  , De Backer  , On Behalf Of The Ears Group  
Published: March 2003

BackgroundThe European Atherosclerosis Research Study (EARS) I had shown that fasting plasma concentrations of apolipoprotein B (apo B) and triglycerides were the most discriminant variables between offspring with a paternal history of coronary heart disease (CHD) and controls. The EARS II study was undertaken to investigate whether a paternal history of CHD was associated with differences in postprandial lipemia.DesignMale subjects with a paternal history of CHD (cases, n = 407) and age‐matched male controls (n = 415) were recruited from 14 European universities. All subjects had an oral fat tolerance test.ResultsIn the sample as a whole, the postprandial triglyceride responses did not significantly differ between the two groups. However, in the upper tertile of fasting triglycerides, cases displayed a higher area under the curve (5.71 vs. 4.49 mmol.h L−1, P < 0.001), a higher peak (1.76 vs. 1.43 mmol L−1, P < 0.001) and a more delayed time to peak (3.15 vs. 2.91 h, P < 0.05) than controls. In the upper tertile, fasting apo B levels (P < 0.05) and triglyceride area under the curve (P = 0.002) significantly discriminated cases from controls in a multivariate analysis. Cases had also higher Lp C‐III:B levels at 4 h than controls (11.2 vs. 9.9 mg dL−1, P < 0.01) and this difference remained significant after adjustment for apo B and triglyceride levels.ConclusionsThese results indicate that in subjects with a moderate elevation of fasting triglycerides, an impaired postprandial response to a fat load constitutes an early biological expression of a paternal history of premature CHD.
The increased insulin sensitivity in growth hormone‐deficient adults is reduced by growth hormone replacement therapy
Authors: Riedl  , Ludvik  , Pacini  , Clodi  , Kotzmann  , Wagner  , Kautzky‐Willer  , Prager  , Luger  
Published: March 2003

BackgroundGrowth hormone deficiency is associated with increased morbidity and mortality from cardiovascular diseases, which might be related to changes in glucose and lipid metabolism.DesignTo assess the influence of long‐term growth hormone replacement therapy (GHRT) on glucose metabolism we examined eight growth hormone‐deficient (GHD) adults (seven female/one male; age, 46 ± 3 years; body mass index, 31 ± 2 kg m−2) over a period of 18 months in comparison to an adequate control group consisting of eight obese subjects matched for age, sex, and body mass index. We performed frequently sampled intravenous glucose tolerance tests (FSIGT) with minimal model analysis before the study, and after 12 and 18 months.ResultsFollowing GHRT, insulin‐like growth factor‐1 (IGF‐1) increased significantly from a basal level of 75.9 ± 18.9 to 200.8 ± 31.0 μg L−1 after 12 months of therapy and remained stable, thereafter. GHRT did not affect fasting blood glucose, basal insulin, cholesterol, blood pressure and body weight. However, at 12 months, HbA1c (6.0 ± 0.1 vs. 5.6 ± 0.1% at basal, P < 0.05) and triglyceride (2.3 ± 0.4 vs. 1.4 ± 0.3 mmol L−1) significantly increased but returned to pretreatment values at 18 months. Insulin sensitivity was higher in GHD (8.2 ± 3.1) compared to controls (3.6 ± 0.53 × 10−4 min−1/(μU mL−1), P = 0.06) and decreased significantly after 18 months of GHRT to 5.1 ± 2.6, P < 0.05. Basal insulin secretion was similar to that in the control group and increased significantly after 12 and 18 months, total insulin secretion only after 12 months. SG (glucose effectiveness)was lower in GHD patients (0.0095 ± 0.001 min−1) compared to controls (0.020 ± 0.003 min−1, P < 0.05) and increased significantly after 12 and 18 months of GHRT (0.016 ± 0.002, and 0.015 ± 0.001 min−1, P < 0.05), respectively. Hepatic insulin extraction rate was similar in both groups and remained unchanged following GHRT.ConclusionWe conclude that long‐term GHRT induces a significant decrease of the increased insulin sensitivity in GHD patients to levels observed in body mass index‐matched control subjects. This is accompanied by an increase in basal and total insulin secretion as well as in glucose effectiveness as a possible compensatory mechanism.
Influence of vitamin D administration on bone ultrasound measurements in patients on anticonvulsant therapy
Authors: Pedrera J.D. , Canal M.L. , Carvajal J. , Postigo S. , Villa L.F. , Hernández E.R. , Rico H. 
Published: March 2003

BackgroundThe objective of the study was to evaluate bone mass status (as measured by bone ultrasound) in patients on anticonvulsant therapy, and the influence that Vitamin D administration exerts over it.Materials and methodsWe measured and compared the basal serum levels of 25(OH)D3, parathyroid hormone (PTH), and phalangeal bone ultrasound (Ad‐SOS), in 30 adult patients who were taking anticonvulsant drugs, with a control group of similar age and sex. We then gave the patients a large oral dose of 3 mg (120.000 UI) of 25(OH)D3, and repeated the measurements after one month.ResultsBasal 25(OH)D3 and Ad‐SOS values were significantly lower, and PTH values significantly higher (P < 0.0001 in all), in the patient group. The low Ad‐SOS values for the patients were independent of the treatment, but directly related to basal 25(OH)D3 levels (r = 0.45, P < 0.01). There was a negative association between PTH and 25(OH)D3 (r = −0.64, P < 0.0001), and no correlation between PTH y Ad‐SOS (r = −0.20, p NS). After ingestion of the large dose of the vitamin D, the patient group registered a significant (P < 0.0001) increase in 25(OH)D3 levels, their Ad‐SOS values increased (P < 0.0001) nearly to the mean basal value of the control group, and PTH decreased significantly (P < 0.0001).ConclusionsThese findings justify the need to assure adequate vitamin D intake in patients being treated with anticonvulsants, independently of the treatment, age, sex, and activity status, in order to prevent osteomalacia.
Diurnal triglyceride profiles in healthy normolipidemic male subjects are associated to insulin sensitivity, body composition and diet
Authors: Van Oostrom A. J. H. H. M. , Castro Cabezas M. , Ribalta J. , Masana L. , Twickler TH. B. , Remijnse T. A. , Erkelens D. W. 
Published: March 2003

BackgroundElevated fasting and postprandial triglycerides (TG) are established risk factors for Coronary Heart Disease (CHD). Usually, fasting plasma TG are measured, although TG are mainly produced in a postprandial state. Our objective was to investigate diurnal TG profiles using serial capillary TG measurements, in normolipidemic healthy males.Materials and MethodsForty‐eight, non‐obese, non‐smoking males (range: 20–55 years, mean age: 32 ± 12 years), measured diurnal capillary TG, at six fixed timepoints during the day on three different days and recorded their food intake. Insulin sensitivity was estimated by HOMA. Diurnal capillary TG profiles were calculated as integrated area under the mean capillary TG curve (TGc‐AUC).ResultsAll subjects had normal fasting plasma TG and cholesterol. The average TGc‐AUC was 23.6 ± 6.7 mmol h L−1. Significant correlations with TGc‐AUC were: fasting insulin (r = 0.40, P < 0.005), HOMA (r = 0.32, P < 0.05), relative fat mass (r = 0.31, P < 0.05), dietary protein‐(r = 0.31, P < 0.05) and saturated fat intake (r = 0.30, P < 0.05). Age was not associated to diurnal triglyceridemia. After subdividing the group into quartiles on the base of TGc‐AUC, differences were found between the highest (n = 12) and lowest quartile (n = 12) for: fasting capillary TG, fasting insulin, HOMA and systolic blood pressure. Fasting plasma TG and dietary intake were not different.ConclusionDiurnal TG profiles in healthy normolipidemic males are not age‐dependent, but are associated to insulin sensitivity, fat mass and diet. Diurnal capillary TG profiles may be a valuable additional tool in estimating a risk profile for CHD since significant differences in diurnal TG are not always reflected by elevated fasting plasma TG.
Additive effects of Simvastatin beyond its effects on LDL cholesterol in hypertensive type 2 diabetic patients
Authors: Tonolo G. , Melis M. G. , Formato M. , Angius M. F. , Carboni A. , Brizzi P. , Ciccarese M. , Cherchi G. M. , Maioli M. 
Published: March 2003

BackgroundExperimental evidence indicates that statins might have direct vascular effects independently from low‐density lipoprotein (LDL) cholesterol reduction and we reported that the reduction in urinary albumin excretion rate during Simvastatin treatment in type 2 diabetic patients was not correlated with LDL‐cholesterol decrease. However in humans there are no data regarding possible additional effects of Simvastatin on blood pressure and urinary albumin excretion beyond its capacity to lower serum cholesterol.Patients and methodsTwenty‐six microalbuminuric hypertensive type 2 diabetic patients (diastolic blood pressure — after four months wash‐out from the previous antihypertensive therapy — consistently > 90 and < 100 mmHg; plasma LDL‐cholesterol > 3.9 and < 6.5 mmol L−1) were enrolled in the study. In random order, these patients received Simvastatin (20 mg day−1) or Cholestyramine (6 g three times a day) for a period of 10 months and after three months of wash‐out (cross‐over) the sequence was reversed for an additional 10 months. Blood pressure, lipid parameters, glycated haemoglobin and urinary albumin excretion were measured during the study. Additionally, in eight patients, urinary glycosaminoglycan excretion (GAG) was also measured during the study.ResultsSimvastatin and Cholestyramine were equally effective in reducing total and LDL cholesterol. Only during Simvastatin treatment a significant reduction in diastolic blood pressure and both 24 h urinary albumin and GAG excretion rates were observed, while no significant changes were seen with Cholestyramine treatment.ConclusionsOur results clearly show for the first time that the reduction of blood pressure, together with 24 h urinary albumin excretion rate — two established cardiovascular risk factors, obtained during Simvastatin therapy in hypertensive type 2 diabetic patients — is in large part independent from the reduction of LDL Cholesterol.
Intra‐adrenal regulation of androgen synthesis
Authors: L'Allemand D. , Biason‐Lauber A. 
Published: March 2003

The adrenal cortex encloses the neuroendocrine medulla and is itself subdivided into three distinct zones, each having a specific function and regulation. While the glomerulosa and the fasciculata control vital systems of mineral and energy supply, which are stringently regulated by higher control factors, the function of the reticularis is less clear, beyond supplying a pool of weak androgens, and consequently we do not understand its redundant regulation.The following questions need to be answered: 1 How is the formation of dehydroepiandrosterone (DHEA) and androstenedione differently regulated from glucocorticoid synthesis in normally functioning adrenals? 2 How might growth factors, which increase prepubertally [1], prime the adrenarche? 3 The regulation of the 17/20‐lyase enzyme activity is one of the key factors of adrenal androgen secretion (review [2]). How can the two activities of the P450c17 enzyme be differently regulated in the same cell in a developmentally dependent fashion?This review focuses on the intra‐adrenal growth factor system and on the role of 17/20‐lyase regulation, as well as on their possible interactions. The increase of activity of the 17/20‐lyase enzymatic activity is necessary for the rise of C19 steroids [3], while the relative increase of formation of DHEA is only possible in the presence of a low 3β‐hydroxysteroid‐dehydrogenase (3βHSD) activity [4].
Dehydroepiandrosterone – a neurosteroid
Authors: Friess E. , Schiffelholz T. , Steckler T. , Steiger A. 
Published: March 2003

Dehydroepiandrosteone (DHEA) and its sulfate ester (DHEAS) are the major secretory products of the human adrenal glands and serve as precursors for both androgenic and estrogenic steroids. DHEA/S concentrations are particularly high in the brain, and DHEA/S and related steroids can be synthesized de novo in brain glial cells. Therefore, the term ‘neurosteroids’ has been coined for these compounds.This review summarizes findings in neurosteroid physiology on a cellular and molecular level, and outlines current concepts of how these compounds modulate physiological functions of the brain. Today, despite promising preclinical and human data the present clinical studies provide only weak evidence, if any, in favour of a DHEA replacement therapy.
Homocysteine and the MTHFR 677C→T allele in premature coronary artery disease. Case control and family studies
Authors: Pintó X. , Vilaseca M. A. , Garcia‐Giralt N. , Ferrer I. , Palá M. , Meco J. F. , Mainou C. , Ordovás J. M. , Grinberg D. , Balcells S. ,   the Baix Llobregat Homocysteine Study Group
Published: March 2003

Background The aim of this work was to evaluate the role of homocysteine, and the MTHFR 677C→T allele as risk factors for premature coronary artery disease and to analyse the inheritance of this metabolic disorder. Material and methods Case‐control and family studies were performed in a sample of 76 male patients (age < 55), 95 age‐matched controls and 89 patients' offspring. Plasma total homocysteine concentrations, its nutritional determinants and the frequency of the MTHFR 677C→T allele were measured, in addition to conventional risk factors. Results Mild hyperhomocysteinemia (above the 90th percentile of the control group) was seen in 22·4% of patients (P = 0·02) and was an independent predictor of premature coronary artery disease (odds ratio of 3·2). The frequencies of the 677T allele in patients and controls were 0·37 and 0·36 and those of the TT genotype were 0·15 and 0·14, respectively. Homozygosity for the 677T allele was associated with significantly higher homocysteine values (P < 0·00001). Among TT patients, 64% had mild hyperhomocysteinemia, as compared to 23% of TT controls. Mild hyperhomocysteinemia showed a strong hereditary component, as 36% of patients' offspring had homocysteine levels above the age‐adjusted 90th percentile compared to only 13% of patients' spouses. Among children with the TT genotype, the proportion raised to 83% (P < 0·001). Conclusion In this Spanish population, mild hyperhomocysteinemia is associated with the risk of premature coronary artery disease and is highly prevalent in offspring of patients with this condition. The MTHFR TT genotype is associated with hyperhomocysteinemia, but not with coronary artery disease.
Effect of ischemia on intestinal permeability of lipopolysaccharides
Authors: Drewe J. , Beglinger C. , Fricker G. 
Published: March 2003

The enteral absorption of endotoxin (lipopolysaccharide, LPS) was studied in vitro and in vivo.The absorption of fluorescence (FITC) labelled LPS was investigated by uptake studies with rabbit jejunal brush‐border membrane vesicles (BBMV), the human intestinal cell line Caco‐2 and in rats.FITC‐LPS from Salmonella typhimurium was taken up into BBMV in a dose‐dependent manner. Uptake was neither pH‐ nor Na+‐dependent, nor could it be inhibited by unlabelled LPS. 74·5% of vesicle‐associated fluorescence was due to adhesion to the vesicular membranes, 25·5% was taken up into an osmotically‐sensitive space. Transport of LPS across Caco‐2 cell monolayers was dose‐dependent. The permeation rate increased significantly under ischemic conditions, i.e. when the cells were incubated under oxygen‐depleted conditions. However, no significant differences in transepithelial electrical resistances were observed between oxygen depleted and control cells. The release of lactate dehydrogenase was only marginally different from control cells, indicating cell integrity. In situ, after gut ischemia, a significantly increased uptake of fluorescent LPS was observed by fluorescence laser scanning microscopy. Conclusion LPS is taken up by the intestinal mucosa, predominantly by passive transcellular diffusion. Under ischemic conditions, the permeability of LPS is increased mainly by an enhanced paracellular permeability and epithelial destruction. The findings partly explain the clinically observed development of multiorgan system failure after temporary malperfusion of the gut during major vascular surgery or thromboembolism.
LEPR gene polymorphisms: associations with overweight, fat mass and response to diet in women
Authors: Mammès O. , Aubert R. , Betoulle D. , Péan F. , Herbeth B. , Visvikis S. , Siest G. , Fumeron F. 
Published: March 2003

Background In humans, a mutation of the leptin receptor gene (LEPR) leads to a rare obese syndrome of mendelian inheritance. However, obesity in humans results from interactions between genes and environment, mainly nutritional factors. Variations at the LEPR locus could be involved in the regulation of body weight.Design Genetic variations at the LEPR locus were screened in a selection of 30 French overweight subjects by Single Strand Conformation Polymorphism (SSCP) analysis, then an association study between genotypes and obesity phenotypes was performed in 179 French overweight patients recruited from the Nutrition Department of Bichat Hospital in Paris who were prescribed a low calorie diet and in 387 unrelated volunteers (98 overweight, 289 normal weight) drawn from the Stanislas Family Study in Nancy.Results Two new genetic variants were found: T + 70 → C (exon 1) and Asp (A) 96 Asp (G) (exon 4). In Nancy, the T + 70 → C polymorphism was associated with fat mass adjusted for BMI in women (P = 0·025). The genotype and allele frequencies of the Ser (T) 343 Ser (C) polymorphism (exon 9) were significantly different between normal and overweight women, with the T allele being more frequent in the overweight group (T frequency in Nancy, 0·82; in Nancy + Paris, 0·79) than in the normal weight group (0·69; P = 0·017 vs. Nancy overweight, P = 0·003 vs. Nancy + Paris overweight). In women from Nancy, fat mass adjusted for BMI was significantly associated with this polymorphism (P = 0·01). The overweight women carrying the C allele of this polymorphism lost more weight in response to low calorie diet than the non carriers (P = 0·006).Conclusions In women, genetic variations at the LEPR gene level are associated with overweight and fat mass in a cross sectional study and with response to low calorie diet in an intervention study. These results indicate that variations at the leptin receptor locus are associated with common obesity phenotypes and are a part of the polygenic influences on the response to nutritional environment.