bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphism of the apolipoprotein A‐IV gene and its significance in lipid metabolism and coronary heart disease in a Japanese population
Authors: BAI H. , SAKU K. , LIU R. , ORIBE Y. , YAMAMOTO K. , ARAKAWA K.
Published: November 2003

Apolipoprotein A‐IV (apo A‐IV) is involved in the metabolism of both triglycerides and high‐density lipoproteins (HDLs). Apo A‐IV has been suggested as participating in several stages of reverse cholesterol transport. Uncertainty about the exact biochemical function of apo A‐IV has made the use of genetic apo A‐IV polymorphism (variants) attractive in evaluating its physiological role. To date, although some reports indicate that DNA polymorphisms at this locus play an important role in the metabolism of lipids and lipoproteins in western (Caucasian) populations, no similar comprehensive analysis has been performed in a distinct Japanese population. Using DNA sequencing and a restriction fragment length polymorphism (RFLP) study with polymerase chain reaction (PCR), the following allele frequencies were established: (a) codon −8 (G→A, non‐synonymous) allele 2=0 (n=105); (b) codon 9 (A→G, synonymous) allele 2=0.388 (n=152); (c) codon 347 (A→T, non‐synonymous) allele 2=0 (n=900); (d) codon 360 (T→G, non‐synonymous) allele 2=0 (n=800); (e) VNTR exon 3 [(CTGT)3 and (CTGT)4] (CTGT)3=0.262 (n=105); and (f ) MspI (newly detected polymorphic site) polymorphism (C C/T GG) within intron 2, allele 2=0.096 (n=193). The frequencies of these polymorphisms, except for that of the newly identified MspI site, are completely different from those reported in western populations. Among the 900 subjects examined, we found one ACT (Thr) to ACG (Thr) synonymous mutation at codon 347, which does not change the primary structure of apo A‐IV. The apo A‐IV allele frequency in patients (166 men and 56 women) with angiographically proven coronary heart disease (CHD) was also studied [codon 9 allele 2=0.329 (n=217); VNTR exon 3 (CTGT)3=0.262 (n=84); MspI within intron 2, allele 2=0.092 (n=222)]. Furthermore, we evaluated serum lipid and lipoprotein levels quantitatively in control subjects and Japanese CHD patients. These polymorphisms did not show any consistent and significant association with lipid and lipoprotein parameters. In addition, no gender‐specific effects of apo A‐IV polymorphisms on lipid parameters adjusted for confounding factors were observed in either CHD patients or control subjects. Our results indicate that the apo A‐IV gene is not a major determinant of the risk for CHD in Japanese.
Effects of insulin treatment on endoneurial and systemic oxidative stress in relation to nerve conduction in streptozotocin‐diabetic rats
Authors: VAN DAM P. S. , BRAVENBOER B. , VAN ASBECK B. S. , VAN OIRSCHOT J. F. L. M. , MARX J. J. M. , GISPEN W. H.
Published: November 2003

As increased oxidative stress is probably a pathogenetic factor in the development of diabetic complications, we studied nerve function and endogenous antioxidants in plasma, erythrocytes and sciatic nerve of untreated and insulin‐treated streptozotocin‐diabetic rats. After 18 weeks, the diabetes‐induced sciatic nerve conduction velocity deficits were approximately 65% improved by insulin (P<0.001). Plasma superoxide dismutase was significantly reduced in diabetes (P<0.01); smaller decreases in plasma catalase and glutathione levels were observed. These changes were corrected by insulin treatment. In erythrocytes, decreased superoxide dismutase (P<0.05) and increased total glutathione levels (P<0.05) were found. All effects of diabetes, including a rise in plasma malonyldialdehyde (P<0.05), were partially reversed by insulin treatment. In nervous tissue, diabetes caused increased catalase activity, uninfluenced by insulin (P<0.05). Nerve superoxide dismutase and glutathione did not change. The data suggest that, in diabetes, changes in systemic rather than endoneurial oxidative stress lead to nerve dysfunction.
Lipid profile in patients with microvascular angina
Authors: TSELEPIS A. D. , ELISAF M. , GOUDEVENOS J. , TSELEGARIDIS Th. , BAIRAKTARI E. , SIAMOPOULOS K. C. , SIDERIS D.
Published: November 2003

Lipid, lipoprotein and apolipoprotein levels, as well as the susceptibility of low‐density lipoprotein (LDL) to oxidation, were studied in patients with microvascular angina in comparison with patients with coronary artery disease (CAD) and normal subjects. Total cholesterol, LDL‐cholesterol and apolipoprotein B levels in microvascular angina patients (235±46 mg dL−1, 135±33 mg dL−1 and 146±32 mg dL−1 respectively) were significantly higher than in control subjects (204±40 mg dL−1, 116±35 mg dL−1 and 129±29 mg dL−1 respectively, P<0.01). These parameters were also significantly higher in CAD patients than in control subjects. By contrast, high‐density lipoprotein (HDL)‐cholesterol levels in microvascular angina patients were no different from those in control subjects, although both were significantly higher than in the CAD patients (48±16 mg dL−1 and 45±12 mg dL−1 compared with 40±10 mg dL−1, P<0.01 and P<0.05 respectively). Similar results were obtained for the apolipoprotein AI levels. Furthermore, the atherogenic risk ratio, LDL‐cholesterol/HDL‐cholesterol, in microvascular angina patients was significantly lower than in the CAD patients (3.4±1.2 vs. 4.1±1.5 respectively, P<0.01). Median (range) serum lipoprotein (a) [Lp(a)] levels in microvascular angina patients and CAD patients [13 mg dL− (0.8–92) and 16 mg dL− (0.8–96) respectively] were significantly higher than in control subjects [7 mg–dL− (0.8–44)], P<0.01 and P<0.005 respectively. Sigmoidal curves and electrophoretic mobility of the Cu2+‐oxidized LDL in both microvascular angina and CAD patients were not significantly different from those of control subjects. Finally, no significant differences were found between groups in total triglyceride levels or in very low‐density lipoprotein (VLDL), LDL and HDL triglyceride levels. Our results show that the microvascular angina patients exhibit lipid abnormalities similar to those observed in CAD patients, with the important exception of the HDL‐cholesterol and apolipoprotein AI levels, which are significantly higher in microvascular angina patients. We suggest that the abnormal cholesterol and Lp(a) levels may be involved in the pathophysiology of microvascular angina by affecting endothelial function and endothelium‐mediated vasodilator responses, whereas the higher HDL levels may be a factor contributing to the absence of angiographically documented CAD in microvascular angina patients.
Imaging of Ca2+‐induced cytoplasmic Ca2+ responses in normal and pathological parathyroid cells
Authors: RIDEFELT P. , RASTAD J. , ÅKERSTRO¨M G. , HELLMAN P. , GYLFE E.
Published: November 2003

Ca2+‐induced changes in the cytoplasmic Ca2+ concentration ([Ca2+]i) were studied in bovine and normal and pathological human parathyroid cells using digital image analysis of fura‐2‐loaded cells. When raising external Ca2+ from 0.5 to 3.0 mmol L−1, about 95% of all cells reacted rapidly and simultaneously with sustained elevation of [Ca2+]i. In approximately two out of three bovine parathyroid cells, normal human cells and cells from most patients with hyperparathyroidism (HPT) the sustained phase was preceded by an overshooting [Ca2+]i transient. The proportion of cells with such a transient was decreased in cells from severe cases of uraemic parathyroid hyperplasia only. However, pathological human cells from adenomas and normal‐sized glands associated with adenomas, as well as cells from primary and uraemic hyperplasias, had lower peak and sustained levels than normal human and bovine cells. The results indicate that both normal and pathological parathyroid cells exhibit heterogeneity in their [Ca2+]i responses to elevation of external Ca2+. The Ca2+‐induced [Ca2+]i transients and the sustained elevations are attenuated in pathological human parathyroid cells. However, the presence of the overshooting transient represents physiological variability rather than being a consequence of the pathophysiology associated with HPT.
The influence of growth hormone substitution therapy on erythroid and myeloid progenitor cells and on peripheral blood cells in adult patients with growth hormone deficiency
Authors: KOTZMANN H. , RIEDL M. , CLODI M. , BARNAS U. , KAIDER A. , HO¨CKER P. , LUGER A.
Published: November 2003

It has been reported that hypophysectomized rats exhibit normochromic, normocytic anaemia. Pancytopenia with impaired DNA synthesis in the bone marrow can be restored in these hypophysectomized rats by syngeneic pituitary grafts placed under the kidney capsule or treatment with growth hormone (GH). Until now, adults with hypopituitarism have received adequate replacement therapy with thyroxine, cortisol and sex steroids, but not with GH. We therefore investigated the effects of GH replacement therapy on the proliferation and differentiation of erythroid and myeloid progenitor and peripheral blood cells in 11 adult patients with growth hormone deficiency in a double‐blind, placebo‐controlled study for the first 6 months of therapy. The placebo group showed no changes during the first 6 months without therapy in either insulin‐like growth factor I (IGF‐I) levels, erythroid and myeloid progenitor precursor cells or peripheral blood cells. After commencement of GH therapy, IGF‐I levels rose significantly during 24 months of therapy from 75.3±13.5 to 225±34.7ngmL−1 (P<0.001). Erythroid and myeloid progenitor precursor cells showed a steep and significant increase after 18 and 24 months of therapy (erythroid: from 10.7±3.5 to 261.4±79.8, P<0.02, after 18 months and to 276.8±149.8 × 105 mononuclear cell colonies, P<0.03, after 24 months; granulocyte–macrophage colony‐forming units: from 39.7±9.8 to 316.9±124.6, P<0.002, after 18 months and to 366±188.7×105 mononuclear cell colonies, P<0.03, after 24 months), whereas the peripheral red and white blood cells exhibited only minimal non‐significant changes. The principal regulators of erythropoiesis, such as erythropoietin, and parameters reflecting erythropoiesis in the peripheral blood, such as reticulocytes, remained almost unchanged throughout the whole study period. We therefore conclude that patients with GH deficiency do not have anaemia, but have haematopoietic precursor cells in the lower normal range, and that GH substitution therapy over a period of 24 months has a marked effect on erythroid and myeloid progenitor precursor cells but only negligible effects on peripheral blood cells in GH‐deficient adults.
Maternal plasma levels of vascular endothelial growth factor in normotensive pregnancies and in pregnancies complicated by pre‐eclampsia
Authors: SHARKEY A. M. , COOPER J. C. , BALMFORTH J. R. , MCLAREN J. , CLARK D. E. , CHARNOCK‐JONES D. S. , MORRIS N. H. , SMITH S. K.
Published: November 2003

We have measured the level of vascular endothelial growth factor (VEGF) in maternal plasma during normotensive pregnancy and in pregnancies complicated by pre‐eclampsia. VEGF was measured using a competitive enzyme immunoassay. Plasma VEGF was significantly elevated (P<0.0001) in the pre‐eclamptic group (median value 32.7 ng mL−1, range 10.3–64.0), compared with the normotensive group (median value 11.7 ng mL−1, range 6.3–24.3). VEGF is a potent regulator of endothelial cell function. The increased level found in women with pre‐eclampsia indicates that VEGF may be involved in the maternal endothelial cell dysfunction associated with this condition. An increase in VEGF, a potent regulator of microvascular permeability, may also contribute to the extravasation of plasma proteins and the subsequent development of proteinuria, both characteristic features of pre‐eclampsia.
Apolipoprotein E2 (Arg‐136→Cys), a variant of apolipoprotein E associated with late‐onset dominance of type III hyperlipoproteinaemia
Authors: FEUSSNER G. , ALBANESE M. , MANN W. A. , VALENCIA A. , SCHUSTER H.
Published: November 2003

Type III hyperlipoproteinaemia (HLP) is usually associated with homozygosity for apolipoprotein (apo) E2 (Arg‐158→Cys). We identified a 46‐year‐old white female with severe hyperlipidaemia and the heterozygous apo E3/2* phenotype. Typical clinical characteristics of type III HLP, i.e. palmar xanthomas (orange–yellowish discolorations of the palmar creases) and tuberoeruptive xanthomas, were present in the patient. Without therapy the patient's serum triglycerides (1.098 mg dL−1), cholesterol (546 mg dL–1), very low‐density lipoprotein (VLDL) cholesterol (372 mg dL−1) and the apo E concentration (25.0 mg dL−1) were distinctly elevated as well as her VLDL cholesterol to serum triglyceride (TG) ratio at 0.34 (normal ratio about 0.2). Direct sequencing of polymerase chain reaction (PCR)‐amplified segments of the apo ε gene identified a thymine for cytosine (C→T) exchange in the first base of codon 136 that is predictive for a Cys (TGC) for Arg (CGC) substitution in the encoded amino acid sequence. Two children, an 18‐year‐old female with the heterozygous apo E4/2* phenotype, a 25‐year‐old female with the heterozygous apo E3/2* phenotype and the 73‐year‐old father of the proband with the heterozygous apo E3/2* phenotype are also carriers of the rare mutant. The father has severe atherosclerosis and lipid values compatible with the diagnosis of type III HLP. The affected children have hyper/dyslipidaemia but as yet no clinical expression of the disease. We propose that in the analysed family this rare apo E2 (Arg‐136→Cys) variant is associated with late‐onset dominance of type III HLP.
Altered release of endothelin‐1,2 and thromboxane B2 from trophoblastic cells in pre‐eclampsia
Authors: CERVAR M. , KAINER F. , JONES C. J. P. , DESOYE G.
Published: November 2003

The aim of the study was to investigate whether pre‐eclampsia is associated with an altered release of vasoactive substances from trophoblastic cells in vitro. Trophoblastic cells from 15 uncomplicated control pregnancies and 18 pre‐eclamptic pregnancies at preterm (weeks 31–36; n = 12) and term (weeks 37–40; n = 21) were cultured for 5 days. The concentrations of angiotensin II (AII), endothelin‐1,2 (ET‐1,2), thromboxane B2 (TXB2), 6‐keto‐prostaglandin F1α (6‐keto‐PGF1α) and leukotriene B4 (LTB4) were measured daily in culture media for 5 days by radioimmunoassay. In pre‐eclampsia, concentrations of ET‐1,2 were decreased (P < 0.01) at both preterm and term, TXB2 concentrations were increased P < 0.05) only at preterm and the TXB2–6‐keto‐PGF1α ratio was increased at both preterm and term (P < 0.01) as compared with the controls. Concentrations of AII, 6‐keto‐PGF1α and LTB4 were similar to the controls. The data suggest that pre‐eclampsia is associated with a decreased release of ET‐1 and an increased release of TXB2 from trophoblastic cells in vitro
Partial conservation of the sn‐2 position of dietary triglycerides in fasting plasma lipids in humans
Authors: ZOCK P. L. , GERRITSEN J. , KATAN M. B.
Published: November 2003

The authors investigated the effect of the position of fatty acids within dietary triglycerides on the composition of plasma lipids. Sixty volunteers consumed two diets of equal fatty acid compositions for 3 weeks each. In the palm oil diet 82% of palmitic acid was attached to the sn‐1 and sn‐3, and 18% to the sn‐2 position of glycerol. In the diet rich in a palm oil analogue, Betapol, these figures were 35% and 65% respectively. Oleic and linoleic acid in palm oil were mainly in the sn‐2 position, and in Betapol mainly in the sn‐1 and sn‐3 position. The proportion of palmitic acid in the 2 position of fasting plasma triglycerides was 10.2 g 100 g−1 on palm oil and 12.3 on Betapol; that of oleic acid was 46.9 vs. 43.6 (P < 0.0001). Overall oleic acid content of triglycerides was 1.4 g 100 g−1 lower on Betapol than on palm oil (P = 0.002). Betapol increased palmitic and palmitoleic acid in cholesteryl esters by 1 g 100 g−1 (P < 0.0001) at the expense of oleic and linoleic acid. The positional configuration of dietary fatty acids has small but consistent effects on lipid metabolism that persist beyond fat absorption and chylomicron clearance.
Active surfactant in pharyngeal aspirates of term neonates: lipid biochemistry and surface tension function
Authors: POETS C. F. , ARNING A. , BERNHARD W. , ACEVEDO C. , VON DER HARDT H.
Published: November 2003

Alveolar surfactant is well known for its ability to reduce minimal surface tension at the alveolar air–liquid interface to values below 5 mN m−1. In addition, it has been suggested that surfactant is also present in the airways, particularly in the perinatal period. We isolated surfactant from pharyngeal aspirates obtained from 33 neonates immediately after delivery and analysed it for both phospholipid (PL) composition and surface tension function. PL classes and phosphatidylcholine (PC) molecular species were determined by normal and reversed‐phase high‐performance liquid chromatography (HPLC), respectively. Static and dynamic surface properties of the surfactant were studied in a pulsating bubble surfactometer. Sample volume was 1.3 ± 0.5 mL (mean ± SD) with a total amount of 2.5 ± 1.3 μmol of PL and a concentration of 2.1 ± 1.0 μmol mL−1 PL. HPLC analyses of PL classes revealed a composition identical with surfactant prepared from alveolar washes, i.e. PC 83.6 ± 2.1%, sphingomyelin 1.4 ± 0.5%, phosphatidylglycerol 8.1 ± 1.6%, phosphatidylethanolamine 2.1 ± 0.5% and phosphatidylinositol 2.6 ± 1.1%. Thin‐layer chromatography showed almost identical results but was more time‐consuming and needed more material for analysis. Analysis of PC molecular species revealed a composition typical of human alveolar surfactant with 54.7 ± 3.9% dipalmitoyl PC, 10.3 ± 1.9% palmitoyloleoyl PC and 9.1 ± 1.5% palmitoylmyristoyl PC. Minimal surface tension fell to values below 5 mN m−1 within 5 min of cycling in all subjects. The methods used in this study allowed for complete PL and surface tension analyses of surfactant obtained during routine pharyngeal suctioning after delivery at term. Whether they are also applicable to preterm neonates with respiratory distress remains to be determined.
Chronic fatigue syndrome—aetiological aspects
Authors: DICKINSON C. J.
Published: November 2003

The chronic fatigue syndrome (CFS) has been intensively studied over the last 40 years, but no conclusions have yet been agreed as to its cause. Most cases nowadays are sporadic. In the established chronic condition there are no consistently abnormal physical signs or abnormalities on laboratory investigation. Many physicians remain convinced that the symptoms are psychological rather than physical in origin. This view is reinforced by the emotional way in which many patients present themselves. The overlap of symptoms between CFS and depression remains a source of confusion and difficulty. But even if all CFS patients were rediagnosed as depressives, this would not negate the possibility of an underlying organic cause for the condition, in view of the growing evidence that depression itself has a physical cause and responds best to physical treatments. There is some evidence both for active viral infection and for an immunological disorder in the CFS. Many observations suggest that the syndrome could derive from residual damage to the reticular activating system (RAS) of the upper brain stem and/or to its cortical projections. Such damage could be produced by a previous viral infection, leaving functional defects unaccompanied by any gross histological changes. In animal experiments activation of the RAS can change sleep state and activate or stimulate cortical functions. RAS lesions can produce somnolence and apathy. Studies by modern imaging techniques have not been entirely consistent, but many magnetic resonance imaging (MRI) studies already suggest that small discrete patchy brain stem and subcortical lesions can often be seen in CFS. Regional blood flow studies by single photon‐emission computerized tomography (SPECT) have been more consistent. They have revealed blood flow reductions in many regions, especially in the hind brain. Similar lesions have been reported after poliomyelitis and in multiple sclerosis—in both of which conditions chronic fatigue is characteristically present. In the well‐known post‐polio fatigue syndrome, lesions predominate in the RAS of the brain stem. If similar underlying lesions in the RAS can eventually be identified in CFS, the therapeutic target for CFS would be better defined than it is at present. A number of logical approaches to treatment can already be envisaged.
Search for mutations in the genes for coagulation factors V and VIII with a possible predisposition to activated protein C resistance
Authors: BOKAREWA M. I. , FALK G. , BREMME K. , BLOMBÄCK M. , WIMAN B.
Published: November 2003

A total of 74 non‐pregnant women with a previous episode of thrombosis were investigated for activated protein C (APC) resistance in the aPTT‐based and factor IXa‐X‐based assays and for the presence of mutations in all APC‐cleavage sites in the heavy chains of factor V and factor VIII. DNA fragments were amplified with the polymerase chain reaction (PCR) and those encoding for the Arg‐306 and Arg‐506 (factor V) and for Arg‐740 (factor VIII) cleavage sites were subjected to restriction enzyme analysis. DNA fragments of 29 selected patients corresponding to the Arg‐306 and Arg‐679 cleavage sites in factor V, and to the Arg‐336 and Arg‐562 cleavage sites in factor VIII were sequenced. APC resistance was found in 40 cases, using the aPTT‐based assay and in 35, using the factor IXa‐X‐based assay (23 patients were APC resistant in both assays), whereas 22 individuals had a normal response to APC. Forty‐three patients carried Arg‐506 to Gln mutation in factor V. No other polymorphism or mutation was found in the genes for factors V or VIII in the vicinity of the APC cleavage sites. It was concluded that the difference in response to APC in the two assays may not be explained by the presence of mutations in the APC cleavage sites of factor V and factor VIII in this group of patients. The data do not exclude the presence of mutations elsewhere in the factor V or factor VIII genes.
Small bowel bacterial overgrowth in patients after total gastrectomy
Authors: BRÄGELMANN R. , ARMBRECHT U. , ROSEMEYER D. , SCHNEIDER B. , ZILLY W. , STOCKBRÜGGER R. W.
Published: November 2003

The aim of this study was to elucidate the consequences of small bowel bacterial overgrowth (SBBO) after total gastrectomy. A total of 127 patients, evaluated for SBBO with a radiographically controlled H2‐breath test (subgroup I, without SBBO, n = 80; subgroup II, with SBBO, n = 47) after potentially curative total gastrectomy for gastric malignancy, were uniformly evaluated. Mean time since operation was significantly shorter in subgroup II than in subgroup I [370 days, confidence interval (CI) 96–645 days, vs. 687 days, CI 397–976 days; P < 0.01]. Controlling for this difference, there were no other significant differences in symptoms and signs between the subgroups except for the medicosocial functioning measured with the Edinburgh Rehabilitation Status Scale (ERSS). The mean ERSS showed significantly better medicosocial functioning in subgroup I than in subgroup II [3.7 (CI 2.2–5.2) vs. 5.1 (CI 3.0–7.0); P < 0.05]. After total gastrectomy, patients without SBBO did not differ significantly from patients with SBBO in most parameters. Medicosocial functioning was significantly poorer in the latter.
Lipoprotein(a), tissue plasminogen activator and plasminogen activator inhibitor 1 levels in hyperlipidaemic patients in Kuwait
Authors: AKANJI A. O. , ABDULLAH A. , TAHZEEB S.
Published: November 2003

Plasma levels of lipoprotein(a) [Lp(a)], tissue plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI‐1) were assessed in addition to anthropometry and levels of glucose, total cholesterol, triglycerides, high‐density lipoprotein (HDL), low‐density lipoprotein (LDL) and apo A1 and B in 73 patients (36 men and 37 women) with primary hyperlipidaemia (group NDHL) in Kuwait. Lp(a) levels (212 mg L−1, 8–600 mg L−1, median and range) were similar to those obtained in a matched group of 32 non‐insulin‐dependent diabetes mellitus (NIDDM) patients with hyperlipidaemia (218 mg L−1, 50–610 mg L−1) and slightly higher, although not significantly so (P = 0.06), than levels seen in 68 healthy normolipidaemic control subjects (182 mg L−1, 70–488 mg L−1). tPA levels (8.4 ng mL−1, 3.8–18.4 ng mL−1, median and range) in group NDHL were lower than in the diabetic group (11.4 ng mL−1, 5.2–14.2 ng mL−1) but higher than in the healthy control subjects (7.4 ng mL−1, 2.8–12.6 ng mL−1). PAI‐1 levels in group NDHL (40.4 ng mL−1, 8.6–55 ng mL−1, median and range) were higher than in the control subjects (32.5 ng mL−1, 14.6–46.4 ng mL−1) but lower than in diabetic patients (43.8 ng mL−1, 15.6–55 ng mL−1). Hyperlipidaemia phenotype (hypercholesterolaemia or hypertriglyceridaemia) did not influence tPA and PAI‐1 levels, but Lp(a) levels were significantly lower with hypertriglyceridaemia. Gender, cigarette smoking and racial origin (Kuwaitis, other Arabs or South Asians) did not affect Lp(a), tPA and PAI‐1 levels, but tPA levels were higher in postmenopausal subjects. Low‐density lipoprotein (LDL) levels (whether in total cholesterol or as apo B) correlated significantly (P < 0.05) with Lp(a) levels. tPA levels were correlated with age and the plasma levels of glucose and uric acid (P < 0.05); this correlation with glucose may explain the high levels associated with diabetes, whereas the age association might account not only for the differences observed between group NDHL and the younger control group but also for the higher levels in the postmenopausal women. PAI‐1 levels correlated with tPA and triglyceride (TG) levels in the groups of subjects (normo‐ and hyperlipidaemic). In the normolipidaemic control group, the significant associations of tPA and PAI‐1 were with body mass, expressed as the body mass index or the waist–hip ratio. These results suggest that different factors influence the plasma levels of the prothrombotic factors Lp(a), tPA and PAI‐1 in healthy control subjects and in patients with hyperlipidaemia. In the latter, hyperlipidaemia phenotype, age, glycaemic status and uric acid levels are important determinants of the levels of these prothrombotic variables, whereas in the healthy, young control population, body mass was the single important association with tPA and PAI–1.
Comparison of the effect of two low‐density lipoprotein receptor class mutations on coronary heart disease among French‐Canadian patients heterozygous for familial hypercholesterolaemia
Authors: VOHL M.‐C. , GAUDET D. , MOORJANI S. , TREMBLAY G. , PERRON P. , GAGNÉ C. , LESIÈGE D. , BERGERON J. , LUPIEN P. J. , DESPRÉS J‐P.
Published: November 2003

The aim of this study was to compare the age at first elective coronary angiogram and the age at first revascularization (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) in 102 patients without familial hypercholesterolaemia (FH), who were matched for age and sex with 76 heterozygous FH patients carrying a defective allele at the low‐density lipoprotein (LDL) receptor gene (LDL‐R) and 26 heterozygous FH patients bearing a null mutation at the LDL‐R. The prevalence of diabetes was significantly higher in the non‐FH group than in the two FH groups (P < 0.05). Furthermore, mean body mass index (BMI) and waist circumference values were also higher in the non‐FH group than in the two FH heterozygous groups (P < 0.005). However, FH patients who were null allele carriers had the highest plasma total and LDL‐cholesterol levels and the highest cholesterol/HDL‐cholesterol ratio, whereas the defective allele carriers group had intermediate levels between null allele carriers and non‐FH patients. Comparison of the age at first coronary angiography revealed that the null allele carriers group were younger at first angiogram than the non‐FH patients (P < 0.005). In addition, a trend was observed for a younger age at first angiogram in FH heterozygotes bearing a null allele than in carriers of a defective allele (P = 0.06). Moreover, null allele carriers were younger at first revascularization than defective allele carriers (P < 0.005) or non‐FH patients (P < 0.005). Finally, the mean number of diseased vessels with > 50% stenosis was higher in null allele carriers than in non‐FH patients and tended to be higher than among defective allele carriers (P < 0.01). Although no difference in plasma Lp(a) levels were noted between null allele carrier and non‐FH patients, plasma Lp(a) concentrations were higher in the defective allele group than in the other two groups. In summary, the development of coronary artery disease as estimated by the age at first elective coronary angiography or at first revascularization is premature in FH patients carrying a null mutation compared with defective allele carriers or with non‐FH patients. Moreover, the higher number of stenosed vessels among null allele carriers suggests that coronary artery disease was more severe in FH subjects with a null allele at the LDL‐R locus.
Neutrophil superoxide release and interleukin 8 in acute myocardial infarction: distinction between complicated and uncomplicated states
Authors: RIESENBERG K. , LEVY R. , KATZ A. , GALKOP S. , SCHLAEFFER F.
Published: November 2003

Superoxide release in neutrophils and sera levels of interleukin 8 (IL‐8) were determined in 15 patients with complicated acute myocardial infarction (MI) and 15 patients with uncomplicated MI. All patients showed increased superoxide release in unstimulated and stimulated neutrophils compared with healthy control subjects, indicating priming of these cells. Superoxide release of unstimulated or stimulated neutrophils was found to be significantly higher in patients with complicated MI than in patients with uncomplicated MI. Thrombolytic therapy did not affect the rates of superoxide release. The neutrophil chemoattractant/activator IL‐8 was detected in the sera of all patients, with significantly higher levels in those with complicated MI. The highest levels of IL‐8 were detected at admission to the Coronary Care Unit and significantly decreased thereafter, suggesting its contribution to neutrophil‐mediated tissue injury. The high levels of IL‐8 may be one of the major contributors to the priming of neutrophils in these patients.
Long‐term use of smokeless tobacco and physical performance in middle‐aged men
Authors: BOLINDER G. , NORÉN A. , WAHREN J. , DE FAIRE U.
Published: November 2003

To determine the influence of prolonged nicotine exposure on maximal physical working capacity, a study of clinical measures of physical fitness and cardiovascular response to exercise was performed in 144 healthy men, 35–60 years old, subdivided into smokeless tobacco users, smokers and non‐users of tobacco. Regular users of smokeless tobacco, with exposures of more than 20 years, showed similar maximal oxygen uptake (mean 3.48 L min−1, SD 0.49, n = 48) to non‐users (mean 3.51 L min−1, SD 0.51, n = 65). In smokeless tobacco users, higher blood pressure and heart rate values were observed at rest and at submaximal work, after exposure to tobacco shortly before the exercise test, but not at maximal work. However, significantly lower maximal oxygen uptake was found for smokers (mean 2.88 L min−1, SD 0.49, n = 31) compared with non‐users (P < 0.001). Plasma concentration of cotinine, the main metabolite of nicotine, was significantly higher in smokeless tobacco users (mean 347 ng mL−1, SD 175, n = 48) than in smokers (mean 253 ng mL−1, SD 153, n = 31, P < 0.001). The findings indicate that long‐term use of smokeless tobacco does not significantly influence exercise capacity in healthy, physically well‐trained subjects.
The 13C‐mixed triglyceride breath test in healthy adults: determinants of the 13CO2 response
Authors: KALIVIANAKIS M. , VERKADE H. J. , STELLAARD F. , VAN DER WERF M. , ELZINGA H. , VONK R. J.
Published: November 2003

Defects in lipolysis due to pancreatic insufficiency can be diagnosed by the mixed triglyceride (MTG) 13CO2 breath test. However, the effects of various test conditions on the 13CO2 response have only been partially elucidated. In healthy adults, we performed the 13CO2 mixed triglyceride breath test and we compared (a) the inter‐ and intra‐individual variation in the 13CO2 response; (b) the effect of two different test meals; (c) the effect of an additional meal during the test; and (d) the effect of physical exercise during the test. Upon repeating the test in the same individual (test meal cream), repeatability coefficients were large, with respect to either time to maximum 13C excretion rate (3.8 h), maximum 13C excretion rate (4.9% 13C dose h−1) or cumulative recovery of 13C over the 9‐h study period (22.7% 13C dose). The cumulative 13C expiration over 9 h obtained with the test meal composed of cream was quantitatively similar to that obtained with bread and butter: 42.2 ± 8.4% and 47.7 ± 6.3% respectively. Fasting for 9 h during the test resulted in similar 13C expiration rates and cumulative 13C expiration (43.4% ± 7.2%) when compared with consumption of an additional meal 3 h after the start of the test (38.3 ± 5.3%). The 13CO2 response increased in five out of seven subjects, but decreased in the other two, when moderate exercise was performed (bicycle ergometer, 50 W for 5 h). We conclude that the repeatability of the MTG test in healthy adults is low. The present results indicate that a solid and a liquid test meal, containing a similar amount of fats, give similar cumulative 13CO2 responses, and that stringent prolonged fasting during the test is unnecessary. Standardization of physical activity seems preferable, since the unequivocal effects of moderate exercise on the 13CO2 response were observed in the individuals studied.
Expression of follicle‐stimulating hormone receptor in human ovary
Authors: MINEGISHI T. , TANO M. , IGARASHI M. , ROKUKAWA S. , ABE Y. , IBUKI Y. , MIYAMOTO K.
Published: November 2003

The gonadotropins, follicle‐stimulating hormone (FSH) and luteinizing hormone (LH), are key hormones in the regulation of ovarian function. The acquisition of FSH receptors during folliculogenesis is believed to be a key event in the subsequent development of the follicle. However, the binding and biochemical properties of the human FSH receptor are not well‐characterized owing to the low abundance of these receptors and the limited availability of human tissue. The binding experiments show that, while the affinity of the FSH receptor does not change through the menstrual cycle, the total number of FSH receptors in the leading follicles increases by about two‐fold at mid‐follicular phase compared with those at other periods. Northern blot analysis was used to measure relative levels of FSH receptor mRNA, and in situ hybridization was used to localize FSH receptor transcripts. Northern blot analysis of human ovaries detected two transcripts (4.1 and 2.4 kb) for the FSH receptor. The FSH receptor mRNA was abundant in the preovulatory follicle, with expression decreased by about 50% in the corpus luteum. Using in situ hybridization, FSH receptor mRNA was found to be confined to the granulosa cells of developing follicles. A reverse transcription–polymerase chain reaction amplification was used to detect the expression of different isoforms of the FSH receptor mRNA in human corpus luteum and placenta.
Bile acid inhibition of interferon activity in human lymphocytes: no evidence of oxidative stress
Authors: PODEVIN P. , BLANC M.‐C. , VAUBOURDOLLE M. , VEYRUNES C. , BONNEFIS M.‐T. , POUPON R.
Published: November 2003

Cholestasis and bile acids are two factors involved in resistance to interferon therapy in patients with chronic hepatitis C. As bile acids inhibit the biological activity of this cytokine in vitro and are capable of generating oxidative stress in hepatocytes, we investigated the potential involvement of such a mechanism in human lymphocytes. Thus, we evaluated (a) the effects of bile acids (0–200 μmol L−1) on lymphocyte reduced glutathione content and malondialdehyde production and (b) the ability of antioxidants to prevent the inhibitory effect of chenodeoxycholic acid on interferon‐induced lymphocyte 2′,5′‐oligoadenylate synthetase activity, an index of the biological activity of interferon. We found that treatment of lymphocytes with bile acids for 24 h did not induce malondialdehyde release or significantly modify cellular reduced glutathione content. Synthetic precursors of glutathione (N‐acetylcysteine and S‐adenosylmethionine) and antioxidants (superoxide dismutase and catalase) had no preventive influence on the inhibitory effect of chenodeoxycholic acid on interferon‐induced 2′,5′‐oligoadenylate synthetase activity. These negative results do not provide evidence for the use of glutathione precursors in cholestatic conditions associated with viral diseases.
Antioxidant status in patients with uncomplicated insulin‐dependent and non‐insulin‐dependent diabetes mellitus
Authors: MAXWELL S. R. J. , THOMASON H. , SANDLER D. , LEGUEN C. , BAXTER M. A. , THORPE G. H. G. , JONES A. F. , BARNETT A. H.
Published: November 2003

Oxidative damage by free radicals has been implicated in the pathogenesis of vascular disease in diabetes. We compared the radical‐scavenging antioxidant activity of serum from 28 patients with insulin‐dependent diabetes mellitus and 24 patients with non‐insulin‐dependent diabetes mellitus uncomplicated by vascular disease with age‐matched non‐diabetic control subjects. Patients with insulin‐dependent diabetes had significantly reduced total antioxidant activity (320.2 ± 11.3 vs. 427.5 ± 19.2 μmol L−1; P < 0.001). This was attributable to lower urate (209.4 ± 10.4 vs. 297.1 ± 16.7 μmol L−1; P < 0.001) and vitamin C levels (63.6 ± 6.0 vs. 87.5 ± 4.9 μmol L−1; P < 0.01). Patients with non‐insulin‐dependent diabetes had lower total antioxidant activity than age‐matched control subjects (433.8 ± 25.4 vs. 473.9 ± 30.2 μmol L−1; NS), reflecting lower urate (299.5 ± 19.4 vs. 324.8 ± 21.4 μmol L−1; NS) and vitamin C levels (38.6 ± 5.7 vs. 58.5 ± 5.3 μmol L−1; P < 0.05). Multiple regression analysis showed that urate, vitamin C and vitamin E were the major contributors to serum total antioxidant activity. These results show that diabetic patients have significant defects of antioxidant protection, which may increase vulnerability to oxidative damage and the development of diabetic complications.
Plasma endothelin‐1 levels during transient acute myocardial ischaemia in men: effects of coronary revascularization
Authors: FERRI C. , DE MARZIO P. , DESIDERI G. , BALDONCINI R. , BELLINI C. , MORELLI S. , SANTUCCI A.
Published: November 2003

The endothelium‐derived peptide endothelin‐1 (ET‐1) was evaluated in 14 male patients [mean age 52.74 years (SEM 1.10)] affected by coronary artery disease during a bicycle electrocardiographic stress test and dipyridamole echocardiogram. Both tests were performed before and after coronary revascularization. Fourteen healthy male subjects served as controls [mean age 53.21 years (SEM 1.63)]. Baseline plasma endothelin‐1 levels were higher (P < 0.0001) in ischaemic patients [1.81 pg mL−1 (0.15, n = 14)] than in control subjects [0.61 pg mL−1 (0.03, n = 14)], but did not increase with exercise in both groups. Similar results were obtained with dipyridamole infusion. Endothelin‐1 levels significantly decreased after coronary revascularization [before: mean 1.81 pg mL−1 (SEM 0.15, n = 14); after: mean 1.16 pg mL−1 (SEM 0.11), P < 0.002], without changes in the peptide response to both tests. In conclusion, elevated plasma endothelin‐1 concentrations were found in patients with stable angina compared with non‐ischaemic subjects. No changes were observed during exercise or dipyridamole infusion in both groups. Coronary revascularization was followed by a significant decrease in plasma endothelin‐1 levels.
Structural and compositional modifications of diabetic low‐density lipoproteins influence their receptor‐mediated uptake by hepatocytes
Authors: KRÄMER‐GUTH A. , QUASCHNING T. , GALLE J. , BAUMSTARK M. W. , KÖNIGER M. , NAUCK M. , SCHOLLMEYER P. , MÄRZ W. , WANNER C.
Published: November 2003

Dyslipoproteinaemia is an important risk factor for the development of atherosclerosis in non‐insulin‐dependent diabetes mellitus (NIDDM). This study shows that the uptake of low‐density lipoproteins (LDLs) prepared from the plasma of patients with NIDDM in cultured human hepatoma cells is largely reduced. In addition, diabetic LDL was less effective in suppressing intracellular cholesterol synthesis. This is because of physicochemical and biochemical differences between lipoproteins from diabetic and from normal individuals. LDL from patients with NIDDM was abnormal with regard to charge, the degree of glycation, the lipid composition and the conformation of the apolipoprotein B receptor‐binding domain. The diminished receptor‐mediated uptake of apolipoprotein B‐containing lipoproteins in diabetic individuals most probably leads to the accumulation of these lipoproteins in vivo and may be of great importance to the pathogenesis of atheroclerosis in these patients.
No effect of calcitriol on insulin‐mediated glucose uptake in healthy subjects
Authors: FLISER D. , STEFANSKI A. , FRANEK E. , FODE P. , GUDARZI A. , RITZ E.
Published: November 2003

Administration of active vitamin D (calcitriol) improves insulin sensitivity in uraemic patients. These patients have subnormal plasma calcitriol concentrations in parallel with increased intact parathyroid hormone (PTH) concentrations. It is therefore unclear whether the improvement in insulin sensitivity results from a direct effect of calcitriol or from amelioration of secondary hyperparathyroidism. So far, no evidence has been presented that insulin sensitivity is specifically affected by calcitriol in healthy subjects. We investigated the effect of (supra)therapeutic doses of calcitriol on insulin sensitivity in healthy volunteers. In a double‐blind parallel group design, 18 healthy male subjects received in random order either placebo or 1.5 μg of calcitriol per day by mouth for 7 days. Insulin‐mediated glucose uptake, i.e. insulin sensitivity, was assessed using the euglycaemic clamp technique. Mean glucose disposal rate, i.e. M‐value, was not significantly affected by placebo or calcitriol treatment (placebo: 7.1 ± 1.3 mg kg−1 min−1 before and 7.2 ± 1.5 mg kg−1 min−1 after treatment; calcitriol 7.0 ± 1.4 mg kg−1 min−1 and 7.2 ± 1.4 mg kg−1 min−1). There were no significant changes in mean plasma glucose, insulin, phosphate, bicarbonate and ionized calcium concentrations after administration of placebo or calcitriol. Furthermore, platelet intracellular calcium concentration (assessed by fluorescence spectroscopy) and mean arterial blood pressure (24 h ambulatory measurement) did not change with placebo and calcitriol treatment. On the other hand, mean intact PTH concentration decreased significantly (P < 0.01) with calcitriol treatment, but not with placebo. In addition, mean 24 h urinary calcium excretion increased significantly (P < 0.05) with calcitriol administration but was unchanged with placebo. Administration of (supra)physiological doses of calcitriol has no effect on insulin sensitivity in healthy subjects, despite a significant decrease in PTH concentrations. These observations are compatible with the notion that the effect of calcitriol on insulin sensitivity is present only in uraemic calcitriol‐depleted patients.
Circulating anti‐(xanthine oxidoreductase) antibodies in healthy human adults
Authors: BENBOUBETRA M. , GLEESON A. , HARRIS C. P. D. , KHAN J. , ARRAR L. , BRENNAND D. , REID J. , RECKLESS J. D. , HARRISON R.
Published: November 2003

Levels of free anti‐(xanthine oxidoreductase) (XOR) antibodies in the serum of normal healthy human subjects were determined, using both human and bovine enzyme as antigen, in an enzyme‐linked immunosorbent assay (ELISA). Levels of IgM class anti‐(human XOR) antibodies were found to be particularly high (mean values representing approximately 3% of total IgM) and to be significantly higher than levels of IgM anti‐(bovine XOR) antibodies, indicating that endogenous XOR, rather than ingested bovine milk XOR, is the immunogen. IgM anti‐XOR antibody levels were significantly higher in women under 50 years than in age‐matched men, or in older women. Levels of IgG class anti‐XOR antibodies were much lower and showed no correlation with gender or age. Affinity‐purified anti‐(human XOR) antibodies only partially inhibited enzymic activities of XOR. The majority of both IgM and IgG anti‐(human XOR) antibodies in serum occurred as immune complexes, suggesting that the specific antibodies have a protective role in removing potentially damaging XOR from the circulation.
Vasoactive substances in early dumping syndrome: effects of dumping provocation with and without octreotide
Authors: VECHT J. , GIELKENS H. A. J. , FRÖLICH M. , LAMERS C. B. H. W. , Masclee A. A. M.
Published: November 2003

In patients after gastric surgery, early dumping symptoms can be provoked by oral glucose challenge. Octreotide effectively prevents the occurrence of dumping symptoms. We have studied plasma renin activity (PRA), aldosterone and atrial natriuretic peptide (ANP) concentrations in nine patients with early dumping, 10 surgical control subjects and nine healthy control subjects after an oral glucose challenge preceded by either placebo or 25 μg of octreotide subcutaneously (s.c.). In the dumping group, basal PRA was signifi‐cantly (P < 0.01) higher (3.9 ± 0.6 μg L−1 h−1) than in either surgical or healthy control subjects (1.1 ± 0.3 μg L−1 h−1 and 1.1 ± 0.2 μg L−1 h−1 respectively) and showed a significant rise after glucose ingestion to 5.4 ± 0.9 μg L−1 h−1 that did not occur in control subjects. Aldosterone concentration showed a concomitant rise. In dumping patients, plasma ANP decreased after glucose ingestion from 31 ± 6 ng L−1 to 21 ± 5 ng L−1 (P < 0.05). This decrease did not occur in control subjects. Early dumping is associated with an activation of the renin–aldosterone axis and a decrease in plasma ANP, reflecting a hypovolaemic state. Octreotide prevents the occurrence of these changes.
Increased expression of CD11b/CD18 on phagocytes in ischaemic disease: a bridge between inflammation and coagulation
Authors: MAZZONE A. , DE SERVI S. , MAZZUCCHELLI I. , FOSSATI G. , GRITTI D. , CANALE C. , CUSA C. , RICEVUTI G.
Published: November 2003

The aim of this study was to assess the expression of CD11b/CD18 integrin adhesion molecules on the phagocytes of patients with ischaemic diseases, and to evaluate the concentration of soluble adhesion molecules that are released from endothelium (sICAM‐1) and from phagocytes (sL‐selectin). A total of 370 patients were enrolled: 120 with coronary artery disease (CAD); 50 with peripheral artery occlusive disease (PAOD); and 200 control subjects with no clinical manifestations of ischaemic disease. CD11b/CD18 integrin was detected by flow cytometry, whereas sL‐selectin and sICAM‐1 concentrations were detected using a sandwich‐type immunoassay. CD11b/CD18 integrin expression was found to be higher in the patients with ischaemic disease than in the control subjects (P < 0.001). The PAOD patients had higher values of CD11b/CD18 integrin than the CAD ones (P < 0.01). The concentration of soluble adhesion molecules did not show any significant differences within the three groups (P = NS). The high expression of CD11b/CD18 integrin in ischaemic disease patients may depend on the increased, but probably stable, cytokine network that has been demonstrated to occur in chronic ischaemic diseases: the difference observed between PAOD and CAD patients could be the consequence of higher inflammatory activation probably resulting from the greater extent of the atherosclerotic process in PAOD, or of the more localized ischaemic area in CAD patients. CD11b/CD18 can therefore be considered a marker of chronic phagocyte activation during ischaemic disease. On the other hand, sICAM and sL‐selectin concentrations were found to be within the normal range; they have recently been considered as a marker for acute ischaemic events and acute inflammatory process activation. Our results confirm that in uncomplicated atherosclerosis no acute inflammatory process activation should occur.