bluuebunny/crossref_metadata_2025 huggingface dataset:
Large platelets continue to circulate in an activated state after myocardial infarction
Authors: SCHULTHEIß H. P. , TSCHOEPE D. , ESSER J. , SCHWIPPERT B. , ROESEN P. , NIEUWENHUIS H. K. , SCHMIDT‐SOLTAU C. , STRAUER B.
Published: March 2008

Abstract This study was intended to investigate the actual platelet activation status after an acute coronary event. The activation status of circulating platelets was assayed directly by measuring the membrane activation markers CD62 and CD63 with the Düssel‐dorf III flow cytometry test in 22 patients with the diagnosis of acute myocardial infarction during the 48‐h observation period following the acute event. The number of activated, marker‐positive sample platelets was significantly increased in the post‐MI patients: CD62: 5·8%× 2·25±1 vs. 3·5%× 2·32±1, P≤ 0·05; CD63: 18·7%× 1·77±1 vs. 4·6%× 2·16±1, P≤ 0·00·1. The platelet volume and count were concomitantly increased (12·1 ± 2·4 fl/ 236 ± 90 times 103μl‐1 compared to 8·3 ± 1·6 fl/187 ± 42 times 103μl‐1) in the control group. Particularly large platelets were identified as being activated documented by the exponential increase in the difference in CD63‐binding sites per sample platelet above the 90%‐percentile and below the 10%‐percentile of the volume distribution: Δ+ 1341 ± 903 (MI patients) vs. Δ+ 276 ± 126 (controls), P≤ 0·00·1. Significant creatine kinase elevation and decrease in platelet count was found in the non‐survivor subset (n= 5). We conclude that predominantly large platelets continue to circulate in an activated state after MI. This study provides direct evidence that the assumption of an increased thrombotic potential becomes operative in vivo in MI patients. Besides CK elevation and decrease in platelet count this might possibly constitute a prognostic factor for the short‐term outcome of the patients.
Systemic lupus erythematosus is associated with increased auto‐antibody titers against calreticulin and Grp94, but calreticulin is not the Ro/SS‐A antigen
Authors: BOEHM J. , ORTH T. , NGUYEN P. VAN , SÖLING H.‐D.
Published: March 2008

Abstract Auto‐antibodies against purified human calreticulin were determined by an ELISA in sera from patients with systemic lupus erythematosus (SLE) and from healthy persons or patients without an autoimmune disease. More than 80% of patients with SLE had titers exceeding the highest value obtained in the group without SLE. Almost 30% of the patients had also elevated auto‐antibody titers against purified rat grp94, another resident ER‐protein of the KDEL‐protein family, but not against rat ERp72 (CaBP2), an ER‐resident protein of the proteindisulfide isomerase family. It could, however, be excluded that calreticulin is the Ro/SS‐A antigen on the basis of the following observations: 1) Calreticulin purified from rat, bovine or human liver contained far less than 1 mol of phosphate per mol of calreticulin, showed an E280/E260‐absorption ratio of about 2·0, and did not contain extractable RNA; 2) Sera from patients with SLE did not react with or precipitate endogenous calreticulin from Hep G2 cells; they did, however, precipitate hY‐RNA from these cells; 3) Sera from SLE‐patients, but not anti‐calreticulin antisera precipitated [32P]‐hY‐RNA from [32P]‐labelled Hep G2 cells.
Strain gauge plethysmography and Doppler ultrasound in the measurement of limb blood flow
Authors: PALLARÉS L. C. M. , DEANE C. R. , BAUDOUIN S. V. , EVANS T. W.
Published: March 2008

Abstract The maintenance of adequate oxygen delivery (DO2) and tissue uptake (VO2) has become central dogma in the management of the critically ill. However, these parameters are derived using gas tensions measured in mixed venous blood and may not reflect changes in regional blood flow. Therefore, it has become necessary to provide estimates of blood flow to specific organs and to evaluate the most adequate techniques available.

In order to define the best means of assessing blood flow to the lower limb noninvasively in normal subjects, measurements of superficial femoral arterial blood flow using Doppler ultrasound (DU) and strain gauge plethysmography (SGP) were compared in 10 normal volunteers at rest and during exercise. To evaluate the effect of strain gauge positioning, results of measurements made under four different combinations of cuff/strain gauge placement were compared in 15 other volunteers.

The correlation of the limb blood flow obtained using the two methods at rest and exercise was 0·57 and 0·62 and the limits of agreement (d±2SD) were 0·40±2·49 and ‐0·86±5·22 ml 100 ml‐1 tissue min‐1 at rest and on exercise, respectively. Results obtained using SGP were more reproducible (Coef. repeat. 0·45 vs. 0·94 ml 100 ml‐1 tissue min‐1, for SGP and DU, respectively). The various combinations of cuff/strain gauge positioning showed a tendency to over‐read when the latter was placed on the thigh, but were not significantly different (P<0·05).

Measurements of limb blood flow obtained using DU and SGP correlate poorly over a wide range of blood flow and do not agree, the results from the latter being more reproducible. Although the same position of cuff and strain gauge should be maintained throughout an experiment, varying the positions studied yields comparable results.
Effects of insulin‐like growth factor‐I (IGF‐I), insulin and combined IGF‐I‐insulin infusions on protein metabolism in dogs
Authors: UMPLEBY A. M. , SHOJAEE‐MORADIE F. , THOMASON M. J. , KELLY J. M. , SKOTTNER A. , SONKSEN P. H. , JONES R.H.
Published: March 2008

Abstract The effect of infusions of recombinant insulin‐like growth factor‐I (IGF‐I) (34, 103 or 688 pmol min‐1 kg‐1), insulin (3·4, 10·3 or 68·8 pmol min‐1 kg‐1) or combined infusions (34 pmol IGF‐I+ 3·4 pmol min‐1 kg‐1 insulin or 103 pmol IGF‐I+ 3·4 pmol min‐1 kg‐1 insulin) on protein metabolism, using an infusion of [1‐14C] leucine was investigated in anaesthetized fasted dogs. Leucine concentration, production rate (measure of protein degradation), oxidation rate and non‐oxidative disappearance rate (measure of protein synthesis) were decreased in a similar dose dependent manner by the IGF‐I and insulin infusions (P <0·01). The decrease in these measurements of leucine metabolism were greater following 34 pmol IGF‐I + 3·4 pmol insulin than with either component infused alone (P <0·05). Free fatty acid concentrations were decreased by all insulin doses (P < 0·01) but only by 103 and 688 pmol min‐1 kg‐1 insulin‐like growth factor (P < 0·05, P < 0·01). These data demonstrate that IGF‐I, like insulin, has a dose dependent effect on protein metabolism and that combined insulin and IGF‐I infusions have additive effects on protein metabolism.
Effect of endogenous organic hyperinsulinaemia on blood pressure and serum triglycerides
Authors: VETTOR R. , MAZZONETTO P. , MACOR C. , SCANDELLARI C. , FEDERSPIL G.
Published: March 2008

Abstract Hyperinsulinaemia and insulin resistance have been hypothesized to be the common pathophy‐siological factor of hypertension, NIDDM and obesity. To evaluate the possible role of hyperinsulinaemia and insulin resistance on hypertension, we studied a group of 37 patients with insulinoma who were admitted to our department in the period from 1966 to 1990. We recorded blood pressure and assayed blood glucose, plasma insulin, plasma triglycerides and serum uric acid levels, before and after surgery, in these patients and in a 37‐subject control group. No significant increase in blood pressure and triglyceride plasma levels was recorded in the chronic hyperinsulinaemic hypoglycaemic patients, suggesting the lack of a direct role of hyperinsulinaemia on hypertension.
Urodilatin: a new approach for the treatment of therapy‐resistant acute renal failure after liver transplantation
Authors: CEDIDI C. , MEYER M. , KUSE E.‐R. , SCHULZ‐KNAPPE P. , RINGE B. , FREI U. , PICHLMAYR R. , FORSSMANN W.‐G.
Published: March 2008

Abstract A pilot study was performed in patients after liver transplantation (Ltx) to examine the effect of continuous intravenous urodilatin (URO, CDD/ANP‐95–126)‐infusion as an alternative therapy of acute renal failure (ARF) resistant to conventional therapy. Eight patients who developed ARF after liver transplantation and fulfilled requirements for haemo‐dialysis/haemofiltration were treated. After URO infusion was started, renal function improved and all patients developed a strong diuresis and natriuresis within 2–4h. The extracellular expansion due to sodium and water retention in anuric/oliguric ARF lead to an increased central venous pressure (CVP) and elevated blood pressure. During the URO infusion CVP declined and systolic, as well as diastolic, blood pressure were stable. In six patients where haemodialysis/haemofiltration could be avoided, serum creatinine (SC) and blood urea nitrogen (BUN) declined during URO treatment and creatinine clearance (CC) also improved significantly. Fluid and electrolyte disturbances changed promptly and normalized. This was in concordance with renal excretion of electrolytes. Two patients still required haemodialysis/haemofiltration. The six patients who did not require haemodialysis/haemofiltration after URO treatment normalized concerning their renal function and did well in a control period of 12 weeks. The study shows that continuous low dose URO infusion may present a new concept for treatment of postoperative acute renal failure resistant to conventional therapy.
The pathophysiology of the insulin‐like growth factor axis in fetal growth failure: a basis for programming by undernutrition?
Authors: LANGFORD K. , BLUM W. , NICOLAIDES K. , JONES J. , McGREGOR A. , MIELL J.
Published: March 2008

Abstract. Recent evidence suggests that a number of adulthood conditions, including non‐insulin dependent diabetes mellitus (NIDDM) and lipid and cardiovascular abnormalities are associated with intra‐uterine growth retardation (IUGR). It is possible that this arises from programming of endocrine axes during development as a result of an adverse intra‐uterine environment. Insulin‐like growth factors (IGFs) are mitogenic polypeptides which stimulate cellular proliferation and differentiation and are important in human fetal development. The functions of IGFs are modulated by specific high affinity binding proteins (IGFBPs). IGFBP‐1 is antagonistic to the insulin‐like and growth promoting effects of IGF‐I, and IGFBP‐3 holds IGFs in the circulation by associating with IGFs and an acid labile subunit to form a ternary complex. Using specific radioimmunoassays and fetal serum obtained during diagnostic cordocentesis we have investigated the role of the IGF/IGFBP axis in human fetal development. In a study of 130 singleton pregnancies we have examined levels of immunoreactive IGFs and IGFBPs in normally grown fetuses (AGA), starved small fetuses affected by uteroplacental insufficiency (UPI), and non‐starved small fetuses (SGA). IGF‐1 was significantly lower in the UPI group (n= 14, 7·8±0·6 μg l‐1), than in either the SGA group (n= 22, 31·4±3·5 μg l‐1, P= 0·0001) or the AGA group (n= 94, 36·3±1·9 μg l‐1, P= 0·0001). IGFBP‐3 showed similar changes (UPI: 682·6±50·0 μg l‐1; SGA: 831·9±55·5 μg l‐1; AGA: 847·7±19·8 μg l‐1). In contrast, IGFBP‐1 levels were significantly higher in the UPI group (312·4±57·5 μg l‐1) than in either the SGA group (132·6±39·5 μg l‐1, P= 0·009) or the AGA group (116·9±25·4 μg l‐1, P= 0·003), and the normal inverse relationship between IGFBP‐1 and insulin levels was lost in the UPI group. IGFBP‐2 levels showed a similar pattern (UPI: 2510·3±178·0 μg l‐1; SGA: 878·5±80·3μg l‐1, P= 0·0001; AGA: 791·6±27·0 μg l‐1, P= 0·0001). Thus, there are clear differences between the two groups of SGA fetuses. It is possible that in utero‘programming’ of the IGF/IGFBP axis, as a result of fetal undernutrition, may be important in the pathogenesis of disease in adulthood.
Identification of defective binding of low density lipoprotein by the U937 proliferation assay in German patients with familial defective apolipoprotein B‐100
Authors: SCHEWE C.K. , SCHUSTER H. , HAILER S. , WOLFRAM G. , KELLER C. , ZÖLLNER N.
Published: March 2008

Abstract. Familial defective apolipoprotein B‐100 (FDB) is a dominantly inherited disorder characterized by decreased binding of low density lipoprotein (LDL) to the LDL receptor due to a substitution of glutamine for arginine in residue 3500 of apolipoprotein B‐100. We present the results of the U937 cell proliferation assay for the detection of familial defective apo B100 in 13 German FDB patients. Due to a defect in the pathway of cholesterol synthesis the human myelomonocytic tumour cell line U937 lacks the ability to synthesize cholesterol which makes proliferation of these cells dependent on the presence of exogenous LDL‐cholesterol. U937 cells were incubated with LDL from 13 FDB‐patients, 10 healthy normocholesterolaemic individuals (NC) and 26 patients with familial hypercholesterolaemia due to a defective LDL‐receptor (FH). At LDL‐cholesterol concentrations below 1 μg ml‐1 no proliferation occurred. In the presence of LDL from FDB patients at concentrations between 2·5 μg ml‐1 and 15·0 μg ml‐1, the proliferation was significantly reduced compared to LDL from FH‐patients and normocholesterolaemic controls. At 5 μg ml‐1 the reduction was 31–80% regardless of age, sex, apo E genotype, Lp (a)‐ and lipid levels. At concentrations above 25·0 μg ml‐1 no further differences were observed. The present results indicate that the U937 proliferation assay is a reliable test for the detection of defective LDL‐binding due to the 3500 mutation in FDB patients. It may be useful for the detection of defective binding of LDL due to other mutations in the apo B‐100 gene.
Human leucocyte‐endothelial interactions in peripheral arterial occlusive disease
Authors: CIUFFETTI G. , LOMBARDINI R. , PALTRICCIA R. , SANTAMBROGIO L. , MANNARINO E.
Published: March 2008

Abstract. This ex vivo study determined the expression of leucocyte adhesion receptors for endothelial adhesion molecules in 10 patients with peripheral arterial occlusive disease (PAOD) and in 10 healthy controls before and after treadmill exercise. Granulocytes from venous blood samples were separated on a Ficoll‐Hypaque gradient and the phenotypical expression of CD11a/CD18 (LFA‐1), CD11b/CD18 (Mac‐1) and CD11c/CD18 (p150,95) was observed by double indirect immunofluorescence using specific monoclonal antibodies. The total and differential white blood cell counts were monitored before and after exercise. In the PAOD patients a significant reduction in the number of granulocytes expressing CD11b/CD18 (Mac‐1) and CD11c/CD18 (p150,95) associated with a significant neutropenia was observed after exercise, suggesting that leucocyte‐endothelial interactions occur during ischaemia.
Enhanced arterial intimal thickening after balloon catheter injury in diabetic animals accompanied by PDGF β‐receptor overexpression of aortic media
Authors: KANZAKI T. , SHINOMIYA M. , UEDA S. , MORISAKI N. , SAITO Y. , YOSHIDA S.
Published: March 2008

Abstract. Cultured aortic smooth muscle cells (SMC) of diabetic rats and rabbits, which overexpress platelet‐derived growth factor (PDGF) β‐receptor compared with controls, have a unique phenotype. In this study we report on the PDGF β‐receptor overexpression in aortas of diabetic animals and the increased intimal thickening of carotid arteries in diabetic rabbits after balloon catheter injury compared with that in controls. In diabetic aortas with no treatments of balloon catheter injury, intimal thickening was not observed in spite of the overexpression of PDGF β‐receptor, indicating that the growth property of medial SMC in diabetic aortas was changed before the intimal thickening could take place. PDGF is known to be the main contributor to the intimal thickening induced by balloon catheter injury, which is one of several forms of arterial injuries. Intimal thickening after balloon catheter injury in diabetic rabbits increased compared with that in controls. These results imply that PDGF β‐receptor overexpression of SMC in medial layers plays an important role in intimal thickening in the formation of advanced diabetic macroangiopathy.
Venous compliance and the venodilatory effect of nitroglycerin in insulin‐dependent diabetic patients with and without (incipient) nephropathy
Authors: SCHAPER N. C. , HOUBEN A. J. H. M. , SCHOON Y. , KOOMAN J. P. , HUVERS F. C. , KRUSEMAN A. C. NIEUWENHUIJZEN
Published: March 2008

Abstract. The venous system plays a pivotal role in volume and blood pressure homeostasis. We tested the hypothesis that the visco‐elastic properties of the peripheral venous system are reduced in patients with (incipient) diabetic nephropathy. Twenty‐two normotensive patients with long‐term insulin‐dependent diabetes mellitus (IDDM), 11 without and 11 with (incipient) nephropathy (eight microalbuminuria and three proteinuria, serum creatinine below 100 μmol l‐1), and 14 healthy age/sex matched controls were studied. Forearm venous compliance (VENCOMP) was determined using strain gauge plethysmography and direct intravenous pressure measurements. Furthermore, the venodilatory effect of 0·4 mg sublingual nitroglycerin (NTG) was studied. In comparison with healthy controls, VENCOMP was decreased in patients without and with (incipient) nephropathy, without any differences between the two diabetic groups: 0·059 (0·052–0·066), 0·044 (0·038–0·059) and 0·049 (0·046–0·058) ml 100 ml‐1 mmHg‐1, respectively (medians and interquartile ranges) (P<0·05). No differences in the increase of forearm volume after NTG were observed: 0·34 (0·11–0·51), 0·37 (0·19–0·50) and 0·39 (0·20–0·55) ml 100 ml‐1, respectively. In conclusion, the visco‐elastic properties of the peripheral venous system are reduced in patients with long‐term IDDM. This reduction is not related to the presence of nephropathy. No major differences were observed in NTG‐induced venodilation between diabetic patients and healthy subjects.
Repression of ALA synthase by heme and zinc‐mesoporphyrin in a chick embryo liver cell culture model of acute porphyria
Authors: RUSSO S. M. , PEPE J. A. , CABLE E. E. , LAMBRECHT R. W. , BONKOVSKY H. L.
Published: March 2008

Abstract. We characterize a liver cell culture model for acute hepatic porphyrias that recapitulates the biochemical features of the human syndrome. In chick embryo liver cells in primary culture exposed to glutethimide and 4,6‐dioxoheptanoic acid, heme alone produced a transient dose‐dependent decrease in 6‐aminolevulinate synthase and a concomitant increase in heme oxygenase. The addition of low concentrations of zinc‐mesoporphyrin (50–200 nM), an inhibitor of heme oxygenase, led to more prolonged decreases in activity of the synthase and to an additive effect with heme. These effects of zinc‐mesoporphyrin were associated with prolonged inhibition of heme oxygenase. These results suggest that the treatment of choice of acute porphyric syndromes may be the combination of low doses of heme and zinc‐mesoporphyrin or another similarly non‐toxic inhibitor of heme oxygenase.
Erythropoietic activity and iron metabolism in autologous blood donors during recombinant human erythropoietin therapy
Authors: BIESMA D. H. , WIEL A. VAN DE , BEGUIN Y. , KRAAIJENHAGEN R. J. , MARX J. J. M.
Published: March 2008

Abstract. The use of recombinant human erythropoietin (rhEPO) to intensify the erythropoietic response in autologous donors may reduce homologous blood requirement. We studied the effect of subcutaneous rhEPO (500 U kg‐1 body weight twice weekly during a 3 week period) on variables of erythropoiesis and iron metabolism in 62 autologous blood donors, of whom 32 received rhEPO (epo group) and 30 did not (control group). Patients donated only 2 units of blood and received oral iron in order to restrict phlebotomyinduced decrease of iron stores. Pre‐phlebotomy haemoglobin concentration (14·0±0·8 g dl‐1) was completely regenerated in the epo group at surgery (13·7±1·3 g dl‐1); haemoglobin concentration in the control group fell from 13·5±1·4 g dl‐1 to 11·6±1·4 g dl‐1 after the phlebotomies and did not improve during the pre‐operative phase. Total erythropoietic activity expressed as serum transferrin receptor concentration (sTfR) showed a 4‐fold increase from 3·8±0·9 μg ml‐1 to 14·9±4·8 μg ml‐1 in the epo group. Effective erythropoietic activity measured by absolute reticulocyte count, however, declined after the fourth rhEPO injection in the epo group. Serum ferritin was lower in the epo group, but no differences in serum iron, transferrin concentration and transferrin saturation were observed between the groups. A marked increase in free erythrocyte protoporphyrin (FEP) was observed in the epo group, whereas FEP levels in the controls remained within normal ranges. Despite oral iron supplementation and the limited number of phlebotomies, the effect of rhEPO therapy in autologous donors is restricted by iron depletion.
Heterozygous familial hypercholesterolaemia is associated with pathological exercise‐induced leakage of muscle proteins, which is not aggravated by simvastatin therapy
Authors: SMIT J. W. A. , BÄR P. R. , GEERDINK† R. A. , ERKELENS D. W.
Published: March 2008

Abstract. The objective of this study was to assess the relationship between therapy with the HMG‐CoA reductase inhibitor simvastatin and muscle damage and the possible causal role of hypercholesterolaemia. The exercise‐induced release of muscle proteins as a parameter of muscle damage was studied in two equicholesterolaemic groups of male patients with heterozygous familial hypercholesterolaemia (FH); one group without treatment, the second group on simvastatin. To assess the role of cholesterol, a third group of healthy male volunteers was studied as well. The study took place at the Lipid Clinic of an 800‐bed University Hospital. One group of 21 male patients with heterozygous FH did not receive treatment, except for a lipid‐lowering diet. A second group of 13 male FH patients were treated with 40 mg simvastatin day‐1 for at least 1 year and matched for cholesterol levels with the first group. A third group consisted of 25 normocholesterolaemic male controls. All subjects underwent a 45 min lean body mass (LBM) standardized ergometer muscle provocation test (2 Watt/kg LBM). Levels of creatine kinase (CK) and myoglobin (Mb) were assessed before and 1 and 8 h after exercise and compared with baseline levels. The exercise‐induced release of muscle proteins is reflected by peak CK and Mb levels expressed as a percentage of baseline levels. The exercise‐induced increase in Mb and CK levels did not differ between untreated and simvastatin‐treated FH patients. However, the increase in Mb 1 h after exercise in untreated FH patients (181% of baseline level) and in simvastatin‐treated patients (144% of baseline level) differed significantly from controls (107% of baseline level, P < 0.025, Mann‐Whitney test). We conclude that hypercholesterolaemia may be associated with muscle damage, and the CK rises observed under therapy with HMG‐CoA reductase inhibitors might be attributed to hypercholesterolaemia per se.
Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease
Authors: BERG M. VAN DEN , BOERS G. H. J. , FRANKEN D. G. , BLOM. H. J. , VAN KAMP G. J. , JAKOBS C. , RAUWERDA J. A. , KLUFT C. , STEHOUWERT C. D. A.
Published: March 2008

Abstract. Hyperhomocysteinaemia, defined as an abnormally high plasma homocysteine concentration after an oral methionine load, is common in young (≤ 50 years) patients with peripheral arterial occlusive disease. It is thought to predispose to atherosclerosis by injuring the vascular endothelium. Treatment with pyridoxine and/or folic acid may lower plasma homocysteine levels. In mildly hyperhomocysteinaemic patients with peripheral arterial occlusive disease, we studied the effect of daily treatment with pyridoxine (250 mg) plus folic acid (5 mg) on homocysteine metabolism (i.e. plasma concentrations in the fasting state and after methionine loading, in 48 patients) and on endothelial function (in 18 patients). Endothelial function was estimated as the plasma concentrations of the endothelium‐derived proteins, von Willebrand factor (vWF), thrombomodulin (TM), and tissue‐type plasminogen activator (tPA). At baseline, fasting homocysteine levels were above normal in 24 of the 48 patients (50%); post‐load levels, by definition, were above normal in 100% of patients. After 12 weeks of treatment, fasting and post‐load levels were normal in 98 and 100% of patients, respectively. Endothelial function was assessed in 18 patients who completed 1 year of treatment. At baseline, median vWF (235%) and TM (57.1 ng mL‐1) levels were above normal. At follow‐up, vWF levels had decreased to 170% (P= 0.01) and TM levels had decreased to 49 ng mL‐1 (P= 0.04). tPA levels were normal at baseline and did not change. Endothelial dysfunction is present in young patients with peripheral arterial occlusive disease and hyperhomocysteinaemia. Pyridoxine plus folic acid treatment normalizes homocysteine metabolism in virtually all patients, and appears to ameliorate endothelial dysfunction.
Response of digital arteries to endothelium dependent and independent vasodilators in patients with Raynaud's phenomenon
Authors: SINGH S. , TRAFFORD J. C. DE , BASKERVILLE P. A. , MARTIN J. F.
Published: March 2008

Abstract. The cause of the digital artery spasm seen in Raynaud's phenomenon (RP) is unclear. A dysfunction of endothelium‐dependent vasodilation might contribute to the development of this spasm. We studied the digital artery responses to endothelium‐dependent and independent vasodilators in eight Raynaud's phenomenon patients and eight sex‐matched controls. A sequential series of infusions alternating with physiological saline were administered at a rate of l mL min‐1 via the radial artery. The infusions contained acetylcholine chloride (ACh) 110 nm mL‐1 and 550 nm mL‐1, L‐arginine 50 μmol mL‐1, prostacyclin (PGI2) 2.5 ng mL‐1 and glyceryl trinitrate (GTN)4.5 nm mL‐1. Digital artery diameter (DAD) and cutaneous temperature were measured. DAD was measured using a high frequency A‐mode ultrasound scanner. There was no significant difference in mean brachial artery pressure, digital cutaneous temperature and DAD between the two groups at the start of the study. Comparing responses in the groups, there was a significantly greater increase in DAD and cutaneous temperature to Ach (endothelium‐dependent vasodilator) at both concentrations in controls. A significantly greater increase in DAD was obtained in response to GTN (endothelium‐indepen‐dent vasodilator) in the RP subjects. There was no significant difference in response to L‐arginine and PGI2 between the groups. These results suggest that a dysfunction of endothelium‐dependent vasodilation is present in RP patients.
Sulphydryl group control of sodium‐lithium countertransport kinetics: a membrane protein control abnormality in essential hypertension
Authors: THOMAS T. H. , RUTHERFORD P. A. , WEST I. C. , WILKINSON R.
Published: March 2008

Abstract. Erythrocyte sodium‐lithium countertransport (SLC) is an obligatorily coupled equimolar exchange of intracellular sodium or lithium with extracellular sodium or lithium. SLC is partially inhibited by N‐ethylmaleimide (NEM) but only when a transported ion (sodium or lithium) is present in the extracellular medium. In essential hypertensive patients with a strong family history of hypertension the Km of SLC for extracellular sodium was lower and Vmax tended to be higher than in normal controls, but the ratio Vmax/ Km gave a much clearer distinction between the two groups. After NEM treatment, the remaining SLC activity in normal individuals had a lower Vmax and Km for sodium but Vmax/Km was not affected. In essential hypertensives the remaining SLC activity after NEM again had lowered Vmax and Km but in these patients the Vmax/Km was much lower than in untreated erythrocytes and was then the same as in normal controls. On the assumption that NEM reacts with a ‐SH group on a membrane protein that regulates SLC, and that the ratio Vmax/Km reflects a rate constant for binding extracellular sodium to the unloaded carrier, the results suggest that (a) essential hypertensives have an increased rate of sodium binding to the transporter and (b) this is due to abnormal behaviour of a membrane ‐SH group.
Platelet function and fibrinolytic activity during rest and exercise in borderline hypertensive patients
Authors: GLEERUP G. , VIND J. , WINTHER K.
Published: March 2008

Abstract. In this study we examined whether the reduced fibrionolysis and increased platelet activity that are known to occur in hypertension are already present in borderline hypertension. Twelve patients with ‘borderline’ hypertension (diastolic blood pressure 90–95 mmHg) were found to have substantially reduced fibrinolytic activity, both at rest and during exercise, compared with 12 normotensive controls. Euglobulin clot lysis time (ECLT) was significantly higher in hypertensive subjects (218 min vs. 145 min; P < 0.05), and this difference persisted during exercise. Resting tissue plasminogen activator activity (t‐PA) did not differ in the two groups, but the brisk increase in t‐PA in controls during exercise (0.64 rising to 1.4IU mL‐1; P < 0.01) did not occur to the same extent in the borderline hypertensive subjects. Levels of the fast‐acting t‐PA inhibitor, normally referred to as PAI‐1, were considerably higher in hypertensives (9.22 vs. 4.41 IU mL‐1; P < 0.02), and this difference persisted in the upright posture, indicating a decrease in fibrinolytic activity. Platelet aggregability induced by ADP in vitro was not significantly higher in the hypertensive subjects, but indices of platelet activity in vivo (B‐TG and PF‐4 levels) revealed enhanced platelet function in the hypertensives. These results indicate that the indicators of altered haemostatic function known to occur in hypertension, namely diminished fibrinolytic activity and increased platelet function, are already detectable during the very earliest stage of the disease.
Severe hypotension and bradycardia after continuous intravenous infusion of urodilatin (ANP 95–126) in a patient with congestive heart failure
Authors: KENTSCH M. , DRUMMER C. , GERZER R. , MÜLLER‐ESCH G.
Published: March 2008

Abstract. The effects of a continuous i.v. infusion of urodilatin at a dose of 30 ng kg‐1 min‐1 were studied in a patient with congestive heart failure. After 30 min, urodilatin had induced a marked stimulation of plasma cyclic GMP concentrations. In parallel haematocrit increased. No significant diuresis and no change of invasive haemodynamics was observed. After 2 h the patient developed a profuse perspiration. Eighty minutes later he suffered from dizziness due to hypotension (blood pressure 80/40 mmHg) and a sudden bradycardia (50bpm). Urodilatin was discontinued and symtoms were relieved by bed tilt and rapid infusion of isotonic saline solution. Mechanisms contributing to these adverse effects may be fluid extravasation to the third space and sympathoinhibitory effects known to occur with natriuretic peptide infusion.
Non‐invasive assessment of unstimulated forearm arterial compliance in human subjects. Impaired vasoreactivity in hypercholesterolaemia
Authors: BALDASSARRE D. , GIANFRANCESCHI G. , PAZZUCCONI F. , SIRTORI C. R.
Published: March 2008

Abstract. A study was carried out in order to determine the feasibility and reproducibility of a direct plethysmographic assessment of unstimulated forearm arterial compliance (FAC) in hypercholestero‐laemic and normocholesterolaemic subjects. Simultaneous recordings of forearm pulse volume and blood pressure over the whole cardiac cycle are used to establish the pulse volume blood pressure relationship. FAC was measured on‐line by computing the ratio of dV/dP. The area under the curve (FAC(AUC)) of FAC/blood‐pressure curve was determined in a standard range of blood pressure (70–130 mmHg). The method was validated by demonstrating its capacity to detect changes in FAC(AUC) induced by nitrate and by muscarinic stimuli. The results show a reduced FAC(auc) in hypercholesterolaemic patients vs. controls (2.28±0.8 times 10‐3 vs. 4.12 ± 1.06 times 10‐3 (mL 100 mL‐1 forearm mmHg‐1) mmHg; P= 0.0001). The method appears to be highly sensitive to nitrate and muscarinic stimuli. The new technique provides a potentially useful tool to detect and monitor in vivo, without stimulating arterial dilatation, e.g. by acetylcholine infusion, the functional arterial changes in subjects with a major risk factor for arterial disease as well as the effects of dietary/drug treatments.
Skeletal muscle and the control of ventilation on exercise: evidence for metabolic receptors
Authors: CLARK A. L. , PIEPOLI M. , COATS A. J. S.
Published: March 2008

Abstract. Patients with chronic heart failure have an increased ventilatory response to exercise, and have metabolically abnormal skeletal muscle. It has been proposed that a neural signal to ventilation arising from exercising muscle may be heightened in chronic heart failure. Our objective was to detect evidence for such a signal in normal subjects by studying ventilatory behaviour during exercise with muscles in different metabolic states. Fifteen normal subjects undertook treadmill exercise both with and without cuffs inflated around each thigh to suprasystolic pressure. In a second experiment, a group of 11 normal subjects undertook cycle exercise using arms or legs at the same absolute work load. Metabolic gas exchange was measured using mass spectrometry with indicator gas dilution. The ventilatory response was greater at a given workload when subjects exercised with inflated cuffs. Oxygen consumption was reduced in keeping with the isolation of the exercising muscle bulk from the circulation. The ventilation/carbon dioxide output relationship was described by a linear regression function, but the slope of the relationship was increased by 25% from 20.9 (0.46) to 25.43 (0.73) P< 0.001). Arm exercise at the same load as leg exercise resulted in unchanged oxygen consumption indicating that the same external work was being performed. There was an increase in ventilation at a given workload. The ventilation/carbon dioxide output slope was increased by 25% (from 21.9 (0.9) to 26.3 (0.8))(P<0.001).There is a signal to ventilation arising from exercising skeletal muscle which is enhanced by the ischaemia induced by cuff inflation during exercise. This signal appears to be neural. Second, the signal to ventilation is a function of work per unit muscle rather than total external work. These finding may have possible implications for the understanding of the increased ventilatory response to exercise in patients with heart failure, in whom there are both metabolic muscle abnormalities and a reduction in skeletal muscle bulk.
Effect of hypertriglyceridaemia on lipoprotein (a) serum concentrations
Authors: WALEK T. , ECKARDSTEIN A. VON , SCHULTE H. , ASSMANN G.
Published: March 2008

Abstract. Numerous studies have shown lipoprotein (a) [Lp(a)] serum levels above 0.3 gL‐1to be a genetically determined and independent risk factor for atherosclerotic vascular disease. In this study of sera from 1009 patients attending our lipid clinics, multivariate regression analysis revealed an inverse correlation between the serum concentrations of triglycerides (TG) and Lp(a) (r=—0.31; P < 0.001) as determined by electroimmunodiffusion. This was not observed in 1237 controls from a random population. Detailed analysis of the frequency distribution of Lp(a) levels at different degrees of hypertriglyceridaemia (HTG) revealed a decreasing dosage effect of HTG on Lp(a) serum levels. In 60% of patients with TG > 9.12mmolL‐1, this effect led to undetectable serum Lp(a) levels. Dilution of hypertriglyceridaemic samples with normotriglyceridaemic sera containing high levels of Lp(a) revealed that analytical interference in part accounts for the decreasing effect of TG‐rich lipoproteins on Lp(a). Re‐evaluation of 45 hypertriglyceridaemic samples by enzyme immuno‐assay and immunoblotting revealed the presence of small amounts of Lp(a) in several samples which were considered to be free of Lp(a) upon electroimmunodiffusion. We conclude that TG‐rich lipoproteins interfere with the quantification of Lp(a), at least by electroimmunodiffusion. However, HTG may also decrease Lp(a) plasma concentrations in vivo, possibly by increased clearance of TG‐rich Lp(a).
Transforming growth factor β1 modulates angiotensin induced calcium influx in vascular smooth muscle
Authors: ZHU Z. , TEPEL M. , NEUSSER M. , ZIDEK W.
Published: March 2008

Abstract. The modulatory effects of transforming growth factor β1 (TGF β1) on the angiotensin II (Ang II)‐induced increase in cytosolic free calcium concentration ([Ca2+]i) were investigated in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto rats (WKY). [Ca2+]i in VSMC was measured using the fluorescent dye fura‐2. When TGF β1 was applied 30 s prior to Ang II, the Ang II‐induced [Ca2+]i increase was significantly enhanced in VSMC from SHR (P < 0.05 compared to control), whereas after the preincubation with TGF β1 for 30 min, the Ang II‐induced [Ca2+]i increase was significantly reduced in VSMC from both strains. Using the manganese‐quenching technique, it was confirmed that short‐term exposure to TGF β1 enhanced the Ang II‐induced trans‐plasma‐membrane calcium influx in SHR. The inhibition of protein kinase C by calphostin C abolished the stimulatory effect of TGF β1 on the Ang II‐induced [Ca2+]i increase. It is concluded that TGF β1 modulates the Ang II‐induced calcium handling in VSMC.
Severe hypercholesterolaemia: unusual inheritance in an Italian pedigree
Authors: ZULIANI G. , VIGNA G. B. , CORSINI A. , MAIOLI. M. , ROMAGNONI F. , FELLIN R.
Published: March 2008

Abstract. A family presenting several cases of severe primary hypercholesterolaemia and/or premature sudden death was studied. This family is characterized by consanguinity, absence of vertical transmission, bimodal distribution of plasma cholesterol values, and reduction of reproductive fitness in affected individuals. The probands have clinical traits of homozygous familial hypercholesterolaemia, including hypercholesterolaemia, xanthomas and early coronary atherosclerosis, while the parents and grandparents are clinically normal. Eight relatives on the mother's side experienced premature sudden death, and in four cases hypercholesterolaemia was diagnosed. Haplotype segregation analysis of the inheritance of the LDL receptor and apo B genes in the probands' family excluded the involvement of these two genes in the pathogenesis of the disease. LDL receptor activity, as well as the ability of LDL to bind to the LDL receptor, and plasma vegetal sterols were within normal limits both in probands and in their relatives. The study of this pedigree suggests that hypercholesterolaemia is not produced by defects in the LDL receptor or LDL particles, and disease inheritance is consistent with an autosomal recessive trait.
Surgical removal of insulinoma restores glucose recovery from hypoglycaemia but does not normalize insulin action
Authors: KREUTZENBERG S. VIGILI DE , RICCIO A. , DORELLA M. , AVOGARO A. , MARESCOTTI M. C. , TIENGO A. , PRATO S. DEL
Published: March 2008

Abstract. In the present study we have evaluated the effects of chronic hyperinsulinaemia secondary to insulinoma, on insulin sensitivity and on counter‐regulatory responses to hypoglycaemia. We studied six patients (M/F = 3/3; age = 40 ± years), before and 6–9 months after surgical ablation of the neoplasia, by means of an euglycaemic‐hyperinsulinaemic clamp (1 mUkg‐1min‐1). Seven normal subjects (M/F = 4/ 3; age = 38 ± 6 years) underwent the same experimental study as the control subjects. In insulinoma patients after 100 min of the euglycaemic‐hyperinsulinaemic clamp, glycaemia was allowed to drop to a minimum value of l.9mmol L‐1, and recovery evaluated after interrupting insulin infusion. During the entire study, 3‐3H‐glucose was infused to determine hepatic glucose production and glucose utilization. Surgical removal of the pancreatic adenoma was followed by a reduction in body weight (BMI=25.7 ±l.9vs. 23.0 ± 1.6 kgm‐2; P0.005), normalization of fasting plasma levels of glucose (2.94 ±0.16 vs. 4.83± 0.11 mmol L‐1), insulin (162 ± 24 vs. 48 ±12 pmol L‐1) and of basal hepatic glucose production (7.6 ± 0.7 vs. 12.2 ± 1.11μmol kg‐1min‐1). Before the operation, insulin‐mediated glucose disposal was significantly lower than in the controls (30.8 ±3.1 vs. 4.91± 3.1 μmol kg‐1min‐1). Six to nine months after surgical removal of the adenoma, glucose utilization was unchanged (30.5 ±3.3 μmol kg‐1min‐1) and still significantly lower than in controls (P<0.0). After the euglycaemic phase, the plasma glucose level dropped to the same hypoglycaemic nadir (2.0±0.1 vs. 2.2 ±0.2 mmol L‐1) in both studies. Upon withdrawal of insulin infusion, recovery from hypoglycaemia was much slower before than after removal of the insulinoma (0.66±0.16vs. 2.50 ± 0.38 μmol min‐1; P<0.01). The impaired recovery from hypoglycaemia was associated with a sluggish rise in plasma glucagon concentration (+ 49 ± 15vs. +95 ±27 ng L‐1), growth hormone (+16±6vs.+ 30±3*mu;g L‐1), and cortisol (+156 ±41 vs. +361 ±62nmol L‐1; all P<0.05–0.005). In contrast to that found after adenoma removal, hepatic glucose production in insulinoma patients remained suppressed even after induction of hypoglycaemia. Our data suggest that in hyperinsulinaemic insulinoma patients restoration of normal insulin levels (a) ameliorates the response of some parameters of the counter‐regulation to acute hypoglycaemia; but (b) is not able to restore normal insulin sensitivity.
High lipoprotein(a) levels with predominance of high molecular weight apo(a) isoforms in patients with pulmonary embolism
Authors: CSÁSZÁR A. , KARÁDI I. , JUHÁSZ E. , ROMICS L.
Published: March 2008

Abstract. Lipoprotein(a) (Lp(a)) may interact with the cellular components and protein co‐factors of fibrino‐lysis. To evaluate the effect of Lp(a) in thromboem‐bolic diseases of the venous system, we measured serum levels and the isoform distribution of apo(a) in 25 patients with pulmonary embolism (18 men, 7 women, aged 21—77 years). The control group was adjusted for sex and age (P= 0.189). Serum Lp(a) concentration was significantly higher in the study group (median: 9.3 vs. 4.3 mg dL‐1). As the distribution of high and low molecular weight subtypes of apo(a) did not show any differences (P= 0.127) between the two groups, the elevated Lp(a) levels in patients with pulmonary embolism could not be attributed to the investigated kringle‐4 polymorphism of the apo(a) gene and therefore other genetic or non‐genetic implications are indicated.
Induction of net mass lipid transfer reactions in plasma by wine consumption with dinner
Authors: TOL A. VAN , GROENER J. E. M. , SCHEEK L. M. , GENT T. VAN , VEENSTRA J. , POL H. VAN DE , HENDRIKS H. F. J. , SCHAAFSMA G.
Published: March 2008

Abstract. Moderate alcohol consumption is associated with a reduced risk of coronary heart disease. Alcohol may exert protection through its effects on the metabolism of plasma lipoproteins. In the present study we investigated the effects of moderate wine consumption with an evening dinner on lipoprotein composition and parameters of reverse cholesterol transport (plasma lipid transfer reactions and cholesterol esterification) in eight healthy middle‐aged men. Wine consumption, if compared with mineral water, resulted in increased postprandial plasma levels of triglyceride‐(TG)‐rich lipoproteins (P < 0.005 or <0.002 at two different time points) and in increased net mass transfer of cholesterylesters (CE) from high‐density lipoprotein (HDL) to apolipoprotein B‐containing lipoproteins during in vitro incubation of plasma (P < 0.001). Net mass transfer of TG (in the opposite direction) was also significantly increased by wine (P= 0.014). The concentrations of total plasma cholesterol, HDL‐cholesterol and apolipoproteins A‐I, A‐II and B did not change postprandially and were not affected significantly by wine, but the CE TG‐1 in HDL was affected postprandially and decreased by wine consumption. It is concluded that moderate wine consumption with evening dinner induces transfer reactions of CE and TG between HDL and TG‐rich lipoproteins. Due to the fact that wine raises plasma TG, it also causes changes in plasma cholesterol metabolism and lipoprotein composition, without major effects on total plasma cholesterol concentration.
Sustained weight reduction in moderately obese women results in decreased activity of skeletal muscle lipoprotein lipase
Authors: ECKEL R. H. , YOST T. J. , JENSEN D. R.
Published: March 2008

Abstract. Obesity is an increasingly prevalent problem, and long‐term maintenance of the weight‐reduced state is difficult for the obese individual. Following weight reduction, many metabolic changes occur. Among these is an increase in adipose tissue lipoprotein lipase (ATLPL), which predicts an alteration in lipid fuel partitioning which may then contribute to resumption of the obese state. The purpose of this study was to test whether changes in skeletal muscle LPL (SMLPL) and its response to insulin/ glucose after sustained weight reduction also indicate a potential altered partitioning of lipid fuels away from oxidative pathways in muscle to storage in adipose tissue. Biopsies of vastus lateralis muscle were carried out in premenopausal obese women (n= 11, 94 ± 4 kg, mean ± SEM) before and after consumption of a 900 kcal day‐1 diet for 3 months followed by 3 months of isocaloric maintenance of the reduced weight (n= 11, 82 ± 4 kg). SMLPL activity was measured in the fasted state and after 6 h insulin/ glucose infusion, before and after sustained weight loss. SMLPL activities were also measured in six normal weight women. Fasting SMLPL activity in obese women (3.9 ± 0.3 nmol FFA min‐1 g‐1) was similar to that measured in normal weight control women (4.4 ± 0.5). Unlike normal weight controls in whom a 6h insulin/glucose infusion decreased SMLPL activity, in obese women the response of SMLPL was positive (normal weight vs. obese: Δ‐ 0.8 ± 0.3 vs. Δ 1.6 ± 0.5, P= 0.002). Following maintained weight reduction, fasting SMLPL in the obese group was reduced to 1.2 ± 0.3 (obese before weight loss vs. obese after: P= 0.0001). This change in fasting SMLPL activity following weight loss/maintenance correlated with the resultant change in per cent body fat (rs= 0.663, P= 0.026). Following sustained weight reduction in the obese women, the change in SMLPL activity in response to insulin/ glucose infusion was unchanged by statistical comparison. However, the trend of the direction of that change was toward a more normal value. Overall, the decrease in SMLPL which occurred following sustained weight loss may explain, in part, why prolonged weight reduction in obese subjects is difficult to maintain.
A comparison of the effects of IGF‐I and insulin on glucose metabolism, fat metabolism and the cardiovascular system in normal human volunteers
Authors: RUSSELL‐JONES D. L. , BATES A. T. , UMPLEBY A. M. , HENNESSY T. R. , BOWES S. B. , HOPKINS K. D. , JACKSON N. , KELLY J. , SHOJAEE‐MORADIE F. , JONES R. H. , SONKSEN P. H.
Published: March 2008

Abstract. The metabolic and cardiovascular effects of recombinant human IGF‐I were compared to insulin in six normal subjects. Subjects were studied twice and intravenously received an infusion of [6,6‐2H2]glucose (0–480 min) and in random order either IGF‐I 20μg kg‐1 h‐1 (43.7 pmol kg‐1 min‐1) or insulin 0.5 mU kg‐1 min‐1 (3.4 pmol kg‐1 min‐1) with an euglycaemic clamp. One subject was withdrawn following a serious adverse event. During the IGF‐I infusion glucose appearance rate (Ra) decreased from 1.79 ± 0.13 at baseline (150–180 min) to 0.35 ± 0.26 mg kg‐1 min‐1 (P < 0.01) at 360min, and glucose utilization rate (Rd) increased from 1.79 ± 0.28 to 4.17 ± 0.84 mg kg‐1 min‐1 (P < 0.01). There was no change in free fatty acids (FFA) and an increase (percentage change from pre‐infusion mean) in cardiac output + 37.3%± 9% (P < 0.01), heart rate + 13%± 2% (P < 0.01) and stroke volume + 21%± 7% (P < 0.05). During the insulin infusion glucose Ra decreased from 1.89 ± 0.13 to 0.34 ± 0.33 mg kg‐1 min‐1 (P < 0.01) and FFA from 0.546 mmoll‐1 to 0.198 mmoll‐1 (P < 0.01), glucose Rd increased from l.89 ± 0.18 to 5.41 ± l.47mg kg‐1 min‐1 (P < 0.01) and there were no significant changes in the cardiovascular variables.