bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of digoxin and digitoxin on circadian blood pressure profile in healthy volunteers
Authors: Grossmann  , Jamieson  , Kirch
Published: March 2003

Background

The aim of the study was to investigate the potential effects of chronic digoxin or digitoxin treatment on circadian blood pressure profile in normotensive subjects.

Methods

In two randomized double‐blind, placebo‐controlled cross‐over protocols, 22 healthy normotensive subjects were enrolled, 12 subjects in either study. After adequate loading doses, digoxin 0.25 mg twice daily or digitoxin 0.1 mg daily was given for a total of 10 days. Automatic 24‐h ambulatory blood pressure measurements were carried out at days 4 and 10 of either glycoside or placebo.

Results

Digoxin treatment significantly decreased heart rate (HR) and diastolic blood pressure (DBP) during the overnight sleeping phase of day 10 compared with placebo (HR, 4 beats min−1; DBP, 8 mmHg; P < 0.05). Digitoxin treatment significantly decreased heart rate and diastolic blood pressure during the overnight sleeping phase of day 4 (HR, 8 beats min−1; DBP, 7 mmHg) and day 10 (HR, 7 beats min−1; DBP, 5 mmHg) compared with placebo (P < 0.05). Neither digoxin nor digitoxin significantly affected systolic blood pressure.

Conclusions

Both digoxin and digitoxin, within therapeutic steady‐state plasma concentrations, reduce diastolic blood pressure and heart rate during overnight sleep, presumably because of increased parasympathetic activity or decreased sympathetic activity.
Increased risk for endogenous hypertriglyceridaemia is associated with an apolipoprotein C3 haplotype specified by the SstI polymorphism
Authors: Hoffer  , Sijbrands  , De Man  , Havekes  , Smelt  , Frants
Published: March 2003

Background

Hypertriglyceridaemia is a common metabolic disorder frequently found in patients with coronary heart disease. Numerous studies have revealed an association between the SstI polymorphism in the APOC3 gene and increased plasma apoC3 and triglyceride levels. In addition, two different variants within the promoter region have been recently suggested to be the mutations of the APOC3 gene leading to hypertriglyceridaemia.

Methods

In the present study, we have applied haplotype analysis to investigate whether these promoter polymorphisms are involved in the lipid disorders of patients with distinct types of hypertriglyceridaemia: combined hyperlipidaemia (CHL), familial dysbetalipoproteinaemia (FD) and endogenous hypertriglyceridaemia (HTG).

Results

The −482 and −455 polymorphisms were significantly more frequent in FD patients (P = 0.017) and endogenous HTG patients (P < 0.0001) than in CHL patients and a control group. The SstI polymorphism was only significantly more frequent in HTG patients (P < 0.0001). However, we did not find differences in frequencies for these polymorphisms in the APOC3 gene between CHL patients and a control group. Haplotype analysis indicates that the SstI polymorphism arose on the allele containing both promoter polymorphisms.

Conclusion

The haplotype containing the SstI polymorphism is found five times more frequently among HTG patients (OR 5.28, 95% CI 1.65–16.90), which strongly suggests it is associated with an increased risk for severe hypertriglyceridaemia.
Endothelin‐1 receptor antagonism does not influence myocardial function in hypertensive dogs
Authors: Massart  , Hodeige  , Van Mechelen  , Heyndrickx  , Donckier
Published: March 2003

Background

As endothelin‐1 exerts positive inotropic effects, the present study evaluated whether the hypotensive effects of the endothelin‐1 receptor antagonist bosentan were partially related to a decrease in myocardial performance.

Methods

In group I, eight anaesthetized open‐chest dogs with perinephritic hypertension received four cumulative doses of bosentan (B1–B4). In group II, eight animals received the same doses of bosentan after autonomic blockade. Indices of heart function were derived from the pressure–length loops obtained during vena cava occlusion.

Results

In group I, bosentan decreased left ventricular systolic pressure (LVSP) and mean aortic pressure (MAP) dose dependently, reaching 21% and 23% respectively at B4 (LVSP from 190 ± 8 to 150 ± 5 mmHg, P < 0.001; MAP from 167 ± 7 to 128 ± 5 mmHg, P < 0.001). These effects were only related to peripheral vasodilatation, without depression of myocardial contractility, as systemic vascular resistance dropped (from 670 ± 83 to 446 ± 53 mmHg mL−1 min−1 × 104; P < 0.05), and the end‐systolic pressure–length relationship (ESPLR) remained unchanged (4.0 ± 0.4 vs. 4.3 ± 0.7 mmHg mm−1 kg−1). Concomitantly with pressure decline, heart rate tended to increase in this group (from 150 ± 4 to 156 ± 6 beats min−1). When autonomic system was blocked (group II), administration of bosentan induced similar hypotensive effects as in group I (26% and 28% reduction in LVSP and MAP respectively, P < 0.001) whereas ESPLR did not change (3.0 ± 0.9 vs. 3.1 ± 0.5mmHg−1 mm kg−1 ). Under these sympathetically blocked conditions, heart rate significantly fell after bosentan infusion (from 120 ± 4 to 110 ± 6 beats min−1, P < 0.001).

Conclusions

Without influencing heart function, bosentan is an efficient and safe therapy that opens up new therapeutic perspectives in human essential hypertension.
Acute hyperglycaemia causes severe disturbances of mesenteric microcirculation in an in vivo rat model
Authors: Schäffler  , Arndt  , Schölmerich  , Palitzsch
Published: March 2003

Background

Chronic hyperglycaemia in diabetes is suggested to be a major cause of diabetic angiopathy. Up until now, the effects of acutely induced hyperglycaemia in non‐diabetic subjects as well as hyperglycaemic effects in early diabetes, on mesenteric microcirculation and leucocyte endothelial cell interaction have not been investigated extensively.

Methods

The aim of this study was to examine rat mesenteric microcirculatory parameters such as leucocyte adhesion, leucocyte emigration, venular shear rate and leucocyte rolling velocity using a new rat model both with continuous venous glucose infusion and with continuous arterial measurement of blood glucose concentration while observing mesenteric microcirculation with in vivo capillary microscopy in the non‐diabetic and diabetic state.

Results

In normal non‐diabetic rats, acute elevation of glucose concentration resulted in a highly significant, rapid and step‐by‐ step enhancement of adhesion and emigration in a dose dependent manner. Leucocyte rolling velocity was reduced with rising glucose levels. Venular shear rate showed a similar reduction at all hyperglycaemic levels. In streptozotocin‐induced diabetes, adhesion and emigration were significantly enhanced while shear rate and leucocyte rolling velocity were severely reduced, resembling the effects of glucose infusion experiments. Longer duration of diabetes resulted in a further enhancement of leucocyte adhesion and reduction of leucocyte rolling velocity while emigration and shear rate were not influenced by a longer period of diabetes manifestation.

Conclusion

Experiments using different mannitol concentrations revealed that most of the observed glucose effects can be mimicked by mannitol and are therefore — at least in part — due to changes in osmolarity by yet unknown mechanisms.
Repaglinide, a new oral antidiabetic agent: a review of recent preclinical studies
Authors: Malaisse
Published: March 2003

Repaglinide is a new carbamoylmethyl benzoic acid derivative that is structurally related to meglitinide. In common with all active oral hypoglycaemic agents, it displays a comparable U‐shaped configuration. Repaglinide exerts its effects by binding to a site on the plasma membrane of β‐cells, thereby closing ATP‐sensitive potassium channels. This causes depolarization of the β‐cell and the opening of voltage‐sensitive calcium channels allowing the influx of extracellular calcium ions. This increase in intracellular calcium, in turn, stimulates insulin release. The insulinotropic effect of repaglinide is not related to its ionophoretic capacity. Repaglinide does not cause insulin release in the absence of exogenous glucose, nor does it inhibit the biosynthesis of proinsulin. In vivo administration of an ester of succinic acid potentiates the insulin secretory response to concomitantly administered repaglinide. Repaglinide causes a more rapid increase in plasma insulin levels in rats than either glibenclamide or glimepiride.
Do only circulating pyrogenic cytokines act as mediators in the febrile response? A hypothesis
Authors: Netea  , Kullberg  , Van der Meer
Published: March 2003

The classical model of the pathogenesis of fever suggests that pyrogenic cytokines, produced by leucocytes in the bloodstream in response to exogenous pyrogens, represent the distal mediators of the febrile response. They are recognized at the level of the organum vasculosum of the lamina terminalis in the central nervous system, where they induce synthesis of protaglandins representing the central mediators of the coordinated responses leading to fever. This classical model is challenged by studies showing inconsistencies between the febrile response and the cytokine pattern, as well as by data demonstrating paradoxical hyperfebrile reactions in knock‐out mice lacking cytokines or cytokine receptors. Moreover, no measurable cytokine concentrations are to be found in a variety of specific patients groups with febrile conditions. There are recent data in the literature suggesting that alternative pathways may be involved in the induction of fever, ranging from the use of vagal fibres to transmit the signals leading to fever, to local production of cytokines at the level of the hypothalamus, or the use of membrane‐bound cytokines as mediators. A multipathway mechanism for the induction of fever is suggested.
Effects of spiroglumide, a gastrin receptor antagonist, on acid secretion in humans
Authors: Beltinger J. , Hildebrand P. , Drewe J. , Christ A. , Hlobil K. , Ritz M. , D'Amato M. , Rovati L. , Beglinger C.
Published: March 2003

Background

A gastrin receptor antagonist, CR2194 (spiroglumide), was used to explore the physiological role of gastrin in regulating gastric acid secretion in humans.

Materials and methods

The effect of CR2194 on inhibition of gastrin‐stimulated acid output was evaluated in a four‐period crossover study. Each subject received intravenous doses of 1, 2.5 or 7.5 mg kg−1 h−1 CR2194 or saline (control) followed by graded increasing doses of gastrin (6.4–800 pmol kg−1 h−1). Secondly, the effect of CR2194 on meal‐stimulated intragastric acidity was evaluated by infusing either saline (control) or CR2194 (7.5 mg kg−1 h−1) before and after food ingestion.

Results

Acid secretion was dose‐dependently inhibited by CR2194. With CR2194, acidity was significantly reduced in the pre‐meal and post‐prandial period (P < 0.01 and 0.002 respectively), and the integrated gastrin response was augmented to 8.0 ± 1.4 ng mL−1 240 min compared with 1.5 ± 0.8 ng mL−1 240 min in the control experiment (P < 0.01). Finally, acid secretion in response to sham feeding was significantly reduced: 15.9 ± 0.9 mmol 90 min−1 in the control experiment compared with 2.8 ± 0.9 mmol 90 min−1 during CR2194 infusion (P < 0.05).

Conclusion

Gastrin receptor blockade with CR2194 alters gastric acid secretion in response to food ingestion or to sham feeding. The results support a physiological role for gastrin in regulating acid secretion in humans.
Proteolytic destruction of functional proteins by phagocytes in human peritonitis
Authors: Jochum  , Billing  , Fröhlich  , Schildberg  , Machleidt  , Cheronis  , Gippner‐Steppert  , Fritz
Published: March 2003

Background

Besides phagocyte‐derived oxidative autoaggression, proteolytic destruction of functional proteins in the peritoneal cavity may also be involved in the pathomechanism of secondary peritonitis. To evaluate the pattern of proteolysis, 43 patients undergoing initial operation for acute peritonitis (n = 30) or scheduled abdominal lavages (Etappenlavage) for resolution of persistent peritonitis (n = 13) and 16 surgical patients with abdominal exudation without peritonitis were enrolled in our study.

Materials and methods

Thirty blood samples and purulent exudates were taken simultaneously in each peritonitis group at the surgical interventions. Sixteen clear exudates were obtained from patients with post‐operative non‐infectious irritations. The following parameters were measured: (a) elastase (from neutrophils) and cathepsin B (from monocytes/macrophages); (b) α1‐proteinase inhibitor (α1PI) and overall cysteine proteinase inhibitor capacity; and (c) opsonic activity and degradation products of fibrinogen, complement C3 and immunoglobulin IgG.

Results

Circulating levels of phagocyte proteinases and of α1PI were significantly elevated, whereas antigen concentrations and opsonic activity of C3 and IgG were slightly reduced in peritonitis patients compared to healthy volunteers. No degradation products were detectable in patients’ blood. Discharge of phagocyte proteinases was even more pronounced in both types of peritonitis exudates. Although most of the elastase was complexed with α1PI, active elastase and its specific fibrinogen split product was found along with significantly reduced inhibitory capacity for elastase and cysteine proteinases. Local opsonic activity was dramatically diminished because of proteolytic degradation of C3 and IgG. Despite some phagocyte proteinase release, no destruction of functional proteins was seen in clear exudates.

Conclusions

Higher values of extracellularly released phagocyte proteinases concomitant with lower opsonin activity in exudates from patients with persistent peritonitis can be taken as a further hint of the involvement of local proteolysis‐induced pathomechanisms in the development of lethal multiple organ failure, which occurred more frequently in patients with persistent peritonitis (54%) than in those with acute peritonitis (27%).
Effects of tumour necrosis factor α and melphalan on the cytokine production of circulating T cells in patients with cancer
Authors: Stam  , M. Eggermont  , G. Swaak
Published: March 2003

Background

The objective of the present study was to investigate the effects of isolated limb perfusion (ILP) with tumour necrosis factor α (TNF‐α) and melphalan on circulating T cells from cancer patients using two different methods.

Design

Eight patients undergoing an ILP entered the study. At first, the number of T cells at several time points was determined using FACScan. Subsequently, production of interferon gamma (IFN‐γ) (T‐helper 1) and interleukin (IL) 4 (T‐helper 2) was measured at the intracytoplasmic level after stimulation with phorbol 12‐myristate 13‐acetate (PMA) and ionomycin. IFN‐γ, IL‐4 and IL‐2 (also T‐helper 1) production in the whole‐blood cell culture system was then determined after stimulation with a combination of anti‐CD3/anti‐CD28 monoclonal antibodies.

Results

An enormous decrease in the number of circulating T cells was observed. In the remaining T‐cell population cytokine production (IL‐2, IL‐4, IFN‐γ) was depressed, showing the same pattern in both methods. No difference could be detected between the effect of TNF‐α and melphalan on Th1 cells and Th2 cells.

Conclusions

The results demonstrate that TNF‐α and melphalan reduce the number of circulating T cells and at the single‐cell level decrease cytokine production in the remaining circulating T cells. No selective effect of TNF‐α on Th1 or Th2 cells could be detected. If the impaired T‐cell function is representative of all T cells remaining in the systemic circulation, this could help to explain the tolerability of high TNF concentrations after ILP, perhaps by decreasing the synthesis and production of T‐cell‐derived cytokines.
Effect of inhibiting HMG‐CoA reductase on 7α‐hydroxy‐4‐cholesten‐3‐one, a marker of bile acid synthesis: contrasting findings in patients with and without prior up‐regulation of the latter pathway
Authors: Naoumova  , O'Neill  , Dunn  , Neuwirth  , Taylor  , Axelson  , Thompson
Published: March 2003

Background

Atorvastatin is a potent inhibitor of 3‐hydroxy‐3‐methyl‐glutaryl coenzyme A reductase, but its effect on bile acid synthesis is unknown. The objectives of the study were to determine the effect of atorvastatin on bile acid synthesis in patients in whom this process had not been or had been previously up‐regulated by pharmacological or surgical means.

Materials and methods

Four patients with heterozygous familial hypercholesterolaemia (FH) and partial ileal bypass (PIB) and 19 FH heterozygotes without PIB were treated with placebo, atorvastatin 10 mg and atorvastatin 40 mg daily, each regimen for 4 weeks. The non‐PIB group was subsequently treated with bile acid (BA) sequestrant 8–16 g daily followed by co‐administration of atorvastatin 10 mg, each for 4 weeks. Plasma 7α‐hydroxy‐4‐cholesten‐3‐one (7α‐HCO), a well‐validated marker of BA synthesis was measured using high‐performance liquid chromatography with UV detection.

Results

The plasma 7α‐HCO concentration was tenfold higher with placebo in the PIB than in the non‐PIB group (418.5 ng mL−1 vs. 39.6 ng mL−1P = 0.0001). Levels decreased in PIB patients treated with atorvastatin 10 mg and 40 mg daily (350.1 ng mL−1 and 174.0 ng mL−1, P = 0.007 respectively) but did not change significantly in the non‐PIB group (44.7 ng mL−1 and 28.3 ng mL− respectively). Administration of BA sequestrant to non‐PIB patients increased 7α‐HCO to 197.4 ng mL−1; this decreased to 106.0 ng mL−1 during co‐administration of atorvastatin 10 mg daily (P = 0.0001).

Conclusion

Atorvastatin decreases the rate of BA synthesis only if the latter is up‐regulated by PIB or BA sequestrants, presumably by limiting the supply of newly synthesized free cholesterol.
Impaired antiplatelet effects of aspirin associated with hypoxia and ATP release from erythrocytes. Studies in a system with flowing human blood
Authors: Bozzo  , Hernández  , Galán  , Heras  , Ordinas  , Escolar
Published: March 2003

Background

We have explored how hypoxic conditions may affect the antiplatelet effects of aspirin.

Materials and methods

For this purpose, a perfusion system containing a damaged vessel segment was modified in order to induce hypoxia (low Po2) in flowing blood. Blood samples were incubated with 50 μmol L−1 aspirin and divided into two aliquots, one being perfused under standard conditions (normoxic) and the other under hypoxic conditions. The interaction of platelets with the subendothelium was morphometrically evaluated.

Results

In studies with untreated blood under normoxic conditions, platelet interaction with the subendothelium was 0.3 ± 0.1% of contact, 5.3 ± 1.6% of adhesion, 24.3 ± 3.3% of thrombus and 29.9 ± 2.7% of total covered surface. Aspirin‐treated blood perfused under normoxic conditions showed a marked decrease in thrombus with a concomitant increase in both platelet adhesion and covered surface percentages. However, when aspirin‐treated blood was perfused under hypoxic conditions, platelet interaction was not significantly different from that observed in untreated blood. Hypoxia induced a 10‐fold increase in ATP release from erythrocytes in the perfusates. If apyrase was added to the perfusates, ATP release was prevented and aspirin effects were evident again.

Conclusion

Our results suggest that, under hypoxic conditions, the presence of aspirin would not help to inhibit further platelet activation.
Differences between men and women in the response of serum cholesterol to dietary changes
Authors: Weggemans  , Zock  , Urgert  , Katan
Published: March 2003

Background

Hypercholesterolaemia is initially treated by diet. However, most studies of diet and cholesterol response have been carried out in men, and it is not known whether women react to diet to the same extent as men do. We therefore studied sex differences in the response of serum cholesterol and lipoproteins to diet.

Materials and methods

We measured the responses of serum cholesterol to a decrease in dietary saturated fat in seven trials involving 126 men and 147 women, to a decrease in dietary trans fat in two trials (48 men and 57 women) and to a decrease in dietary cholesterol in eight trials (74 men and 70 women). We also measured responses to the coffee diterpene cafestol, which occurs in unfiltered coffee, in nine trials (72 men and 61 women). All subjects were lean and healthy.

Results

The response of total cholesterol (± standard deviation) to a decrease in the intake of saturated fat was greater in men (−0.62 ± 0.39 mmol L−1) than in women (−0.48 ± 0.39 mmol L−1; 95% confidence interval, 0.04–0.23 mmol L−1). The response of total cholesterol to a decrease in the intake of cafestol was also larger in men (−1.01 ± 0.49 mmol L−1) than in women (−0.80 ± 0.49 mmol L−1; 95% confidence interval, 0.04–0.39 mmol L−1). Responses to trans fat and to dietary cholesterol did not differ between men and women.

Conclusion

Men have larger responses of total and low‐density lipoprotein cholesterol to saturated fat and cafestol than women do.
Detection of WT1 mRNA in urine from patients with kidney diseases
Authors: Kubo  , Miyagawa  , Yamamoto  , Hamasaki  , Kanda  , Fujita  , Yamamoto  , Yazaki  , Mimura
Published: March 2003

Detachment of glomerular epithelial cells (GEC) from glomerular basement membrane (GBM) could account for a part of the pathogenic mechanism of proteinuria seen in primary and secondary renal diseases. The Wilms' tumour suppresser gene (WT1) is strictly expressed in GEC in the adult kidney. Mutations of WT1 gene have been implicated in progressive renal damage. Utilizing nested RT‐PCR we detected mRNA of WT1 in the urine of patients with renal diseases. Seven of 20 (35%) chronic glomerulonephritis (CGN), eight of 20 (40%) diabetes mellitus (DM) with proteinuria, and two of 24 (8.3%) rheumatic diseases were WT1 positive. Interestingly, only one of 51 (2%) DM without proteinuria was WT1 positive. None of the healthy volunteers or cystitis patients were WT1 positive. This is the first report describing the detection of endogenous WT1 mRNA, an important gene in progressive renal failure, from patients' urine. This technique could be a powerful tool in the search for information about glomerular damage in clinical settings as well as for WT1 mutations or isoform imbalance at the research level without renal biopsy.
Nef protein induces differential effects in CD8+ cells from HIV‐1‐infected patients
Authors: Silvestris  , Camarda  , Del Prete  , Tucci  , Dammacco
Published: March 2003

Background

The Nef protein of HIV‐1 is suspected to play a role in the depletion of uninfected CD4+ lymphocytes that leads to AIDS. By contrast its effect on CD8+ cells, whose functions are also deregulated during HIV‐1 infection, is presently unclear. Here we describe a number of derangements induced in vitro by Nef in CD8+ cells from HIV‐1‐infected patients.

Design

Peripheral lymphocytes from 16 HIV‐1+ subjects and 9 uninfected individuals were cultivated on a Nef‐transfected mouse fibroblast layer exposing the carboxyl‐terminal region of the viral protein on cell membrane. The cultures were then measured for both apoptosis and proliferation by subdiploid DNA content and Ki67 expression, respectively, whereas the molecular analysis of purified CD8+ cells investigated the Fas‐L mRNA levels in Nef‐treated CTLs. In addition, we evaluated the Nef‐induced variation in the extent of CD8+/HLA‐DR+ subset, which includes non cytotoxic cells secreting T‐cell antiviral factor (CAF) and a soluble factor inhibiting the HIV‐1 replication.

Results

The viral protein induced in peripheral blood lymphocytes (PBL) a moderate tendency to proliferate, as measured by the increment of Ki67 antigen, particularly on the CD8+ subset of HIV‐1 infected individuals (P < 0.05). This profile was particularly evident in cultures from patients with severe CD4+ lymphopenia and paralleled an apparent expansion of the CD8+/CD57+ suppressor cell subset. Molecular analysis of purified CD8+ cells revealed a defective expression of Fas‐L mRNA in Nef‐cultured CTLs, whereas the viral protein exerted a down modulatory effect on the CD8+/HLA‐DR+ subset (P < 0.05), thus suggesting a potential inhibition of CAF.

Conclusions

These results support a potential role of Nef in the progression of HIV‐1 infection as a number of cellular functions are affected in the CD8+ subset. In particular, the defective functions of CD8+ cells induced by the viral protein could contribute, at least partly, to the escape of HIV‐1 from the immune control of these cells.
Renal hemodynamic changes during smoking: effects of adrenoreceptor blockade
Authors: Benck  , Clorius  , Zuna  , Ritz
Published: March 2003

Background

Cigarette smoking accelerates progression of renal failure in diabetic and nondiabetic renal disease. Renal hemodynamics during smoking are characterised by a reversible decrease in glomerular filtration rate (GFR) and filtration fraction (FF) accompanied by increased renovascular resistance (RVR), systemic blood pressure, heart rate and plasma catecholamine concentrations.

Materials and methods

To further assess the role of sympathetic overactivity we compared the effects of different pharmacological interventions on smoking‐induced changes of renal hemodynamics in occasional smokers. In a first series, placebo pretreatment plus smoking was compared to Prazosin pretreatment (3 mg) plus smoking. In a second study, placebo pretreatment plus smoking was compared to Atenolol pretreatment (50 mg) plus smoking.

Results

Basal blood pressure was significantly lower with Prazosin and Atenolol. On placebo, GFR and FF decreased significantly during smoking and RVR increased. With Prazosin pretreatment compared to placebo pretreatment no statistically significant differences for the changes of GFR, FF, RPF and RVR were seen. In contrast, with Atenolol pretreatment compared to placebo pretreatment, the smoking‐induced changes in active renin, GFR and RVR were significantly smaller.

Conclusion

It is suggested that the acute renal hemodynamic effects of smoking are mediated, at least in part, via increased sympathetic activity operating mainly through beta‐1 adrenergic mechanisms.
Vitamin E supplementation in hyperlipidaemic patients: effect of increasing doses on in vitro and in vivo low‐density lipoprotein oxidation
Authors: Wen  , Killalea  , Norris  , Cooke  , Feely
Published: March 2003

Background

Vitamin E supplementation is associated with a reduced risk of developing atherosclerotic events; probably because it inhibits low‐density lipoprotein (LDL) oxidation, an initial step in atherosclerosis. Metal ion‐dependent LDL oxidation is a commonly used method to estimate oxidizability of LDL, but the effect of antioxidant supplementation on the levels of autoantibodies to oxidised LDL (ox‐LDL), an in vivo indicator of LDL oxidation, is unknown.

Design

This double‐blind, placebo‐controlled study investigated the susceptibility of LDL to copper induced oxidation and malondialdehyde (MDA) derivatized‐LDL (MDA‐LDL) in hyperlipidaemic patients on supplements of vitamin E. The vitamin E group (n = 20) took vitamin E 100 IU daily and the dose was doubled at six‐weekly intervals to 1600 IU daily. The control group (n = 17) received placebo in the same fashion. Blood samples were obtained at baseline and each subsequent visit to measure vitamin E status and oxidation of LDL.

Results

A significant increase in both α‐tocopherol levels and the lengths of lag phase was seen in the vitamin E group after first week of supplementation (100 IU day−1). This continued to rise in a dose‐dependent fashion with a doubling of the lag phase on 1600 IU daily. However, the titre of antibodies to MDA‐LDL was not altered.

Conclusions

The results suggest that although regarded as an in vivo marker of LDL oxidation, antibodies to MDA‐LDL may not be a suitable measure to evaluate the effect of short‐term antioxidant supplementation. The failure of autoantibody titres to fall despite reduced oxidizability of LDL may possibly be attributable to a long half‐life of the antibody or, once initiated, a continuous immunological response to ox‐LDL contained in atherosclerotic lesions of the arterial wall.
rhIGF‐I/IGFBP‐3 complex, but not free rhIGF‐I, supports muscle protein biosynthesis in rats during semistarvation
Authors: Svanberg  , Ohlsson  , Kimball  , Lundholm
Published: March 2003

Background

The aim of this study was to evaluate the effect of insulin like growth factor‐I (rhIGF‐I) in complex with binding protein 3 (IGFBP 3) compared to the effect of free IGF‐I on muscle protein biosynthesis in undernourished animals.

Methods

Three groups of female Sprague–Dawley rats (200 g) were initially semi‐starved for 3 days and then treated with saline (controls), rhIGF‐I (1 μg g−1) or equimolar amounts of rhIGF‐I/rhIGFBP‐3 complex (5 μg g−1) i.v. twice daily for 3 days during continuous semistarvation. Protein metabolism in hind limb skeletal muscle was studied by incorporation of L‐[14C‐U]phenylalanine into proteins, western blot determination of translation initiation factors involved in the binding of the 40S ribosomal subunit to mRNA, and quantification of mRNA content for IGF‐I, IGF‐IR and GH‐R. Plasma measurements of insulin, IGF‐I and amino acids were also performed.

Results

rhIGF‐I/rhIGFBP‐3, but not rhIGF‐I alone, stimulated protein synthesis by 177 ± 26% (P ≤ 0.05) in semi‐starved rats. This stimulation was associated with dissociation of the 4E‐BP1.eIF‐4E complex, implicating increased binding of the 40S ribosomal subunit to mRNA, and hence increased initiation of protein synthesis in these animals. Muscle content of IGF‐I mRNA was reduced in semi‐starved animals, whereas IGF‐I receptor mRNA was unaltered despite food restriction. Plasma concentration of IGF‐I was 20% (P ≤ 0.05) higher in rhIGF‐I/rhIGFBP‐3 treated animals as compared to rats treated with saline or free IGF‐I. Plasma concentrations of amino acids were increased in rhIGF‐I/rhIGFBP‐3 treated animals (P ≤ 0.05 vs. semi‐starved controls).

Conclusion

rhIGF‐I/rhIGFBP‐3 (SomatoKine) was a significant stimulator of muscle protein synthesis in chronically semi‐starved animals whereas IGF‐I alone failed to increase protein synthesis during the same experimental conditions. This stimulation was because of increased initiation of translation, likely induced by more physiologic concentrations/kinetics of plasma IGF‐I and amino acids following rhIGF‐I/rhIGFBP‐3 treatment, compared to IGF‐I in its free form.
Serum homocysteine is weakly associated with von Willebrand factor and soluble vascular cell adhesion molecule 1, but not with C‐reactive protein in type 2 diabetic and non‐diabetic subjects — The Hoorn Study
Authors: Becker  , Van Hinsbergh  , Kostense  , Jager  , Dekker  , Nijpels  , Heine  , Bouter  , Stehouwer
Published: March 2003

Background

Hyperhomocysteinaemia may constitute an independent risk factor for cardiovascular disease, but it is still unclear by which pathophysiological mechanisms homocysteine (tHcy) may promote atherothrombosis. The aim of this study was firstly to examine whether tHcy is associated with endothelial dysfunction, increased adherence of leukocytes, and/or chronic low‐grade inflammation, as estimated from plasma levels of von Willebrand factor (vWf), soluble vascular cell adhesion molecule 1 (sVCAM‐1) and C‐reactive protein (CRP), respectively. Secondly we investigated whether the presence of type 2 diabetes modifies these associations.

Materials and Methods

Six hundred and ten subjects of a general population of middle‐aged and elderly subjects, 170 of whom had type 2 diabetes, participated in this cross‐sectional study. Linear regression analyses were used to study whether tHcy was associated with vWf, sVCAM‐1 and CRP, and whether the presence of diabetes modified these associations.

Results

After adjustment for confounders, tHcy was significantly but weakly associated with vWf (β = 0.15, P = 0.05) and sVCAM‐1 (β = 0.082, P = 0.04). tHcy was not significantly associated with CRP (β = 0.02, P = 0.91). The presence of diabetes did not significantly modify these associations.

Conclusions

This study provides evidence that tHcy is, at most, weakly associated with endothelial dysfunction as estimated from plasma vWf, and with leukocyte adhesion as estimated from plasma sVCAM‐1. tHcy was not significantly associated with chronic low‐grade inflammation as estimated from plasma CRP. Our data thus suggest that the link between tHcy and atherothrombosis cannot be explained by associations of tHcy with vWf, sVCAM‐1 or CRP.
Apolipoproteins A–I, A–II and B, lipoprotein(a) and the risk of ischaemic heart disease: the Caerphilly Study
Authors: Sweetnam P. M. , Bolton C. H. , Downs L. G. , Durrington P. N. , Mackness M. I. , Elwood P. C. , Yarnell J. W. G.
Published: March 2003

Apolipoproteins B, A–I and Lp(a) have been proposed as independent predictors of subsequent ischaemic heart disease (IHD) improving on the prediction obtained by routine lipid measurements. In this report we have investigated the relative predictive ability of apolipoproteins and plasma lipids in a prospective study of middle aged men.

2398 men aged 49–65 years from the general population of Caerphilly, South Wales, UK were screened for evidence of IHD. After an overnight fast 2225 men each provided a venous blood sample on which plasma lipids, apolipoproteins B, A–I, A–II, and lipoprotein (a) (Lp(a)) were measured.

Over a follow‐up period of nearly 9 years, 282 (12%) men developed major IHD. Multiple logistic regression analysis showed that after adjusting for standard cardiovascular risk factors other than lipids there was a strong trend (standardised relative odds (SRO) = 1·20; P = 0·009) for incidence of IHD to increase with apolipoprotein B. However, on further adjusting for total cholesterol this trend largely disappeared (SRO = 1·05; P = 0·57). Similarly, a trend for incidence of IHD to increase with decreasing apolipoprotein A–I (SRO = 1·18; P = 0·02) disappeared when HDL cholesterol was added to the model. Levels of apolipoprotein A–II were not related to risk of subsequent IHD. Incidence of IHD was effectively constant over nearly 90% of the range of Lp(a). Only among the 5% of men with Lp(a) greater than 70 mg dL−1 was the risk of IHD significantly (P = 0·04) greater than among men with Lp(a) less than 10 mg dL−1.

Apolipoproteins B and A–I do not improve on the prediction of risk of IHD provided by total and HDL cholesterol, respectively. Apolipoprotein A–II was not related to risk of IHD. Lp(a) may be independently associated with incident IHD among the 5–10% of men with the highest levels.
Hepatic damage in C282Y homozygotes relates to low numbers of CD8+ cells in the liver lobuli
Authors: Cardoso E. M. P. , Hagen K. , De Sousa M. , Hultcrantz R.
Published: March 2003

Background Although most Caucasian patients with hereditary haemochromatosis (HH) show the same mutation in the HFE gene, the phenotypic expression of the disease varies greatly. We have previously shown that patients with HH who have high iron stores have low numbers of circulating CD8+ T lymphocytes.

Patients and methods Liver and peripheral blood were studied in 37 C282Y homozygous HH patients; nine normal livers and 11 livers from patients with cirrhosis due to hepatitis C virus or alcoholic liver disease were also investigated. Eleven jejunal biopsies from HH patients and 17 normal biopsies were studied. The numbers of CD8+ cells were determined in peripheral blood by fluorescence‐activated cell sorting analysis, and in the liver or small intestine by immunohistochemistry.

Results In HH patients the number of CD8+ T lymphocytes in peripheral blood correlated significantly with the number of CD8+ cells in the liver lobuli but not with that in the small intestine. Body iron stores correlated negatively with the number of CD8+ T lymphocytes in peripheral blood and in the liver, but not with the number in the small intestine. HH patients with cirrhosis had the lowest CD8+ cell count in liver sections, in contrast with other forms of cirrhosis.

Conclusion The results indicate that HH patients with the HFE C282Y mutation and low numbers of CD8+ cells in the liver lobuli have higher iron stores and are more prone to develop liver cirrhosis.
Effect of acute exogenous hyperinsulinaemia on very low density lipoprotein subfraction composition in normal subjects
Authors: Annuzzi G. , Iovine C. , Mandarino B. , Patti L. , Di Marino L. , Riccardi G. , Rivellese A. A.
Published: March 2003

Subtle abnormalities of very‐low‐density lipoprotein (VLDL) composition and distribution seem to be associated with increased cardiovascular risk. The aims of this study were first, to evaluate whether hyperinsulinaemia per se is able to produce VLDL abnormalities and second, whether this occurs through a stimulation of lipolytic enzymes.

Eight normal male volunteers, age 36 ± 7 years (M ± SD), body mass index (BMI) 26±3 kg m−2, underwent a 5‐h euglycaemic hyperinsulinaemic clamp (1·2 mU insulin/kg b.w. min−1). Nine sex, age and BMI comparable subjects underwent control experiments (saline infusion). Three VLDL subfractions of decreasing size were isolated by density gradient ultracentrifugation; lipoprotein lipase (LPL) and hepatic lipase (HL) post‐heparin plasma activities were determined by the 3H‐labelled triolein method.

Hyperinsulinaemia (∼65 mU mL−1) produced the expected plasma free fatty acid suppression. Triglyceride levels were reduced in total VLDL (− 27 ± 32% vs. + 38 ± 52% after saline, P < 0·05) and in the larger VLDL (− 56 ± 19 vs. + 34 ± 38, P < 0·001). Moreover the relative contribution of the larger subfraction was decreased (− 39 ± 15% vs. − 3 ± 21%, P < 0·01), while the percentage of smaller particles was increased (+17 ± 20 vs. − 9 ± 22, P < 0·05). LPL and HL activities were decreased to the same degree during either insulin or saline infusion.

Exogenous hyperinsulinaemia produced lipoprotein abnormalities partially similar to those previously shown in type 1 diabetic patients, indicating that these abnormalities may be secondary to insulin therapy.
Macrophage migration inhibitory factor in the sera and at the colonic mucosa in patients with ulcerative colitis: clinical implications and pathogenic significance
Authors: Murakami H. , Akbar SK. MD. Fazle , Matsui H. , Onji M.
Published: March 2003

Background Inflammatory cytokines produced by activated macrophages are implicated in the pathogenesis of ulcerative colitis (UC). With the theory that macrophage migration inhibitory factor (MIF) may have a role in the accumulation of macrophages, we studied MIF in UC.

Materials and methods A total of 27 patients with UC, 14 patients with Crohn's diseases (CD), 11 patients with other forms of colitis and 26 normal controls were enrolled in the study. The levels of MIF in the sera and culture supernatant were measured by an enzyme‐linked immunosorbent assay. MIF, macrophages and T cells were localized at the colonic mucosa by immunohistochemistry.

Results The levels of MIF in the sera were significantly higher in UC than in normal controls (P < 0·05), in serum C‐reactive protein (CRP) ‐positive cases with UC than in CRP‐negative cases with UC (P < 0·05), and in patients with severe colitis with UC than in mild colitis with UC (P < 0·05). There was a positive relationship between serum MIF levels with the CRP levels and activities of colitis. However, the levels of MIF in patients with CD and other forms of colitis were not significantly different from their levels in normal controls and UC. Infiltrating cells at the colonic mucosa in UC and CD expressed MIF.

Conclusions These data suggest a role of MIF in the pathogenesis of UC. MIF may be used as a marker of disease activity in UC and control of MIF production may have therapeutic implications.
Noninvasive diagnosis of the degree of hepatic fibrosis using ultrasonography in patients with chronic liver disease due to hepatitis C virus
Authors: Hirata M. , Akbar S. M. F. , Horiike N. , Onji M.
Published: March 2003

Background Chronic liver disease is characterized by progressive hepatic fibrosis and changes in hepatic haemodynamics. This study has addressed the possibility of a noninvasive diagnosis of the degree of hepatic fibrosis by evaluating the velocity of blood in the hepatic vasculature.

Materials and methods The maximum velocity of blood at the portal vein and hepatic artery was measured in 80 patients with chronic liver diseases (19 with liver cirrhosis; 61 with chronic hepatitis) and in 20 normal volunteers by Doppler ultrasonography. The arterio‐portal ratio (A/P ratio) was calculated by dividing the maximum velocity of blood (Vmax) in the hepatic artery with the Vmax in the portal vein. Multivariate analysis was used to disclose the independent predictors of the degree of hepatic fibrosis.

Results The levels of A/P ratio were significantly higher in patients with liver cirrhosis (LC) compared to those with chronic hepatitis (CH) and normal controls. Probit analysis revealed that the value of A/P ratio at which CH becomes LC was A/P ≥ 3·5. The levels of A/P ratio were also significantly higher in patients with severe fibrosis compared with mild (P < 0·0001) and moderate (P < 0·0001) fibrosis. Multivariate analysis disclosed right A/P ratio (P = 0·0001), left A/P ratio (P = 0·013), and platelet counts (P = 0·0172), as the only independent predictors of the degree of hepatic fibrosis.

Conclusions A/P ratio may be used for the noninvasive diagnosis of the degree of hepatic fibrosis in patients with chronic liver diseases.
Two newly identified SNPs in the APO AI‐CIII intergenic region are strongly associated with familial combined hyperlipidaemia
Authors: Groenendijk M. , Cantor R. M. , Funke H. , Dallinga‐Thie G. M.
Published: March 2003

Background We previously reported linkage and association of the apoAI‐CIII‐AIV gene region on chromosome 11 with familial combined hyperlipidaemia (FCHL). However, the observed epistasis resulting in an increased susceptibility to FCHL still remains unexplained. We hypothesize that the region between the apo AI and apo CIII genes may harbour functional mutations that might be in linkage disequilibrium with the already identified SstI and MspI polymorphisms, and provide an alternative explanation for the observed relationship.

Methods Using sequence analysis, we identified four new single nucleotide polymorphisms (SNPs) in the apo AI‐CIII intergenic region. These four variants, T3213C, A3235C, T3287C and A5132C, were studied in 30 FCHL probands, 159 hyperlipidaemic relatives, 327 normolipidaemic relatives, and 218 spouses from the same families in which the original results were obtained.

Results The allele frequencies were significantly different between probands and spouses (P < 0·05). Transmission/disequilibrium test (TDT) analyses revealed more frequent transmission of the minor alleles to the affected offspring. The minor genotype was associated with elevated plasma cholesterol and triglyceride levels. The T3213C and MspI, and the A3235C and SstI SNPs were in complete linkage disequilibrium, resulting in two different major haplotypes 2‐2‐1‐2‐2‐1 and 1‐1‐2‐2‐2‐2 (MspI‐T3213C‐A3235C‐T3287C‐A5132C‐SstI). Both haplotypes appear to predispose to FCHL independently, and account, together with the wild‐type, for almost 90% of those occurring in these FCHL families, extending the high‐risk combination of haplotypes that were reported previously.

Conclusion These newly identified additional intergenic SNPs therefore provide an alternative explanation for the observed association of the SstI and MspI polymorphisms to the increased susceptibility for FCHL.
In vitro effect of advanced glycation end‐products on human polymorphonuclear superoxide production
Authors: Bernheim J. , Rashid G. , Gavrieli R. , Korzets Z. , Wolach B.
Published: March 2003

Background Advanced glycation end‐products (AGEs) are elevated in the sera of diabetic patients. The latter are prone to severe bacterial infections. Advanced glycation end‐products have been shown to modulate immune competent cell activities. In this study we examined the in vitro effect of advanced glycation end‐products on superoxide anion generation by human polymorphonuclear leukocytes.

Materials and methods Advanced glycation end‐products were prepared by incubation of bovine serum albumin (BSA) with glucose for 90 days. Superoxide production was measured as the superoxide dismutase‐inhibitable reduction of ferricytochrome c. The effect of advanced glycation end‐products on superoxide production was evaluated in both baseline (nonstimulated) and stimulated (by either formyl‐methionyl‐leucyl‐phenylalanine, or phorbol‐myristate‐acetate) polymorphonuclear leukocytes.

Results The baseline superoxide production of polymorphonuclear leukocytes was significantly increased by advanced glycation end‐products in a dose–dependent manner. In contrast, in stimulated polymorphonuclear leukocytes advanced glycation end‐products significantly inhibited superoxide production, again in a dose–dependent manner. This inhibitory effect of advanced glycation end‐products was observed after dialyzing AGE‐BSA, thereby eliminating the possible influence of reactive carbohydrates. No modification of superoxide production was seen with BSA and only a mild inhibitory effect of glucose at high concentrations.

Conclusions Advanced glycation end‐products depress superoxide production by stimulated polymorphonuclear leukocytes. As superoxide plays an essential role in bactericidal activity, this polymorphonuclear leukocyte dysfunction may be a contributory factor to the increased prevalence and severity of bacterial infection seen in diabetic patients.
Effects of long‐term octreotide treatment on the response of portal‐systemic collaterals to vasopressin in portal hypertensive rats
Authors: Wang S.‐S. , Chan C.‐C. , Lee F.‐Y. , Chang F.‐Y. , Lin H.‐C. , Chen C.‐T. , Huang H.‐C. , Tai C.‐C. , Lai I.‐N. , Lee S.‐D.
Published: March 2003

Background Chronic portal hypertension is associated with the development of portal‐systemic collaterals. Long‐term octreotide treatment has been shown to enhance the constrictive response to vasopressin in the mesenteric arteries of portal hypertensive rats. This study investigated the effects of long‐term octreotide treatment on the response of portal‐systemic collaterals to vasopressin in portal hypertensive rats.

Methods Partially portal vein‐ligated rats were divided into two groups to receive subcutaneous injection of either placebo (5% dextrose in water) or octreotide (30 µg kg−1) twice daily for 7 days. Two series of experiments were performed to measure: (a) the systemic and portal hemodynamics and cumulative concentration‐response curves of collateral vessels to vasopressin (10−10 to 10−7 M) and (b) the slopes of the flow‐pressure curves of collaterals (an index of portal‐systemic shunting). The cumulative concentration‐response curves and flow pressure curves were determined by the in situ collateral perfusion.

Results Long‐term octreotide treatment significantly lowered the portal pressure without changes in the mean arterial pressure. Vasopressin significantly and similarly increased the perfusion pressure of collateral vessels in both the placebo‐ and octreotide‐treated groups. In addition, long‐term octreotide treatment exerted no effect on the EC50 of vasopressin (−8·25 ± 0·19 vs. –8·20 ± 0·10, P > 0·05) and the slopes of flow‐pressure curves (0·97 ± 0·02 vs. 0·94 ± 0·04, P > 0·05) in the collaterals.

Conclusion Despite lowering the portal pressure, long‐term octreotide treatment did not enhance the vasoconstrictive effect of vasopressin in the collateral vessels of portal hypertensive rats and ameliorate the degree of portal‐systemic shunting.