bluuebunny/crossref_metadata_2025 huggingface dataset:
Aphid population dynamics: does resistance to parasitism influence population size?
Authors: Hufbauer R. A.
Published: March 2003

1. Insect population size is regulated by both intrinsic traits of organisms and extrinsic factors. The impacts of natural enemies are typically considered to be extrinsic factors, however insects have traits that affect their vulnerability to attack by natural enemies, and thus intrinsic and extrinsic factors can interact in their effects on population size.

2. Pea aphids Acyrthosiphon pisum Harris (Hemiptera: Aphididae) in New York and Maryland that are specialised on alfalfa are approximately two times more physiologically resistant to parasitism by Aphidius ervi Haliday (Hymenoptera: Braconidae) than pea aphids specialised on clover. To assess the potential influence of this genetically based difference in resistance to parasitism on pea aphid population dynamics, pea aphids, A. ervi, and other natural enemies of aphids in clover and alfalfa fields were sampled.

3. Rates of successful parasitism by A. ervi were higher and pea aphid population sizes were lower in clover, where the aphids are less resistant to parasitism. In contrast, mortality due to a fungal pathogen of pea aphids was higher in alfalfa. Generalist aphid predators did not differ significantly in density between the crops.

4. To explore whether intrinsic resistance to parasitism influences field dynamics, the relationship between resistance and successful field parasitism in 12 populations was analysed. The average level of resistance of a population strongly predicts rates of successful parasitism in the field. The ability of the parasitoid to regulate the aphid may vary among pea aphid populations of different levels of resistance.
A synoptic key for differentiation of Monilinia fructicola, M. fructigena and M. laxa, based on examination of cultural characters
Authors: Lane C. R.
Published: March 2003

A synoptic key for the identification of three morphologically similar species of Monilinia principally affecting stone and pome fruit is described. Seven morphological characters were assessed after 10 days incubation under well‐defined cultural conditions. No one character was found to separate the species. However, the synoptic key resulted in the correct identification of all isolates tested when compared with a molecular method.
Erythrocyte membrane thiol proteins associated with changes in the kinetics of Na/Li countertransport: a possible molecular explanation of changes in disease
Authors: Thomas  , Rutherford  , Vareesangthip  , Wilkinson  , West
Published: March 2003

Background

Abnormal erythrocyte Na/Li countertransport is associated with diseases such as essential hypertension and diabetic renal disease. Although it seems unlikely that Na/Li countertransport contributes to any disease process, it may be abnormal because of a change in the cell membrane that is part of the disease process.

Methods

We have shown that Na/Li countertransport kinetics are modified by two types of thiol group. One of these, which we have called ‘type 1’, is rapidly alkylated by N‐ethylmaleimide to give a kinetic pattern similar to that in the above diseases.

Results

At pH 6 and 2 °C, both N‐ethylmaleimide and iodoacetamide cause the Km of Na/Li countertransport to decrease to completion in 300 s, with 78% (SEM 6%) of the decrease occurring in 30 s. Using these reaction conditions, N‐ethylmaleimide reacted with a unique thiol group on a 33‐kD protein, blocking its subsequent reaction with biotin maleimide. This 33‐kD protein was present in rabbit erythrocytes, which have high levels of Na/Li countertransport, but absent from rat erythrocytes, which have no Na/Li countertransport. Iodoacetyl biotin labelled a 60‐kD protein that was specifically blocked by iodoacetamide.

Conclusion

We suggest that these proteins are members of a cluster of membrane proteins that can modify Na/Li countertransport and may have a functional role in the disease processes.
Antioxidant defences are reduced during the oral glucose tolerance test in normal and non‐insulin‐dependent diabetic subjects
Authors: Ceriello  , Bortolotti  , Crescentini  , Motz  , Lizzio  , Russo  , Ézsol  , Tonutti  , Taboga
Published: March 2003

Background

Free radical production has been reported to be increased in patients with diabetes mellitus, and it has been suggested that hyperglycaemia may directly contribute to the generation of oxidative stress. The aim of the present study was to evaluate the effects of an acute increase in glycaemia on plasma antioxidant defences.

Results

During the oral glucose tolerance test (OGTT), plasma concentration of protein‐bound sulphydryl (SH) groups, vitamin C, vitamin E and uric acid significantly decreased in normal as well as non‐insulin‐dependent diabetes mellitus (NIDDM) subjects. Total plasma radical‐trapping activity, which evaluates plasma antioxidant capacity due to known and unknown antioxidants present in the plasma as well as their mutual co‐operation, was also significantly reduced.

Conclusion

This finding supports the hypothesis that hyperglycaemia may, even acutely, induce an oxidative stress.
Growth effects of α‐interferon but not of bombesin or angiotensin II are mediated by activation of STAT proteins
Authors: Pansky  , Hildebrand  , Heim  , Eberhard  , Kissel  , Beglinger
Published: March 2003

Background

The recently discovered Jak/STAT signal transduction pathway is associated with cytokine or growth factor receptors; whether members of the G protein‐coupled receptor superfamily also activate this pathway is not yet clear. As a first member, the angiotensin (AT)1A receptor has been demonstrated to phosphorylate Jak and STAT proteins. Bombesin, a neurotransmitter and growth factor in many cells and tissues, activates its G protein‐coupled receptor and in addition phosphorylates proteins that might be members of the Jak/STAT family. This study investigated whether bombesin‐ or angiotensin‐mediated growth effects are associated with STAT protein activation.

Methods

Functional receptors were characterized using ligand‐binding studies, second‐messenger activation and determination of ligand‐mediated growth effects. STAT protein activation was analysed by electrophoretic mobility shift assay (EMSA) using labelled DNA response elements recognizing all known STAT proteins.

Results

Functional bombesin receptors mediating mitogenic effects were demonstrated on Swiss 3T3 fibroblasts, human melanoma cells (A375‐6) and primary human lung fibroblasts; however, bombesin‐related STAT protein activation was not observed by EMSA. Interferon‐α typically activated a STAT1‐STAT2‐p48 heterotrimer, as well as STAT1‐3 hetero‐ and homodimers in human melanoma cells and significantly inhibited growth of this cell line in vitro. Functional AT1A receptors on primary rat cardiac fibroblasts mediated angiotensin‐stimulated growth effects but, in contrast to recently published data, did not activate any known STAT protein.

Conclusion

Interferon α‐stimulated growth inhibition is mediated by activation of the Jak/STAT pathway, whereas bombesin or AT1A receptor‐mediated effects on cellular proliferation do not involve phosphorylation of STAT proteins.
Acute and chronic exposure of rat intestinal mucosa to dextran promotes SGLT1‐mediated glucose transport
Authors: Debnam  , Denholm  , Grimble
Published: March 2003

Background

The intestinal handling of dextran, an α‐1,6‐linked glucose polymer, is poor compared with starch, and some ingested dextran might therefore reach the lower small intestine. As luminal sugar up‐regulates SGLT1 (sodium‐dependent glucose transporter) locally, we report the effects of a dextran‐enriched diet on jejunal and ileal brush border membrane (BBM) glucose uptake.

Methods

Rats were maintained on a diet containing 65% maltodextrin or 32.5% maltodextrin + 32.5% dextran (10 kD or 40 kD) for 8–10 days, and the kinetics of phlorizin‐sensitive [3H]‐glucose uptake by purified BBM vesicles was determined.

Results

Ingestion of 40‐kD but not 10‐kD dextran increased Vmax for jejunal and ileal glucose uptake (+64.3% and +61.8% respectively, both P < 0.02). The transport response to 40‐kD dextran was in keeping with lower levels of expired H2 at the end of the feeding period. High‐performance liquid chromatography (HPLC) analysis of luminal contents indicated extensive hydrolysis of ingested dextran. Finally, 3‐h jejunal exposure to 40‐kD dextran in vivo increased the Vmax for glucose uptake by jejunal BBM.

Conclusion

It is likely that increased SGLT1‐mediated glucose uptake after short or longer term mucosal exposure to dextran results from luminal dextran per se or a hydrolysis product. The clinical implications of this up‐regulation are discussed.
Plasma acylation stimulating protein (ASP) as a predictor of impaired cellular biological response to ASP in patients with hyperapoB
Authors: Zhang  , Cianflone  , Genest  , Sniderman
Published: March 2003

Background

The objective of this study was to examine specific membrane binding of [125I]‐acylation stimulating protein (ASP) in cultured human skin fibroblasts obtained from normal subjects and patients with hyperapoB. ASP is a small basic protein isolated from human plasma that stimulates triglyceride synthesis (TGS) and glucose transport (GT) in human skin fibroblasts and adipocytes.

Design

In the present study, three groups were studied: normal (NASP‐NB) subjects, hyperapoB subjects with normal plasma ASP (NASP‐HB) and hyperapoB subjects with high plasma ASP (HASP‐HB).

Results

ASP‐induced TGS in fibroblasts from HASP‐HB subjects was significantly less than in the two control groups with normal plasma ASP (NASP‐NB and NASP‐HB). Similarly, ASP stimulation of GT was less in HASP‐HB fibroblasts than in the NASP‐HB fibroblasts or the NASP‐NB subjects. Insulin‐induced TGS was similar in all three groups as was insulin‐stimulated GT. As well, protein kinase C‐mediated stimulation was equivalent among the three groups both for GT and for TGS. There was no significant difference in the binding affinity (Kd) of [125I]‐ASP to intact cells in any group. By contrast, binding of [125I]‐ASP revealed a significantly lower Bmax of the HASP‐HB cell lines than the NASP‐NB cells and the NASP‐HB cells.

Conclusion

A decrease in the ASP cell‐surface receptor concentration is responsible for decreased ASP stimulation of TGS, and GT and may contribute to the inefficient post‐prandial triglyceride (TG) clearance in HASP‐HB subjects.
Nitric oxide and inflammatory bowel diseases
Authors: Guslandi
Published: March 2003

Nitric oxide (NO) production, as detectable by indirect and direct methods, as well as the expression of inducible nitric oxide synthase (iNOS) in the intestinal mucosa appear to be enhanced in active ulcerative colitis and, when in excess, to play a proinflammatory role in the disease. Despite some conflicting data, there is evidence that NO production is also increased in Crohn's disease. Many inflammatory features of inflammatory bowel disease are in keeping with the physiological properties of NO, and toxic megacolon, a complication of chronic colitis characterized by acute colonic dilatation, is associated with an enhanced intestinal synthesis of NO.  The drugs currently used in the treatment of inflammatory bowel disease (steroids, salicylates) do not seem to exert substantial effects on intestinal NO synthesis. The possible therapeutic role of selective iNOS inhibitors is still under investigation
Death risk factor analysis in primary hyperparathyroidism
Authors: Hedbäck  , Odén
Published: March 2003

Background

Patients treated for primary hyperparathyroidism run an increased risk of death. The aim of this study was to analyse several factors that may influence their risk of death.

Methods

General, laboratory, physical and clinical variables, altogether 34 variables, were defined as possible risk factors for death and were studied in a patient series of 845 patients operated on during the period 1953–82. Mean follow‐up time was 10.5 years (SD 5.9); 253 patients were deceased at follow‐up. Cox's proportional hazard model was used.

Results

We found seven variables with independent influence on the risk of death: age, sex, diabetes, cardiovascular disease, glomerular filtration rate, renal tubular concentration capacity and amount of diseased parathyroid tissue. The remaining 27 variables were separately tested, one at a time, using the same method and with the influence of age and sex eliminated. In this test situation, the year of surgery, peak serum calcium, serum creatinine level, body mass index, hypertension, psychiatric symptoms and a history of crisis were all significantly related to the risk of death. The analyses also gave information on the direction and magnitude of the effect of the variables on the risk of death.

Conclusion

Primary hyperparathyroidism itself is a risk factor for death, but it was concluded that well‐preserved renal function at surgery seems to have a protective role. We also found that the greater the amount of diseased parathyroid tissue the lesser the renal function and, furthermore, that hyperparathyroidism of substantial degree or long duration may bring about renal impairment that is not necessarily disclosed by the creatinine value alone.
Diabetic dyslipidaemia
Authors: Betteridge
Published: March 2003

Type 2 diabetic patients have an increased risk of cardiovascular disease and, although many factors contribute to this risk, it is likely that diabetic dyslipidaemia plays an important role. Dyslipidaemia in Type 2 diabetic patients is characterized by low levels of HDL cholesterol and high triglyceride levels. In Type 2 diabetes, the total amount of LDL cholesterol is the same as in healthy people, but there are qualitative changes, e.g. a shift to smaller, denser LDL particles and an increased susceptibility to oxidation. Oxidized LDL may promote the development of atherosclerosis. It is possible to modify the major abnormalities of diabetic dyslipidaemia by combining lifestyle modifications (e.g. increased physical activity, cessation of smoking and weight reduction) with improved glycaemic control and hypolipidaemic drugs to reduce the burden of CVD within this high‐risk population.
Neurone‐specific enolase and N‐acetyl‐aspartate as potential peripheral markers of ischaemic stroke
Authors: Stevens  , Jakobs  , De Jager  , Cunningham  , Korf
Published: March 2003

Background

After stroke, brain‐specific proteins (including neurone‐specific enolase) leak into the blood. The question addressed in the present study was whether N‐acetyl‐aspartate (amino acid derivative localized in cerebral neurones) could also serve as a peripheral marker of ischaemic damage. N‐acetyl‐aspartate levels were determined in the blood of stroke patients and related to clinical outcome, volume of infarction and to serum neurone‐specific enolase.

Methods

Blood samples from 19 patients (seven women, 12 men, mean age of 73 years, range 56–88 years) were collected during the first 4 days after stroke and analysed for neurone‐specific enolase (radioimmunoassay) and/or N‐acetyl‐aspartate (mass spectrometry). Clinical outcome was assessed using the Glasgow Outcome Score, and volume of infarction was calculated using computerized tomography (CT). Control values of N‐acetyl‐aspartate, determined in six female and nine male volunteers (mean age 47.4 years; range 28–73 years) were 0.26 ± 0.02 μmol L−1.

Results

The increase in serum N‐acetyl‐aspartate was highly significant (P < 0.0001) within the first 24 h and at 72 h after stroke and correlated (P < 0.05) with volume of infarction only in patients with a bad prognosis (Glasgow Outcome Score < 5). Serum N‐acetyl‐aspartate at 24 h and neurone‐specific enolase at 72 h were negatively correlated, suggesting that more N‐acetyl‐aspartate reaches the blood when brain tissue is less irreversibly affected.

Conclusion

Serum N‐acetyl‐aspartate appears to be an early peripheral marker of ischaemically affected brain neurones, and the ratio of N‐acetyl‐aspartate to a protein marker, such as NSE, may serve as an index of irreversibility.
Characterization of antigens from the human exocrine pancreatic tissue (Pag) relevant as target antigens for autoantibodies in Crohn's disease
Authors: Fricke  , Birkhofer  , Folwaczny  , Meister  , Scriba
Published: March 2003

Background

The present study was performed to analyse the immunological properties of the autoantigens recognized by autoantibodies against exocrine pancreas (PAb), which have been described in Crohn's disease.

Methods

Autoantibodies were detected by indirect immunofluorescence. Inhibition studies were performed by preincubating tissue sections with various glycoproteins and the different fractions obtained in fractioned salt precipitation of pancreas homogenate with ammonium sulphate. Immunoblotting of human pancreas homogenate was conducted using PAb‐positive sera.

Results

In size exclusion chromatography, the molecular weight of the pancreas autoantigen (PAg) was determined as > 800 kD. In the fractionated salt precipitation, the autoantigen could be detected in fractions I (0–25% ammonium sulphate) and III (50–90% ammonium sulphate). In immunoblotting, a number of protein bands were observed (at 16, 18, 19, 24, 27, 29, 31 and 34 kD), and the binding pattern showed little variation between individual patients.

Conclusions

The protein that is recognized by PAb appears to be a large protein complex consisting of several subunits which exhibit reactivity to PAb.
Pulmonary surfactant protein A binds to Cryptococcus neoformans without promoting phagocytosis
Authors: Walenkamp  , Verheul  , Scharringa  , Hoepelman
Published: March 2003

Background

Evidence is accumulating that the alveolar collectin surfactant protein A (SP‐A) plays an important role in the first line of defence against infiltrating pathogenic micro‐organisms and viruses. The ability of SP‐A to facilitate the binding and uptake of acapsular Cryptococcus neoformans by monocyte‐derived macrophages, human alveolar macrophages, monocytes and polymorphonuclear leucocytes was investigated.

Materials and methods

Binding, competition and phagocytosis experiments were performed using a flow cytometry technique.

Results

SP‐A bound to both the acapsular and the encapsulated form of C. neoformans in a concentration‐dependent manner. SP‐A showed a threefold better binding to the acapsular yeast: this binding was partly calcium dependent and could be inhibited by mannose (ID50 = 3 mmol L−1) and glucose (ID50 = 2.1 mmol L−1) but not by galactose (ID50 = 391 mmol L−1). SP‐A did not function as an opsonin in phagocytosis of acapsular C. neoformans for any of the phagocytes studied.

Conclusion

Our results indicate that SP‐A binds in a concentration‐dependent manner to both encapsulated and acapsular C. neoformans. Despite SP‐A binding to the acapsular C. neoformans, phagocytosis by various phagocytes was not enhanced.
Lipid and lipoprotein analysis of cats with lipoprotein lipase deficiency
Authors: Ginzinger  , Clee  , Dallongeville  , Lewis  , Henderson  , Bauje  , Rogers  , Jensen  , Eckel  , Dyer  , Innis  , Jones  , Fruchart  , Hayden
Published: March 2003

Background

We have previously described a colony of domestic cats with a naturally occurring mutation in the lipoprotein lipase (LPL) gene. We have now further characterized cats homozygous for LPL deficiency (LPL −/−, homozygotes), and have contrasted these with heterozygotes (LPL +/−) and normal cats (LPL +/+).

Materials and methods

Density gradient ultracentrifugation with subsequent lipid analysis, agarose and polyacrylamide gel electrophoresis was used to examine detailed liproprotein differences between the genotypes. Oral fat loading studies and breast milk fatty acid analysis were also performed to further characterize the phenotypic expression of LPL deficiency in this model system.

Results

Several lipid abnormalities associated with homozygosity for LPL deficiency were evident. Triglyceride‐rich lipoprotein‐triglycerides (TRL‐TG) and cholesterol (TRL‐C) were higher (TRL‐TG 2.09 ± 1.14 vs. 0.15 ± 0.04 mmol L−1, P < 0.001; TRL‐C 0.42 ± 0.30 vs. 0.11 ± 0.16 mmol L−1, P < 0.05) in male −/− than in male +/+ cats, as was HDL‐cholesterol (HDL‐C, 1.75 ± 0.24 vs. 1.41 ± 0.14 mmol L−1, P < 0.05). LDL‐C levels were lower in homozygous cats than in control cats, similar to what is seen in human LPL deficiency. Oral fat loading studies revealed that homozygous cats have a marked reduced ability to clear plasma TGs in terms of peak time (7 h vs. 3 h), peak height (9.36 vs. 1.1 mmol L−1), area under the TG clearance curve (AUC, 280.3 vs. 2.2 h mmol L−1) and time to return to baseline. Fasting lipid and lipoprotein levels were not significantly different between heterozygous and normal cats. However, oral fat loading in heterozygotes revealed an intermediate phenotype (peak of 2.35 mmol L−1 at 5 h, AUC 13.1 h mmol L−1), highlighting the impaired TG clearance in these animals.

Conclusion

Thus, LPL deficiency in the cat results in a lipid and lipoprotein phenotype that predominantly parallels human LPL deficiency, further validating the use of these animals in studies on the pathobiology of LPL.
Salt sensitivity correlates positively with insulin sensitivity in healthy volunteers
Authors: Ter Maaten  , Voordouw  , Bakker  , Donker  , Gans
Published: March 2003

Background

The aim of the study was to assess the relationship between insulin sensitivity and salt sensitivity in healthy subjects who display a wide range of insulin sensitivity. As a secondary objective, we assessed the relationship between salt sensitivity and the other characteristics of the insulin resistance syndrome.

Study design

Forty‐seven normotensive volunteers (age 34 ± 15 years) with a normal glucose tolerance test were selected. We measured insulin sensitivity using the hyperinsulinaemic euglycaemic clamp (50 mU kg−1 h−1), blood pressure, waist‐to‐hip ratio, fasting insulin levels, serum lipids and uric acid levels. In a subset of 21, representing a wide range of insulin sensitivity, salt sensitivity was determined as the difference in mean arterial blood pressure (MAP) at the end of a high‐salt diet (10 g of NaCl per day for 1 week) vs. a low‐salt diet (2 g of NaCl per day for 1 week).

Results

Insulin sensitivity (M/I value, range 0.49–4.41 mg kg−1 min−1 per pmol L−1 × 100) was negatively correlated with MAP (r = –0.54, P < 0.001) and waist‐to‐hip ratio (r = − 0.59, P < 0.001) but positively correlated with salt sensitivity (r = 0.47, P = 0.03). Salt sensitivity also correlated with high‐density lipoprotein (HDL)‐cholesterol (r = 0.46, P = 0.038) but not with waist‐to‐hip ratio, fasting insulin levels, low‐density lipoprotein cholesterol, serum triglycerides or serum uric acid.

Conclusions

In healthy normotensive subjects who display a wide range of insulin sensitivity, as measured with the euglycaemic clamp technique, salt sensitivity correlates positively with insulin sensitivity and HDL‐cholesterol, but not with the other characteristics of the insulin resistance syndrome.
Nitric oxide diffusion across membrane lungs protects platelets during simulated extracorporeal circulation
Authors: Keh  , Gerlach  , Kürer  , Spielmann  , Kerner  , Busch  , Hansen  , Falke  , Gerlach
Published: March 2003

Background

The absence of a protective endothelial surface on membrane oxygenators during extracorporeal circulation (ECC) promotes platelet trapping and damage, leading to increased bleeding complications. We investigated the effects of transmembranous diffusion of gaseous nitric oxide (NO) on platelets during simulated ECC.

Material and methods

Two paired circuits were run in parallel with fresh, heparinized (1 U mL−1) blood from healthy human donors for 240 min. To one of the paired circuits, 20 ppm NO was added transmembranously.

Results

NO significantly attenuated platelet trapping and reduced intracircuit platelet activation evaluated by the release of β‐thromboglobulin, platelet factor 4 and soluble P‐selectin. Furthermore, NO significantly preserved platelet reactivity to stimulating agents (ADP and adrenaline), evaluated as the ability to expose P‐selectins and activate glycoprotein (GP)‐IIb‐IIIa. Nevertheless, circulating activated platelets expressing P‐selectin or activated GPIIb‐IIIa were not different and were not significantly increased. The mean fluorescence intensity of GPIb and GPIIb‐IIIa decreased in both circuits equally.

Conclusions

Transmembranous diffusion of gaseous NO revealed protective effects on platelets by reducing thrombocytopenia/pathia and preserving platelet reactivity.
Perioperative catecholamine changes in cardiac risk patients
Authors: Sametz  , Metzler  , Gries  , Porta  , Sadjak  , Supanz  , Juan
Published: March 2003

Background

It has previously been found that in cardiac risk patients undergoing non‐cardiac surgery post‐operative cardiac complications are correlated with high post‐operative serum levels of troponin T (TNT) and troponin I (TNI). We investigated whether perioperative changes in the release of free (fCAs) and conjugated catecholamines (cCAs) correlate with the increased serum level of TN (TN↑).

Materials and methods

Plasma levels of CAs were determined in 28 patients at risk for or with definite coronary artery disease. Blood sampling was performed in the morning on the day before surgery, on the day of surgery before induction of anaesthesia and until the fifth post‐operative day for measurement of CAs by high‐performance liquid chromatography.

Results

The plasma concentrations of free and conjugated noradrenaline (fNA and cNA) as well as of free and conjugated adrenaline (fA and cA) were increased significantly in TN↑ patients post‐operatively. The plasma levels of free as well as of conjugated NA and A in TN↑ patients were significantly higher than in TN0 patients over the whole post‐operative period.

Conclusion

This study demonstrates that increased post‐operative release of fNA and fA as well as of cNA and cA correlates with high post‐operative serum levels of troponins in cardiac risk patients undergoing non‐cardiac surgery.
Oral folate enhances endothelial function in hyperhomocysteinaemic subjects
Authors: Bellamy  , W. McDowell  , Ramsey  , Brownlee  , Newcombe  , Lewis
Published: March 2003

Background

Elevated plasma homocysteine (Hcy) is a risk factor for vascular disease. A postulated mechanism is vascular endothelial damage by homocysteine. Hcy levels are inversely related to blood concentrations of folate and can be lowered by folate supplements. The effect of oral folic acid on endothelial function was investigated in healthy adults with mild hyperhomocysteinaemia.

Patients and methods

Eighteen healthy subjects (Hcy > 13μmol L−1 at entry), from a screening population of 890 volunteers, were entered into a randomised double‐blind placebo‐controlled crossover study of oral folic acid (5 mg daily for six weeks) with a six week interval between treatments. Flow‐mediated (endothelium‐dependent) and (endothelial‐independent) glyceryl trinitrate (GTN)‐mediated brachial artery dilatation were measured by high resolution wall tracking.

Results

Folate supplementation enhanced endothelium‐dependent responses (+0.08 ± 0.05 vs. +0.04 ± 0.04 mm, P = 0.015) but endothelium‐independent responses (GTN) were unchanged. Folate reduced Hcy (8.7 ± 2.5 vs. 12.1 ± 3.6 μmol L−1).

Conclusion

High dose folic acid supplementation enhances endothelium‐dependent vascular function and lowers plasma Hcy. This provides preliminary evidence that folate may have beneficial cardiovascular effects in adults with mild hyperhomocysteinaemia.
NADH/NADPH oxidase p22phox C242T polymorphism and coronary artery disease in the Australian population
Authors: Cai  , Duarte  , Wilcken  , Wang
Published: March 2003

Background

Oxidative stress induced by the superoxide anion (.O2−) has been implicated in atherogenesis. The NADH/NADPH oxidase system is involved in .O2− production and p22 phox is an essential component of that system.

Material and methods

We analysed the p22 phox C242T polymorphism in 689 consecutive Australian Caucasians aged ≤ 65 years with and without angiographically documented coronary artery disease (CAD)

Results

We report the rare T allele frequency of 0.33, which is 3 fold higher than that reported in the Japanese population by Inoue et al. [
7]. The genotype distributions were not different among patients with CAD (CC:0.422, CT:0.459 and TT: 0.119 in men; 0.447, 0.439 and 0.114 in women) and without CAD (0.479, 0.420 and 0.101%, χ2 = 0.794, P = 0.672 in men; 0.443, 0.471 and 0.86, χ2 = 0.442, P = 0.802 in women). The frequencies of the rare TT homozygotes or of the ‘T’ allele frequency were also not associated with the number of significantly stenosed vessels (χ2 = 4.466, P = 0.614 in men; χ2 = 4.736, P = 0.578 in women) or with a myocardial infarction (MI) history (χ2 = 2.310, P = 0.315 in men; χ2 = 1.178, P = 0.555 in women). However, when the analysis was conducted in young male patients aged ≤ 45 years (n = 44), TT + TC patients tended to have an increased risk for CAD (odds ratio: 5.71 95% CI: 1.22–26.75, P = 0.0271).

Conclusion

The p22 phox C242T polymorphism is not associated with the occurrence or severity of CAD or with a history of MI in Australian Caucasian patients aged ≤ 65 years. However, the polymorphism could be associated with an increased CAD risk in young patients, which requires confirmation in large populations.
Angiogenesis extent and expression of matrix metalloproteinase‐2 and ‐9 correlate with upgrading and myometrial invasion in endometrial carcinoma
Authors: Iurlaro  , Loverro  , Vacca  , Cormio  , Ribatti  , Minischetti  , Ria  , Bruno  , Selvaggi
Published: March 2003

Background

Changes in angiogenesis and expression of extracellular matrix‐degrading enzymes have been substantiated during tumour changeover and progression.

Methods

Tissues from 64 biopsies of endometrial carcinoma (EC) and 15 biopsies of normal (control) endometrium were investigated immunohistochemically to determine their microvessel number, and by in situ hybridisation to determine the expression of mRNA of the matrix metalloproteinase‐2 (MMP‐2, gelatinase A) and metalloproteinase‐9 (MMP‐9 gelatinase B). EC were grouped according to both histological grade (G) G1 to G3 and depth of myometrial (M) invasion M1 to M3.

Results

EC as a whole gave significantly higher counts over control endometria. Counts of the G1 group overlapped those of the control group, increased significantly in the G2 and even more in the G3 group. G3 biopsies in particular also displayed most microvessels widely scattered in the tumour tissue, in close association with tumour cells, and as winding and arborized tubes, often dilated in microaneurysmatic segments. Counts also increased in M2 and M3. Expression of the MMP‐2 and MMP‐9 mRNA, evaluated as percentages of positive biopsies and intensity of expression, were upregulated with the transition from control and G1 groups to G2 and G3, and in relation to advancing depth of invasion. In EC, MMP‐2 and MMP‐9 mRNA were also expressed by host stromal cells, including microvascular endothelial cells, fibroblasts and macrophages. In the control biopsies, poor expression of MMP‐2 mRNA in few endothelial cells and no expression of MMP‐9 mRNA were detected.

Conclusion

These in situ data suggest that angiogenesis and degradation of extracellular matrix occur simultaneously with EC upgrading and advancing depth of invasion, and that EC cells and some host stromal cell populations cooperate in tumour progression.
Complement activation by oxidatively modified low‐density lipoproteins
Authors: Wieland  , Dorweiler  , Bonitz  , Lieser  , Walev  , Bhakdi
Published: March 2003

Background

Oxidatively modified low‐density lipoproteins (LDLs) have been implicated in the pathogenesis of atherosclerosis and are found in human vascular lesions. There is increasing evidence that complement activation may also play a role in atherogenesis. Activated complement proteins have been demonstrated to be present in early atherosclerotic lesions, and lipids isolated from lesions have been shown to activate complement, hence their designation as lesion complement activator (LCA). The question now arose whether oxidized LDLs would also activate complement.

Material and methods

The complement‐activating capacity of a lesion complement activator preparation and of minimally as well as heavily oxidized LDL was investigated by measuring SC5b‐9 formation in normal human serum. In addition, C3 conversion was followed using two‐dimensional immunoelectrophoresis.

Results

Minimally and heavily oxidized LDL generated small but significant amounts of SC5b‐9 (7.9 μg mL−1, SD 3.5, and 10.8 μg mL−1, SD 1.2, respectively; n = 6) compared with native LDL (3.3 μg mL−1, SD 1.4; P < 0.05), whereas LCA generated substantially larger amounts of the terminal complex (32.0 μg mL−1, SD 3.2). Both oxidized LDL preparations caused only minor C3 conversion.

Conclusions

These findings show that oxidation does not confer relevant complement‐activating properties on LDL, suggesting that the lesion complement activator is not directly related to oxidized LDL. Oxidized LDL is probably of minor importance for complement activation in atherosclerotic lesions.
Comparative inhibitory potential of differently modified antisense oligodeoxynucleotides on hepatitis C virus translation
Authors: Alt  , Eisenhardt  , Serwe  , Renz  , Engels  , Caselmann
Published: March 2003

Background

A completely modified phosphorothioate antisense oligodeoxynucleotide (cS‐ODN 4) directed against nucleotides 326–348 of the hepatitis C virus (HCV) 5′ non‐coding region (NCR) efficiently inhibits viral gene expression. As cS‐ODN exerts undesired side‐effects in vivo, we synthesized partially modified ODN 4 that contained only six modified nucleotides which are located at the ODN termini or are scattered along the molecule. The tested modifications were polar phosphorothioates (S) and non‐polar methyl‐ (M) or benzylphosphonates (B).

Results

In an in vitro translation system, specific inhibition of HCV gene expression by M‐ODN 4 or B‐ODN 4 was observed if terminally modified ODN were used; the maximal inhibition was 92.3% ± 1.9% and 87.1% ± 3.7%, respectively, at 10 μmol L−1 concentration. S‐ODN 4 specifically suppressed viral translation irrespective of the location of the modifications, resulting in a maximal inhibition of 86.3% ± 3.3%. For all terminally modified ODNs the therapeutic index was high, with tB‐ODN 4 the second best at 3.8. Inhibition correlated with efficient RNase H‐associated cleavage of target RNA. In transient co‐transfection experiments of HepG2 cells with a reporter gene construct and the ODN, terminally modified B‐ODN 4 was the most effective and specific inhibitor. At a concentration of 5 μmol L−1 the suppression of HCV translation was 96.3% ± 0.7%.

Conclusion

These data demonstrate that terminally modified B‐ODN 4 is a potent inhibitor of HCV gene expression in vitro and in HepG2 cell culture and may be valuable for future antiviral treatment.
Short‐term hormone replacement therapy: reduced plasma levels of soluble adhesion molecules
Authors: Van Baal  , Emeis  , Kenemans  , Kessel  , Peters‐Muller  , Schalkwijk  , Van Der Mooren  , Stehouwer
Published: March 2003

Background

Epidemiological data have suggested that the use of hormone replacement therapy (HRT) is associated with a decreased risk of cardiovascular disease. Vascular endothelium and adhesion molecules play an important role in the initiation and progression of atherosclerosis.

Material and methods

Prospective, randomized, placebo‐controlled 12‐week study. Sixty healthy, normotensive postmenopausal women received either micronised oestradiol 2 mg alone (n = 16, E2 group), or sequentially combined with a progestagen; E2 + P groups trimegestone 0.5 mg (E2 + T, n = 14) or dydrogesterone 10 mg (E2 + D group, n = 14) or placebo (n = 16). Data were collected at baseline and at 4 and 12 weeks.

Results

Twelve weeks of treatment with E2 or E2 + P was associated with a significant decrease in the plasma concentrations of soluble intercellular adhesion molecule‐1 (sICAM‐1), vascular cell adhesion molecule‐1 (sVCAM‐1), and thrombomodulin (sTM). The average decrease in these markers was about 9%. In women treated with trimegestone the decreases were larger than in those treated with dydrogesterone; for sICAM‐1 (−15% vs. −2%; P < 0.0001), sVCAM‐1 (−15% vs. +3%; P = 0.003) and sTM (−9% vs. −4%; P = 0.11). Plasma levels of endothelin‐1 (ET‐1) decreased (by 13%) only in women treated with E2 + P. In the E2 group, flow‐mediated, endothelium‐dependent vasodilatation increased by 6 percentage points after 12 weeks (P = 0.07 vs. baseline, P = 0.02 vs. E2 + P, and P = 0.17 vs. placebo).

Conclusion

Short‐term treatment with E2 or E2 + trimegestone reduces plasma levels of sICAM‐1, sVCAM‐1 and sTM. ET‐1 decreased only in the E2 + P groups. Different types of progestagens may differentially affect sICAM‐1, sVCAM‐1 and sTM levels, which may be relevant for the choice of type HRT.
Capillary permeability is increased in normo‐ and microalbuminuric Type 1 diabetic patients: amelioration by ACE‐inhibition
Authors: Oomen  , Jager  , Hoogenberg  , Dullaart  , Reitsma  , Smit
Published: March 2003

Background

Capillary leakage of sodium‐fluorescein (NaF) in the skin reflects capillary permeability and may be a marker of diabetes‐associated microcirculatory abnormalities.

Design

We evaluated transcapillary skin NaF leakage by fluorescence videodensitometry in 10 normoalbuminuric, 10 microalbuminuric Type 1 diabetic men (diabetes duration > 10 years) and 10 healthy subjects. The microalbuminuric patients were restudied after 6 weeks treatment with the ACE‐inhibitor enalapril, 10 mg once daily. All measurements were performed at a blood glucose level of 5 mmol L−1.

Results

Transcapillary NaF leakage was strongly increased in normoalbuminuric Type 1 diabetic patients compared to healthy subjects (P < 0.001) and was still further increased in microalbuminuric Type 1 diabetic patients (P < 0.01 compared to normoalbuminuric patients). Enalapril reduced NaF leakage (P < 0.05), mean arterial blood pressure (P < 0.05) and microalbuminuria (P < 0.05). After treatment, NaF leakage was not different from that in normoalbuminuric patients.

Conclusions

Capillary permeability, as determined by NaF leakage, is elevated in normoalbuminuric Type 1 diabetic patients with long‐standing disease, and the excess elevation in microalbuminuric Type 1 diabetic patients is ameliorated by ACE‐inhibition. Skin NaF videodensitometry seems a useful tool to document capillary permeability in intervention studies.
Pretreatment renal vascular tone predicts the effect of specific renin inhibition on natriuresis in essential hypertension
Authors: Van Paassen  , Navis  , De Jong  , De Zeeuw
Published: March 2003

Background

In essential hypertension an elevated renal vascular resistance (RVR) may be a marker of renin‐angiotensin‐aldosterone system‐mediated impairment of renal sodium excretion. This hypothesis was tested by investigating whether, in subjects with essential hypertension, the natriuretic response to specific renin‐angiotensin‐aldosterone system (RAAS) blockade by renin‐inhibitor remikiren could be predicted from pretreatment renal vascular tone.

Materials and methods

Renal hemodynamics, and the effects of single (n = 17) and multiple doses (n = 8, 8 days) of remikiren (600 mg day−1) on sodium excretion were studied under conditions of carefully controlled sodium balance.

Results

Pretreatment renal vascular tone showed considerable individual differences: filtration fraction (FF) ranged from 21.2 to 30.3% and RVR from 18.8 to 33.5 10−2 mmHg min mL−1 in the single dose study, and FF from 20.8 to 24.9% and RVR from 14.8 to 28.8 10−2 mmHg min mL−1 in the multiple dose study. Remikiren induced a fall in blood pressure, FF and RVR, with considerable interindividual variability in natriuretic response. During single dose, cumulative sodium loss was 5.1 mmol per 5 h (−8.8 to +24.6), whereas after 8 days treatment cumulative sodium loss was 72 ± 30 mmol (−46 to +187). The natriuretic response to remikiren during single as well as multiple dose significantly correlated with pretreatment renal vascular tone (estimated from FF and RVR) but not with remikiren‐induced changes in renal hemodynamics or in hormonal parameters. Cumulative sodium loss was largest in patients with a higher pretreatment FF and RVR (r = 0.74, P < 0.001 and r = 0.52, P < 0.05, respectively, single dose; and r = 0.75, P < 0.05 and r = 0.73, P < 0.05, respectively, multiple dose).

Conclusion

These data support the hypothesis that in essential hypertension an elevated renal vascular tone is a marker of RAAS‐mediated impairment of sodium excretion.
Suppression of the nocturnal rise in growth hormone reduces subsequent lipolysis in subcutaneous adipose tissue
Authors: Samra  , Clark  , Humphreys  , Macdonald  , Bannister  , Matthews  , Frayn
Published: March 2003

Background

The aim of this study was to examine the effect of the nocturnal rise in growth hormone (GH) concentration on lipolysis in adipose tissue the following morning.

Methods

Eight healthy subjects were studied on two occasions (control vs. suppression of GH secretion) and six were studied on a third occasion (control vs. replacement of GH). Lipolysis in the whole body was assessed by measurement of systemic glycerol turnover. Lipid metabolism in the subcutaneous adipose tissue of the anterior abdominal wall was studied by measurement of arterio‐venous differences.

Results

Suppression of the nocturnal rise in GH did not affect systemic glycerol turnover. However, in subcutaneous abdominal adipose tissue it led to a significant reduction in the veno‐arterial differences in nonesterified fatty acid (NEFA, P = 0.041) and glycerol (P = 0.014) concentrations, reflecting a reduction in intracellular lipolysis (P = 0.011). Although arterialized plasma triacylglycerol (TG) concentrations were reduced in the absence of the nocturnal GH pulse, the extraction of TG in subcutaneous abdominal adipose tissue remained unchanged.

Conclusion

We conclude that the normal nocturnal rise in plasma GH concentration leads to site‐specific regulation of lipolysis in adipose tissue on the following day, with preferential fat mobilization from central depots.
Cholesteryl ester transfer protein gene polymorphisms are associated with carotid atherosclerosis in men
Authors: Kakko  , Tamminen  , Päivänsalo  , Kauma  , Rantala  , Lilja  , Reunanen  , Kesäniemi  , Savolainen
Published: March 2003

Background

The cholesteryl ester transfer protein (CETP) is involved in the reverse cholesterol transport and is therefore a candidate gene for atherosclerosis.

Design

The prevalences of the I405V and the R451Q polymorphisms were studied in a population sample of 515 men and women. Genotypes were determined by PCR and carotid atherosclerosis by ultrasonography as the mean intima‐media thickness (IMT) of the carotid arteries.

Results

The Q451 allele was associated with significantly lower intima media thickness in men (P = 0.001). The Q451 allele was, in our earlier study, associated with high plasma CETP activity in men. The VV405 genotype was associated with lower plasma CETP activity compared with the II405 genotype (P < 0.01 for the difference). In the general linear model general factorial procedure the interaction between alcohol consumption and the I405V genotype on IMT was significant (P = 0.013) in men, and when the interaction term was taken into the model the I405V genotype also significantly affected IMT (P = 0.008). The VV405 genotype seems to be most harmful for men with the highest alcohol consumption.

Conclusions

We describe two polymorphisms of the CETP gene associated with intima media thickness in men. A significant interaction was found between alcohol consumption and the I405V genotype on IMT.
Association of serum sialic acid and MMP‐9 with lipids and inflammatory markers
Authors: Kalela  , Pönniö  , Koivu  , Höyhtyä  , Huhtala  , Sillanaukee  , Nikkari
Published: March 2003

Background

Inflammation of the arterial wall has emerged to be an important contributor to the process of atherosclerosis, the major cause of coronary heart disease. Several factors are currently under investigation as inflammatory markers of atherosclerosis. Serum sialic acid and matrix metalloproteinase‐9 may provide such markers. We studied their association with the lipid profile and with the inflammatory markers C‐reactive protein and leukocyte count in a clinically healthy population of men.

Materials and methods

Cardiovascular risk‐related laboratory tests were carried out in 65 consecutive male employees in connection with an occupational health survey in 1996. The subjects were divided into tertiles on the basis of serum sialic acid or matrix metalloproteinase‐9 concentration.

Results

In a stepwise polychotomous logistic regression model adjusting for coronary heart disease risk factors, serum sialic acid concentration was not associated with markers of inflammation but rather with the lipid risk factors of atherosclerosis: inversely with HDL cholesterol (OR = 0.081, 95% CI 0.0068–0.97) and positively with total cholesterol (OR = 2.4, 95% CI 1–5.6). Matrix metalloproteinase‐9 levels had a significant positive correlation with the leukocyte count (OR = 2.3, 95% CI 1.4–4).

Conclusions

Serum sialic acid does not appear to be an indicator of inflammation but is somehow connected with the level of total and HDL cholesterol. Serum matrix metalloproteinase‐9 may provide a useful marker of inflammation because it correlates with the leukocyte count and is not associated with the lipid profile.
Alcohol consumption and insulin resistance in young adults
Authors: Flanagan  , Moore  , Godsland  , Cockington  , Robinson  , Phillips
Published: March 2003

Background

Alcohol may have a cardioprotective effect. One possible mechanism is by reducing insulin resistance, a known cardiovascular risk factor. The aim of this study was to assess the relationship between alcohol consumption, insulin resistance and other parameters determining glucose tolerance in 154 young men and women.

Subjects and methods

Subjects completed a questionnaire documenting weekly alcohol consumption. Insulin sensitivity and glucose tolerance were measured using the intravenous glucose tolerance test with minimal model analysis. Height, weight, usual level of exercise, smoking habits and socio‐economic status were also recorded.

Results

Insulin sensitivity correlated inversely with body mass index (r = − 0.529, P < 0.001) but not with level of physical fitness. Women were significantly less insulin sensitive than men (4.19 and 5.63 104 min−1 pmol−1 L−1, respectively; P < 0.001). Insulin sensitivity correlated positively with alcohol consumption and this trend remained significant allowing for body mass index and gender (β = 0.17, P < 0.014). First‐phase insulin secretion showed a weak but non‐significant trend in the opposite direction. Fasting glucose, fasting insulin and glucose tolerance showed no relationships with alcohol consumption.

Conclusion

These data suggest a close relationship between alcohol consumption and insulin resistance in young adults. Regular alcohol consumption is associated with decreased insulin resistance and this may partly explain the cardioprotective effect of alcohol.