bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and characterization of Pepino mosaic potexvirus in tomato
Authors: Van Der Vlugt R. A. A. , Cuperus C. , Vink J. , Stijger I. C. M. M. , Lesemann D.‐E. , Verhoeven J. Th. J. , Roenhorst J. W.
Published: March 2003

At the beginning of 1999, a new virus disease occurred in protected tomato crops in The Netherlands. Initial diagnostic tests revealed the presence of a potexvirus but serological tests ruled out the presence of Potato X potexvirus (PVX). Tests for other potexviruses reported from solanaceous crops provisionally identified the virus as Pepino mosaic potexvirus (PepMV). The virus was purified, and an antiserum was produced, which showed strong reactions with both the type isolate of PepMV from pepino and two other isolates from tomato. Host range and symptomatology of the pepino and tomato isolates of PepMV revealed clear differences from PVX. However, differences were also observed between the pepino and tomato isolates of PepMV. Sequence alignment of DNA fragments of 584 bp derived from the RNA polymerase cistron showed almost 95% identity with the pepino isolate, whereas the identity with PVX appeared to be < 60%. Together, these results identified PepMV as the causal agent of the new virus disease in tomato. Based on the differences from the type isolate from pepino (Solanum muricatum), the isolates from tomato should be considered as a distinct strain of PepMV for which the name tomato strain is proposed.
The response of smooth muscle cells to α‐thrombin depends on its arterial origin: comparison among different species
Authors: Varela  , Martínez‐González  , Badimon
Published: March 2003

Background

Thrombin plays a pivotal role in the pathogenesis of arterial thrombosis and exerts a wide spectrum of effects on the cells of vessel walls.

Methods

In this paper we focus on the direct role of thrombin as a mitogen for smooth muscle cells (SMCs) derived from different vessels from the vascular tree (coronary artery, aorta, carotid artery and pulmonary artery) of different species (human and pig). All cell populations examined responded mitogenically to α‐thrombin, however the extent of this response was dependent on both vascular origin and the species from which vessels were derived.

Results

Thrombin (1–100 nmol L−1) induced DNA synthesis ranging from 1.5‐ to 4‐fold baseline depending on cell type. Porcine coronary SMCs showed the highest response to thrombin (100 nmol L−1) in terms of protein and DNA synthesis (4.0 ± 0.2‐fold) and cell division (53.4 ± 8.8%) among the tested cells. In these cells recombinant (r)‐hirudin, a specific thrombin inhibitor, exhibited maximal effectiveness to block the mitogenic effect of thrombin. Human SMC response ([3H]‐thymidine incorporation) to either sera or thrombin was lower than that of porcine cells. In contrast, c‐fos mRNA levels induced by thrombin in human SMCs were higher than those induced in porcine cells. In human cells, thrombin elicited an overexpression of c‐fos and a lower rate of [3H]‐thymidine incorporation than in porcine cells. Insulin‐like growth factor I but not insulin showed additive mitogenic effects with thrombin in human coronary SMCs. The response of these cells to thrombin from different sources was a function of thrombin specific activity.

Conclusion

These results suggest that the cell system chosen to check thrombin mitogenicity not only determines thrombin quantitative effects but also may affect the effectiveness of an inhibitor to block its biological activity.
Accumulation of chylomicron remnants in homozygous subjects with familial hypercholesterolaemia
Authors: Mamo  , Smith  , Yu  , Kawaguchi  , Harada‐Shiba  , Yamamura  , Yamamoto
Published: March 2003

Background

Post‐prandial lipoprotein kinetics were investigated in subjects who lack functioning low‐density lipoprotein (LDL) receptors [homozygous familial hypercholesterolaemia (FH)].

Methods

An oral fat load was given, and chylomicron plasma kinetics was determined by monitoring the clearance of triglyceride, retinyl palmitate and apolipoprotein B48, calculated as the area under the curve, for 7.5 h. In addition, the binding and uptake of chylomicron remnants by fibroblasts of FH and control subjects were assessed in vitro.

Results

Based on the plasma kinetics of chylomicron triglyceride, retinyl palmitate and apolipoprotein B48 after a lipid meal, chylomicron clearance was found to be substantially delayed compared with normolipidaemic control subjects. Consistent with involvement of the LDL receptor in chylomicron clearance, binding and uptake of chylomicron remnants by fibroblasts of FH subjects was found to be substantially less than in cells from control subjects.

Conclusion

This study shows that, in addition to LDL, chylomicron metabolism is severely impaired in FH and that the LDL receptor is significantly involved in the clearance of post‐prandial lipoproteins. Moreover, this study raises the possibility that in FH, and in other disorders in which LDL receptor expression is reduced, atherogenesis might be a post‐prandial disease.
Expression of cGMP‐dependent protein kinase I and its substrate VASP in neointimal cells of the injured rat carotid artery
Authors: Mönks  , Lange  , Silber  , Markert  , Walter  , Nehls
Published: March 2003

Background

Neointimal fibroproliferative lesions after balloon angioplasty remain a major clinical problem, frequently leading to restenosis of initially successfully dilated coronary arteries. The cGMP‐dependent protein kinase type I (cGMP‐PK I) and its substrate vasodilator‐stimulated phosphoprotein (VASP), molecular targets of the atrial natriuretic factor (ANF) and nitric oxide (NO) signalling pathways, are likely to be involved in various aspects of vascular wall regulation and restenosis formation.

Methods

To investigate the occurrence of cGMP‐PK I and VASP in neointimal cells in situ, we performed immunohistochemistry and immunoblotting experiments on denuded rat carotid arteries.

Results

Although the soluble cGMP‐PK I showed a homogeneous distribution throughout the neointima, VASP apparently was more concentrated in smooth muscle cells (SMCs) lining the artery lumen, possibly reflecting enhanced growth factor stimulation of luminal SMCs. The membrane‐associated cGMP‐PK type II could not be detected in both the non‐injured vessel wall and the restenotic tissue.

Conclusion

The presence of both cGMP‐PK I and VASP, major regulators of the actin cytoskeleton and cell motility, in neointimal tissue suggest that this emerging signal transduction pathway could be a target for the regulation and control of restenosis.
Carbohydrate‐deficient transferrin is not a useful marker for the detection of chronic alcohol abuse
Authors: Schmitt  , Stieber  , Jüngst  , Bilzer  , Wächtler  , Heberger  , Seidel
Published: March 2003

Background

The role of carbohydrate‐deficient transferrin (CDT) as a reliable marker for the detection of chronic alcohol abuse has been discussed controversially.

Methods

Therefore, we investigated CDT in the sera from 405 subjects with different alcohol intake. Besides healthy control subjects (n = 42), inpatients and outpatients in a department of gastroenterology (n = 325) and patients admitted to a department of otorhinolaryngology (n = 38) were studied. A total of 213 patients suffered from various forms of liver diseases, and 89 patients had liver transplantation. CDT values were determined by a double‐antibody radioimmunoassay.

Results

In the 241 alcohol‐abstinent subjects, CDT levels ranged from 3 to 90 units L−1 (median = 12); the 92 moderate drinkers (20–60 g of alcohol per day) showed values from 3 to 40 units L−1 (median = 12), and the 72 subjects with chronic alcohol abuse (> 60 g per day) revealed CDT levels from 3 to 100 units L−1 (median = 16). The diagnostic specificity for alcohol abuse was 86.8% for men (sensitivity 36.9%) and 95% for women (sensitivity 0%).

Conclusion

Our data indicate that measurement of CDT does not reach clinical use in the detection of chronic alcohol abuse in an unselected population because of its insufficient specificity and sensitivity.
Relative hyperoxaluria, crystalluria and haematuria after megadose ingestion of vitamin C
Authors: Auer  , Auer  , Rodgers
Published: March 2003

Background

Long‐term or high‐dosage consumption of vitamin C may play a role in calcium oxalate kidney stone formation. The present study was undertaken to determine the biochemical and physicochemical risk factors in a male subject who developed haematuria and calcium oxalate crystalluria after ingestion of large doses of ascorbic acid for 8 consecutive days.

Methods

Twenty‐four‐hour urine samples were collected before and during the ascorbic acid ingestion period as well as after the detection of haematuria. A special procedure was implemented for urine collections to allow for oxalate, ascorbate and other urinalyses. Oxalate was determined in the presence of EDTA to prevent in vitro conversion to ascorbic acid, whereas ascorbate itself was determined by manual titration in a redox method using the dye dichlorophenolindophenol. Urinalysis data were used to compute calcium oxalate relative supersaturations and Tiselius risk indices, whereas scanning electron microscopy was used to examine urinary deposits.

Results

Oxalate excretion increased by about 350% during ascorbate ingestion before haematuria. Ascorbate concentrations also increased dramatically but appeared to reach a plateau maximum. Increasing calcium excretion was accompanied by decreasing potassium and phosphate values. The calcium oxalate relative supersaturation and Tiselius risk index increased during vitamin C ingestion and large aggregates of calcium oxalate dihydrate crystals were observed by scanning electron microscopy immediately after the detection of haematuria.

Conclusion

High percentage metabolic conversion of ascorbate to oxalate in this subject caused relative hyperoxaluria and crystalluria, the latter manifesting itself as haematuria. Clinicians need to be alerted to the potential dangers of large dose ingestion of vitamin C in some individuals.
In vitro modulation of	L‐arginine transport in trophoblast cells by glucose
Authors: Eaton  , Sooranna
Published: March 2003

Background

The uptake of the semi–essential amino acid, L‐arginine, into trophoblast cells was measured with the aim of determining the effect of different glucose concentrations on
L‐arginine influx kinetics.

Methods

This study used a novel superfused microcarrier culture system of BeWo cells (an established choriocarcinoma cell line with many characteristics of normal human trophoblast) and a rapid, paired‐tracer dilution technique to measure unidirectional influx into the cells.

Results

At 10 mmol L−1D‐glucose,
L‐arginine unidirectional influx across the microvillous border of the cells was saturable with a Km of 1.14 ± 0.14 mmol L−1 and a Vmax of 121.36 ± 5.89 nmol mg−1 protein min−1. When cells were preincubated for 24 h in the presence of 30 mmol L−1D‐glucose, there was a significant increase in the Vmax for
L‐arginine of nearly 30%. Similarly, preincubation in the presence of 1 mmol L−1D‐glucose and 12.5 mIU mL−1 human insulin reduced the Km for
L‐arginine influx by over 55%.

Conclusion

These data suggest that the modulation of placental transport of L‐arginine by glucose and insulin could contribute to the fetal macrosomia observed in diabetic mothers.
Relationship between impaired glucose tolerance, non‐insulin‐dependent diabetes mellitus and obesity
Authors: Ferrannini  , Camastra
Published: March 2003

Plasma glucose concentration is the best predictor for the development of non‐insulin‐dependent diabetes mellitus (NIDDM). However, obesity is also a recognized risk factor for development of the disease, and is easier to track over time. Thus obesity could be of considerable clinical importance as a predictor of diabetes. Studies have shown that the degree of overweight, the change in weight and the duration of overweight are all separate predictors of diabetes. The British Regional Heart Study showed that an increasing body mass index (BMI) was associated with increased risk of developing diabetes, even at BMI values not considered obese. A separate study showed that weight gain increased the risk of diabetes independently of BMI, while weight loss decreased the risk. The duration of obesity was also an important factor in developing NIDDM. A long duration increased the risk of diabetes, irrespective of the final BMI value. The effects of obesity on insulin action have also been investigated. Studies have shown that insulin sensitivity is inversely related to insulin secretion, with a disproportionate increase in insulin secretion seen with decreasing sensitivity. A recent European study showed that the prevalence of both insulin hypersecretion and insulin resistance increased with increasing BMI. Thus, in obesity, higher insulin levels are necessary to maintain glucose tolerance, leading to increased stress on the β‐cells. In obese individuals, weight loss improved insulin sensitivity in proportion to the degree of weight loss, leading to decreased insulin secretion. Weight loss can therefore, at least in the short term, act to decrease the risk of developing diabetes by reducing insulin resistance, and thus relieving β‐cell stress, the factor ultimately responsible for hyperglycaemia in predisposed individuals.
The effect of circulating non‐esterified fatty acids on the entero‐insular axis
Authors: Ranganath  , Norris  , Morgan  , Wright  , Marks
Published: March 2003

Background

Circulating non‐esterified fatty acids (NEFAs) have been causally associated with impairment of glucose metabolism, although their effect on the entero‐insular axis, either in obesity or health, is unknown.

Materials and methods

Glucose, insulin, glucagon‐like peptide‐1 (7–36 amide) (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) responses to 100 g of carbohydrate in 400 mL water were evaluated during simultaneous modulation of circulating non‐esterified fatty acids (NEFAs). A total of 10 000 units of heparin (to increase serum NEFAs) and 500 mg of acipimox (2 h before oral carbohydrate ingestion to reduce serum NEFAs) were administered to seven obese [mean ± SEM: age 40 ± 3.7 years; body mass index (BMI) 38.9 ± 2.1 kg m−2] and seven lean (age 39.6 ± 3.6 years; BMI 22.4 ± 0.4 kg m−2) women.

Results

Higher fasting levels and post‐heparin total integrated NEFAs (P < 0.05) and glycerol (P < 0.05) responses were seen in the obese than in the lean group. Incremental integrated GLP‐1 responses to oral carbohydrate post‐heparin in lean (P < 0.01) and obese (P < 0.05) subjects were significantly lower than after acipimox. Total integrated GIP (P < 0.05) and glucose (P < 0.01) responses were higher post heparin than after acipimox in obese subjects only.

Conclusion

The inverse relationship in GIP and GLP‐1 responses in the obese group after modulation of NEFAs indicates that reciprocal changes between these two hormones may exist to ensure constancy of B‐cell stimulation. Our results suggest that in obese subjects compensatory secretion of GIP was incomplete and could not prevent impairment in glucose tolerance after heparin‐induced rise in NEFAs. These results may be important in understanding the role of the insulinotropic hormones in carbohydrate metabolism characterized by high NEFA levels such as obesity and diabetes mellitus.
Relationship of Helicobacter pylori CagA(+) status to gastric juice vitamin C levels
Authors: Rokkas  , Liatsos  , Petridou  , Papatheodorou  , Karameris  , Ladas  , Raptis
Published: March 2003

Background

To date it is not known whether gastric juice vitamin C levels are influenced by Helicobacter pylori CagA(+) strains. The aim of the present study, therefore, was to study the impact of H. pylori CagA status on gastric juice vitamin C levels.

Materials and methods

We studied 30 H. pylori(+) patients, and the results were compared with 10 endoscopically and histologically normal H. pylori(−) subjects (control group) who were similar to the H. pylori(+) group in terms of age and sex. In all patients, gastric juice vitamin C levels were determined and the severity of gastritis was graded on a scale of 0 (absent) to 3 (severe). CagA was determined by immunoblotting the sera from patients against H. pylori antigens.

Results

Among 30 H. pylori(+) patients, 20 were CagA(+) and 10 CagA(−). In the entire group of H. pylori(+) patients, the median gastric juice vitamin C levels (mg L−1) were 16.35 (range 3.5–33.6) and were significantly lower (P < 0.001) than in the control group of H. pylori(−) patients [35.5 (23.1–50.2)]. In addition, in the entire group of H. pylori(+) patients there was a highly significant (P < 0.0001) inverse correlation between the gastritis activity score and the gastric juice vitamin C levels. In the group of H. pylori CagA(+) patients, the median levels of gastric juice vitamin C were 13.8 (3.5–31.2) and were significantly lower than the corresponding levels in both the H. pylori CagA(−) group [24.8 (22–33.6), P < 0.01] and the H. pylori(−) control group [35.5 (23.1–50.2), P < 0.001], the last groups being similar. Furthermore, the gastritis activity median score in the H. pylori CagA(+) group [2 (1–3)] was significantly higher (P < 0.05) than in the H. pylori CagA(−) group [1 (1–2)].

Conclusion

These data indicate that infection with CagA(+) H. pylori strains significantly lowers the gastric juice vitamin C levels in comparison with CagA(−) H. pylori strains, which might have a significant impact on gastric carcinogenesis.
Invasive aspergillosis in neutropenic patients: rapid neutrophil recovery is a risk factor for severe pulmonary complications
Authors: Todeschini  , Murari  , Bonesi  , Pizzolo  , Verlato  , Tecchio  , Meneghini  , Franchini  , Giuffrida  , Perona  , Bellavite
Published: March 2003

Background

In invasive aspergillosis, the duration of neutropenia is an accepted risk factor, and recovery from neutropenia is generally associated with a favourable outcome. However, the rapidity of granulocyte recovery may rarely be associated with adverse sequelae. The purpose of this study was to define the relationship between neutrophil (polymorphonuclear, PMN) recovery after chemotherapy‐induced bone marrow aplasia and the occurrence of severe pulmonary complications (haemoptysis, pneumothorax and death) in patients with haematological malignancies who developed invasive fungal pneumonias.

Methods

Twenty consecutive patients were retrospectively studied; eight of them had developed pulmonary events between 5 and 11 days after neutrophil recovery that followed deep neutropenia (PMN < 100 μL−1).

Results

Five patients had haemoptysis (one of these also had pneumothorax) and three had pneumothorax. According to the multiplicative logistic model, the odds of occurrence of a pulmonary event increased significantly with increasing PMN count on the fifth day (P < 0.001). Five of the eight patients who had pulmonary complications died. Also, the risk of death was larger in the presence of rapid neutrophil recovery, although the difference was not statistically significant (P = 0.111). Analysis of clinical and laboratory data showed that the risk of pulmonary complications significantly increased when the neutrophil concentration was > 4500 μL−1 on day 5 after deep granulocyte neutropenia (PMN < 100 μL−1). There was no correlation between pulmonary complications, dosage of amphotericin B and deaths.

Conclusion

The occurrence of life‐threatening complications in patients with invasive fungal pneumonia is closely related to rapid PMN recovery.
Microcirculation in venous ulcers and the surrounding skin: findings with capillary microscopy and a laser Doppler imager
Authors: Gschwandtner  , Ambrózy  , Fasching  , Willfort  , Schneider  , Böhler  , Gaggl  , Ehringer
Published: March 2003

Background

To obtain more information about microcirculatory disturbances in venous ulcers, we studied their laser Doppler flux images and capillary densities.

Materials and methods

On photographs of venous ulcers and the adjacent skin of 17 patients, four regions of interest were marked: one non‐granulation tissue area (NGTA) within the venous ulcer, one granulation tissue area (GTA) within the ulcer, one adjacent skin area (ASA) and one distant skin area (DSA). Within these four regions the average laser Doppler area fluxes and capillary densities were determined for each patient using a laser Doppler imager and capillary microscopy respectively.

Results

The laser Doppler area flux (mean ± SD in AU) was significantly lower in NGTA (1.39 ± 1.12) than in GTA (4.06 ± 1.52) or DSA (3.86 ± 1.54) (P < 0.00001). In addition, the ASA flux (1.95 ± 1.39) was significantly lower than the GTA or DSA flux (P < 0.0001). Capillary density (capillaries per mm2) in NGTA (0.82 ± 1.98) was significantly lower than that in GTA (6.00 ± 2.55), ASA (13.88 ± 5.16) or DSA (10.29 ± 3.41) (P < 0.0001). In addition, the capillary density of ASA was significantly higher than that of GTA or DSA (P < 0.05).

Conclusion

The four areas showed the following characteristics: NGTA, low laser Doppler area flux and lowest capillary density (possible sign of ulcer area without healing tendency); GTA, high laser Doppler area flux and second lowest capillary density (possible sign of wound healing); ASA, low laser Doppler area flux and highest capillary density (possible sign of healing process nearly completed; scar); DSA, high laser Doppler area flux and second highest number of capillaries (sign of microcirculation of chronic venous disorder).
Decreased vitamin A levels in common variable immunodeficiency: vitamin A supplementation in vivo enhances immunoglobulin production and downregulates inflammatory responses
Authors: Aukrust  , Müller  , Ueland  , Svardal  , Berge  , Frøland
Published: March 2003

Background

Vitamin A has a broad range of immunological effects, and vitamin A deficiency is associated with recurrent infections. Common variable immunodeficiency (CVI) is a group of B‐cell deficiency syndromes with impaired antibody production and recurrent bacterial infections as the major manifestations, but the immunological dysfunctions may also include T cells and macrophages. In the present study we examined the possible role of vitamin A deficiency in CVI.

Patients and methods

We analysed plasma vitamin A levels in 20 CVI patients and 16 controls, and examined the relationships between vitamin A and clinical, immunological and metabolic parameters in CVI. In the six CVI patients with the lowest vitamin A levels we also studied the effect of vitamin A supplementation in vivo on several immunological functions in these patients.

Results

(i) The majority of CVI patients had decreased vitamin A levels compared with healthy controls, as found in both cross‐sectional and longitudinal testing. (ii) Low vitamin A levels were associated with the occurrence of chronic bacterial infections and splenomegaly as well as high neopterin levels. Decreased levels of carrier protein and malabsorption were not observed. (iii) Vitamin A supplementation in patients with low vitamin A levels resulted in increased interleukin‐10 (IL‐10) and decreased tumour necrosis factor‐α (TNFα) levels, as found in both plasma and monocyte supernatants, possibly favouring anti‐inflammatory net effects. (iv) Vitamin A supplementation in vivo also enhanced anti‐CD40‐stimulated IgG production, serum IgA levels and phytohaemagglutinin (PHA)‐stimulated peripheral blood mononuclear cell (PBMC) proliferation.

Conclusion

A considerable subgroup of CVI patients appears to be characterized by low vitamin A levels. Our findings support a possible role for vitamin A supplementation in CVI, perhaps resulting in enhanced immunoglobulin synthesis and downregulated inflammatory responses.
Non‐transferrin‐bound iron is present in serum of hereditary haemochromatosis heterozygotes
Authors: De Valk  , Addicks  , Gosriwatana  , Lu  , Hider  , M. Marx
Published: March 2003

Background

Hereditary haemochromatosis (HH) is a common autosomal recessive disease. Recently, HH heterozygosity has been identified as an independent risk factor for myocardial infarction and cardiovascular mortality. Iron may play an important role in atherogenesis by catalyzing peroxidation of low‐density‐lipoprotein (LDL), an essential step in atherogenesis. In iron overload conditions, non‐transferrin‐bound iron (NTBI) is found in serum, which can catalyze lipid peroxidation. We investigated whether sera of HH heterozygotes contain more NTBI than sera of normal controls.

Methods

In 27 treated HH homozygotes, 22 HH heterozygotes and 17 healthy control subjects, conventional parameters of iron status (serum iron, transferrin saturation, serum ferritin) were measured. NTBI was detected using HPLC after addition of nitrilotriacetic acid and pretreatment with cobalt.

Results

The conventional parameters of iron status were similar in the HH heterozygous group and the control group. NTBI was significantly higher in homozygotes compared to heterozygotes (1.79 μmol L−1 vs. 0.51 μmol L−1, 95% CI of the difference = 0.6–1.95, P < 0.001), and controls (1.79 μmol L−1 vs. − 0.3 μmol L−1, 95% CI of the difference = 1.36–2.81, P < 0.001). The difference in NTBI between the heterozygous subjects and control subjects was also significant (0.51 μmol L−1 vs. − 0.3 μmol L−1, 95% CI of the difference = 0.05–1.57, P < 0.05).

Conclusion

Phlebotomy treated HH homozygotes maintain a high and potentially harmful serum NTBI. HH heterozygotes have a higher serum NTBI than normal controls. The reported increased risk of cardiovascular events in heterozygous haemochromatosis may be explained by NTBI‐catalyzed LDL peroxidation.
Cytochrome P450 2D6 and glutathione S‐transferase M1 genotypes and migraine
Authors: Mattsson  , Bjelfman  , Lundberg  , Rane
Published: March 2003

Background

Migraine is thought to be a disease of the brain and trigeminovascular system. Migraine patients often claim that stress, food, and beverages trigger their attacks. Chemical substances in these foodstuffs with the property of triggering migraine attacks have not yet been characterised. Cytochrome P450 2D6 (CYP2D6) and glutathione S‐transferase M1 (GSTM1) are thought to be present in the brain. They metabolise numerous environmental compounds. The genes exhibit genetic polymorphism that is associated with altered enzyme activity. The aim of this study was to determine if the genotypes of these two enzymes are associated with migraine.

Materials and methods

The study included 100 female patients and 245 female controls from the general population. Genomic DNA was isolated from whole blood. Allele specific PCR methods were used to identify the normal CYP2D6*1 allele and the mutated CYP2D6*3 and CYP2D6*4 alleles. Initially all samples were genotyped only for GSTM1 plus (+) and GSTM1 null (−) variants. All samples positive for GSTM1 were further analysed for the presence of allelic variants GSTM1*A and GSTM1*B.

Results

None of the CYP2D6 and GSTM1 genotypes was associated with migraine. We observed an odds ratio (OR) for the poor metaboliser genotype of CYP2D6 of 1.4 (95% CI = 0.5–3.6) and for the GSTM1 null genotype of 1.0 (95% CI = 0.6–1.5).

Conclusion

The results of this study indicate that deficient metabolism because of mutated CYP2D6 alleles or GSTM1 allele variants is not important in the aetiology of migraine.
Low levels of colonic glutathione S‐transferase in patients with X‐linked agammaglobulinaemia
Authors: Grubben  , Van Den Braak  , Peters  , Van Der Meer  , Nagengast
Published: March 2003

Background

Patients with X‐linked agammaglobulinaemia, a primary immunodeficiency disorder, suffer from recurrent infections of the respiratory and intestinal tract. Rapidly progressive colorectal cancer was diagnosed in three unrelated young adults with X‐linked agammaglobulinaemia. This finding implies a 30‐fold increase of risk for this cancer in this patient group. Glutathione S‐transferases are a family of biotransformation enzymes involved in the detoxification of cytotoxic and carcinogenic compounds, that may function in the prevention of carcinogenesis. We investigated the possible role of the glutathione S‐transferase enzyme system in the apparently increased colorectal cancer risk in X‐linked agammaglobulinaemia patients.

Materials and methods

We analysed the glutathione levels and the glutathione S‐transferase enzyme activity and iso‐enzyme composition in normal colonic biopsies of eight X‐linked agammaglobulinaemia patients, 25 patients with a recent history of colonic adenomas and 10 healthy volunteers.

Results

X‐linked agammaglobulinaemia patients had significantly lower glutathione S‐transferase enzyme activities at all sites in the normal colonic mucosa as compared to adenoma patients. In X‐linked agammaglobulinaemia patients the rectal glutathione S‐transferase enzyme activity was lower than in the proximal colon and significantly lower as compared to controls.

Conclusion

This lower glutathione S‐transferase enzyme activity might play a role in the apparently increased colorectal cancer risk in X‐linked agammaglobulinaemia patients, assuming that detoxification of carcinogenic compounds plays a role in the aetiology of colon cancer of these patients.
Postprandial response to a fat tolerance test in young adults with a paternal history of premature coronary heart disease — the EARS II study
Authors: Tiret  , Gerdes  , Murphy  , Dallongeville  , Nicaud  , J. O'Reilly  , Beisiegel  , De Backer  , On Behalf Of The Ears Group
Published: March 2003

Background

The European Atherosclerosis Research Study (EARS) I had shown that fasting plasma concentrations of apolipoprotein B (apo B) and triglycerides were the most discriminant variables between offspring with a paternal history of coronary heart disease (CHD) and controls. The EARS II study was undertaken to investigate whether a paternal history of CHD was associated with differences in postprandial lipemia.

Design

Male subjects with a paternal history of CHD (cases, n = 407) and age‐matched male controls (n = 415) were recruited from 14 European universities. All subjects had an oral fat tolerance test.

Results

In the sample as a whole, the postprandial triglyceride responses did not significantly differ between the two groups. However, in the upper tertile of fasting triglycerides, cases displayed a higher area under the curve (5.71 vs. 4.49 mmol.h L−1, P < 0.001), a higher peak (1.76 vs. 1.43 mmol L−1, P < 0.001) and a more delayed time to peak (3.15 vs. 2.91 h, P < 0.05) than controls. In the upper tertile, fasting apo B levels (P < 0.05) and triglyceride area under the curve (P = 0.002) significantly discriminated cases from controls in a multivariate analysis. Cases had also higher Lp C‐III:B levels at 4 h than controls (11.2 vs. 9.9 mg dL−1, P < 0.01) and this difference remained significant after adjustment for apo B and triglyceride levels.

Conclusions

These results indicate that in subjects with a moderate elevation of fasting triglycerides, an impaired postprandial response to a fat load constitutes an early biological expression of a paternal history of premature CHD.
The increased insulin sensitivity in growth hormone‐deficient adults is reduced by growth hormone replacement therapy
Authors: Riedl  , Ludvik  , Pacini  , Clodi  , Kotzmann  , Wagner  , Kautzky‐Willer  , Prager  , Luger
Published: March 2003

Background

Growth hormone deficiency is associated with increased morbidity and mortality from cardiovascular diseases, which might be related to changes in glucose and lipid metabolism.

Design

To assess the influence of long‐term growth hormone replacement therapy (GHRT) on glucose metabolism we examined eight growth hormone‐deficient (GHD) adults (seven female/one male; age, 46 ± 3 years; body mass index, 31 ± 2 kg m−2) over a period of 18 months in comparison to an adequate control group consisting of eight obese subjects matched for age, sex, and body mass index. We performed frequently sampled intravenous glucose tolerance tests (FSIGT) with minimal model analysis before the study, and after 12 and 18 months.

Results

Following GHRT, insulin‐like growth factor‐1 (IGF‐1) increased significantly from a basal level of 75.9 ± 18.9 to 200.8 ± 31.0 μg L−1 after 12 months of therapy and remained stable, thereafter. GHRT did not affect fasting blood glucose, basal insulin, cholesterol, blood pressure and body weight. However, at 12 months, HbA1c (6.0 ± 0.1 vs. 5.6 ± 0.1% at basal, P < 0.05) and triglyceride (2.3 ± 0.4 vs. 1.4 ± 0.3 mmol L−1) significantly increased but returned to pretreatment values at 18 months. Insulin sensitivity was higher in GHD (8.2 ± 3.1) compared to controls (3.6 ± 0.53 × 10−4 min−1/(μU mL−1), P = 0.06) and decreased significantly after 18 months of GHRT to 5.1 ± 2.6, P < 0.05. Basal insulin secretion was similar to that in the control group and increased significantly after 12 and 18 months, total insulin secretion only after 12 months. SG (glucose effectiveness)was lower in GHD patients (0.0095 ± 0.001 min−1) compared to controls (0.020 ± 0.003 min−1, P < 0.05) and increased significantly after 12 and 18 months of GHRT (0.016 ± 0.002, and 0.015 ± 0.001 min−1, P < 0.05), respectively. Hepatic insulin extraction rate was similar in both groups and remained unchanged following GHRT.

Conclusion

We conclude that long‐term GHRT induces a significant decrease of the increased insulin sensitivity in GHD patients to levels observed in body mass index‐matched control subjects. This is accompanied by an increase in basal and total insulin secretion as well as in glucose effectiveness as a possible compensatory mechanism.
Metabolic age modelling: the lesson from centenarians
Authors: Paolisso G. , Barbieri M. , Bonafè M. , Franceschi C.
Published: March 2003

Evolutionary theories of ageing, and data emerging from cellular and molecular biology of ageing, suggested that animals and humans capable of reaching an age close to the extreme limit of the life span should be equipped with a very efficient network of anti‐ageing mechanisms. Indeed several evidences have demonstrated that starting from young to very old subjects, ageing is associated with a progressive remodelling. Thus, a new paradigm, the remodelling theory of age, was proposed. This theory, focusing on the human immune system, suggested that immunosenescence is the net result of the continuous adaptation of the body to the deteriorative changes occurring over time. According to this hypothesis, body resources are continuously optimized, and immunosenescence must be considered a very dynamic process including both loss and gain. Whether the metabolic pathways and the endocrine functions are also part of the age remodelling is not investigated. The aim of this review is to focus on the age‐related changes in metabolic pathways and endocrine functions and to demonstrate that healthy centenarians (HC) represent the best living example of successful age‐remodelling in whom the age remodelling has occurred without problems. In order to design the clinical picture of such successful ageing, anthropometric, endocrine and metabolic characteristics of healthy centenarians (HC), compared with aged subject, have been outlined.
Influence of vitamin D administration on bone ultrasound measurements in patients on anticonvulsant therapy
Authors: Pedrera J.D. , Canal M.L. , Carvajal J. , Postigo S. , Villa L.F. , Hernández E.R. , Rico H.
Published: March 2003

Background

The objective of the study was to evaluate bone mass status (as measured by bone ultrasound) in patients on anticonvulsant therapy, and the influence that Vitamin D administration exerts over it.

Materials and methods

We measured and compared the basal serum levels of 25(OH)D3, parathyroid hormone (PTH), and phalangeal bone ultrasound (Ad‐SOS), in 30 adult patients who were taking anticonvulsant drugs, with a control group of similar age and sex. We then gave the patients a large oral dose of 3 mg (120.000 UI) of 25(OH)D3, and repeated the measurements after one month.

Results

Basal 25(OH)D3 and Ad‐SOS values were significantly lower, and PTH values significantly higher (P < 0.0001 in all), in the patient group. The low Ad‐SOS values for the patients were independent of the treatment, but directly related to basal 25(OH)D3 levels (r = 0.45, P < 0.01). There was a negative association between PTH and 25(OH)D3 (r = −0.64, P < 0.0001), and no correlation between PTH y Ad‐SOS (r = −0.20, p NS). After ingestion of the large dose of the vitamin D, the patient group registered a significant (P < 0.0001) increase in 25(OH)D3 levels, their Ad‐SOS values increased (P < 0.0001) nearly to the mean basal value of the control group, and PTH decreased significantly (P < 0.0001).

Conclusions

These findings justify the need to assure adequate vitamin D intake in patients being treated with anticonvulsants, independently of the treatment, age, sex, and activity status, in order to prevent osteomalacia.
Diurnal triglyceride profiles in healthy normolipidemic male subjects are associated to insulin sensitivity, body composition and diet
Authors: Van Oostrom A. J. H. H. M. , Castro Cabezas M. , Ribalta J. , Masana L. , Twickler TH. B. , Remijnse T. A. , Erkelens D. W.
Published: March 2003

Background

Elevated fasting and postprandial triglycerides (TG) are established risk factors for Coronary Heart Disease (CHD). Usually, fasting plasma TG are measured, although TG are mainly produced in a postprandial state. Our objective was to investigate diurnal TG profiles using serial capillary TG measurements, in normolipidemic healthy males.

Materials and Methods

Forty‐eight, non‐obese, non‐smoking males (range: 20–55 years, mean age: 32 ± 12 years), measured diurnal capillary TG, at six fixed timepoints during the day on three different days and recorded their food intake. Insulin sensitivity was estimated by HOMA. Diurnal capillary TG profiles were calculated as integrated area under the mean capillary TG curve (TGc‐AUC).

Results

All subjects had normal fasting plasma TG and cholesterol. The average TGc‐AUC was 23.6 ± 6.7 mmol h L−1. Significant correlations with TGc‐AUC were: fasting insulin (r = 0.40, P < 0.005), HOMA (r = 0.32, P < 0.05), relative fat mass (r = 0.31, P < 0.05), dietary protein‐(r = 0.31, P < 0.05) and saturated fat intake (r = 0.30, P < 0.05). Age was not associated to diurnal triglyceridemia. After subdividing the group into quartiles on the base of TGc‐AUC, differences were found between the highest (n = 12) and lowest quartile (n = 12) for: fasting capillary TG, fasting insulin, HOMA and systolic blood pressure. Fasting plasma TG and dietary intake were not different.

Conclusion

Diurnal TG profiles in healthy normolipidemic males are not age‐dependent, but are associated to insulin sensitivity, fat mass and diet. Diurnal capillary TG profiles may be a valuable additional tool in estimating a risk profile for CHD since significant differences in diurnal TG are not always reflected by elevated fasting plasma TG.
Additive effects of Simvastatin beyond its effects on LDL cholesterol in hypertensive type 2 diabetic patients
Authors: Tonolo G. , Melis M. G. , Formato M. , Angius M. F. , Carboni A. , Brizzi P. , Ciccarese M. , Cherchi G. M. , Maioli M.
Published: March 2003

Background

Experimental evidence indicates that statins might have direct vascular effects independently from low‐density lipoprotein (LDL) cholesterol reduction and we reported that the reduction in urinary albumin excretion rate during Simvastatin treatment in type 2 diabetic patients was not correlated with LDL‐cholesterol decrease. However in humans there are no data regarding possible additional effects of Simvastatin on blood pressure and urinary albumin excretion beyond its capacity to lower serum cholesterol.

Patients and methods

Twenty‐six microalbuminuric hypertensive type 2 diabetic patients (diastolic blood pressure — after four months wash‐out from the previous antihypertensive therapy — consistently > 90 and < 100 mmHg; plasma LDL‐cholesterol > 3.9 and < 6.5 mmol L−1) were enrolled in the study. In random order, these patients received Simvastatin (20 mg day−1) or Cholestyramine (6 g three times a day) for a period of 10 months and after three months of wash‐out (cross‐over) the sequence was reversed for an additional 10 months. Blood pressure, lipid parameters, glycated haemoglobin and urinary albumin excretion were measured during the study. Additionally, in eight patients, urinary glycosaminoglycan excretion (GAG) was also measured during the study.

Results

Simvastatin and Cholestyramine were equally effective in reducing total and LDL cholesterol. Only during Simvastatin treatment a significant reduction in diastolic blood pressure and both 24 h urinary albumin and GAG excretion rates were observed, while no significant changes were seen with Cholestyramine treatment.

Conclusions

Our results clearly show for the first time that the reduction of blood pressure, together with 24 h urinary albumin excretion rate — two established cardiovascular risk factors, obtained during Simvastatin therapy in hypertensive type 2 diabetic patients — is in large part independent from the reduction of LDL Cholesterol.
Intra‐adrenal regulation of androgen synthesis
Authors: L'Allemand D. , Biason‐Lauber A.
Published: March 2003

The adrenal cortex encloses the neuroendocrine medulla and is itself subdivided into three distinct zones, each having a specific function and regulation. While the glomerulosa and the fasciculata control vital systems of mineral and energy supply, which are stringently regulated by higher control factors, the function of the reticularis is less clear, beyond supplying a pool of weak androgens, and consequently we do not understand its redundant regulation.

The following questions need to be answered:

1 How is the formation of dehydroepiandrosterone (DHEA) and androstenedione differently regulated from glucocorticoid synthesis in normally functioning adrenals?

2 How might growth factors, which increase prepubertally [1], prime the adrenarche?

3 The regulation of the 17/20‐lyase enzyme activity is one of the key factors of adrenal androgen secretion (review [2]). How can the two activities of the P450c17 enzyme be differently regulated in the same cell in a developmentally dependent fashion?

This review focuses on the intra‐adrenal growth factor system and on the role of 17/20‐lyase regulation, as well as on their possible interactions. The increase of activity of the 17/20‐lyase enzymatic activity is necessary for the rise of C19 steroids [3], while the relative increase of formation of DHEA is only possible in the presence of a low 3β‐hydroxysteroid‐dehydrogenase (3βHSD) activity [4].
Dehydroepiandrosterone – a neurosteroid
Authors: Friess E. , Schiffelholz T. , Steckler T. , Steiger A.
Published: March 2003

Dehydroepiandrosteone (DHEA) and its sulfate ester (DHEAS) are the major secretory products of the human adrenal glands and serve as precursors for both androgenic and estrogenic steroids. DHEA/S concentrations are particularly high in the brain, and DHEA/S and related steroids can be synthesized de novo in brain glial cells. Therefore, the term ‘neurosteroids’ has been coined for these compounds.

This review summarizes findings in neurosteroid physiology on a cellular and molecular level, and outlines current concepts of how these compounds modulate physiological functions of the brain. Today, despite promising preclinical and human data the present clinical studies provide only weak evidence, if any, in favour of a DHEA replacement therapy.
Homocysteine and the MTHFR 677C→T allele in premature coronary artery disease. Case control and family studies
Authors: Pintó X. , Vilaseca M. A. , Garcia‐Giralt N. , Ferrer I. , Palá M. , Meco J. F. , Mainou C. , Ordovás J. M. , Grinberg D. , Balcells S. ,   the Baix Llobregat Homocysteine Study Group
Published: March 2003

Background The aim of this work was to evaluate the role of homocysteine, and the MTHFR 677C→T allele as risk factors for premature coronary artery disease and to analyse the inheritance of this metabolic disorder.

Material and methods Case‐control and family studies were performed in a sample of 76 male patients (age < 55), 95 age‐matched controls and 89 patients' offspring. Plasma total homocysteine concentrations, its nutritional determinants and the frequency of the MTHFR 677C→T allele were measured, in addition to conventional risk factors.

Results Mild hyperhomocysteinemia (above the 90th percentile of the control group) was seen in 22·4% of patients (P = 0·02) and was an independent predictor of premature coronary artery disease (odds ratio of 3·2). The frequencies of the 677T allele in patients and controls were 0·37 and 0·36 and those of the TT genotype were 0·15 and 0·14, respectively. Homozygosity for the 677T allele was associated with significantly higher homocysteine values (P < 0·00001). Among TT patients, 64% had mild hyperhomocysteinemia, as compared to 23% of TT controls. Mild hyperhomocysteinemia showed a strong hereditary component, as 36% of patients' offspring had homocysteine levels above the age‐adjusted 90th percentile compared to only 13% of patients' spouses. Among children with the TT genotype, the proportion raised to 83% (P < 0·001).

Conclusion In this Spanish population, mild hyperhomocysteinemia is associated with the risk of premature coronary artery disease and is highly prevalent in offspring of patients with this condition. The MTHFR TT genotype is associated with hyperhomocysteinemia, but not with coronary artery disease.
Effect of ischemia on intestinal permeability of lipopolysaccharides
Authors: Drewe J. , Beglinger C. , Fricker G.
Published: March 2003

The enteral absorption of endotoxin (lipopolysaccharide, LPS) was studied in vitro and in vivo.

The absorption of fluorescence (FITC) labelled LPS was investigated by uptake studies with rabbit jejunal brush‐border membrane vesicles (BBMV), the human intestinal cell line Caco‐2 and in rats.

FITC‐LPS from Salmonella typhimurium was taken up into BBMV in a dose‐dependent manner. Uptake was neither pH‐ nor Na+‐dependent, nor could it be inhibited by unlabelled LPS. 74·5% of vesicle‐associated fluorescence was due to adhesion to the vesicular membranes, 25·5% was taken up into an osmotically‐sensitive space. Transport of LPS across Caco‐2 cell monolayers was dose‐dependent. The permeation rate increased significantly under ischemic conditions, i.e. when the cells were incubated under oxygen‐depleted conditions. However, no significant differences in transepithelial electrical resistances were observed between oxygen depleted and control cells. The release of lactate dehydrogenase was only marginally different from control cells, indicating cell integrity. In situ, after gut ischemia, a significantly increased uptake of fluorescent LPS was observed by fluorescence laser scanning microscopy. Conclusion LPS is taken up by the intestinal mucosa, predominantly by passive transcellular diffusion. Under ischemic conditions, the permeability of LPS is increased mainly by an enhanced paracellular permeability and epithelial destruction. The findings partly explain the clinically observed development of multiorgan system failure after temporary malperfusion of the gut during major vascular surgery or thromboembolism.