bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatitis C virus core protein does not inhibit apoptosis in human hepatoma cells
Authors: Dumoulin  , Von Dem Bussche  , Söhne  , Sauerbruch  , Spengler
Published: March 2003

Background

Viral persistence is a major problem after infection with the hepatitis C virus. Recently, it has been reported that hepatitis C virus core protein inhibits cis‐platin induced apoptosis in human cervical carcinoma cells and apoptosis induced by overexpression of c‐myc in Chinese hamster ovary cells.

Materials and methods

This study investigated whether different variants of hepatitis C virus core or E2 protein interfere with tumour necrosis factor α or Fas (CD95/ APO‐1) antibody‐induced programmed cell death in transiently transfected human hepatoma (HepG2) cells.

Results

While neither full length or C‐terminally truncated variants of hepatitis C virus core protein nor hepatitis C virus E2 protein inhibited tumour necrosis factor α‐ or Fas antibody‐induced apoptosis, a strong inhibition was observed with the cowpox virus cytokine response modifier A protein.

Conclusions

Thus, it is unlikely that hepatitis C virus core or E2 protein inhibit apoptosis mediated by apoptosis‐signalling pathways sensitive to cytokine response modifier A protein. Discrepancies to previous reports probably reflect specific effects of hepatitis C virus core protein on different apoptotic pathways and/ or cell lines.
Acute effect of H.E.L.P. treatment on radical scavenging enzyme activities, total glutathione concentrations in granulocytes, and selenium in plasma
Authors: Schettler  , Methe  , Schuff‐Werner  , Müller  , Wieland
Published: March 2003

Background

It has been suggested that granulocytes are activated on artificial surfaces such as dialyzer membranes or by plasma separation procedures resulting in the generation of free radicals. We reported recently that free radical scavenging enzyme (FRSE) activities of red blood cells obtained from patients undergoing hemodialysis and LDL‐apheresis (LA) do not reflect an acute oxidative stress. However, because mature red cells are free of DNA and RNA, enzymes cannot be regulated on the gene level. In contrast, granulocytes are nucleated cells in which genes can be regulated, e.g. by redox sensitive transcription factors activated by extracellular oxidative stress. Therefore, granulocyte FRSE may better reflect acute oxidative stress caused by extracorporeal treatment.

Materials and methods

Hyperlipidemic patients (n = 18) with coronary heart disease (CHD) were treated with the Heparin‐induced‐Extracorporeal‐LDL‐Precipitation (H.E.L.P.) system. Glutathione peroxidase (GSH‐Px), glutathione reductase (GSSG‐R), superoxide dismutase (SOD) activities, and total glutathione were determined in granulocytes before and immediately after a single LA treatment. Selenium (Se) concentrations were assessed in plasma.

Results

As a result of the H.E.L.P. treatment GSSG‐R activity was significantly induced (+ 20%) and the GSH concentration increased (+ 41%) in granulocytes. GSH‐Px activity in granulocytes (– 19%) and Se in plasma (– 27%) were significantly reduced whereas SOD activity in granulocytes was not affected by the H.E.L.P. procedure.

Conclusion

These results show that the defence against oxygen radicals in granulocytes is affected but not severely compromised in patients undergoing regular H.E.L.P‐LDL‐apheresis treatment, which points to the safety of this system with respect to oxidative stress.
Dermatitis herpetiformis is associated with atrophic but not with goitrous variant of Hashimoto's thyroiditis
Authors: Zettinig  , Weissel  , Flores  , Dudczak  , Vogelsang
Published: March 2003

Background

Dermatitis herpetiformis (DH) is a gluten‐sensitive skin disease that is associated with a variety of autoimmune disorders. Several investigations demonstrated an association between DH and autoimmune thyroid disease. However, it has not been shown if DH is associated with atrophic or goitrous variant of Hashimoto's thyroiditis.

Materials and methods

We investigated a cohort of 41 DH patients (18 male, 23 female) and a control group (11 male, 19 female; sex and age matched healthy volunteers) to find out which variant of Hashimoto's thyroiditis is associated with DH. All patients had thyroid hormones and antibodies measured. In addition to that, thyroid sonography as well as detailed history‐taking of previous thyroid disease were performed.

Results

In the control group no individual with elevated levels of thyroid antibodies nor abnormal thyroid hormones nor thyroid atrophy was found. Median thyroid volume in the control group was 11 mL (range 4.8–24.7 mL). However, in nine DH patients (22%) elevated levels of antithyroid microsomal (TM) antibodies were seen (P < 0.01). Three of them had abnormal thyroid hormones (7%). In the group of DH patients a significantly smaller thyroid volume was found (median 8 mL, range 1.6–25.2 mL; P < 0001). Thyroid atrophy (volume < 4.4 mL) was found in 10 DH patients (24%) of whom 9 were females. All patients with elevated levels of TM antibodies or abnormal thyroid hormones and all patients with a history of previous hypothyroidism had a thyroid volume < 7 mL. Goitrous variant of Hashimoto's thyroiditis was not seen in any of the DH patients.

Conclusions

Our findings demonstrate that DH is associated with atrophic but not with goitrous variant of Hashimoto's thyroiditis.
Nutritional supplements combined with dietary counselling diminish whole body protein catabolism in HIV‐infected patients
Authors: Berneis  , Battegay  , Bassetti  , Nuesch  , Leisibach  , Bilz  , Keller
Published: March 2003

Background

Weight loss and protein malnutrition are frequent complications in HIV‐infected patients. The effect of an oral nutritional supplement combined with nutritional counselling on whole body protein metabolism was assessed.

Materials and methods

HIV‐infected individuals with a body mass index < 21 kg m−2 or CD4‐T cells < 500 μ L−1 in stable clinical condition were randomly allocated to [
1] receive either oral nutritional supplements (containing 2510 kJ, complete macro‐ and micronutrients) and dietary counselling (n = 8), or [
2] identical monitoring but no supplements or specific nutritional advice (controls, n = 7). Whole body leucine kinetics and leucine oxidation rate were determined by [1–13C]‐leucine infusions and lean and fat mass were measured before and 12 weeks after intervention.

Results

Leucine oxidation (protein catabolism) decreased in the group receiving nutritional intervention from 0.33 ± 0.02 to 0.26 ± 0.02 μmol kg−1 min−1 after 12 weeks (P < 0.05; P < 0.05 vs. control group) but remained unchanged in the control group. Whole body leucine flux showed a tendency to decrease in the intervention group from 1.92 ± 0.19 to 1.73 ± 0.14 μmol kg−1 min−1 (P = 0.07) and remained unchanged in the control group (2.21 ± 0.16 and 2.27 ± 0.14 μmol kg−1 min−1, respectively). Lean body mass determined by bioelectrical impedance analysis increased in the nutritional intervention group from 84 ± 2 to 86 ± 2 per cent (P < 0.05) and fat mass decreased from 17 ± 2 to 14 ± 2 per cent (P < 0.05) of total body weight whereas neither mass changed in the control group. Nutritional intervention had no significant effect on lymphocyte CD4 counts, on plasma TNFR 55, TNFR 75 and ILR 2 concentrations and on quality of life.

Conclusions

The data demonstrate an anticatabolic effect of nutritional supplements combined with dietary counselling in HIV‐infected subjects. They suggest that diminished whole body protein catabolism resulted in a change of body composition (increased lean mass, decreased fat mass).
The Space Mission MIR'97: operational aspects
Authors: Ewald R. , Lohn K. , Gerzer R.
Published: March 2003

Background

A German astronaut visited the MIR space station between 10 February and 2 March 1997. Together with his Russian colleagues, he conducted a series of scientific investigations before, during and after his stay aboard the MIR station. Research performed during this flight was part of a global space life sciences programme and focused on metabolic homeostasis, fluid balance, calcium homeostasis and cardiovascular regulatory mechanisms. The main goal of the scientific experiments was to use this mission as a milestone to establish international networks of scientific collaboration using space research as a tool for focused research in respective fields. Thus, in most cases the results obtained from the astronaut complemented a series of results obtained on ground and from other flights. In other cases, they extended previous results and opened new fields for future research.

Participants

Human space flight with astronauts serving as operators and at the same time as test subjects is very complex. Many people, including mission control, a science management team, medical operations, ethics committees and a medical board, participated to harmonize the different requirements, thus making a maximal scientific outcome possible.

Conclusion

In summary, this space mission may be seen as a model for focused long‐term multidisciplinary international research, and demonstrates that space medicine is no longer adventure but science.
Evaluation of factors controlling glucose tolerance in patients with HCV infection before and after 4 months therapy with interferon‐α
Authors: Konrad  , Zeuzem  , Vicini  , Toffolo  , Briem  , Lormann  , Herrmann  , Berger  , Kusterer  , Teuber  , Cobelli  , Usadel
Published: March 2003

Background

Epidemiological data suggest that chronic hepatitis C virus (HCV) infection may contribute to the development of diabetes mellitus. Therapy of HCV infection with recombinant interferon‐α (r‐IFN‐α) can also impair of glucose metabolism.

Methods

To investigate the impact of HCV infection and the therapy with r‐IFN‐α on glucose metabolism we measured insulin sensitivity, glucose effectiveness, and first and second phase insulin secretion, using the minimal modelling analysis of frequently sampled intravenous glucose tolerance tests in 13 nondiabetic patients with HCV‐induced liver disease before and after therapy with r‐INF‐α (6 × 106 U, subcutaneously, three times a week over 4 months). Liver biopsy was performed to evaluate and score liver fibrosis as a marker of HCV‐induced cell injury.

Results

Insulin sensitivity (r = − 0.59, P < 0.05) and first phase insulin secretion (r = − 0.66, P < 0.03) were negatively related to the fibrosis score. Insulin sensitivity rose from 1.96 (SEM 0.37, n = 8) to 5.69 (SEM 0.99, n = 8) 10−4 min−1 per μU mL−1 (P < 0.01) in responders and from 2.51 (SEM 0.61, n = 5) to 6.95 (SEM 1.99, n = 5) in nonresponders after 4 months r‐INF‐α therapy. Fasting free fatty acids decreased significantly to about 50% (P < 0.01) in patients with and without therapy response after 4 months, whereas first phase insulin secretion did not change.

Conclusions

HCV‐induced liver injury is related to the deterioration of insulin sensitivity and first phase insulin response, thus impairing glucose homeostasis in these HCV‐infected patients. The administration of r‐INF‐α three times a week over 4 months is not associated with an impairment of glucose homeostasis.
Speed of sound, bone mineral density and bone strength in ooforectomized rats
Authors: Calero  , Curiel  , Moro  , Carrascal  , R. Santana  , Avial
Published: March 2003

Background

The aim of this study was to determine the sensitivity of bone mineral density (BMD), ultrasounds (SOS) and resistance to torsion (T) to detect experimental osteopenia induced in rats 3 and 6 months after ooforectomy.

Materials and methods

Seventy‐four rats were used, divided into four groups, ooforectomized rats analysed 3 and 6 months after the operation and their respective control groups, in which BMD (Hologic QDR 1000 S/N 277), SOS (DBM Sonic 1200) and T (adapted test machine) were determined in the right femur.

Results

The results of the three techniques distinguished the ooforectomized groups from the controls, both 3 and 6 months after the ooforectomy, obtaining more significant differences with BMD (P = 0.0006, P = 0.001, respectively) than SOS and T, where a significance of only P = 0.05 was obtained. In the correlation study among the three techniques, a significant correlation was observed between BMD and SOS (r = 0.39, P = 0.0008), as well as between BMD and T (r = 0.31, P = 0.03). However, significance was not observed between the SOS and T tests.

Conclusion

In the study of sensitivity and specificity of the techniques used to detect the osteopenia caused by the ooforectomy, by means of calculation of the area under the receiver operation characteristic (ROC) curve, it was proven that although the three techniques distinguished between the two analysed populations, BMD presented an area under the ROC curve that was superior (0.87, 0.85) to that obtained with SOS (0.73, 0.67) and T (0.73, 0.68), both 3 and 6 months after the operation.
Antithrombin III and local serum application: adjuvant therapy in peritonitis
Authors: Schorr  , Siebeck  , Zügel  , Welcker  , Gippner‐Steppert  , Czwienzek  , Gröschler  , Jochum
Published: March 2003

Background

Patients with diffuse peritonitis show an overall mortality of about 20%, probably caused by the breakdown of local defence mechanisms combined with a systemic outspread of bacteria and toxins, which often results in sepsis syndrome.

Design

In a prospective, randomized, controlled study 50 patients with diffuse secondary peritonitis were included. Patients in the therapy group were treated with an adjuvant medication consisting of a continuous intravenous infusion of antithrombin III and two intraperitoneal instillations of fresh frozen human donor serum. The aim of the study was the reduction of mortality and incidence of multiple organ failure.

Results

Mean antithrombin III plasma levels in the therapy group were raised above 140% for 4 days and were significantly higher than in the control group. With the intraperitoneal application of fresh frozen serum and antithrombin III opsonic capacity as well as thrombin, inhibitory activity in the exudate could be significantly elevated over 2 days. The 90‐day‐mortality rate was 6/26 (23%) in the control group and 6/24 (25%) in the therapy group. Although no improvement of mortality was achieved, a slight but not significant reduction of the severity of the multiple organ failure was seen.

Conclusions

The chosen therapeutic approach was feasible and showed no side‐effects. Yet, neither mortality nor multiple organ failure were significantly improved by the applied short‐term adjuvant therapy. Thus, for future trials in severely‐ill patients a longer treatment period and/or combinations of antithrombin III with other anti‐inflammatory agents should be considered.
The effect of cholesterol lowering on carotid and femoral artery wall stiffness and thickness in patients with familial hypercholesterolaemia
Authors: Smilde  , Van Den Berkmortel  , Wollersheim  , Van Langen  , Kastelein  , Stalenhoef
Published: March 2003

Background

Early in the process of atherosclerosis, changes in vessel wall stiffness and thickness may occur. The present study evaluates the effect of cholesterol reduction on artery wall stiffness and intima media thickness in patients with familial hypercholesterolaemia (FH).

Materials and methods

Forty‐five patients with familial hypercholesterolaemia (mean age 46 ± 10 years) with untreated LDL cholesterol concentration > 9 mmol L−1, were studied before and after one year of cholesterol lowering therapy with statins (simvastatin, atorvastatin 40–80 mg day−1). The distensibility (DC in 10−3 kPa−1) and compliance (CC in mm2. kPa−1) of the common carotid artery (CCA) (right and left side) and common femoral artery (CFA) (right side) were determined by a wall track system (Pie Medical). The intima media thickness (IMT) (both right and left) of the CCA, bulb (BUL), internal carotid artery (ICA) and CFA were measured in mm by high‐resolution ultrasound (Biosound).

Results

The mean concentration of total cholesterol (TC), LDL‐cholesterol (LDL‐C) and triglycerides (TG) were reduced significantly by 43%, 51% and 25%, respectively, whereas HDL‐cholesterol (HDL‐C) increased by 13% (P < 0.001). In the CFA, the DC and CC increased significantly (DC from 7.9 ± 3.0 to 9.1 ± 3.7 in 10−3 kPa−1; CC 0.5 ± 0.2–0.6 ± 0.3 in mm2. kPa−1), whereas the DC and CC did not change in the CCA. In contrast, the IMT of the CCA decreased significantly in both men and women whereas an IMT decrease was also seen in the BUL and ICA in premenopausal women. A LDL‐cholesterol reduction of 44.8% and 45.4% was necessary to induce significant decreases in IMT and increases in DC and CC.

Conclusions

One year of cholesterol lowering therapy in FH decreases the wall stiffness in the CFA and the arterial wall thickness in the CCA.
Neuropeptide variability in man
Authors: Onuoha  , Nugent  , Hunter  , Alpar  , McEneaney  , S. Campbell  , Shaw  , Buchanan  , Nicholls
Published: March 2003

Background

Previous studies have established short‐term variability in the circulating plasma levels of cardiac peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Our aim was to investigate whether such variable patterns could be observed in other vasoactive peptides.

Methods

We measured the immunoreactivity of vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), endothelin‐1 (ET‐1) and calcitonin gene‐related peptide (CGRP) in peripheral venous plasma collected at 2‐min intervals over a 20‐min period from patients with chronic cardiac failure (CCF) and from control subjects. In a second study, blood samples were obtained at 2‐min intervals from the pulmonary artery, femoral artery and antecubital vein from patients with normal cardiac function while right atrial pressure and heart rate were constant.

Results

Peripheral blood VIP, NPY and ET‐1 had peaks and troughs (levels > 2SD from the mean) in both patients and controls, with approximate intervals of 10 min. Levels of CGRP showed little variation. The overall levels [median (range); pmol L−1] of VIP [patients 27 (2.1–85.5); controls 9.8 (0–34)] and NPY [patients 20 (0–110); controls 12 (5–19)] were higher in patients (P < 0.05). Circulating plasma levels of ET‐1 and CGRP were about the same in both groups [ET‐1: patients 18 (2–84); controls 18 (0–48); CGRP: patients 4 (1–18.5), controls 5.5 (1–15); P = NS]. Levels of CGRP, VIP and ET‐1 were similar in the pulmonary and femoral arteries, whereas systemic arterial levels of NPY were higher than in the pulmonary artery.

Conclusions

The data demonstrate marked variability in circulating levels of the neuropeptides studied. In addition, peaks and troughs were observed every 10–15 min from all three vascular beds. If these peptides are secreted in a pulsatile pattern, then interpretations of single measurements should be guarded. Furthermore, this study raises interesting questions about the physiology of hormone secretion in man.
The polysaccharide fucoidan inhibits microvascular thrombus formation independently from P‐ and l‐selectin function in vivo
Authors: Thorlacius  , Vollmar  , Seyfert  , Vestweber  , Menger
Published: March 2003

Background

Adhesion molecules of the selectin family (mainly P‐ and L‐selectin) have been suggested to mediate interactions between platelets, leukocytes and endothelial cells in thrombus formation. The polysaccharide fucoidan has anticoagulative properties, but is also able to bind and block the function of the selectins. Here, we investigated in vivo (i) if fucoidan can prevent microvascular thrombus formation, and (ii) whether this is potentially mediated by the inhibition of P‐and/or L‐selectin.

Materials and Methods

For this purpose, we used intravital microscopy in the mouse cremaster microcirculation in which thrombosis was induced photochemically by light exposure to individual arterioles and venules after intravenous (i.v.) injection of FITC‐dextran.

Results

We found that intravenous administration of fucoidan significantly prolonged the time required for complete occlusion in arterioles and venules by almost seven‐ and nine‐fold, respectively. In contrast, treatment with monoclonal antibodies against P‐ and L‐selectin had no effect on the development of microvascular thrombosis. Fucoidan and also the anti‐P‐selectin antibody completely inhibited baseline venular leukocyte rolling in the cremaster muscle, indicating that these treatment regimes abolished P‐selectin function. Importantly, fucoidan and the anti‐P‐selectin antibody had no effect on systemic platelet and leukocyte counts. On the other hand, we found that fucoidan treatment significantly altered coagulation parameters, including prothrombin time (Quick percentage), activated partial thromboplastin time (APTT) and thrombin clotting time (TCT), which may explain the potent in vivo anticoagulative effect of fucoidan observed here.

Conclusions

Taken together, our novel findings suggest that fucoidan effectively prevents microvascular thrombus formation induced by endothelial damage in arterioles and venules in vivo. This protective effect of fucoidan is not attributable to inhibition of P‐ and
L‐selectin function but may instead be related to the anticoagulative capacity of fucoidan.
Cardiovascular response to lower body negative pressure stimulation before, during, and after space flight
Authors: Baisch F. , Beck L. , Blomqvist G. , Wolfram G. , Drescher J. , Rome J‐L. , Drummer C.
Published: March 2003

It is well known that space travel cause post‐flight orthostatic hypotension and it was assumed that autonomic cardiovascular control deteriorates in space. Lower body negative pressure (LBNP) was used to asses autonomic function of the cardiovascular system.

LBNP tests were performed on six crew‐members before and on the first days post‐flight in a series of three space missions. Additionally, two of the subjects performed LBNP tests in‐flight. LBNP mimics fluid distribution of upright posture in a gravity independent way. It causes an artificial sequestration of blood, reduces preload, and filtrates plasma into the lower part of the body. Fluid distribution was assessed by bioelectrical impedance and anthropometric measurements.

Heart rate, blood pressure, and total peripheral resistance increased significantly during LBNP experiments in‐flight. The decrease in stroke volume, the increased pooling of blood, and the increased filtration of plasma into the lower limbs during LBNP indicated that a plasma volume reduction and a deficit of the interstitial volume of lower limbs rather than a change in cardiovascular control was responsible for the in‐flight response. Post‐flight LBNP showed no signs of cardiovascular deterioration. The still more pronounced haemodynamic changes during LBNP reflected the expected behaviour of cardiovascular control faced with less intravascular volume. In‐flight, the status of an intra‐and extravascular fluid deficit increases sympathetic activity, the release of vasoactive substances and consequently blood pressure. Post‐flight, blood pressure decreases significantly below pre‐flight values after restoration of volume deficits.

We conclude that the cardiovascular changes in‐flight are a consequence of a fluid deficit rather than a consequence of changes in autonomic signal processing.
Water and sodium balances and their relation to body mass changes in microgravity
Authors: Drummer C. , Hesse C. , Baisch F. , Norsk P. , Elmann‐Larsen B. , Gerzer R. , Heer M.
Published: March 2003

Since the very beginning of space physiology research, the deficit in body mass that is often observed after landing has always been interpreted as an indication of the absolute fluid loss early during space missions. However, in contrast to central hypervolemic conditions on Earth, the acute shift of blood volume from the legs to the upper part of the body in astronauts entering µ‐gravity (µ‐G) has neither stimulated diuresis and natriuresis nor resulted in negative water‐and sodium‐balances.

We therefore examined the kinetics of body mass changes in astronauts (n = 3) during their several weeks aboard the space station MIR. A continuous diet monitoring was performed during the first mission (EuroMIR94, 30 days). The second mission (MIR97, 19 days) comprised a 15‐day metabolic ward period (including predefined constant energy and sodium intake). Water and sodium balances were calculated and the kinetic of changes in basal concentrations of fluid‐balance‐related hormones during flight were determined.

The data suggest firstly that loss of body mass during space flight is rather a consequence of hypocaloric nutrition. Secondly, µ‐G provokes a sodium retaining hormonal status and may lead to sodium storage without an accompanying fluid retention.
Histopathological classification of adrenal tumours
Authors: Saeger W.
Published: March 2003

Tumours in the adrenals originate from the adrenal cortex, the adrenal medulla or as metastases from extra‐adrenal primaries. Differentiating between these three groups is the first task a pathologist has to tackle when dealing with specimens from the adrenal region. Whereas this is possible in every case with total removal of the adrenal tumour it may be impossible in fine needle biopsies of such tumours. The second great problem is the dignity of adrenal tumours, which cannot be determined in many adrenomedullary and some adrenocortical tumours. Immunostainings are helpful but the basic method remains the histopathological examination of paraffin sections. This review gives an update of pathological findings in several adrenal tumour entities, and provides guidelines for the diagnosis of these tumours in the light of recently published data.
New polymorphisms in the interleukin‐10 gene – relationships to myocardial infarction
Authors: Donger C. , Georges J‐L. , Nicaud V. , Morrison C. , Evans A. , Kee F. , Arveiler D. , Tiret L. , Cambien F.
Published: March 2003

Background

Interleukin‐10 (IL‐10) is a cytokine with anti‐inflammatory and B‐cell‐stimulating activity. IL‐10 is expressed in human atherosclerotic plaques and recent studies have shown the involvement of IL‐10 in the atherosclerotic process. Therefore, we hypothesized that polymorphisms in the IL‐10 gene might be associated with a predisposition to coronary heart disease.

Materials and methods

To identify new polymorphisms in the human IL‐10 gene, the entire coding sequence and the 3′ flanking sequence of the gene were screened by polymerase chain reaction–single strand conformation polymorphism (PCR‐SSCR ) followed by sequencing. The polymorphisms identified, and three others which have been previously described in the promoter region of the IL‐10 gene (G‐1082A, C‐819T, C‐592A), were then investigated in the ECTIM Study, a large population‐based case–control study of myocardial infarction.

Results

Four new polymorphisms were identified: one in exon 1 (G+78/ex1A), which predicts a Glycine to Arginine change at position 15 in the putative signal peptide of the protein, two in the intron 3 (C+19/in3T, T+953/in3C) and one in the 3′ flanking region (C+117T). All the IL‐10 polymorphisms were in complete or nearly complete pairwise linkage disequilibrium. No case–control difference was found in genotype or allele frequencies for any of the polymorphisms.

Conclusions

Our results suggest that IL‐10 polymorphisms are not associated with an increased risk of myocardial infarction.
Aspects of gene polymorphisms in cardiovascular disease: the renin‐angiotensin system
Authors: Carluccio M. , Soccio M. , De Caterina R.
Published: March 2003

The renin‐angiotensin system (RAS) plays a central role in cardiovascular homeostasis. Angiotensin is the key peptide of the RAS, and exerts its influence on the heart and blood vessels both through its haemodynamic effects (via its influence on after‐load and pre‐load and determining coronary vasoconstriction) and through its direct cellular effects (via its actions on cell proliferation). Numerous studies in the past 10 years have demonstrated that the pharmacological inhibition of angiotensin converting enzyme (ACE), one of the two critical enzymes of the RAS, improves the outcome in patients with several cardiovascular disorders (hypertension, heart failure, ischaemic heart disease). These studies suggest a role of the RAS as a major determinant of cardiovascular risk. Recent data suggest that genetics may in turn contribute to modulating the effects of angiotensin on coronary vascular biology and ischaemia. This paper reviews the physiologic characteristics of the RAS and recent research developments related to angiotensin cell biology and pathobiology in heart disease. In particular, this review will cover the genetic aspects of RAS and their implications in cardiovascular disease.
The improvement of renal concentration capacity after surgery for primary hyperparathyroidism
Authors: Hedbäck G. , Abrahamsson K. , Odén A.
Published: March 2003

Background Improvement of renal concentration capacity was long ago shown to occur after surgery for primary hyperparathyroidism (pHPT). Study of concentration capacity is of interest, as it was also shown to be a predictive factor for the risk of death in patients with pHPT, and it affected the risk of death independently of 33 other variables in multivariate analysis.

Methods There were 98 patients with verified pHPT operated on in the years 1958–81, who had urine osmolality determinations performed both before and after surgery: 63 immediately after, and 35 with mean 3·9 years delay (SD = 1·8). Another seven patients with pHPT had urine osmolality determinations performed preoperatively only. Non‐parametric sign tests, regression analysis, and correlation tests were performed.

Results Both patients with severe or moderate, and mild pHPT showed a substantial change of renal concentration capacity, with mean increase of 28·3% (SD = 28·4). The increase generally occurred soon after surgery. In eight out of 98 patients, there was no improvement. A relationship was found between improvement and preoperative peak serum calcium level. In seven out of seven patients followed, untreated for mean 5·3 years (SD = 3·2), there was a mean 15% (SD = 8·0) deterioration of renal concentration capacity.

Conclusions The findings of this study add cause for surgery in patients with pHPT and give no reason for different treatment of severe, moderate or mild disease.
Why is soluble intercellular adhesion molecule‐1 related to cardiovascular mortality?
Authors: Becker A. , Van Hinsbergh V. W. M. , Jager A. , Kostense P. J. , Dekker J. M. , Nijpels G. , Heine R. J. , Bouter L. M. , Stehouwer C. D. A.
Published: March 2003

Increased plasma levels of soluble adhesion molecules are associated with an increased risk of atherothrombosis. The pathophysiological mechanisms responsible for these associations are not known. The aim of the present study was to investigate the association of soluble intercellular adhesion molecule‐1 (sICAM‐1) concentration and risk of cardiovascular and all‐cause mortality among individuals with and without type 2 diabetes. In addition, we assessed potential pathophysiological mechanisms by which sICAM‐1 may promote mortality.

Six hundred and thirty‐one subjects taken from a general population of the middle‐aged and elderly participated in this prospective cohort study. Baseline data collection was performed from 1989 to 1992; subjects were followed until 1 January 2000.

Subjects who died had higher levels of sICAM‐1 than those who survived (506(164) vs. 477(162) ng mL−1, respectively). After adjustment for age, gender and glucose tolerance status, subjects with sICAM‐1 levels in the upper quartile (≥550 ng mL−1) had a relative risk of cardiovascular mortality of 2·05 (95% confidence interval, 1·10–3·81) compared to subjects with sICAM‐1 levels in the other quartiles. Further adjustment for classical cardiovascular risk factors or indicators of (sub)clinical atherosclerosis, endothelial dysfunction, inflammation and renal function did not materially alter this relative risk. A high sICAM‐1 level was more frequent in subjects with type 2 diabetes than in subjects with a normal glucose tolerance (33·3 vs. 17·8%).

Individuals with a plasma concentration of sICAM‐1 higher than 550 ng mL−1 had a cardiovascular mortality risk that was twice that of individuals with a lower concentration. Classical cardiovascular risk factors (sub)clinical atherosclerosis, endothelial dysfunction and inflammation do not explain this excess risk.
Decreased trabecular bone biomechanical competence, apparent density, IGF‐II and IGFBP‐5 content in acromegaly
Authors: Ueland T. , Ebbesen E. N. , Thomsen J. S. , Mosekilde L. , Brixen K. , Flyvbjerg A. , Bollerslev J.
Published: March 2003

Background Earlier studies on the effect of excess growth hormone (GH) on trabecular bone have been conflicting. Since insulin‐like growth factors (IGFs) and their binding proteins (IGFBPs) in part mediate the effects of GH, the present study aimed to investigate trabecular bone composition of these growth factors in relation to biomechanical properties in acromegaly.

Materials and methods Trabecular bone biomechanical competence (compression test), apparent density (peripheral quantitative computed tomography, pQCT), and bone matrix contents of calcium (HCl hydrolysis) and IGFs (guanidinium–HCl extraction) were measured in iliac crest biopsies from 13 patients with active acromegaly (two women and 11 men, aged 21–61 years) and 21 age‐ and sex‐matched controls (four women and 17 men, aged 23–64 years).

Results Trabecular bone pQCT was reduced in acromegalic patients compared with controls (P = 0·005), as was biomechanical competence (P < 0·05 for all measures). These parameters were significantly positively correlated in both acromegalic patients and controls. The calcium content of trabecular bone was significantly increased in patients compared with controls. No significant differences were found in trabecular bone content of IGF‐I, IGFBP‐3, or osteocalcin. However, IGF‐II and IGFBP‐5 content was decreased (P < 0·001 and P < 0·05, respectively).

Conclusions The present study demonstrates reduced trabecular biomechanical competence and apparent density in acromegaly, supporting previous observations of an unfavourable effect of chronic excess GH on the axial skeleton. Furthermore, we demonstrate decreased trabecular bone content of IGF‐II and IGFBP‐5 in these patients. However, we found no direct causal relationship between trabecular bone density and bone content of IGF‐system components.
Angiogenesis extent and expression of matrix metalloproteinase‐2 and ‐9 agree with progression of ovarian endometriomas
Authors: Ria R. , Loverro G. , Vacca A. , Ribatti D. , Cormio G. , Roccaro A. M. , Selvaggi L.
Published: March 2003

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

Methods  Tissues from 44 biopsies of stage III and IV ovarian endometriomas, and 10 biopsies of normal (control) endometrium were investigated immunohistochemically to count microvessels, and by in situ hybridization to assess the expression of mRNA of matrix metalloproteinase‐2 (MMP‐2) and MMP‐9. Implants of the tissues were investigated in the chick embryo chorioallantoic membrane (CAM) assay to determine their angiogenic capacity.

Results  The endometriomas displayed significantly higher counts than normal endometria and the highest values were associated with the deepest invasion level (stage IV). Microvessels localized in close association with ectopic endometrial cells in the form of winding and arborized tubes, often dilated in microaneurysmatic segments. These were absent in normal endometrium. Expression of MMP‐2 and MMP‐9 mRNA, evaluated as percentages of positive biopsies and intensity of expression, was up‐regulated in endometriomas and more pronounced in stage IV. MMP‐2 and MMP‐9 mRNA were also expressed by host stromal cells, including microvascular endothelial cells, fibroblasts and macrophages, whereas the control endometrium showed very little expression of MMP‐2 mRNA in a few endothelial cells and no expression of MMP‐9 mRNA. Implants from stage IV endometrioma induced a more intense vasoproliferative response than those from stage III, while no vasoproliferative response was induced by the normal endometrium.

Conclusion  These data suggest that angiogenesis and degradation of extracellular matrix occur together in endometriosis and are more pronounced in stage IV, and that endometriosis cells and some host stromal cell populations co‐operate in disease progression.
Inhibition of cell proliferation and fibronectin biosynthesis by Na ascorbate
Authors: Péterszegi G. , Dagonet F. B. , Labat‐Robert J. , Robert L.
Published: March 2003

Background The importance of ascorbate on the production of extracellular matrix proteins (as elastin and collagens) is now well documented, but no studies have been published concerning its effects on fibronectin biosynthesis. Fibronectin is important for cell attachment and for proliferation.

Materials and methods The effects of Na ascorbate were investigated on cell attachment, proliferation, viability and fibronectin biosynthesis by human skin fibroblasts in vitro. Proliferation was followed by the monitoring of [3H]‐thymidine incorporation; viability by the MTT‐test, cell adherence by counting adherent and nonadherent cells and fibronectin biosynthesis by immunoprecipitation of biosynthetically labelled fibronectin.

Results In the presence of ascorbate, the fibroblasts showed a biphasic growth pattern. At 500 µM ascorbate, [3H]‐thymidine incorporation was stimulated by 15% as compared to the controls. Higher concentrations gradually decreased proliferation up to 36% of the control value at 5 mM. These effects of ascorbate on DNA synthesis were followed to > 1·25 mM by a strong inhibition, cytotoxic effect and cell death. The non‐adherent cell count increased to 10% of the total population at 2·5 mM and to 31% at 5·0 mM ascorbate.

Increasing concentrations of ascorbate resulted in a dose‐dependent decrease of fibronectin biosynthesis, both in the culture supernates and cell extracts. This inhibition mainly concerned cell membrane‐associated fibronectin.

Superoxide‐dismutase or catalase could inhibit Na ascorbate‐induced cytotoxicity and partially re‐establish fibronectin biosynthesis. Desferrioxamine, ergothionein and vitamin E were inefficient.

Conclusions

Our results indicate that ascorbate decreases fibronectin biosynthesis of cultured human skin fibroblasts, thereby producing cell detachment and decreased proliferation. This effect is mainly mediated by the reactive oxygen species and can be inhibited by superoxide‐dismutase and catalase.
Enhanced DNA damage‐induced p53 peptide phosphorylation and cell‐cycle arrest in Sjögren’s syndrome cells
Authors: Henriksson G. , Brant M. , Sallmyr A. , Fukushima S. , Manthorpe R. , Bredberg A.
Published: March 2003

Background Cells from primary Sjögren’s syndrome (SS) patients have been reported to show alterations in DNA repair and p53 expression. The DNA‐dependent protein kinase (DNA‐PK) autoantigen may be involved in both of these alterations in relation to cellular DNA damage responses. We conducted this study of cell‐cycle kinetics and p53 to find additional evidence for an abnormal stress response role in the pathogenesis of SS.

Design DNA‐dependent protein kinase activity, p53 peptide phosphorylation and p53 protein levels were determined in gamma‐irradiated long‐term T lymphocyte cultures. Cell‐cycle progression of peripheral blood mononuclear cells was analysed with flow cytometry.

Results No significant differences in the DNA‐PK activities or p53 protein levels appeared between the SS patients and the healthy individuals. However, patients with the SS hallmark Ro/SS‐A and La/SS‐B autoantibodies showed enhancement of both p53 peptide phosphorylation (P = 0·036) and G1 cell‐cycle arrest (P = 0·015) in response to gamma radiation.

Conclusions Sjögren’s syndrome cells express an enhanced G1 checkpoint function which may be mediated partly by p53 phosphorylation, suggesting that an abnormal stress response in SS is of relevance for the development of this autoimmune disease.
Tauroursodeoxycholic acid mobilizes α‐PKC after uptake in human HepG2 hepatoma cells
Authors: Glasova Helena , Berghaus Thomas M. , Kullak‐Ublick Gerd A. , Paumgartner Gustav , Beuers Ulrich
Published: March 2003

Background Tauroursodeoxycholic acid (TUDCA) may exert anticholestatic effects via Ca++‐ and α‐protein kinase C (α‐PKC)‐dependent apical vesicular insertion of canalicular transporters in cholestatic hepatocytes (Hepatology 2001; 33: 1206–16). Tauroursodeoxycholic acid is mainly taken up into liver cells by Na+‐taurocholate cotransporting polypeptide (Ntcp). Tauroursodeoxycholic acid selectively translocates α‐PKC, a key mediator of regulated exocytosis, to hepatocellular membranes. It is unclear whether TUDCA exerts its effects on α‐PKC after carrier‐mediated uptake into liver cells or by interaction with extracellular/membraneous structures.

Materials and methods Human hepatoblastoma HepG2 cells lacking Ntcp were stably transfected with pcDNA3·1/Ntcp or sham‐transfected with pcDNA3·1 [+]. Distribution of α‐PKC was studied using a Western blotting technique. Uptake of [3H]taurocholic acid (TCA) was determined radiochemically.

Results [3H]taurocholic acid uptake was approximately 180‐fold higher in Ntcp‐transfected than in sham‐transfected cells. Phorbol 12‐myristate 13‐acetate (1 µmol L−1; positive control) increased membrane binding of α‐PKC by 34% in Ntcp‐transfected and by 37% in sham‐transfected cells. Tauroursodeoxycholic acid (10 µmol L−1) increased membrane‐associated α‐PKC by 19% in Ntcp‐transfected, but not in sham‐transfected cells (−13%). Taurocholic acid (10 µmol L−1) did not affect the distribution of α‐PKC.

Conclusion Carrier‐mediated uptake is a prerequisite for TUDCA‐induced translocation of α‐PKC to hepatocellular membranes.
Therapy of circadian rhythm disorders in chronic fatigue syndrome: no symptomatic improvement with melatonin or phototherapy
Authors: Williams G. , Waterhouse J. , Mugarza J. , Minors D. , Hayden K.
Published: March 2003

Background Patients with chronic fatigue syndrome (CFS) show evidence of circadian rhythm disturbances. We aimed to determine whether CFS symptoms were alleviated by melatonin and bright‐light phototherapy, which have been shown to improve circadian rhythm disorders and fatigue in jet‐lag and shift workers.

Design Thirty patients with unexplained fatigue for > 6 months were initially assessed using placebo and then received melatonin (5 mg in the evening) and phototherapy (2500 Lux for 1 h in the morning), each for 12 weeks in random order separated by a washout period. Principal symptoms of CFS were measured by visual analogue scales, the Shortform (SF‐36) Health Survey, Mental Fatigue Inventory and Hospital Anxiety and Depression Scale. We also determined the circadian rhythm of body temperature, timing of the onset of melatonin secretion, and the relationship between these.

Results Neither intervention showed any significant effect on any of the principal symptoms or on general measures of physical or mental health. Compared with placebo, neither body temperature rhythm nor onset of melatonin secretion was significantly altered by either treatment, except for a slight advance of temperature phase (0·8 h; P = 0·04) with phototherapy.

Conclusion Melatonin and bright‐light phototherapy appear ineffective in CFS. Both treatments are being prescribed for CFS sufferers by medical and alternative practitioners. Their unregulated use should be prohibited unless, or until, clear benefits are convincingly demonstrated.
Longitudinal evolution of HIV‐1‐associated lipodystrophy is correlated to serum cortisol:DHEA ratio and IFN‐α
Authors: Christeff N. , De Truchis P. , Melchior J.‐C. , Perronne C. , Gougeon M.‐L.
Published: March 2003

Background We have previously shown that lipid alterations in HIV‐1‐associated lipodystrophy (LD) are correlated with decreased serum dehydroepiandosterone (DHEA) and increased cortisol:DHEA ratio and IFN‐α levels.

Objective To evaluate in a longitudinal study whether steroid and cytokine modifications are associated with the evolution of physical changes and lipid alterations associated with LD.

Methods Thirty‐four HIV‐1‐positive men were followed during 32·5 ± 4·0 months and tested at four time‐points. The patients were subdivided into five groups according to physical changes and anthropometric measurements: LD‐negative, initially LD‐negative becoming LD‐positive, LD‐positive unchanged, aggravated or improved. Serum lipids, apolipoproteins, adrenal steroids and cytokines were measured and compared with baseline values.

Results (1) LD aggravation is associated with persistent elevated lipids, a decrease in serum DHEA, an increase in cortisol:DHEA ratio and persistent high levels of IFN‐α. (2) LD improvement is associated with normalization of serum lipids, an increase in serum DHEA leading to normalization in cortisol:DHEA ratio, and normalization of IFN‐α levels. (3) In LD‐positive men evolution of VLDL cholesterol is negatively correlated with DHEA (r = −0·56, P < 0·01) and positively with cortisol:DHEA ratio (r = 0·62, P < 0·004) and with IFN‐α (r = 0·57, P < 0·01). (4) The switch to LD is associated with a decrease in serum DHEA. (5) Patients who remained LD‐negative maintained normal lipids, elevated cortisol and DHEA, and normal cortisol:DHEA ratio and normal levels of IFN‐α.

Conclusions This study indicates that cortisol:DHEA ratio and serum IFN‐α levels are closely associated with clinical evolution and atherogenic lipid alterations in LD.
Haemochromatosis mutations and ferritin in myocardial infarction: a case‐control study
Authors: Claeys D. , Walting M. , Julmy F. , Wuillemin W. A. , Meyer B. J.
Published: March 2003

Background  Iron accumulation may contribute to coronary heart disease by catalysing free radical formation and promoting oxidation of low‐density lipoprotein cholesterol. Epidemiological studies of iron status and coronary heart disease are conflicting.

Design  To test whether genetic haemochromatosis is associated with myocardial infarction, we determined the prevalence of three mutations in the HFE gene (Cys282Tyr, His63Asp and Ser65Cys) in a 2 : 1 case‐control study including 177 patients who survived an acute myocardial infarction and 89 controls. Genotypes were determined by PCR amplification of genomic DNA followed by restriction enzyme digestion. We also studied the relationship between plasma ferritin and myocardial infarction.

Results  The carrier frequencies of these three mutations were not statistically different among patients and controls (Cys282Tyr: 12·4 vs. 10·1%; His63Asp: 26·5 vs. 31·5%; Ser65Cys: 2·8 vs. 1·1%). Mean ferritin levels were elevated among patients (176 ± 155 µg L−1) compared with controls (131 ± 106 µg L−1, P = 0·015). Subjects with plasma ferritin concentrations of 300 µg L−1 or more had a 2·9‐fold (95% CI: 1·2–7·3, P = 0·02) unadjusted risk for a myocardial infarction compared with those with normal levels. In a univariate analysis, ferritin was significantly associated with myocardial infarction. Upon multiple regression analysis adjusting for smoking, hypertension, diabetes, body‐mass index and total cholesterol, significance was no longer present.

Conclusions

No direct association was found between genetic haemochromatosis and myocardial infarction among Swiss whites. Raised ferritin levels among patients suggest a role of increased iron stores in myocardial infarction, but iron overload was not an independent risk factor for Swiss coronary heart disease patients.
Novel intronic variants of MICB (MHC class I chain‐related gene B)
Authors: Fischer G. , Argüello J. R. , Pérez‐Rodríguez M. , Cox S. T. , McWhinnie A. , Marsh S. G. E. , Madrigal J. A.
Published: March 2003

We report an eight‐nucleotide duplication in intron 4 of the MICB allele 01021, which was found in samples from different ethnic backgrounds and in association with several HLA‐B alleles. We suggest that this new MICB allele is evolutionarily older than HLA‐B alleles.