bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of digoxin on circadian blood pressure values in patients with congestive heart failure
Authors: Kirch  , Grossmann  , Fischer  , Neumeister  , Kirch
Published: March 2003

Background

The aim of the study was to investigate the effect of chronic digoxin treatment on circadian blood pressure profile in normotensive patients with mild congestive heart failure.

Methods

In a randomized double‐blind, placebo‐controlled cross‐over protocol, 12 normotensive patients with mild congestive heart failure took digoxin or placebo for a total of 7 days. Automatic 24‐h ambulatory blood pressure measurements were carried out at day 7, of either digoxin or placebo.

Results

Diastolic blood pressure significantly decreased and systolic blood pressure significantly increased during overnight sleep in the digoxin phase compared to placebo. Digoxin had no effect on either systolic or diastolic blood pressure during daytime. Heart rate decreased in the overnight sleeping phase but did not differ significantly between placebo and digoxin phase.

Conclusions

Digoxin significantly decreases diastolic blood pressure during overnight sleep in patients with congestive heart failure. This effect is likely to be caused by reduction of sympathetic activity or increase of parasympathetic activity. Increase of systolic blood pressure during sleep is probably caused by the positive inotropic effect of the drug.
Association between alpha‐1‐antichymotrypsin polymorphism and susceptibility to chronic obstructive pulmonary disease
Authors: Ishii  , Matsuse  , Teramoto  , Matsui  , Hosoi  , Fukuchi  , Ouchi
Published: March 2003

Background

The antiproteases, including alpha‐1‐antitrypsin, are supposed to prevent lungs from becoming emphysematous. Genetic susceptibility to smoking injury may confer a risk for the development of chronic obstructive pulmonary disease (COPD).

Methods

We have investigated the association between the polymorphism of alpha‐1‐antichymotrypsin (AACT), one of the antiproteases, and susceptibility to the development of COPD among heavy smokers. Blood samples obtained from both patients with COPD (n = 53) and control subjects (n = 65) at the Tokyo University Hospital, the Juntendo University Hospital and the Tokyo Kenbikyoin Clinic were used for this genotyping assay. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were performed to genotype the AACT biallelic polymorphism in the signal peptide (−15 alanine to threonine), and the two polymorphisms of the exon (Pro229Ala and Leu55Pro).

Results

The proportion of AACT/Ala‐15 homozygotes was significantly higher in the COPD patients than in the control subjects (COPD 37.7% vs. control 18.5%). The odds ratio for AACT/Ala‐15 homozygotes vs. all other genotypes was 2.7 (95% CI 1.2–6.2) for the COPD group. We could not find any association between the other two polymorphisms and COPD.

Conclusions

Genetic polymorphism in the signal peptide of AACT may be associated with individual susceptibility to the development of COPD, because the AACT/Ala‐15 genotype is predominantly found in patients with COPD. It is suggested that AACT/Ala‐15 genotype may be less protective against smoking injury.
Microgravity inhibits intestinal calcium absorption as shown by a stable strontium test
Authors: Zittermann A. , Heer M. , Caillot‐Augusso A. , Rettberg P. , Scheld K. , Drummer C. , Alexandre C. , Horneck G. , Vorobiev D. , Stehle P.
Published: March 2003

Little is known about the onset and degree of biochemical and functional alterations in calcium metabolism during microgravity.

To evaluate the effect of microgravity on intestinal calcium absorption and calcium‐regulating hormones under metabolic ward conditions.

Fractional calcium absorption (Fc240 in percentage of dose administered) was determined pre‐flight, in‐flight and post‐flight, by use of a stable strontium test in one cosmonaut who spent 20 days in space. Moreover, a sequence of blood samples was collected for the determination of serum parathyroid hormone (PTH), 25‐hydroxyvitamin D, calcitriol and serum C‐telopeptide (CTx, biomarker of bone resorption) levels. During all periods of data collection, calcium intake was held constant at a minimum level of 1·000 mg day−1 and a daily supplement of 16·6 µg vitamin D2 was given. Personal ultraviolet (UV) light exposure was measured during the whole mission using a biologically weighting UV dosimeter.

Fc240 was markedly reduced on flight day 19 (4·4%) as compared to pre‐flight and post‐flight data (13·4% and 17·2%, respectively). Serum calcitriol levels fell from 40·6 pg mL−1 (mean pre‐flight level) to 1·3 pg mL−1 on flight day 18 and returned into the normal range after recovery. Serum CTx increased during the flight, while serum PTH and 25‐hydroxyvitamin D levels did not change significantly.

Intestinal calcium absorption can be diminished after only three weeks of microgravity. Changes are associated with a severe suppression of circulating calcitriol levels, but are independent of exogenous vitamin D supply and serum PTH levels.
Apolipoprotein E‐deficient mice have an impaired immune response to Klebsiella pneumoniae
Authors: De Bont  , Netea  , Demacker  , Kullberg  , Van Der Meer  , Stalenhoef
Published: March 2003

Background

All lipoproteins are able to bind to bacterial lipopolysaccharide (LPS), thereby neutralizing its deleterious effects. However, we demonstrated, recently, that in the absence of apolipoprotein E (apoE), eight‐fold increased very‐low‐density lipoprotein levels were not sufficient to protect apoE‐deficient (apoE−/−) mice against LPS. During a live Gram‐negative infection, mechanisms other than LPS‐neutralization may play a role in the pathogenesis of the disease. In the present study we further examined the role of apoE in Gram‐negative sepsis.

Methods

Survival, bacterial outgrowth in liver, spleen, kidneys and blood, and tumour necrosis factor‐α (TNF‐α) production were measured in apoE−/− mice and control C57BL/6J mice, after an intravenous infection with Klebsiella pneumoniae.

Results

Mice that lack apoE showed higher mortality in response to K. pneumoniae than control mice (90% vs. 23% respectively after 2 weeks). ApoE−/− mice had 10–100 times more outgrowth of the bacteria in their organs than controls. Furthermore, circulating TNF‐α concentrations 90 min after a challenge, were almost twice as high in the apoE−/− mice compared to controls (13.0 ± 2.9 ng mL−1 vs. 7.6 ± 3.8 ng mL−1). When apoE−/− and control mice were rendered neutropenic, the discrepancy in survival and outgrowth of K. pneumoniae disappeared.

Conclusions

The apoE−/− mice were more susceptible than control C57BL/6 mice to a K. pneumoniae infection. The absence of apoE may render these mice more susceptible, since this protein is of importance in the detoxification of lipopolysaccharide of Gram‐negative bacteria. On the other hand, the phagocytic capacity of granulocytes seems to be decreased in apoE−/− mice, resulting in increased outgrowth and mortality.
LDL–apheresis in patients with nephrotic syndrome: effects on serum albumin and urinary albumin excretion
Authors: Stenvinkel P. , Alvestrand A. , Angelin B. , Eriksson M.
Published: March 2003

Background

Hyperlipidemia is a common feature of the nephrotic syndrome (NS). From retrospective studies, it has been suggested that aggressive lipid‐lowering with low‐density lipoprotein apheresis (LDL–A) may not only improve dyslipidemia but also decrease urinary albumin excretion and increase serum levels of albumin in patients with focal segmental sclerosis.

Methods

Seven patients (6 males) aged 44 ± 7 years (SEM) with NS (duration 29 ± 11 months) of diverse etiologies were investigated in a prospective study. A fixed protocol of LDL–A was designed for treatment twice‐a‐week for 3 weeks and then once a week for 7 weeks. The effects of LDL–A on lipid parameters (cholesterol, triglycerides, HDL, Lp(a), apo A‐I, apo B) and renal parameters (iohexol clearance, serum albumin and 24‐h urinary albumin excretion) were evaluated.

Results

Following treatment by LDL–A a remission in the severity of the NS was observed in two patients whereas a clear improvement was observed in four of the patients. A small, but significant (P < 0.05), increase in serum albumin levels from 20 ± 2 to 24 ± 2 g L−1 was noted after LDL–A. As expected, serum lipid parameters improved during LDL–A, and significant decreases in serum cholesterol, apo B and plasma Lp(a) were observed at different time‐points of LDL–A. Conversely, no significant changes in either triglyceride, HDL or apo A‐I levels were observed during LDL–A.

Conclusions

The present uncontrolled prospective study shows that LDL–A causes a rapid 30–40% decrease in serum cholesterol and plasma Lp(a) levels in patients with NS. The present prospective study also suggests that short‐term LDL–A treatment may increase serum albumin levels in nephrotic patients.
New p53 mutations in hilar cholangiocarcinoma
Authors: Tullo  , D'Erchia  , Honda  , Kelly  , Habib  , Saccone  , Sbisà
Published: March 2003

Background

Inactivation of the tumour suppressor gene, p53, is the commonest genetic abnormality in human cancer. The study of the type of p53 mutation in a given tumour may provide prognostic information, clues to aetiology and become useful for therapeutics.

Materials and Methods

The molecular characterisation of p53 was performed by restriction analysis, denaturing gradient gel electrophoresis, and gene sequencing for exons 5–9.

Results

We report, p53 mutational analysis in exons 5–9 in 29 European patients with hilar cholangiocarcinoma who underwent attempted resection. Four patients (14%) showed somatic single nucleotide substitutions with amino acid changes (146, 163, 175, 158, and 175) with one showing mutations in two different positions involving a loss of two CfoI sites. All the mutations occurred in exon 5. Three patients had a germline polymorphism (10%) with a silent substitution in codon 213 (exon 6).

Conclusions

The systematic screening for p53 mutations in European patients with hilar cholangiocarcinoma has shown that the type of mutation (except 175) is different and its incidence is much lower when compared to the pattern previously reported for intrahepatic cholangiocarcinoma in East Asian patients. A probable explanation is that the presence and type of p53 mutation is dependent on geographic and environmental factors which vary in different populations.
ACE‐inhibition modulates some endothelial functions in healthy subjects and in normotensive type 1 diabetic patients
Authors: Schalkwijk C. G. , Smulders R. A. , Lambert J. , Donker A. J. M. , Stehouwer C. D. A.
Published: March 2003

Background

The usefulness of treatment with an angiotensin‐converting enzyme‐inhibitor (ACE‐inhibitor) in normotensive patients with type 1 diabetes is controversial. We investigated whether ACE‐inhibition improves endothelial function in such patients and compared the responses to those in healthy subjects.

Design

We studied 23 healthy volunteers (controls, aged 29.8 [SD 7.0] years) and 24 type 1 diabetic patients (aged 28.7 [9.6] years; HbA1c 8.1 [1.2]%; diabetes duration 13.8 [2–30] years; blood pressure < 140/90 mmHg; 7 with microalbuminuria) after 5 weeks of ACE‐inhibition (quinapril, 10 mg day−1) and placebo in a randomized, double‐blind cross‐over design. Estimates of endothelial function obtained were by flow‐mediated vasodilation and plasma levels of endothelium‐derived proteins.

Results

As estimated from the measurements on placebo, type 1 diabetic patients, as compared to the controls, had some impairment of endothelial function: plasma tissue‐type plasminogen activator levels were lower (3.5 vs. 5.4 ng mL−1, P < 0.05), but there were no significant differences in brachial artery flow‐mediated vasodilation or plasma levels of von Willebrand Factor, endothelin‐1, plasminogen activator inhibitor‐1, soluble E‐selectin or vascular cell adhesion molecule‐1. As compared to placebo, ACE‐inhibition increased flow‐mediated vasodilation in controls (by 3.84% points [95% CI, 0.66 − 7.02], P < 0.05), but not in type 1 diabetic patients (0.82% points [95% CI, −2.72 − 4.36], P = 0.64; P = 0.08 vs. controls). On ACE‐inhibition soluble E‐selectin levels decreased both in controls (from 43.0 to 37.0 ng mL−1, P < 0.01) and in type 1 diabetic patients (from 41.0 to 39.0 ng mL−1, P = 0.09). Other endothelial markers did not change during ACE‐inhibition.

Conclusion

Normotensive type 1 diabetic patients with normoalbuminara or microalbuminuria have mild endothelial dysfunction. Short‐term ACE‐inhibition improves endothelial function as reflected by a decreased sE‐selectin in healthy subjects and in normotensive type 1 diabetic patients. In healthy subjects, ACE‐inhibition increases flow‐mediated vasodilation. In contrast, in type 1 diabetic patients, ACE‐inhibition does not affect flow‐mediated vasodilation.
Cellular immune–endocrine interaction in adrenocortical tissues
Authors: Marx C. , Bornstein S. R. , Wolkersdörfer G. W.
Published: March 2003

Background

The detection of important immunocompetence‐like features on endocrine steroid cells raises questions about direct intercellular communication between the adrenal and immune systems. This article summarizes our recent work and new data on immune–adrenal interactions.

Materials and methods

RT‐PCR and immunohistochemistry were performed to examine MHC class II (HLA‐DR) expression in adrenocortical tumours. Coculture systems of NCI‐H295 adrenocortical carcinoma cells and HLA‐matched lymphocytes were used to examine effects on steroid production and survival of lymphocytes..

Results

HLA‐DR m‐RNA is found in both benign and malignant adrenals, except the NCI‐H295 cell line. Under direct coculture conditions with NCI‐H295 cell line, spontaneous apoptosis of immune cells was reduced. Synthesis of cortisol and especially of dehydroepiandrosterone production of tumour cells was markedly increased. Differences by separating CD4+ and CD8+ T cells were not detected.

Conclusions

Direct cellular contact between lymphocytes and adrenocortical cells seems to be involved in the peripheral regulation of androgen synthesis in the adrenal. The molecular basis of this interaction is no tknown. With regard to normal adrenals, ligation of MHC class II antigens could be a potential mechanism for a peripheral regulation of androgen secretion.
Leptin and the adrenal gland
Authors: Glasow A. , Bornstein S. R.
Published: March 2003

Background

Leptin is involved in the maintenance of energy balance acting on food intake, thermogenesis and energy expenditure. Via its receptor in the hypothalamus, leptin modulates the functioning of the hypothalamic–pituitary–adrenal axis and the systemic sympathetic/adrenomedullary system, which are closely linked to the regulation of energy balance and body weight. In regard of potential interactions of leptin and adrenal hormones this study intended to characterize the role of leptin in the human adrenal gland.

Materials and methods

A novel technique of laser capture microdissection was used to separate cortical and chromaffin cells for mRNA expression studies of leptin receptor isoforms and leptin mRNA in adrenal tissue and cell line NCI‐H295. Immunostaining was used to localize leptin receptor in human adrenal slices. The influence of leptin on basal and ACTH‐stimulated steroid hormone secretion and enzyme expression was assessed. The effect of leptin on proliferation and viability of adrenal cells in primary culture and of the NCI‐H295 cell line was studied by the WST‐1 assay and by 3H‐thymidine test.

Results

Our data demonstrate that leptin can regulate the human adrenal function directly, via its receptors on adrenocortical cells. Leptin decreased the corticotropin‐stimulated release of steroid hormones in vitro without any effect on cell proliferation. No influence of leptin on the expression of cytochrome P45017α and P450SCC mRNA was detected.

Conclusions

The adipo–adrenal interaction mediated by leptin further underscores the close link of metabolism and stress regulation in humans.
Molecular adrenocortical tumourigenesis
Authors: Reincke M. , Beuschlein F. , Slawik M. , Borm K.
Published: March 2003

Adrenocortical neoplasms are the most frequent abnormality of the adrenal cortex. Most of these lesions are clinically silent and are detected incidentally by ultrasound or computed tomography. The prevalence of these so‐called ‘incidentalomas’ in the general population is around 1%, increasing with age and reaching 6% among those in the age range 60–70 years. In contrast, primary adrenocortical carcinoma, a highly malignant tumour, is rare, having an incidence of one case per million per year. Recent progress has been achieved in the understanding of adrenocortical tumourigenesis by mapping and identification of genes responsible for hereditary tumours that involve the adrenal gland. Investigation of the clonal composition of adrenal tumours demonstrates that adrenal carcinomas are monoclonal, whereas adrenal adenoma may be polyclonal in approximately 25–40% of cases. Oncogenes and tumour‐suppressor genes involved in adrenal carcinomas include mutations in the p53 tumour‐suppressor gene and rearrangements of the chromosomal locus 11p15.5 associated with IGF II hyperexpression. Constitutive activation of the ACTH receptor‐G protein‐cAMP signal cascade does not play a role in adrenal tumour formation. Conversely, deletions of the ACTH receptor gene have recently been found in undifferentiated adenomas and in aggressive adrenocortical carcinomas, and, more recently, confirmed in a larger series of tumours. The available literature indicates that the signalling pathways of adrenocortical tumours are different from those of other endocrine neoplasms, such as pituitary and thyroid adenomas.
Closed‐circuit organ perfusion technique for gene transfer into the lungs. An experimental trial on farm pigs
Authors: Parpala‐Spårman T. , Pääkkö P. , Kortteinen P. , Salonurmi T. , Lukkarinen O. , Tryggvason K.
Published: March 2003

In an attempt to develop gene therapy for lung diseases, we have explored a closed‐circuit surgical perfusion method for gene transfer into the lung.

For gene transfer we used a replication defective type 5 adenovirus carrying the E. coliβ‐galactosidase gene as a reporter gene. The middle lobe of the right lung of eight young farm pigs was perfused in vivo via thoracotomy for up to 60 min with the viral solution. The gene transfer was performed using a closed‐circuit organ perfusion method in vivo. The efficiency of gene transfer was assessed visually by analysis of histologic sections after X‐gal, PAS and immunohistochemical stainings.

The lung perfusion resulted in transgene expression in the alveolar epithelial cells, capillary endothelial cells, airway epithelial cells and alveolar macrophages of the lung examined seven days after perfusion.

The present results suggest that operatively performed closed‐circuit warm lung perfusion method may be used for gene transfer in treatment of diseases that have pulmonary manifestations.
Red wine protects diabetic patients from meal‐induced oxidative stress and thrombosis activation: a pleasant approach to the prevention of cardiovascular disease in diabetes
Authors: Ceriello A. , Bortolotti N. , Motz E. , Lizzio S. , Catone B. , Assaloni R. , Tonutti L. , Taboga C.
Published: March 2003

Background Oxidative stress and thrombosis have been reported to be increased in diabetic patients and involved in the pathogenesis of cardiovascular complications. It has been demonstrated in diabetic patients that consumption of a meal is accompanied by the generation of an oxidative stress and of a hypercoagulable state. It is well recognized that red wine shows antithrombotic activity and that its ingestion increases plasma antioxidant capacity in man. In this study the possibility that red wine consumption may reduce the oxidative stress and thrombosis produced postprandially in diabetic patients has been evaluated.

Subjects and methods Twenty type 2 diabetic patients were studied during fasting consumption of 300 mL of red wine, or during a meal accompanied, or not, by red wine ingestion. Plasma glucose, insulin, triglycerides, total plasma radical‐trapping capacity, activated factor VII and prothrombin fragments 1 + 2 were measured in basal state and at 60, 120 and 180 min after the start of each experiment. Low‐density lipoprotein (LDL) oxidation was also evaluated at baseline and after 120 min

Results Plasma glucose, insulin, triglycerides and LDL oxidation significantly increased, while the total plasma radical‐trapping parameter significantly decreased during the meal test. Consumption of red wine in the fasting state significantly increased total plasma radical‐trapping parameter activity, while wine ingestion with a meal counterbalanced the decrease of total plasma radical‐trapping parameter and the increase of LDL oxidation. Meal consumption induced an increase in plasma prothrombin fragments 1 + 2 and activated factor VII in diabetic patients. Wine ingestion with the meal significantly reduced the production of both prothrombin fragments 1 + 2 and activated factor VII. Fasting consumption of red wine alone did not show effects on coagulation or LDL oxidation.

Conclusion This finding confirms that in the absorptive phase free radicals are produced in diabetic patients, which reduce serum antioxidant defences, increase LDL oxidation and activate the coagulation system. Red wine consumption during a meal significantly preserves plasma antioxidant defences and reduces both LDL oxidation and thrombotic activation. The consumption of a moderate amount of red wine during meals may have a beneficial effect in the prevention of cardiovascular disease in diabetic patients.
Comparative study on antibodies to human and bacterial 60 kDa heat shock proteins in a large cohort of patients with coronary heart disease and healthy subjects
Authors: Prohászka Z. , Duba J. , Horváth L. , Császár A. , Karádi I. , Szebeni A. , Singh M. , Fekete B. , Romics L. , Füst G.
Published: March 2003

Background Recent observations indicate an association between antibodies against mycobacterial heat shock protein (hsp65) and coronary heart disease (CHD). Previously, we reported on marked differences in antigen specificity and complement activating ability of anti‐hsp65 antibodies and auto‐antibodies against human heat shock protein, hsp60. Here, we investigated whether there are differences between antih‐sp65 and anti‐hsp60 antibodies in their association with CHD.

Design We measured by ELISA the levels of antibodies to hsp65, hsp60 and E. coli‐derived GroEL in three groups: Group I, 357 patients with severe CHD who underwent by‐pass surgery; Group II, 67 patients with negative coronary angiography; Group III, 321 healthy blood donors. Antibodies against Helicobacter pylori were also measured by commercial ELISA.

Results As calculated by multiple regression analysis, the levels of anti‐hsp60 auto‐antibodies were significantly higher in Group I compared to Group II (P = 0·007) or Group III (P < 0·0001). By contrast, although concentrations of anti‐hsp65 and anti‐GroEL antibodies in Group I were higher than in Group III, no significant differences between Group I and Group II were found. Antibodies to the two bacterial hsp strongly correlated to each other, but either did not correlate or weakly correlated to hsp60. In Group I, serum concentrations of anti‐H.pylori antibodies significantly correlated with those of anti‐hsp65 and anti‐GroEL antibodies but they did not correlate with the anti‐hsp60 antibodies.

Conclusion As to their clinical relevance, a remarkable difference become evident between antibodies to human hsp60 and antibodies against bacterial hsp in the extent of association with CHD. On the basis of these findings and some pertinent literature data, an alternative explanation for the association between high level of anti‐hsp antibodies and atherosclerotic vascular diseases is raised.
Assessment of β‐cell function during the oral glucose tolerance test by a minimal model of insulin secretion
Authors: Cretti A. , Lehtovirta M. , Bonora E. , Brunato B. , Zenti M. G. , Tosi F. , Caputo M. , Caruso B. , Groop L. C. , Muggeo M. , Bonadonna R. C.
Published: March 2003

Objective To characterise the performance of β‐cell during a standard oral glucose tolerance test (OGTT).

Design Fifty‐six subjects were studied. A minimal analogic model of β‐cell secretion during the OGTT was applied to all OGTTs (see below). The amount of insulin secreted over 120′ in response to oral glucose (OGTT‐ISR; Insulin Units 120′−1 m−2 BSA) and an index of β‐cell secretory ‘force’ (β‐Index; pmol·min‐2·m‐2 BSA) were computed with the aid of the model. In protocol A, 10 healthy subjects underwent two repeat 75 g OGTT with frequent (every 10′−15′) blood sampling for glucose and C‐peptide to test the reproducibility of OGTT‐ISR and β‐Index with a complete or a reduced data set. In protocol B, 7 healthy subjects underwent three OGTTs (50, 100 or 150 g), to test the stability of the β‐Index under different glucose loads. In protocol C, 29 subjects (15 with normal glucose tolerance, 7 with impaired glucose tolerance and 7 with newly diagnosed type 2 diabetes) underwent two repeat 75 g OGTT with reduced (every 30′ for 120′) blood sampling to compare the reproducibility and the discriminant ratio (DR) of OGTT‐ISR and β‐index with the insulinogenic index (IG‐Index: Δ Insulin 30′ − Basal/Δ Glucose 30′ − Basal). In protocol D, 20 subjects (14 with normal glucose tolerance, 5 with impaired glucose tolerance and 1 with newly‐diagnosed type 2 diabetes) underwent a 75 g OGTT and an intravenous glucose tolerance test (IVGTT) on separate days to explore the relationships between acute (0′−10′) insulin response (AIR) during the IVGTT and β‐index and OGTT‐ISR during the OGTT.

Results In all protocols, the minimal analogic model of C‐peptide secretion achieved a reasonable fit of the experimental data. In protocol A, a good reproducibility of both β‐index and OGTT‐ISR was observed with both complete and reduced (every 30′) data sets. In protocol B, increasing the oral glucose load caused progressive increases in OGTT‐ISR (from 2·63 ± 0·70 to 5·11 ± 0·91 Units·120′−1·m−2 BSA; P < 0·01), but the β‐index stayed the same (4·14 ± 0·35 vs. 4·29 ± 0·30 vs. 4·30 ± 0·33 pmol·min−2·m−2 BSA). In protocol C, both OGTT‐ISR and β‐index had lower day‐to‐day CVs (17·6 ± 2·2 and 12·4 ± 2·4%, respectively) and higher DRs (2·57 and 1·74, respectively) than the IG‐index (CV: 35·5 ± 6·3%; DR: 0·934). OGTT‐ISR was positively correlated to BMI (P < 0·03), whereas β‐index was inversely related to both fasting and 2 h plasma glucose (P < 0·01 for both). In protocol D, β‐index, but not OGTT‐ISR, was significantly correlated to AIR (r = 0·542, P < 0·02).

Conclusions Analogically modelling β‐cell function during the OGTT provides a simple, useful tool for the physiological assessment of β‐cell function.
Quantification of coronary artery calcification in patients with FH using EBCT
Authors: Hoffmann U. , Bodlaj G. , Derfler K. , Bernhard C. , Wicke L. , Herold C. J. , Kostner K.
Published: March 2003

Background Calcification of the coronary vessel wall is regarded as a marker of advanced coronary atherosclerosis.

Methods To test whether patients with heterozygous familial hypercholesterolemia (FH) exhibit excessive calcification of the coronary vessel wall, we quantified coronary artery calcium in LDL‐apheresis treated FH‐patients with known severe coronary artery disease (CAD) (n = 10), in patients with moderate hypercholesterolemia and known severe CAD (n = 10), and in asymptomatic controls (n = 10) using electronic beam CT. The total coronary calcium score (Agatston‐Score), the number of calcified lesions and the calcified plaque volume were evaluated for this study.

Results CAD‐patients with FH, although on average 10 years younger, had a significantly higher total coronary calcium score (702/2018/2890), number of lesions (34/43/49) and calcified plaque volume (700/1818/2313) compared to patients with CAD only (480/641/1362, 10/16·5/22, 480/588/1209, respectively) and controls (10/47/137, 2/4/10, 15/50/144, respectively). Furthermore, we observed a significant correlation (r = 0·93; P < 0·01) between LDL‐cholesterol levels (pretreatment levels of the CAD‐FH group) and the total coronary calcium score in all three groups. Our results demonstrate that coronary artery calcification is more extensive in CAD‐patients with FH than in CAD‐patients with moderate hypercholesterolemia. In addition, we provide evidence that the amount of calcium in the coronary vessel wall in FH patients result from a long lasting history of elevated LDL‐Cholesterol levels.

Conclusion These findings emphasize the significance of LDL‐cholesterol as a risk factor for atherosclerosis and underline the importance of early diagnosis of CAD and early cholesterol lowering therapy in FH patients.
Serum homocysteine does not associate with uncomplicated coronary heart disease
Authors: Nikkari S. T. , Kalela A. , Koivu T. A. , Koivula T. , Alho H. , Jokela H. , Sillanaukee P.
Published: March 2003

Background Elevated serum homocysteine concentrations have been related to coronary heart disease. However, the association has not indisputably been proven, and the mechanisms by which homocysteine may be atherogenic have only partially been elucidated. The objective of the present study was to investigate whether serum homocysteine is associated with angina pectoris and myocardial infarction.

Methods We compared serum homocysteine concentrations in subjects with clinical evidence of angina pectoris or history of myocardial infarction to age‐matched controls. The study included 248 males, who participated in a large cross‐sectional risk factor survey carried out in five geographic areas in Finland.

Results Serum homocysteine concentration was significantly higher in subjects with a history of myocardial infarction compared to controls (15·3 μmol L−1 and 13·9 μmol L−1 respectively, P = 0·037). In a logistic regression model including several cardiovascular risk factors, serum homocysteine was significantly associated with myocardial infarction (95% CI 1·0157–1·2990, P = 0·027). Serum homocysteine concentrations did not differ between subjects with angina pectoris and age‐matched controls (13·9 μmol L−1 and 14·2 μmol L−1 respectively).

Conclusions Our results suggest that elevated serum homocysteine is associated with myocardial infarction but not with uncomplicated coronary heart disease.
Impaired fibrinolysis determines the outcome of percutaneus transluminal coronary angioplasty (PTCA)
Authors: Fornitz G. G. , Nielsen P. , Amtorp O. , Kassis E. , Abildgård U. , Sloth C. , Winther K. , Ørskov H. , Dalsgård J. , Husted S.
Published: March 2003

Background Coronary artery stenosis lesions dilated by percutaneus transluminal coronary angioplasty (PTCA) show a disappointingly frequent recurrence of stenosis. We have investigated the possible role of fibrinolysis and various platelet‐release factors – specifically in the locality of the affected vessel – by following 19 patients for 6 months after PTCA.

Methods PTCA was performed on 19 patients with a significant primary coronary stenosis, proven by quantitative CAAS analysis. Blood for measurement of local fibrinolysis and platelet activity was drawn from the aortic root and the coronary sinus, at three times: just before PTCA, 10 min after it, and 6 months later.

Results The incidence of restenosis at the 6 months follow‐up was 37%. PTCA almost doubled the platelet‐derived growth factor level (PDGF) in coronary sinus blood in all patients. The seven restenosis patients had a substantially higher tissue plasminogen activator inhibitor antigen (PAI‐1ag) level in the aortic root before PTCA than the 12 who remained stenosis‐free (mean 62·4 ± 31·6 ng mL −1 compared with 33·1 + 25·3; P < 0·04) and a lower tissue plasminogen activator activity (t‐PAac) level (mean 0·32 ± 0·19 IU mL−1 compared with 0·68 ± 0·34; P < 0·03). This was corroborated by the levels of tissue plasminogen activator inhibitor activity (PAI‐1ac). At reassessment after 6 months, the restenosis patients had developed, in coronary sinus blood, a large rise of PAI‐1ac (7·7 ± 4·8 IU mL−1 rising to 15·7 ± 13·9, P < 0·04) and a large rise of of PAI‐1ag (48·8 ± 31·3 ng mL−1 vs. 72·4 ± 47·2; P < 0·03). But no such increase occurred in the patients who remained stenosis‐free.

Conclusion Our results indicate that the minor balloon injury, which is inseparable from PCTA, stimulates the local release of PDGF. We suggest that, in those patients whose fibrinolytic activity is inherently low, this rise of PDGF could be a major causative factor in restenosis. We also discuss the possibility that the preoperative level of PAI‐1ac could provide a limited but useful prediction of the outcome of PTCA.
Surfing the insulin signaling web
Authors: Van Obberghen E. , Baron V. , Delahaye L. , Emanuelli B. , Filippa N. , Giorgetti‐Peraldi S. , Lebrun P. , Mothe‐Satney I. , Peraldi P. , Rocchi S. , Sawka‐Verhelle D. , Tartare‐Deckert S. , Giudicelli J.
Published: March 2003

The diverse biological actions of insulin and insulin‐like growth factor I (IGF‐I) are initiated by binding of the polypeptides to their respective cell surface tyrosine kinase receptors. These activated receptors phosphorylate a series of endogenous substrates on tyrosine, amongst which the insulin receptor substrate (IRS) proteins are the best characterized. Their phosphotyrosine‐containing motifs become binding sites for Src homology 2 (SH2) domains on proteins such as SH2 domain‐containing protein‐tyrosine‐phosphatase (SHP)‐2/Syp, growth factor receptor bound‐2 protien, (Grb‐2), and phosphatidyl inositol 3 kinase (PI3 kinase), which participate in activation of specific signaling cascades. However, the IRS molecules are not only platforms for signaling molecules, they also orchestrate the generation of signal specificity, integration of signals induced by several extracellular stimuli, and signal termination and modulation. An extensive review is beyond the scope of the present article, which will be centered on our own contribution and reflect our biases.
Effects of short‐term feeding of a highly palatable diet on vascular reactivity in rats
Authors: Naderali E. K. , Williams G.
Published: March 2003

Background Numerous studies have shown that long‐term consumption of high‐fat, high‐energy diet results in obesity, which in turn, leads to cardiovascular disorders. However, there is little or no data on the acute effects of a highly palatable diet on vascular function.

Material and Methods In this study we aimed to evaluate the changes in metabolic and vascular reactivity in Wistar rats fed a palatable diet for 2 days.

Results Two‐days feeding of rats with a palatable diet did not effect body weight, fat‐pad mass or gasterocnimus muscles weights. Nor there were any changes in plasma glucose, insulin or leptin levels. However, compared with chow‐fed rats, palatable diet‐fed rats had significantly raised plasma free fatty acids and triglycerides levels (for both, P < 0·01). Compared with chow‐fed animals, vasorelaxation responses to carbamylcholine and sodium nitroprusside were significantly attenuated in palatable diet‐fed rats (for both, P < 0·01). However, there were no differences in histamine‐induced vasorelaxation between chow‐fed and palatable diet‐fed rats.

Conclusion These data indicates that diet‐induced endothelium‐dependent and ‐independent vascular dysfunction occurs long before obesity develops.
Postnatal increase of procalcitonin in premature newborns is enhanced by chorioamnionitis and neonatal sepsis
Authors: Janota J. , Stranák Z. , Bělohlávková S. , Mudra K. , Šimák J.
Published: March 2003

To determine the influence of chorioamnionitis and neonatal sepsis on procalcitonin (PCT) levels in very‐low‐birth‐weight (VLBW) infants within the first week of life.

PCT serum levels were measured in cord blood 1 h after delivery and on day 3 and day 7 of life. Chorioamnionitis and neonatal sepsis within the first week were monitored.

Chorioamnionitis was present in eight of 37 patients (21·6%). PCT on day 3 was increased in both the ‘No chorioamnionitis’ (2·54 ng mL−1, SEM 0·51) and ‘Chorioamnionitis’ (6·96 ng mL−1, SEM 2·93) groups of VLBW infants compared with the 1st hour values (0·45 and 0·58 ng mL−1 SEM 0·07 and 0·11, respectively, P < 0·001) of the same patients. The postnatal gain was higher in the ‘Chorioamnionitis’ group (P < 0·01). Neonatal sepsis was diagnosed (after exclusion) in 12 of 32 patients (37·5%). Mean values of maximum PCT in patients with and without sepsis were 8·41 ng mL−1 (SEM 1·87) and 3·02 ng mL−1 (SEM 1·38), respectively (P < 0·05). Sensitivity to sepsis of PCT, ratio of immature to total neutrophils (I : T), and C‐reactive protein (CRP) were 75%, 50% and 25%, respectively.

In the group of VLBW infants the PCT level within 72 h of delivery was markedly increased in patients with chorioamnionitis. Compared with I : T and CRP, PCT appears to be a more sensitive marker of neonatal sepsis.
Plasma homocysteine, methylenetetrahydrofolate reductase gene polymorphism and carotid intima‐media thickness in Italian type 2 diabetic patients
Authors: Scaglione L. , Gambino R. , Rolfo E. , Lillaz E. , Gai M. , Cassader M. , Pagano G. , Cavallo‐Perin P.
Published: March 2003

Abstract Background Moderately elevated levels of homocysteine have been associated with an increased cardiovascular risk in type 2 diabetic patients. The role of methylenetetrahydrofolate reductase gene polymorphism is less clear.

Materials and methods We investigated the contribution of plasma homocysteine levels and the methylenetetrahydrofolate reductase gene polymorphism to the variability of carotid intima‐media thickness in 124 consecutive Italian patients with type 2 diabetes mellitus. Fasting plasma homocysteine was measured by high‐pressure liquid chromatography with an electrochemical detector; methylenetetrahydrofolate reductase genotypes were determined by polymerase chain reaction and restriction enzyme digestion. The carotid intima‐media thickness was evaluated with high‐resolution B‐mode ultrasonography.

Results Age, creatinine and plasma homocysteine levels showed a positive correlation with mean carotid intima‐media thickness values, but only age and creatinine levels were still associated with mean carotid intima‐media thickness values in the multivariate analysis. Plasma homocysteine levels were significantly higher in the patients bearing the 677T/677T genotype of the methylenetetrahydrofolate reductase polymorphism; mean carotid intima‐media thickness values were not different in the three different methylenetetrahydrofolate reductase genotypes.

Conclusion In 124 Italian patients with type 2 diabetes mellitus, basal levels of plasma homocysteine, as well as methylenetetrahydrofolate reductase gene polymorphism, did not explain the variability of mean carotid intima‐media thickness.
Oestrogen attenuates coronary vasoconstriction after angioplasty: role of endothelin‐1
Authors: Lee T‐M. , Su S‐F. , Tsai C‐H.
Published: March 2003

Background and aims There were controversies as to whether endothelin‐1 is released after coronary angioplasty. We sought to determine whether endothelin‐1 is released after coronary angioplasty and whether oestrogen administration can affect coronary vasomotor tone by reducing endothelin‐1 concentrations.

Methods The study was designed to prospectively investigate 24 consecutive patients scheduled for elective coronary angioplasty. Patients were randomized into two groups according to whether they did not (group 1, n = 12) or did (group 2, n = 12) have intracoronary treatment with oestrogen. Quantitative coronary angiography was monitored at baseline, immediately after successful angioplasty, and 15 min after the last deflation. Blood samples for measuring the levels of endothelin‐1 were drawn from the ascending aorta and the coronary sinus simultaneously before angioplasty and 15 min after balloon dilatation.

Results The diameters of the coronary artery at the dilated segments were significantly reduced 15 min after dilation compared with those immediately after dilation in group 1 from 3·20 ± 0·22 to 2·30 ± 0·23 mm (P < 0·001), respectively. The vasoconstriction was significantly blunted in group 2. The endothelin‐1 levels from the coronary sinus rose significantly, by 29%, 15 min after angioplasty in group 1, which was attenuated after administering oestrogen. Significant correlation was found between the changes of coronary vasomotion of the dilated segment and endothelin‐1 levels (r = 0·70, P = 0·01).

Conclusion Endothelin‐1 is released into the coronary circulation after angioplasty, and this vasoactive substance may contribute to the occurrence of vasoconstriction. The vasoconstriction is attenuated by oestrogen by reducing the endothelin‐1 levels. This finding provided a new strategy to treat coronary vasoconstriction after angioplasty.
Influence of apolipoprotein E polymorphism on plasma vitamin A and vitamin E levels
Authors: Gómez‐Coronado D. , Entrala A. , Álvarez J. J. , Ortega H. , Olmos J. M. , Castro M. , Sastre A. , Herrera E. , Lasunción M. Á.
Published: March 2003

Background Plasma concentrations of vitamins A and E are positively correlated with those of concurrent lipids and, on the other hand, lipid levels are influenced by apolipoprotein E polymorphism. Therefore, the effect of this polymorphism on both vitamins was analysed in an adult population.

Materials and methods Subjects were recruited from a working population. Their anthropometric, lifestyle and dietary intake variables and menopausal status were recorded. Their apolipoprotein E phenotype and their plasma vitamins A and E (by high‐performance liquid chromatography) and lipid (enzymatically) concentrations were determined after an overnight fast. The associations of the phenotype with vitamins and lipids were studied in men and women separately and controlling for significant covariates.

Results The apolipoprotein E phenotype was associated with the concentrations of total, low‐density lipoprotein (LDL) and high‐density lipoprotein (HDL) cholesterol in women, whereas no associations with lipids were found in men. Vitamin A and vitamin E levels were higher in men than in women, but only the difference in the former persisted after lipid adjustment. Apolipoprotein E2 slightly increased vitamin A levels in women, an effect which was still evident with lipid adjustment. Actually, both the apolipoprotein E phenotype and triglyceride were selected as significant predictors of this vitamin by multiple regression. This phenotype did not affect vitamin E levels in either sex.

Conclusions Lipids do not mediate the effect of gender on vitamin A levels. Apolipoprotein E polymorphism is an independent determinant of vitamin A levels in women. Pending confirmation by others, we propose that enhancement of this vitamin may contribute to the beneficial impact of the ε2 allele on human ageing and health.
Impact of diabetes duration and cardiovascular risk factors on mortality in type 2 diabetes: the Hoorn Study
Authors: Spijkerman A. M. W. , Dekker J. M. , Nijpels G. , Jager A. , Kostense P. J. , Van Hinsbergh V. W. M. , Bouter L. M. , Heine R. J. , Stehouwer C. D. A.
Published: March 2003

Background Several studies have reported differences in the mortality risk between diabetic subjects detected by screening and known diabetic patients. We studied mortality in relation to diabetes duration, and the contribution of other cardiovascular risk factors to the elevated risk.

Materials and methods Participants were type 2 diabetic subjects (n = 174) of a population‐based cohort study. Of these, 95 were diagnosed by screening. Known diabetic subjects were grouped into two categories of diabetes duration, with a median duration of 2·4 and 11·2 years, respectively. We assessed the contribution of classical cardiovascular risk factors (dyslipidaemia, hypertension, and prior myocardial infarction), and of new cardiovascular risk factors (microalbuminuria, von Willebrand factor, sVCAM‐1 and C‐reactive protein) to the mortality risk during nearly 10 years of follow up. Cox's proportional hazards model was used to study the association of diabetes duration and mortality.

Results The age‐ and sex‐adjusted relative risks of mortality were 2·06 (95% C.I. 1·04–4·10) and 3·19 (1·64–6·20) for the patients with short‐ and long‐term diabetes compared with the screening‐detected diabetic subjects, respectively. Adjustment for cardiovascular risk factors resulted in a reduction of mortality risk in both groups: 1·13 (0·51–2·50) and 2·39 (1·18–4·83), respectively. Mortality risk significantly increased with increasing diabetes duration, even after multiple adjustment (P‐value for trend ranged from < 0·001–0·018).

Conclusions Mortality risk increased with increasing diabetes duration. In subjects with short diabetes duration the mortality risk could largely be attributed to other risk factors. In subjects with a longer diabetes duration, however, the elevated mortality risk was independent of these cardiovascular risk factors.
Cervical carcinoma: human papillomavirus infection and HLA‐associated risk factors in the Spanish population
Authors: Montoya L. , Saiz I. , Rey G. , Vela F. , Clerici‐Larradet N.
Published: March 2003

There is evidence for a link between MHC and squamous cell carcinoma of the cervix (SCCC), and different patterns of association in different patient cohorts have been reported. To investigate this subject in the Spanish population, HLA class I, ‐II serotypings and HLA‐DQB1 oligogenotypings of 142 patients and 138 healthy sex‐age‐matched controls were performed. Comparative analysis of the DR2‐DQ3‐stratified phenotypes demonstrated a strong association between DR2 and DQ3 in SCCC (Pc9 < 7 × 10–8). However, no interaction was observed between the two HLA factors, which seem to confer two weak and independent risks. Thus, phenotypes with DR2 and/or DQ3 (patients, 79%, controls, 60%; P < 5 × 10–4) were over‐represented, while the less common DR2/DQ3‐negative phenotypes with the HLA class I A2 antigen were found to confer the highest risk (EF = 62%, Pc84 < 1 × 10–2) of SCCC. Comparative analysis of allele frequencies revealed two weakly significant increases, one for DQB1*0301 (P < 1 × 10–2) in low–moderate dysplasias (CINI,II), and the other for DQB1*0402 (P < 3 × 10–2) in severe dysplasia in situ (CINIII/CIS), and a trend for an increase of DQB1*0302 among CINIII/CIS and invasive SCCC (ISCCC). With regard to DQB1 genes encoding the DR2‐associated DQ serotypes, there was no significant deviation in patients. In contrast, the frequency of DQB1*0603 was found to be weakly decreased in CINI,II (P < 5 × 10–2) and ISCCC (P < 3 × 10–2), indicating a protective effect for this DR13 serotype‐associated allele. No significant association could be shown between HLA and HPV infective status. However, there is circumstantial evidence that HPV‐infected lesions may have been misassigned in some cases, and the sample size was small, so a role for DQB alleles in modifying the course of HPV‐induced diseases cannot be excluded. The observations in this study suggest A2, DR2, DQB1*0301, DQB1*0402 and DQB1*0603 as independent factors associated with SCCC and as relevant targets in HLA‐restricted peptide presentation. Our results are consistent with the theory that HLA loci may have different contributions in susceptibility and resistance to low–moderate dysplasias, CIS and invasive SCCC.