bluuebunny/crossref_metadata_2025 huggingface dataset:
Bemisia tabaci in Croatia
Authors: Masten T. , Simala M.
Published: March 2003

Bemisia tabaci was reported for the first time in the Mediterranean part of Croatia in 2000. It was found in glasshouses in the agricultural area between the towns of Trogir and Omis, on the following crops: Euphorbia pulcherrima, Thunbergia grandiflora, Cucumis sativus (cucumber), Solanum melongena (aubergine), Phaseolus spp. (beans), Ficus carica (fig), Rubus spp. and several weeds of the families Asteraceae and Solanaceae. In 2001, monitoring for the pest was organized all over the country, in each of the 21 counties. In each county, there were several monitoring points so that all the major vegetable and flower producers were included. A special effort was made to record the spread of B. tabaci in the region where it was first found, bearing in mind that optimal conditions for outdoor spread exist along the Adriatic coast. Yellow sticky traps and visual inspection are used to monitor for B. tabaci. Eradication measures are being applied, and regulatory measures have been taken to prevent further spread of B. tabaci to continental parts of Croatia.
A functional defect in hereditary haemochromatosis monocytes and monocyte‐derived macrophages
Authors: Moura  , Verheul  , Marx
Published: March 2003

Background

Hereditary haemochromatosis (HH) is a disease of the metabolism of iron characterized by increased iron absorption and heavy parenchymal iron deposition, but with the presence of little iron in the mononuclear phagocytic system (MPS).

Methods

To investigate the role of the MPS, the phagocytic ability of HH monocytes (MNs) and in vitro monocyte‐derived macrophages (MDMs) was studied. HH patients with different degrees of iron accumulation were chosen.

Results

We observed that HH patients' MNs and MDMs have a significantly decreased ability to phagocytose rabbit red blood cells (RRBCs) and that HH MNs possess a significantly decreased capacity to phagocytose Staphylococcus aureus (S. aureus). The decrease in the ability to phagocytose S. aureus, however, was kinetic in nature, explaining the absence of increased prevalence of bacterial infections among HH patients. Both RRBCs and S. aureus were preopsonized with heat‐inactivated serum. No alteration in the complement‐dependent phagocytosis of Cryptococcus neoformans was demonstrated when normal human serum was used. The phagocytosis defect was observed in 100% of HH patients and was independent of the magnitude of iron overload, age or liver damage, and affected the antibody‐mediated uptake of bacteria and (R)RBCs.
Effect of thyroid hormone on plasma apolipoproteins and ApoA‐ and ApoB‐containing lipoprotein particles
Authors: Liu  , Rahman  , Bagdade  , Alaupovic  , Kannan
Published: March 2003

Methods

Apolipoprotein and apoB‐ and apoA‐containing lipoprotein particle concentrations were determined in 10 athyreotic patients 4 weeks after withdrawal of Synthroid replacement therapy [T4, 0.96 ± 0.66 μg mL−1; thyroid‐stimulating hormone (TSH), 62.7 ± 22.8 μIU mL−1] and again 4 weeks after reinstitution of treatment.

Results

Thyroid hormone replacement was associated with significant decreases in plasma cholesterol (TC), triglyceride (TG), apolipoprotein B and apolipoprotein C‐III (P < 0.01). Both the cholesterol ester‐rich LP‐B particles and triglyceride‐rich LP‐Bc particles declined significantly in response to thyroid hormone (LP‐B withdrawal 81.6 ± 24.0 vs. replacement 65.1 ± 22.0; LP‐Bc withdrawal 14.3 ± 6.0 vs. replacement 10.9 ± 4.8 mg%, P < 0.01). ApoC‐III also decreased in high‐density lipoprotein (HDL) (apoC‐III‐HS) and in very low‐density lipoprotein (VLDL) + low‐density lipoprotein (LDL) (apoC‐III‐HP), but this reduction was proportionate so that the apo‐C‐III‐HS/apoC‐III‐HP ratio, an indirect estimate of the efficiency of lipoprotein lipase (LPL), was unchanged. Apolipoprotein A‐I concentrations also decreased significantly (withdrawal 140.7 ± 27.0 vs. replacement 127.1 ± 30.0 mg%, P < 0.01) in parallel with the changes in LP‐A‐I and LP‐A‐I:A‐II particles (LP‐A‐I withdrawal 35.8 ± 7.7 vs. replacement 31.5 ± 6.3; LP‐A‐I:AII withdrawal 104.9 ± 20.0 vs. replacement 95.5 ± 26.0; P < 0.05).

Conclusion

These findings indicate that thyroid hormone influences the transport not only of both TG‐rich and cholesterol‐rich apoB‐containing lipoprotein particles but also of those that contain apoAI.
Inflammatory bowel disease: no association between allele combinations of the interleukin (IL) 1β and IL‐1 receptor antagonist gene polymorphisms
Authors: Hacker  , Bidlingmaier  , Gomolka  , Keller  , Eigler  , Hartmann  , Folwaczny Chr. , Fricke  , Albert  , Loeschke  , Endres
Published: March 2003

Background

Interleukin 1 (IL‐1) and its physiological antagonist interleukin‐1 receptor antagonist (IL‐1ra) play a crucial role in the pathogenesis of inflammatory bowel disease. Polymorphisms in the genes coding for these cytokines, the restriction enzyme TaqI polymorphism for IL‐1β and the variable number of tandem repeats (VNTR) polymorphism for IL‐1ra, have been shown to influence cytokine synthesis in vitro. Recently, an association has been described for distinct allele combinations of these two polymorphisms in patients with ulcerative colitis and with Crohn's disease but not in healthy control subjects.

Methods

We studied 56 patients with ulcerative colitis, 64 patients with Crohn's disease and 196 healthy control subjects. All were unrelated Caucasians of European ancestry. After polymerase chain reaction (PCR) the amplification products were analysed on agarose gels. For the IL‐1β polymorphism the PCR product was additionally digested using the restriction enzyme TaqI.

Results

The allele and genotype frequencies as well as the carriage rates of the IL‐1βTaqI polymorphism in healthy control subjects were in agreement with previous findings in other populations. Allele and genotype frequencies of the IL‐1β polymorphism were not different in inflammatory bowel disease patients compared with healthy control subjects. Comparing allele combinations of both polymorphisms no association could be idengified either within healthy control subjects or in the groups of patients with ulcerative colitis or Crohn's disease.

Conclusion

Thus, we could not confirm the results of a previous study reporting an association between the IL‐1ra and IL‐1β gene polymorphisms in patients with inflammatory bowel disease.
Increased risk of death from primary hyperparathyroidism — an update
Authors: Hedbäck  , Odén
Published: March 2003

Background

The aim of this study was to investigate the risk of death among patients treated for primary hyperparathyroidism during the past decade.

Methods

Using the national patient register, all patients operated on for primary hyperparathyroidism in Sweden during 1987–94 were identified and then searched for in the national register of deaths and causes of death during the same period. The control group was the whole Swedish population, matched for age, sex and calendar year.

Results

We found that patients treated for primary hyperparathyroidism run an increased risk of death. The risk ratios for death from cardiovascular disease were 1.71 for male and 1.85 for female patients. These estimations are of high precision because of the large patient series (n = 4461), with 95% confidence limits of 1.34–2.15 and 1.62–2.11 for men and women respectively.

Conclusion

This finding, together with previous findings that parathyroid adenoma weight, serum calcium level and parathyroid hormone level are predictive of the risk of death, suggests the possibility that surgery in patients with primary hyperparathyroidism may offer not only relief from signs and symptoms but also improved prognosis.
Comparison of three fatty meals in healthy normolipidaemic men: high post‐prandial retinyl ester response to soybean oil
Authors: Mero  , Syvänne  , Rosseneu  , Labeur  , Hilden  , Taskinen
Published: March 2003

Background

Oral fat tolerance tests (FTTs) have been widely used as a tool to investigate post‐prandial lipaemia. However, there is no consensus regarding the type and amount of fat used in the tests.

Methods

We compared three commonly used FTTs, each containing 63 g of fat: a mixed meal, a liquid cream meal and a liquid soybean oil meal. The study group consisted of 10 healthy normolipidaemic men. We measured triglycerides (TGs), retinyl esters (REs), apolipoprotein E (apoE), apolipoprotein B‐48 (apoB‐48) and apolipoprotein B‐100 (apoB‐100) in plasma and in triglyceride‐rich lipoprotein (TRL) fractions separated by density‐gradient ultracentrifugation at baseline and 3, 4, 6, and 8 h after the FTTs.

Results

We observed similar TGs, apoE, apoB‐48 and apoB‐100 responses after all three FTTs, despite the different fatty acid composition of the meals. In contrast, the commonly used marker for exogenous particles, RE, differed clearly when polyunsaturated (soybean oil) and saturated fat (cream or mixed meal) were used. The RE response in plasma (P < 0.005, repeated measures
ANOVA), in chylomicrons (P < 0.013) and in very low‐density lipoprotein (VLDL) 1 (P < 0.017), as well as the RE area under the incremental curve in plasma and chylomicron fractions, were markedly increased after the soybean oil meal compared with the mixed meal and cream meal tests. The peak of RE response occurred parallel to the responses of other markers (i.e. TG or apoB‐48) of post‐prandial TRL during soybean oil meal. In contrast, RE peak concentration was delayed after saturated fat‐containing meals. After soybean oil, FTT plasma cholesterol concentration was lower and the chylomicron cholesterol concentration was higher compared with mixed or cream meals, but no differences were detected in post‐prandial high‐density lipoprotein (HDL)‐cholesterol concentration.

Conclusion

When the amount of fat is similar, post‐prandial responses of TG, apoE, apoB‐48, apoB‐100 and HDL‐cholesterol were comparable after different FTTs.
Cardiac natriuretic peptides for diagnosis and risk stratification in heart failure: influences of left ventricular dysfunction and coronary artery disease on cardiac hormonal activation
Authors: Selvais  , Donckier  , Robert  , Laloux  , Van Linden  , Ahn  , Ketelslegers  , Rousseau
Published: March 2003

Background

Cardiac natriuretic peptides are activated in heart failure. However, their diagnostic and prognostic values have not been compared under the routine conditions of an outpatient practice.

Methods

We studied the diagnostic and prognostic value of plasma N‐ and C‐terminal peptides of the atrial natriuretic factor prohormone (N‐proANF and ANF respectively) and brain natriuretic peptide (BNP) to evaluate the severity of congestive heart failure (CHF) as reflected by the New York Heart Association (NYHA) classification and to predict its 2‐year mortality. Peripheral plasma concentrations of the three natriuretic peptides were measured in 27 normal subjects (CTR), in 32 patients with coronary artery disease (CAD) and normal left ventricular ejection fraction and in 101 patients with chronic CHF in functional classes I and II (n = 61) or III and IV (n = 40).

Results

Plasma concentrations of the three peptides increased in the presence of CHF in relation to its severity (P < 0.01). BNP was unable to distinguish CTR from CAD, just as ANF could not differentiate CAD from CHF I–II; only N‐proANF displayed a significant and continuous increase from CTR to CAD, CHF I–II and III–IV. Receiver‐operating characteristic curves showed better evaluation of the degree of CHF by BNP than by ANF or ejection fraction (P < 0.05). Assessment of the 2‐year prognosis revealed that N‐proANF and BNP were the best independent predictors of outcome after the NYHA classification. These peptides identify a very high‐mortality group.

Conclusion

Plasma N‐proANF and BNP concentrations are good indicators of the severity and prognosis of CHF in an outpatient practice. CAD does not stimulate BNP as long as ventricular dysfunction is not present, although increased N‐proANF levels in this setting suggest an early humoral activation.
Plasma and platelet ascorbate pools and lipid peroxidation in insulin‐dependent diabetes mellitus
Authors: Seghieri  , Martinoli  , Di Felice  , Anichini  , Fazzini  , Ciuti  , Miceli  , Gaspa  , Franconi
Published: March 2003

Background

As diabetes mellitus represents a situation in which production of peroxides is increased, the aim of this study was to investigate the relationship between plasma and platelet levels of ascorbic acid (AA)/dehydroascorbic acid (DHA) and those of malonyldialdehyde (MDA), an indirect marker of lipoperoxides, both assayed using high‐performance liquid chromatography (HPLC), in 59 patients with insulin‐dependent diabetes mellitus (IDDM) compared with 51 healthy control subjects matched for sex, age, smoking habits, as well as for dietary intake of energy, alcohol and vitamin C.

Results

Mean plasma and platelet MDA were significantly higher in the patients affected with IDDM than in control subjects. Moreover, the diabetic group was characterized by a huge decrease in plasma AA [8.45 ± 5.5 μmol L−1 (SD) vs. 33.4 ± 7.6 μmol L−1, P = 0.0001], mirrored by a significant increase in plasma DHA (11.9 ± 3.9 μmol L−1 vs. 3.9 ± 2.5 μmol L−1, P = 0.0001). No detectable DHA was observed in the platelets from both diabetic and control subjects, whereas AA was significantly increased in platelets from diabetic patients compared with control subjects (42.6 ± 7.4 vs. 34.8 ± 5.1 nmol 10−9 platelets, P = 0.0001). Platelet AA in the diabetic group was significantly inversely correlated with glycated haemoglobin (r = −0.34; P = 0.04) and directly with plasma AA (r = 0.39; P = 0.02), the sum of plasma AA + DHA (r = 0.44; P = 0.009) and with platelet MDA (r = 0.38; P = 0.02).

Conclusion

(a) The ratio plasma AA/DHA is significantly lowered in IDDM in association with an increase in MDA levels; (b) only AA is detected in platelets, being augmented in the diabetic group; (c) plasma ascorbate depletion does not reflect platelet levels of AA; and, finally, (d) metabolic control, as well as intracellular lipoperoxides, modulates platelet AA in IDDM.
Transdermal nicotine inhibits interleukin 2 synthesis by mononuclear cells derived from healthy volunteers
Authors: Van Dijk  , Meijssen  , Brouwer  , Hop  , Van Bergeijk  , Feyerabend  , Wilson  , Zijlstra
Published: March 2003

Background

Smoking has either a beneficial or harmful effect on the course and recurrence of ulcerative colitis (UC) and Crohn's disease respectively. Transdermal application of nicotine had similar effects in UC and therefore was considered to be an effective basic drug that could be further developed in the search for new compounds in the treatment of acute exacerbations of corticosteroid‐resistant UC. To clarify the hypothesis that nicotine exerts its anti‐inflammatory effect in UC through selective inhibition of T‐cell‐derived cytokine synthesis, we studied in vivo effects of nicotine on cytokine production by human non‐adherent mononuclear cells isolated from peripheral blood in a randomized, double‐blind, placebo‐controlled trial.

Methods

Healthy non‐smoking volunteers applied for 2 weeks of nicotine patches (n = 12) with incremental doses of nicotine during the first week to achieve a maintenance dose of 15 mg per day, or placebo (n = 12). Blood was obtained before treatment and 1, 2, 3 and 6 weeks after the start of treatment. Cells were cultured in the absence or presence of phytohaemagglutinin for 48 h, and total amounts of interleukin 2 (IL‐2), IL‐4, IL‐10, IL‐13, interferon γ (IFN‐γ) and tumour necrosis factor alpha (TNF‐α) were measured.

Results

Transdermal nicotine caused a significant inhibition of IL‐2 after 2 weeks' treatment compared with the placebo group. In addition, a diminished production of IL‐10 and TNF‐α in comparison with day 0 was observed.

Conclusion

The beneficial effect of transdermal nicotine in ulcerative colitis may be mediated by a selective inhibition of the IL‐2 production by mucosal mononuclear cells, which could result in diminished cell proliferation and consequently a reduction in the inflammatory process.
Impaired release of tissue plasminogen activator from the endothelium in Graves' disease — indicator of endothelial dysfunction and reduced fibrinolytic capacity
Authors: Li  , Chen  , Tan  , Wang  , Liang  , Sun
Published: March 2003

Background

Patients with hyperthyroidism have increased plasma levels of von Willebrand factor (vWF). Changes in tissue plasminogen activator (t‐PA) and plasminogen activator inhibitor (PAI‐1), another two endothelium‐derived proteins and modulators of blood fibrinolytic activity, have not been reported in hyperthyroidism.

Methods

The release of t‐PA by vascular endothelial cells after venous occlusion, basal blood concentrations of t‐PA, PAI‐1 and vWF were studied in 33 patients with hyperthyroidism, with most of them followed up 30 days after iodine radiotherapy.

Results

Compared with control subjects, both the basal t‐PA levels in plasma and the increase in t‐PA levels with venous occlusion were significantly decreased in patients (P < 0.001), whereas plasma PAI‐1 and vWF levels were increased greatly (P < 0.001). At follow‐up, patients with normal plasma free thyroxine (T4) and total tri‐iodothyronine (T3) showed similar plasma levels of t‐PA, PAI‐1, vWF and release of t‐PA from endothelial cells as the control subjects (P > 0.05). In those with persistent elevated T4 or T3 levels, however, the basal plasma t‐PA level and the released t‐PA from endothelial cells during venous occlusion were significantly lower than in the control subjects (P < 0.001 and P < 0.005), and blood concentrations of PAI‐1 and vWF did not return to the normal range (P < 0.001 and P < 0.001). In all patients, serum thyroid hormone concentrations were inversely correlated with basal plasma t‐PA (T4: r = –0.549, P < 0.001; T3: r = –0.463, P < 0.001) and released t‐PA by endothelial cells (T4: r = –0.505, P < 0.001; T3: r = –0.450, P < 0.001) but strongly correlated with plasma PAI‐1 (T4: r = 0.613, P < 0.001; T3: r = 0.577, P < 0.001) and vWF (T4: r = 0.457, P < 0.001; T3: r = 0.564, P < 0.001).

Conclusion

Hyperthyroid patients may experience vascular endothelial dysfunction and reduced fibrinolytic activity in blood.
Skeletal muscle metabolic characteristics before and after energy restriction in human obesity: fibre type, enzymatic β‐oxidative capacity and fatty acid‐binding protein content
Authors: Kempen  , Saris  , Kuipers  , Glatz  , Van Der Vusse
Published: March 2003

Background

Skeletal muscle has the ability to adapt as result of dietary, hormonal or pharmacological interventions affecting energy metabolism. The aim of the present study was to investigate the effects of energy restriction on skeletal muscle metabolic characteristics in obese women.

Methods

The effects of 8 weeks' energy restriction on body composition, energy expenditure and skeletal muscle characteristics were investigated in 28 healthy obese women. Subjects were aged 37.9 ± 1.5 years and had a body mass index of 32.0 ± 0.8 kg m−2.

Results

Energy restriction (2800 kJ day−1) resulted in a 10.8 ± 0.5 kg weight loss consisting of 8.6 ± 0.5 kg of fat mass and 2.2 ± 0.3 kg of fat‐free mass. Basal respiratory exchange ratio, sleeping metabolic rate and exercise‐induced thermogenesis significantly declined in response to the diet. These changes were accompanied by an increase (P = 0.038) in the skeletal muscle content of cytosolic fatty acid‐binding protein (H‐FABP), whereas no changes occurred in fibre type distribution or activities of enzymes reflecting β‐oxidation and mitochondrial density (3‐hydroxyacyl‐CoA dehydrogenase and citrate synthase respectively).

Conclusion

The results suggest that increased capacity of intracellular fatty acid transport in skeletal muscle cells is involved in the physiological adaptations of fat metabolism to energy restriction in obese female subjects.
DALI—the first human whole‐blood low‐density lipoprotein and lipoprotein (a) apheresis system in clinical use: procedure and clinical results
Authors: Dräger  , Julius  , Kraenzle  , Schaper  , Toepfer  , Zygan  , Otto  , Steinhagen‐Thiessen
Published: March 2003

Background

The DALI low‐density lipoprotein (LDL) apheresis system is the first whole‐blood apheresis system in regular clinical use. DALI stands for direct adsorption of lipoproteins, which describes the basic principle of operation of this newly developed LDL apheresis procedure.

Methods

The selective removal of LDLs and lipoprotein (a) [Lp(a)] is performed in human whole blood by adsorption onto polyacrylate‐coated polyacrylamide beads in an adsorber. This article describes the results of the first open multicentre clinical trial in 14 patients in whom the safety and the efficacy of the system were tested. All patients were treated on average 17 times on a weekly basis. In total, 238 sessions were carried out during the study without severe side‐effects. On average, 7675 mL of the patients‘ whole blood was processed in about 2 h. Anticoagulation in the extracorporeal system was carried out by first giving a heparin bolus followed by continuous addition of an acid citrate dextrose (ACD‐A) infusion during the treatment.

Results

The processing of nearly 1.6 times the patient blood volumes resulted in a reduction in the median LDL‐cholesterol level by 66–77% (dependent on the system configuration). The Lp(a) concentrations were reduced by 59–73% (dependent on the system configuration). HDL‐cholesterol, blood cell count and the other clinical parameters were not significantly affected.

Conclusion

Based on this short‐term evaluation, the DALI apheresis system is a well‐tolerated, effective and simple way of reducing LDL and Lp(a) in human whole blood. The system has been introduced to clinical practice. However, to use the DALI apheresis system in clinical routine, further evaluation of long‐term effects is required.
Current therapeutic options in Type 2 diabetes
Authors: Heine
Published: March 2003

The prevalence of Type 2 diabetes rises steeply with age and involves β‐cell dysfunction and diminished sensitivity to insulin. β‐cell dysfunction is important in the development of hyperglycaemia while insulin resistance seems to play a major role in the atherogenic process resulting in cardiovascular disease. Current therapeutic options include lifestyle adjustments (exercise and diet), oral hypoglycaemic agents (sulphonylureas, newer β‐cell mediated insulin releasing drugs, alpha‐glucosidase inhibitors, biguanides and thiazolidinediones) and insulin treatment. Oral hypoglycaemic agents are effective only temporarily in maintaining good glycaemic control, their efficacy should be determined from changes in fasting and postprandial glucose levels. Recent studies have shown that the early initiation of insulin therapy can establish good glycaemic control.
Repaglinide: a new short‐acting insulinotropic agent for the treatment of Type 2 diabetes
Authors: Owens
Published: March 2003

Repaglinide, a carbamoylmethyl benzoic acid derivative, is rapidly absorbed, metabolized by the liver and eliminated primarily via the bile. It has a short duration of action and is taken immediately before each main meal. This regimen has been shown to provide superior glycaemic control compared with regular morning and evening dosing. A flexible preprandial only dosing regimen of repaglinide significantly lowers the risk of hypoglycaemia if a meal is missed or postponed. Combination therapy with metformin improves glycaemic control significantly compared with therapy with either drug alone in overweight patients. Repaglinide has an equivalent safety and efficacy profile to the sulphonylureas, although it is superior to glipizide in maintaining long‐term glycaemic control The postprandial glucose levels are significantly lower with repaglinide compared with glibenclamide. In naive patients with Type 2 diabetes, repaglinide lowers fasting glucose concentrations and functions also as a prandial glucose regulator.
Dynamics of reactive oxygen intermediate production in human glioma: n‐6 essential fatty acid effects
Authors: Leaver  , Williams  , Ironside  , Miller  , Gregor  , Su  , Prescott  , Whittle
Published: March 2003

Background

Reactive oxygen intermediates (ROIs) are important signals controlling cell growth and cell death. Local essential fatty acid (EFA) deficiencies in tumour cells may limit tumour ROI generation. This deficiency may be rectified by the addition of exogenous EFA.

Materials and methods

The n‐6 EFA effects on tumour ROIs were analysed in terms of kinetics, dose–response and individual cell type responses using flow cytometry of intracellular 2′,7′‐dichlorofluorescin oxidation. ROI formation in 30 gliomas and five paired samples of normal brain tissue, > 500 000 cells per specimen, was analysed every 10 s for 0–25 min.

Results

Tumour cell basal ROI was lower than normal brain tissue ROI from the same subjects (P < 0.00002). Normal and tumour cell ROIs were stimulated by 4–40 μmol L−1n‐6 EFAs, arachidonic acid (AA) and gamma‐linolenic acid (GLA). The stimulated ROI rate was exponential, with the maximum dependent on EFA concentration and tumour grade.

Conclusions

EFAs stimulated tumour cells more than normal cells (P < 0.0000017, n = 71) and increased ROIs in glial fibrillary acidic protein‐positive cells in tumours. This indicated high sensitivity of glioma cell ROIs to n‐6 EFAs.
Increased frequency of the HLA‐DR15 (B1*15011) allele in German patients with self‐limited hepatitis C virus infection
Authors: Lechmann  , Schneider  , Giers  , Kaiser  , Dumoulin  , Sauerbruch  , Spengler
Published: March 2003

Background

A genetically determined resistance or susceptibility to chronic hepatitis C virus infection (HCV) may make an important contribution to the course of liver disease and may be linked to the human major histocompatibility complex.

Design

Twenty‐one subjects with self‐limited HCV infection as assessed by the presence of HCV antibodies, absence of HCV‐RNA and normal levels of aminotransferases for 2 years were identified from a large pool of blood donors. The frequency of HLA serotypes of these individuals was compared with 49 consecutive patients with chronic hepatitis C.

Results

We detected a significantly higher prevalence of HLA‐DR15 in patients with self‐limited HCV infection than in patients with chronic hepatitis C (10/21 vs. 6/49; relative risk 6.5; P = 0.02; corrected for multiple comparisons). To confirm HLA assignments by serotyping we also performed sequencing of HLA‐DR types in the 27 patients (9 with self‐limited infection, 18 with chronic hepatitis C) who had been enrolled during 1995–96. This analysis confirmed the predominance of HLA‐DR15 (HLA‐DRB1*15011) in self‐limited HCV infection (4/9 vs. 1/18; relative risk 13.6; P = 0.03).

Conclusions

Our data suggest that HLA‐DR15 (B1*15011) might constitute an important genetic factor for the elimination of the hepatitis C virus in Germany.
Increased luminal nitric oxide concentrations in the small intestine of patients with coeliac disease
Authors: Everts  , Stotzer  , Olsson  , Kilander  , Pettersson
Published: March 2003

Background

Inflammation is known to be associated with enhanced nitric oxide production. A role for nitric oxide in coeliac disease has been suggested because of increased expression of the inducible isoform of nitric oxide synthase in the small intestine of patients with untreated coeliac disease.

Design

During small bowel endoscopy in 11 control subjects, 10 patients with untreated coeliac disease and seven patients with treated coeliac disease, gas was aspirated from different parts of the upper gastrointestinal tract and immediately analysed using a chemiluminescence technique. Luminal nitric oxide concentrations were also quantified in 13 control subjects who had undergone colonoscopy.

Results

Jejunal luminal nitric oxide concentrations were more than 20 times higher in patients with coeliac disease than in normal control subjects (mean 755 ± 173 ppb, range 215–1690 ppb, vs. mean 31 ± 9 ppb, range 1–83 ppb, P < 0.001). Jejunal luminal nitric oxide levels in patients with treated coeliac disease (mean 54 ± 18 ppb, range 3–126 ppb) did not differ from those of control subjects.

Conclusions

This study shows that intraluminal jejunal nitric oxide concentrations are significantly increased in patients with untreated active coeliac disease.
Methylenetetrahydrofolate reductase polymorphism, plasma homocysteine and age
Authors: Todesco  , Angst  , Litynski  , Loehrer  , Fowler  , Haefeli
Published: March 2003

Background

Elevated fasting levels of total homocysteine are now accepted as an independent risk factor for the development of arteriosclerotic vascular diseases. A polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR), caused by the C677T point mutation, leads to increased thermolability of the enzyme, with reduced enzyme activity. We studied the frequency of this mutation in different groups of the Swiss adult population.

Patients and methods

DNA from 361 subjects was screened for the thermolabile MTHFR variant with PCR. Included were healthy subjects without vascular disease (n = 118), older healthy subjects (n = 106), patients with coronary artery disease (CAD, n = 75), and patients with peripheral arterial occlusive disease (PAOD, n = 63).

Results

In the different groups studied, homozygosity for the mutation ranged from 4.8 to 16.2%, with a frequency of 16.2% in the healthy cohort. The allele frequencies of the thermolabile allele were 38.5 and 27.3 in young and old controls, and 37.3 and 33.3 in CAD and PAOD patients. In the healthy younger subjects the mutant allele was 1.4 times more frequent compared to the older subjects (P = 0.01). No difference in either MTHFR genotype distribution (P = 0.33) or allele frequencies (P = 0.48) between patients and controls was found. Except for the PAOD group with elevated tHcy levels for the +/+ carriers compared to the other genotypes, no statistically significant difference was found comparing homocysteine levels with genotype.

Conclusion

This study shows no link between the mutation and the occurrence of vascular disease but we found evidence pointing to a correlation between the mutation and longevity in our population.
Paraoxonase activity in two healthy populations with differing rates of coronary heart disease
Authors: Mackness  , Mackness  , Durrington  , Arrol  , Evans  , McMaster  , Ferrières  , Ruidavets  , Williams  , Howard
Published: March 2003

Background

The rate of coronary heart disease is over three‐fold greater in Belfast than in Toulouse and the excess risk cannot be totally explained by ‘classical’ risk factors such as total cholesterol, LDL‐cholesterol, smoking, etc.

Design

The effect of the human serum paraoxonase (PON1) 192‐genetic polymorphism on plasma lipid and lipoprotein concentrations and on PON1 activity and concentration was investigated in 186 randomly selected healthy subjects from Toulouse and 165 from Belfast.

Results

The frequency of the R allele of PON1, which has been related to the risk of coronary heart disease, was significantly higher in Belfast (0.33) than in Toulouse (0.24; χ2 = 7.229, P = 0.0072). Subjects from Belfast also had significantly higher serum cholesterol, triglycerides, LDL‐cholesterol, and apolipoprotein B, and significantly lower HDL‐cholesterol and apolipoprotein A1, but these lipoprotein parameters were independent of the PON1 192‐polymorphisms. PON1 activity towards paraoxon was significantly higher in the Belfast population than in Toulouse (median values: 179.7 vs. 129.4 nmol min−1 mL−1 serum, respectively; P < 0.05), which is consistent with our finding of a greater prevalence of the R allele. The median serum concentration of PON1 was 56.3 μg mL−1 in Belfast, which was significantly lower (P < 0.005) than the level of 71 μg mL−1 in Toulouse.

Conclusions

Our results thus provide further support for the hypothesis that populations at increased CHD risk have diminished serum PON1 concentration and an increased prevalence of the R allele of PON1. They are also consistent with reports that the ability of PON1 to hydrolyse paraoxon is inversely related to its capacity to hydrolyse lipid‐peroxides, and thus to its antiatherogenic action.
Effects of erythromycin on human colonic circular muscle in idiopathic chronic constipation
Authors: Chieppa  , Mansi  , Rinaldi  , Serio  , Nacci  , Montagnani  , Potenza  , De Salvia  , Mitolo  , Rinaldi  , Altomare
Published: March 2003

Background

Erythromycin has been shown to have profound prokinetic effects on the gastrointestinal tract of humans and animals, probably through its action on endogenous motilin receptors. The purpose of this study was to determine both the direct and indirect effects (‘off contraction’) of erythromycin and motilin on ex vivo circular muscle strips of the distal colon from patients with or without idiopathic chronic constipation (ICC).

Materials and methods

Cumulative concentrations of erythromycin (1–20 μM) and motilin (0.05–1 μM) were tested in both control and ICC preparations in order to evaluate the direct drugs effect. A range doses of both erythromycin (0.5–10 μM) and motilin (0.05–0.5 μM) were tested on their ability to affect the off‐contraction that follows the typical inhibitory response evoked by low frequencies of Electrical Field Stimulation (EFS) (1–5 Hz, 20 V, 1 msec pulse trains lasting 1 min).

Results

The direct effect of both erythromycin and motilin was a slight increase (less than 10% of the maximal ACh‐induced contraction) in the basal tension, with no dose–response relationship. The off‐contraction, evoked by EFS, was not affected by drugs pretreament in control preparations. Conversely, in ICC preparations both drugs significantly increased the off‐contraction (about 30%).

Conclusions

Erythromycin causes mainly an indirect contractile effect in circular muscle strips from ICC patients. This effect may be related to the activation of inhibitory neuronal motilin receptors. This activation might potentiate NANC relaxation, proportionally increasing the circumferential reflex contraction that follows the EFS‐induced relaxation.
Characteristics of thyroid carcinomas in aging patients
Authors: Lin  , Chao  , Chen  , Weng  , Lin
Published: March 2003

Background

To investigate the clinical features of thyroid cancer in aging patients and to present the results of treatment. From this we can provide bases for earlier diagnoses and better treatment of thyroid malignancies in older patients.

Materials and methods

In this study a retrospective analysis was performed with 204 thyroid cancer patients aged 60 years or older (132 women, with a mean age of 68.3 ± 6.6 years; 72 men, with a mean age of 67.0 ± 5.3 years).

Results

Of the 204 patients, 142 had well‐differentiated thyroid carcinomas (96 papillary thyroid carcinomas, 43 follicular carcinomas, three Hürthle cell carcinomas) and three medullary carcinomas. Sixty‐nine (33.8%) of the 204 patients died after treatment. Of these, three patients died of causes not related to thyroid cancer. For well‐differentiated thyroid carcinomas, male gender, follicular carcinoma, and a larger tumour size indicated a poor prognosis. Of the 59 non‐well‐differentiated thyroid carcinomas, 39 were anaplastic thyroid carcinomas, nine metastatic cancers of the thyroid, seven lymphomas, and four squamous cell carcinomas. After treatment, 40 (67.8%) of the 59 patients died. In multivariant analysis of the differences in clinical parameters between aging and younger thyroid cancer patients, the current status, tumour size, follow‐up period, sex, and stage at diagnosis were independent factors. From this data the delayed diagnosis of aging patients with thyroid cancer was of note when compared with younger patients.

Conclusion

Thyroid cancer in older patients is not a benign clinical disorder. Early diagnosis and urgent aggressive treatment are recommended courses of action for this type of cancer, especially for non‐well‐differentiated thyroid cancers.
Effect of tauroursodeoxycholic acid on bile acid‐induced apoptosis in primary human hepatocytes
Authors: Benz  , Angermüller  , Otto  , Sauer  , Stremmel  , Stiehl
Published: March 2003

Background/aims

The accumulation of endogenous bile acids contributes to hepatocellular damage during cholestatic liver disease. To evaluate the potential role of apoptotic cell death due to increased concentrations of bile acids, primary human hepatocytes were treated with hydrophobic and hydrophilic bile acids. Because the Fas receptor–ligand system may mediate apoptosis in human liver cells, the effect of toxic bile acids on hepatocellular Fas receptor expression was evaluated.

Materials and methods

Primary human hepatocytes were incubated with 50 and 100 μM glycochenodeoxycholic acid (GCDCA) and co‐incubated with equimolar concentrations of tauroursodeoxycholic acid (TUDCA). To evaluate cytolytic and apoptotic effects, morphological alterations, hepatocellular enzyme release, nuclear DNA fragmentation and hepatocellular Fas receptor expression were evaluated.

Results

Apoptotic cell death was significantly increased after exposure to 50 μM GCDCA. Bile acid‐induced apoptosis was not accompanied by hepatocellular Fas receptor overexpression. Tauroursodeoxycholic acid reduced apoptosis, as indicated by a significant reduction of oligonucleosomal DNA cleavage. Fas receptor expression was not significantly affected by tauroursodeoxycholic acid. At higher concentrations, direct cytolytic cell destruction was observed.

Conclusion

Primary human hepatocytes represent a suitable model to study bile acid‐induced apoptotic cell death. In these hepatocytes, already low bile acid concentrations might induce apoptotic cell death, which is not triggered by hepatocellular Fas receptor overexpression. Apoptotic DNA fragmentation was significantly reduced by co‐incubation with tauroursodeoxycholic acid. The reduction of bile acid‐induced apoptosis by ursodeoxycholic acid and its conjugates may contribute to the beneficial effects of these hydrophilic bile acids used for medical treatment of several cholestatic liver diseases.
Platelet factor 4 and β‐thromboglobulin in inflammatory bowel disease and giant cell arteritis
Authors: Vrij  , Rijken  , Van Wersch  , Stockbrügger
Published: March 2003

Background

As platelet factors are important in the inflammatory response, we examined the course of platelet factor 4 and β‐thromboglobulin in relation to disease activity in inflammatory bowel disease and in giant cell arteritis.

Patients and methods

In a prospective study, the platelet count, platelet factor 4 and β‐thromboglobulin were measured in 20 patients with Crohn's disease, 18 with ulcerative colitis and 19 with giant cell arteritis, during active and inactive disease, as well as in 51 controls without inflammation.

Results

Platelet counts were significantly higher in active vs. inactive Crohn's disease, ulcerative colitis and giant cell arteritis. Levels of platelet factor 4 and β‐thromboglobulin were significantly higher in active inflammatory bowel disease and giant cell arteritis, as well as in inactive inflammatory bowel disease and giant cell arteritis, than in the non‐inflammatory controls. A positive correlation was found between the Crohn's disease activity index and the platelet count, platelet factor 4 and β‐thromboglobulin. Also, a positive correlation was found between the ulcerative colitis activity index and β‐thromboglobulin. However, even after 12 months of follow‐up, in Crohn's disease and ulcerative colitis the mean levels of platelet factor 4 and β‐thromboglobulin were significantly higher than the levels of the controls.

Conclusion

Platelet factors were correlated with inflammatory bowel disease activity. Levels of platelet factor 4 and β‐thromboglobulin, however, were markedly raised for a long time in clinically inactive inflammatory bowel disease, which might point to a pre‐thrombotic state of disease.
Ultrastructural changes of human cardiac atrial nerve endings in diabetes mellitus
Authors: Schramm  , Wagner  , Nellessen  , Inselmann
Published: March 2003

Background

Autonomic neuropathy resulting from long‐term diabetes mellitus may affect heart innervation. However, so far diabetes induced morphological changes of cardiac nerves are not well‐known. In this study human cardiac atrial tissue from diabetic patients was analysed by electron microscopy for structural alterations as a result of diabetic neuropathy.

Methods

In coronary bypass surgery, an edge of the right auricle was routinely resected for reason of extracorporal circulation. Thin cardiac tissue sections of 100 nm were studied by electron microscopy. Atrial tissue samples were collected from 5 patients with long‐standing diabetes (for at least 8 years) and compared to atrial tissue samples from 5 patients without diabetes, equally undergoing coronary bypass surgery.

Results

In all atria‐free nerve endings with unmyelinized, axons were observed. Cross sections of 479 axons from diabetic patients were compared to 419 axons of nondiabetic patients. The number of altered axons was significantly higher in cardiac tissue of diabetic patients (32%) in comparison to normal subjects (17%). In diabetic patients, 20% of the intra‐axonal mitochondria were condensed or hydropic, whereas in nondiabetic patients only 4% of the mitochondria were altered. Membrane fragments were present in 21% of the axons in atria of diabetic patients compared to 10% in nondiabetic subjects. Only in cardiac axons from diabetic patients there were lamellar bodies, dissolved axoplasma and junctions between neighbouring axons in a minor number. Few vacuoles were present in axons of both groups.

Conclusion

In myocardial atrial‐free nerve fibre bundles of diabetic patients, the amount of degenerative changes was higher in comparison to atrial cardiac tissue from nondiabetic subjects. These morphological alterations may indicate manifestation of diabetic neuropathy and might contribute to the impairment of autonomic neural control affecting the heart in long‐standing diabetes mellitus.
Effect of hemipancreatectomy and of pancreatic diversion on the tolerance to a glucose load in humans
Authors: Battezzati  , Zerbi  , Perseghin  , Caumo  , Terruzzi  , Di Carlo  , Luzi
Published: March 2003

Background

The role of the pattern, quantity and site of insulin secretion in the tolerance to a glucose challenge is not fully evaluated in humans because it is difficult to obtain appropriate clinical models.

Design

To address this issue, we studied subjects with reduced pancreatic mass (hemipancreatectomized, HEMI), systemic insulin delivery (pancreas transplant recipients, PTX), and two control groups (healthy, CON; and with uveitis on the same immunosuppression as PTX, UVE), with an hyperglycaemic clamp (study 1, + 4.2 mmol L−1), using a repeat experiment (study 2) with a fixed glucose infusion, calculated to increase by 35% that in study 1.

Results

In study 1, CON increased glucose uptake to 20 ± 3 μmol kg−1 min−1 after a biphasic insulin response. In study 2, CON further increased the glucose uptake via an increment in prehepatic insulin secretion that stimulated insulin sensitivity without changes in peripheral insulin and glucose concentrations. HEMI and PTX had 35% less glucose uptake in study 1, compared to CON, and increased glucose concentrations (+ 1.6 mmol L−1) in study 2. UVE had an intermediate defect. The causes of intolerance were different: HEMI had a defective first‐phase insulin secretion (50% peripheral insulin concentrations) but maintained insulin sensitivity; PTX had normal peripheral insulin but only one‐third of the insulin sensitivity of CON.

Conclusions

Hemipancreatectomy and systemic insulin delivery impair first‐phase insulin secretion; second‐phase peripheral insulinization (HEMI); insulin sensitivity (PTX); and a mechanism evidentiated in study 2 of CON that increases insulin sensitivity in response to prehepatic insulin secretion (both groups). Failure of these mechanisms is largely compensated by hyperglycaemia.
A novel hyperglycaemic clamp for characterization of islet function in humans: assessment of three different secretagogues, maximal insulin response and reproducibility
Authors: Fritsche  , Stefan  , Hardt  , Schützenauer  , Häring  , Stumvoll
Published: March 2003

Background

Characterization of beta‐cell function in humans is essential for identifying genetic defects involved in abnormal insulin secretion and the pathogenesis of type 2 diabetes.

Materials and methods

We designed a novel test assessing plasma insulin and C‐peptide in response to 3 different secretagogues. Seven lean, healthy volunteers twice underwent a 200 min hyperglycaemic clamp (10 mmol L−1) with administration of GLP‐1 (1.5 pmol . kg−1 . min−1) starting at 120 min and an arginine bolus at 180 min. We determined glucose‐induced first and second‐phase insulin secretion, GLP‐1‐stimulated insulin secretion, arginine‐stimulated insulin response (increase above prestimulus, ΔIarg) and the maximal, i.e. highest absolute, insulin concentration (Imax). Insulin sensitivity was assessed during second‐phase hyperglycaemia. On a third occasion 6 subjects additionally received an arginine bolus at > 25 m
m blood glucose, a test hitherto claimed to provoke maximal insulin secretion.

Results

Insulin levels increased from 46 ± 11 p m to 566 ± 202 p
m at 120 min, to 5104 ± 1179 p
m at 180 min and to maximally 8361 ± 1368 p
m after arginine (all P < 0.001). The within subject coefficients of variation of the different secretion parameters ranged from 10 ± 3% to 16 ± 6%. Except for second‐phase which failed to correlate significantly with ΔIarg (r = 0.52, P = 0.23) and Imax (r = 0.75, P = 0.053) all phases of insulin secretion correlated with one another. The insulin concentration after the arginine bolus at > 25 m
m glucose (n = 6) was 2773 ± 855 p
m vs. 7562 ± 1168 p
m for Imax (P = 0.003).

Conclusion

This novel insulin secretion test elicits a distinct pattern of plasma insulin concentrations in response to the secretagogues glucose, GLP‐1 and arginine and is highly reproducible and can be used for differential characterization of islet function.
Sporadic endocrine tumours and their relationship to the hereditary endocrine neoplasia syndromes
Authors: Koper  , J. Lamberts
Published: March 2003

In the last years of the previous century the genes involved in the aetiology of five endocrine tumour syndromes have been identified. The tumour‐suppressor gene that is responsible for Von Hippel–Lindau Disease was cloned in 1993; multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid carcinoma were found to be caused by activating mutations in the ret proto‐oncogene in 1993 and 1994, and most recently the menin‐gene, another tumour‐suppressor gene, was shown to be associated with MEN‐1. As usual, the answer to one question leads to innumerable new questions. And so, now we want to know the extent to which germ‐line mutations (de novo, or otherwise previously undetected) in these genes play a role in the occurrence of the various endocrine tumours that are associated with these syndromes in apparently sporadic cases. We also want to know if the nature of the (germ‐line) mutation conveys any information about the characteristics (phenotype) of the disease. We want to know the role of somatic mutations in these genes in truly sporadic tumours. And finally we want to know the exact function of the proteins that are encoded by these genes. The paper by Roijers et al. [
1] elsewhere in this issue is an example of a small but well‐directed step on the way to address some of these questions with respect to the menin‐gene. It addresses the problem of patient selection when looking for germ‐line mutations in apparently sporadic MEN‐1 patients. In this review we want to give a brief summary of the present status with regard to some of the questions mentioned above, in relation to the endocrine tumour syndromes caused by the vhl, ret and menin genes.