bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of the effect of native glucagon‐like peptide 1 and dipeptidyl peptidase IV‐resistant analogues on insulin release from rat pancreatic islets
Authors: Siegel  , Scharf  , Gallwitz  , Mentlein  , Morys‐Wortmann  , Fölsch  , Schmidt  
Published: March 2003

BackgroundGlucagon‐like peptide 1 (GLP‐1) stimulates insulin secretion and may improve glycaemic control in type 2 diabetes. Therapeutic use is limited by its rapid degradation, primarily by dipeptidyl peptidase IV.Materials and methodsFive GLP‐1 analogues with alterations at cleavage positions were synthesized according to the Fmoc strategy and tested for metabolic stability by incubation with rat kidney membranes containing dipeptidyl peptidase IV activity. Their insulinotropic effect was compared in isolated rat pancreatic islets after 24 h maintenance in tissue culture. Ten islets per vial were incubated for 30 min; insulin was measured radioimmunologically. Each analogue was compared with GLP‐1 in the same experiment.ResultsAll analogues were biologically active in isolated islets in the potency order da2d8 = da2 > d2d9 > da2ds8 > desamino. At 16.7 mmol L−1 glucose, GLP‐1 and GLP‐1 analogues altered as position 2, or 2 and 8 significantly (P < 0.05) increased insulin release at 10−9 mol L−1. N‐terminal modification of GLP‐1 confers resistance to dipeptidyl peptidase IV degradation in rat kidney membranes in vitro.ConclusionsThe analogues tested are biologically active and resistant to degradation by dipeptidyl peptidase IV. Their greater metabolic stability may help to realize the potential of GLP‐1 analogues in diabetes therapy.
Hyperosmolar saline induces airway resistance changes and neuropeptide release: a comparison with the effect of capsaicin, potassium and histamine
Authors: Högman  , Hageman  , Hua  
Published: March 2003

BackgroundHealthy subjects do not show any bronchoconstricting response to inhalation of hypertonic saline, in contrast to subjects with symptoms of asthma. There is evidence indicating that these airway reactions may be related to stimulation of sensory nerves.Materials and methodsWe investigated the effects of hyperosmolar solutions on the changes in airway resistance as well as on release of neuropeptides from an isolated and perfused guinea pig lung model.ResultsWe observed that hyperosmolar saline (HS), capsaicin, potassium and histamine induced different patterns of response in airway resistance and neuropeptide release. HS 3.6% induced a biphasic response in airway resistance. Initially a minor relaxation, 4 ± 1 cmH2O mL–1 min (P < 0.05), followed by a contraction, 22 ± 3 cmH2O mL–1 min (P < 0.01). This was associated with release of calcitonin gene‐related peptide (CGRP) 7.7 ± 1.9 fmol mL–1 g (P < 0.01), but not of neurokinin A (NKA), a known bronchoconstrictor. Mannitol, at the same osmolarity as HS 3.6%, did not elicit a change in airway resistance, CRGP or NKA release. Capsaicin at 10–6 mol L–1 and potassium at 70 mmol L–1 induced a profound increase in airway tone (50 ± 9 and 42 ± 8 cmH2O mL–1 min respectively; P < 0.01) and elevation of both CGRP (6.4 ± 1.9 and 3.9 ± 1.1 fmol mL–1 g respectively; P < 0.05) and NKA (3.3 ± 1.0 and 1.0 ± 0.2 fmol mL–1  respectively; P < 0.05). Histamine increased the airway resistance by 42 ± 8 cmH2O mL–1 min (P < 0.01) but had no effect on either CGRP or NKA release.ConclusionsIn healthy guinea pigs, hyperosmolar saline 3.6% initially caused relaxation of the airways followed by contraction and induced release of CGRP‐LI. This was not seen with mannitol at the same osmolarity as for the hyperosmolar saline.
Influence of structurally different lipid emulsions on human neutrophil oxygen radical production
Authors: Wanten  , Naber  , Kruimel  , Tool  , Roos  , Jansen  
Published: March 2003

BackgroundThe aim of this study was to evaluate immunomodulatory properties of lipid emulsions applied in parenteral nutrition by measuring neutrophil oxygen radical production (the ‘respiratory burst’) after lipid incubation.Materials and methodsNeutrophils, isolated from the blood of 10 healthy individuals, were incubated in medium or in lipid emulsions in a physiological concentration (2.5 mmol L−1) containing long‐chain [Intralipid (LCT)], mixed medium and long‐chain [Lipofundin (LCT/MCT)] or structured triglycerides (SL). After washing and stimulation with phorbol 12‐myristate 13‐acetate (PMA) or serum‐treated zymosan (STZ) particles, the respiratory burst was evaluated by measuring maximum oxygen uptake, superoxide and hydrogen peroxide production rates and chemiluminescence.ResultsUnlike LCT and SL, LCT/MCT increased PMA‐ and STZ‐induced oxygen uptake rate by 45% and 31% respectively (both P = 0.006 compared with medium) as well as superoxide (+56%, P = 0.006) and hydrogen peroxide (+14%, P = 0.04) production, within 5 min after stimulation. Increased LCT/MCT‐mediated early respiratory burst was confirmed by decreased PMA‐ (−65%) and STZ‐stimulated (–54%) chemiluminescence peak time (time after stimulation to peak) in combination with unchanged peak height (maximum rate of radical production). Late respiratory burst (within 2 h) of LCT/MCT, indicated by overall luminescence (overall radical production), remained unchanged (PMA) or decreased (STZ, P = 0.02). The addition of 2.5 mmol L−1 LCT/MCT or MCT emulsion to unstimulated neutrophils, in contrast to LCT and SL, resulted in significant luminescence.ConclusionsEarly neutrophil respiratory burst is accelerated by the LCT/MCT emulsion Lipofundin, whereas LCT (Intralipid) and structured lipid emulsions exert no effect. MCT‐containing emulsions, contrary to LCT and structured lipid emulsions, can induce oxygen radical production in unstimulated neutrophils.
Frequency and significance of the A→G (−3826) polymorphism in the promoter of the gene for uncoupling protein‐1 with regard to metabolic parameters and adipocyte transcription factor binding in a large population‐based Caucasian cohort
Authors: Schäffler  , Palitzsch  , Watzlawek  , Drobnik  , Schwer  , Schölmerich  , Schmitz  
Published: March 2003

BackgroundThe recently described A→G (−3826) point mutation within the distal region of the UCP‐1 promoter is possibly involved in the development of obesity, diabetes and related metabolic disorders. It was the aim of this study to examine the allelic frequency and the prevalence of the three UCP‐1 genotypes in a broad caucasian cohort and to investigate the significance of this polymorphism for obesity and diabetes.Methods1020 subjects were randomly chosen from 6450 participants in the Diabetomobile Study. The UCP‐1 genotype was determined by genomic PCR and Bcl‐I‐RFLP analysis in 1020 subjects and tested for association with a variety of metabolic parameters. In addition, the influence of this mutation on adipocyte nuclear factor binding was investigated by electrophoretic mobility shift assays (EMSA).ResultsThe genotype frequencies in 1020 subjects were: AA genotype, 57.0%; AG genotype, 35.4%; GG genotype, 7.6%; with allelic frequencies of 0.75 for allele A and 0.25 for allele G. No significant differences between the genotypes and age, gender, BMI, leptin, glucose, fasting insulin, C‐peptide, HbA1c, diabetes manifestation, total cholesterol, and HDL cholesterol were found. Analysis of the Trp64Arg polymorphism of the β3‐adrenergic receptor in a subgroup of 343 subjects revealed no additive effect to the UCP‐1 polymorphism. An yet unknown adipocyte‐specific factor of nuclear extracts from 3T3‐L1 adipocytes during differentiation is able to bind specifically to the distal UCP‐1 promoter region and this binding ability can not be abolished by the mutation.ConclusionsWe determined the genotype and allelic frequency of the UCP‐1 promoter polymorphism in the largest known population‐based study. The results from genotyping demonstrate clearly that this polymorphism does not play a major role in the pathogenesis obesity and diabetes. A yet unknown adipocyte derived and differentiation‐dependent regulated transcription factor is able to bind to the distal UCP‐1 promoter surrounding −3826 bp. This binding is not affected by presence of the mutation.
Left atrial systolic function is depressed in idiopathic and preserved in ischemic dilated cardiomyopathy
Authors: Triposkiadis  , Moyssakis  , Hadjinikolaou  , Makris  , Zioris  , Hatzizaharias  , Kyriakidis  
Published: March 2003

BackgroundLeft atrial systolic dysfunction, unexplained by altered loading conditions, has been reported in idiopathic dilated cardiomyopathy suggesting left atrial involvement in the myopathic process.Materials and methodsSeventeen patients with idiopathic dilated cardiomyopathy, 16 with ischemic dilated cardiomyopathy and 18 normal controls were studied with transthoracic echocardiography and cardiac catheterization. Transmitral diastolic flow was evaluated with pulsed Doppler. Left atrial volume (cm3/m2) at mitral valve opening (maximal, Vmax.), onset of atrial systole (P wave of the electrocardiogram, Vp), and mitral valve closure (minimal, Vmin.) was determined with two‐dimensional echocardiography using the biplane area‐length method. The left atrial active emptying fraction (ACTEF = [Vp‐Vmin.] × 100/Vp) served as an index of systolic function.ResultsThe peak early diastolic transmitral flow velocity (cm/sec) was similar in the three groups (idiopathic: 60 ± 16, ischemic: 58 ± 20, control: 56 ± 22; P = NS), whereas the late diastolic transmitral flow velocity was lower but not significantly different in idiopathic compared to ischemic cardiomyopathy, and in both was lower than control (26 ± 12 vs. 34 ± 13 vs. 44 ± 14, respectively; P < 0.05). Vmax. and Vp were similar in idiopathic and ischemic cardiomyopathy and greater than control (44.6 ± 13.6 vs. 48.2 ± 18.3 vs. 26.9 ± 6.2; P < 0.05, and 34.6 ± 13.4 vs. 30.8 ± 10.9 vs. 16.7 ± 3.7, respectively; P < 0.05). ACTEF was lower in idiopathic than in ischemic cardiomyopathy and in the latter it was similar to control (18 ± 10% vs. 32 ± 10% vs. 36 ± 10%, respectively; P < 0.05). Moreover, ACTEF was inversely related to left atrial tension at end‐of atrial systole both in idiopathic and in ischemic cardiomyopathy (r2 = 0.52, P = 0.001 and r2 = 0.57, P = 0.0007, respectively). However, at any given level of left atrial tension at end of atrial systole, ACTEF was lower in idiopathic than ischemic cardiomyopathy.ConclusionLeft atrial systolic function is depressed in idiopathic and preserved in ischemic dilated cardiomyopathy despite similar left atrial loading conditions. This finding suggests left atrial myopathy in the former, and may be related to the differences in the response to medical treatment and clinical outcome observed between the two conditions.
Lack of MEN1 gene mutations in 27 sporadic insulinomas
Authors: Cupisti  , Höppner  , Dotzenrath  , Simon  , Berndt  , Röher  , Goretzki  
Published: March 2003

BackgroundMultiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant familial cancer syndrome characterized by tumours of the parathyroids, anterior pituitary gland and endocrine pancreas. Since the cloning of the MEN1 gene (encoding menin) on chromosome 11q13 by Chandrasekharappa et al. in 1997, it has become possible to identify mutations that are responsible. We examined whether MEN1 gene mutations are present in sporadic insulinomas, a rare sporadic tumour that is seen more frequently in patients with the MEN 1 syndrome.Patients and methodsWe sequenced the coding part of the MEN1 gene (exons 2–10) in tumour tissue of 27 patients suffering from an insulinoma (24 benign, three malignant). To validate our methods we also examined tumour tissue from five patients with primary hyperparathyroidism (HPT) at a younger age and/or multiple gland disease, with increased risk of MEN 1.ResultsWe found no mutations in the nine coding exons of the MEN1 gene in the insulinoma tissues. We could confirm three benign polymorphisms (S145S, R171Q, D418D) reported previously. In the control patients we found two new point mutations (one mis‐sense, one non‐sense mutation) and one deletion.ConclusionMutations of the MEN1 gene do not play an important role in the pathogenesis of sporadic insulinomas. Therefore genetic screening is not cost effective in sporadic insulinoma patients without other indicators of MEN 1. Patients with primary HPT at a younger age and/or multiple gland disease should be screened for MEN1 gene mutations.
Criteria for mutation analysis in MEN 1‐suspected patients: MEN 1 case‐finding
Authors: Roijers  , De Wit  , Van Der Luijt  , Ploos van Amstel  , Höppener  , Lips  
Published: March 2003

BackgroundMultiple endocrine neoplasia type 1 (MEN 1) is an autosomal, dominantly inherited cancer syndrome, with tumours in various endocrine glands. In 1997 the responsible tumour suppressor gene was identified. MEN1 gene germ‐line mutations are detected in the vast majority of MEN 1 patients, however, with regard to case‐finding, unfortunately only at a very low frequency in patients with apparently sporadic MEN 1‐related tumours. In order to increase the detection rate of disease gene carriers among patients with apparently sporadic MEN 1‐related tumours, clinical criteria were needed.Design and ResultsIn this study MEN1 gene germ‐line mutations were revealed in 16/16 MEN 1 patients/families (100%). Based on our clinical experience with MEN 1 patients/families we formulated clinical criteria to identify disease gene carriers among patients with apparently sporadic MEN 1‐related tumours. The criteria for MEN 1‐suspected patients are: young age at onset (< 35 years) and/or multiple MEN 1‐related lesions in a single organ or two distinct organs affected. Application of these criteria yielded MEN1 gene germ‐line mutations in nine of 15 MEN 1‐suspected patients (60%), thus identifying novel MEN 1 families. Follow up was also guaranteed for patients not fulfilling these criteria.ConclusionsThe clinical criteria for MEN 1‐suspected patients increase the detection rate of germ‐line MEN1 gene mutations among patients with apparently sporadic MEN 1‐related tumours. These criteria may be used for (presymptomatic) identification of MEN 1 disease gene‐carriers, thus enabling early detection of tumour development and timely treatment, as well as genetic counselling.
Angiotensin II type‐I receptor and ACE polymorphisms and risk of myocardial infarction in men and women
Authors: Kee F. , Morrison C. , Poirier O. , McCrum E. , Mallet C. , Nicaud V. , McMaster D. , Dallongeville J. , Fruchart J‐C. , Evans A. E. 
Published: March 2003

Findings relating an association between an insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene and myocardial infarction (MI) have been mixed. While other loci, such as the angiotensin II type‐I receptor (AT1R), may modulate risk, few studies have adequately documented the risk in women. We aimed to study whether the findings in respect of ACE and AT1R in UK men were borne out in women.Cases of MI (305 women, 391 men) in Belfast and Glasgow have been compared to controls (291 women, 356 men). These new samples augment the original men (200 cases, 181 controls) included from Belfast in the ECTIM study. Results Among men, the odds ratio for MI for ACE (DD vs. ID + II) was 1·03 (0·79, 1·34) and among women, 0·69 (0·47, 1·01). This heterogeneity between the risks in men and women was significant in Glasgow (P = 0·02). Among men and women the odds ratio for MI for AT1R (CC vs. AC + AA) was 1·02 (0·71, 1·47). There was a small gradient in risk, such that the odds ratio for DD genotype was 0·86 (0·63, 1·17) among subjects homozygous for the common AT1R alelle (AA): 0·94 (0·67, 1·30) among heterozygotes and 1·21 (0·53, 2·77) among CC subjects; but this interaction was not statistically significant.Some of the contradictory findings concerning the ACE polymorphism and the risk of MI may be due to heterogeneity in the risk between men and women. The AT1R1196 polymorphism is not an independent risk factor for MI in either sex.
Changes of gallbladder and gastric dynamics in patients with acute hepatitis A
Authors: Portincasa P. , Moschetta A. , Di Ciaula A. , O. Palmieri V. , Milella M. , Pastore G. , Palasciano G. 
Published: March 2003

Transient alterations of gallbladder morphology and dynamics have been reported in patients with during acute hepatitis A. The presence of dyspepsia also suggests involvement of gastric motility. During a 60‐day follow‐up, we investigated gallbladder and gastric motility in relation to dyspepsia in acute viral hepatitis A patients.Twenty patients were assessed at referral (day 0) and at days 7, 21, 42 and 60 and compared with 20 healthy volunteers. Gallbladder morphology and motility and gastric motility were assessed in the fasting and postprandial period by functional ultrasonography using a liquid test meal. Dyspeptic symptoms were scored.At day 0, fasting gallbladder volume was 5·9 ± 1·3 mL, 32·6 ± 4·6 mL, and 21·5 ± 1·9 mL (mean ± SE) in patients with gallbladder sludge (n = 7), without sludge (n = 13) and controls, respectively (P < 0·05 in sludge vs. no sludge and controls; P < 0·05 in no sludge vs. controls, anova). Small fasting gallbladder volume in patients with sludge increased and sludge disappeared within 7 days. At day 0, patients with sludge also had increased thickness of fasting gallbladder wall and increased serum transaminase levels compared with patients without sludge and controls. Gallbladder contraction was similar in patients and controls. However, patients had delayed gastric emptying, which positively correlated with dyspepsia score.Gallbladder morphological changes observed in the acute phase of hepatitis A are transient and are associated with hepatocellular damage. Gastric emptying is delayed during the first week of disease and is associated with dyspeptic symptoms.
Left ventricular hypertrophy increases transepicardial dispersion of repolarisation in hypertensive patients: a differential effect on QTpeak and QTend dispersion
Authors: Wolk R. , Mazurek T. , Lusawa T. , Wasek W. , Rezler J. 
Published: March 2003

Background Ventricular arrhythmias in left ventricular hypertrophy (LVH) are related to regional electrical heterogeneity. The significance of noninvasive electrocardiographic indices of electrical heterogeneity in LVH has not been established. The aim of the study was to investigate changes in the Tpeak–Tend interval (an index of transmural dispersion of repolarisation) in addition to other traditional electrocardiographic indices of electrical dispersion in patients with hypertensive LVH.Methods Consecutive patients were screened for the presence of hypertensive echocardiographic LVH and compared with a control group. LVH was identified as left ventricular mass > 134 g m−2 in men and > 110 g m−2 in women. Twelve‐lead ECGs were analysed in respect of various indices of electrical dispersion.Results Left ventricular mass was greater in the LVH than in the control group (174 ± 39 vs. 101 ± 18 g m−2, P < 0·0001). The Tpeak–Tend interval was not affected by LVH. The main effect of LVH was an increase in QTpeak dispersion (40 ± 13 vs. 53 ± 21 ms, P < 0·05), which resulted from an increase in the maximum QTpeak interval (337 ± 24 vs. 358 ± 30 ms, P < 0·04), without any change in the minimum QTpeak interval. There was a significant correlation between the left ventricular mass index and QTpeak dispersion (r = 0·40; P < 0·01). In contrast, LVH did not exert any effect on QTend dispersion (65 ± 21 vs. 65 ± 16 ms, ns), because LVH increased both the maximum QTend interval (430 ± 30 vs. 449 ± 28 ms, P < 0·05) and the minimum QTend interval (365 ± 29 vs. 384 ± 27 ms, P < 0·04).Conclusions Hypertensive LVH exerts a differential effect on QTpeak and QTend interval dispersion. The most likely explanation is that these changes reflect a nonuniform prolongation of action potential duration across the epicardium, leading to an increase in transepicardial dispersion of repolarisation.
Damaged myocytes as detected by the colocalization of DNA fragmentation and tissue transglutaminase and their prognostic significance in enterovirus‐associated dilated cardiomyopathy
Authors: Lotze U. , Busch H.‐J. , Aschoff A. , Glück B. , Sigusch H. , Jirikowski G. , Stelzner A. , Figull H. R. 
Published: March 2003

Background Apoptotic cardiac myocytes have been described in chronic heart failure, but no data exist on the relationship between these ‘damaged’ myocytes and myocardial detection of enterovirus RNA often associated with dilated cardiomyopathy (DCM).Design In patients with idiopathic DCM, endomyocardial biopsy samples were studied for enteroviral RNA by one step reverse transcription‐polymerase chain reaction (PCR) and a subsequent hybridization of the PCR product using a Southern blot technique. The endomyocardial biopsies were further investigated for markers of cell damage and apoptosis: DNA fragmentation and expression of tissue‐transglutaminase (TTG) in the myocytes using the in‐situ endlabelling method or an anti‐TTG‐staining, respectively. To assess the prognostic significance of these two markers the correlation between the percentage of myocytes positive both for DNA fragmentation and TTG (the index of damaged myocytes) and the hemodynamic course of the patients during a mean follow‐up period of 15·9 ± 6·2 months was investigated prospectively by echocardiography.Results In 14 (45%) of the 31 patients with idiopathic DCM, enteroviral RNA was found in the endomyocardial biopsy samples, while 17 patients (55%) were enterovirus‐negative. In enterovirus‐positive patients, the index of ‘damaged’ myocytes was significantly lower (10·7 ± 4·9% vs. 19·2 ± 8·8%, P = 0·002) and the left ventricular ejection fraction (LVEF) improved significantly (P = 0·00017 vs. P = 0·13) during long‐term follow‐up. In addition, a weak negative correlation was seen between the index of damaged myocytes and the changes in LVEF in all patients during long‐term follow‐up (r = − 0·48, P = 0·004).Conclusion Our results favour the view that enterovirus‐positive patients with DCM have less damaged myocytes and a better haemodynamic course than enterovirus‐negative patients.
Nonsteroidal anti‐inflammatory drugs stimulate spermidine/spermine acetyltransferase and deplete polyamine content in colon cancer cells
Authors: Turchanowa L. , Dauletbaev N. , Milovic V. , Stein J. 
Published: March 2003

Background Nonsteroidal anti‐inflammatory drugs (NSAIDs) inhibit colonic tumourigenesis and have an established usefulness in cancer prevention. Because polyamines are essential for neoplastic cell growth, the aim of this study was to evaluate the effect of NSAIDs (indomethacin, a nonselective COX‐1 and COX‐2 inhibitor) on polyamine metabolism in colon cancer cells.Methods Both cell counting and thymidine incorporation into cellular DNA were used to assess colon cancer cell growth. Activities of polyamine‐metabolising enzymes, polyamine content (HPLC) and ODC and c‐myc protein expression (Western blot) were measured in colon cancer cells treated with indomethacin during logarithmic phase of proliferation.Results Indomethacin impaired growth of human colon cancer cells (Caco‐2 and HCT‐116). As a result, ornithine decarboxylase activity and c‐myc protein expression were decreased. Treatment with indomethacin induced intracellular oxidant formation in colon cancer cells significantly increased the spermidine/spermine‐acetyltrasferase activity (SSAT) and enhanced polyamine acetylation and efflux from colon cancer cells. Impairment of cell growth by indomethacin could not be reversed by exogenous polyamines.Conclusion Taken together, our results suggest that NSAIDs affect polyamine metabolism in colon cancer cells by inducing SSAT activity, and that polyamine depletion in NSAID‐treated colon cancer cells is mainly due to enhanced polyamine acetylation and irreversible depletion of intracellular polyamine pools.