bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of elevated serum prolactin concentrations on the immunophenotype of human lymphocytes, mitogen‐induced proliferation and phagocytic activity of polymorphonuclear cells
Authors: KÖLLER M. , KOTZMANN H. , CLODI M. , RIEDL M. , LUGER A.
Published: November 2003

It has been suggested that the immune system is an important target tissue of prolactin (PRL). We therefore investigated several immune parameters in nine patients with chronically elevated serum prolactin concentrations. The immunophenotype of lymphocytes, mitogen‐induced lymphocyte proliferation and phagocytic activity of polymorphonuclear cells were determined under high serum prolactin levels and 2 weeks after treatment with dopamine agonists. An increased CD4/CD8 ratio in the hyperprolactinaemic patients could be detected compared with healthy control subjects, which remained high after treatment and did not seem to correlate with serum prolactin concentrations. Peripheral blood B lymphocytes showed an increased expression of CD69 in the treated group but not in untreated patients compared with healthy control subjects. Interleukin 2 receptor, CD45RO, transferrin receptor or HLA‐DR expression of CD4 or CD8 cells, as well as oxidative burst and phagocytic activity of granulocytes, were not affected in the patients with prolactinomas. Lymphocyte transformation response to phytohaemagglutinin in vitro was found not to be influenced by elevated prolactin levels except at the highest mitogen concentration tested. These data together with previous reports suggest that, although PRL is required for lymphocyte maturation to achieve normal immune function, elevated PRL levels do not lead to an ‘overstimulation’ of the immune system in men.
Is the effect of acute hyperglycaemia on interdigestive antroduodenal motility and small‐bowel transit mediated by insulin?
Authors: GIELKENS H. A. J. , VERKIJK M. , FRÖLICH M. , LAMERS C. B. H. W. , MASCLEE A. A. M.
Published: November 2003

Acute hyperglycaemia inhibits antroduodenal motility. In non‐diabetic subjects this inhibitory effect may result from reactive endogenous hyperinsulinaemia. Therefore, we investigated the effects of hyperinsulinaemia during both hyperglycaemia and euglycaemia on interdigestive antroduodenal motility (perfusion manometry) and duodenocaecal transit time (DCTT; lactulose breath‐H2 test). Six healthy volunteers (age 20–26 years) were studied for 240 min on three separate occasions in random order during: (a) i.v. saline (control); (b) acute hyperglycaemic hyperinsulinaemia (HG) with plasma glucose at 15 mmol L−1; and (c) euglycaemic hyperinsulinaemia (HI) with plasma insulin at 80 mU L−1 and glucose at 4–5 mmol L−1. Results: DCTT was significantly (P < 0.05) prolonged during HG (158 ± 23 min) compared with control (95 ± 25 min), whereas HI had no effect (100 ± 17 min). Mean duration of complete migrating motor complex (MMC) cycles was significantly (P < 0.05) reduced during HG (63 ± 9 min) compared with control (103 ± 15 min) and HI (105 ± 16 min), which resulted from a significantly (P < 0.05) shorter duration of phase II. Antral motility was significantly (P < 0.05) reduced during both HI (20 ± 8 contractions 240 min−1) and HG (9 ± 5) compared with control (43 ± 7). It is concluded that in healthy subjects hyperglycaemia prolongs DCTT, increases duodenal MMC cycle frequency and inhibits antral motility. Hyperinsulinaemia reduces antral motor activity but has no effect on interdigestive duodenal motility or DCTT. Thus, other factors, apart from insulin, mediate the inhibitory effect of hyperglycaemia on interdigestive intestinal motility and transit.
Effect of glibenclamide on insulin release at moderate and high blood glucose levels in normal man
Authors: LIGTENBERG J. J. M. , VENKER C. E. , SLUITER W. J. , REITSMA W. D. , VAN HAEFTEN T. W.
Published: November 2003

Insulin release occurs in two phases; sulphonylurea derivatives may have different potencies in stimulating first‐ and second‐phase insulin release. We studied the effect of glibenclamide on insulin secretion at submaximally and maximally stimulating blood glucose levels with a primed hyperglycaemic glucose clamp. Twelve healthy male subjects, age (mean ± SEM) 22.5 ± 0.5 years, body mass index (BMI) 21.7 ± 0.6 kg m−2, were studied in a randomized, double‐blind study design. Glibenclamide 10 mg or placebo was taken before a 4‐h hyperglycaemic clamp (blood glucose 8 mmol L−1 during the first 2 h and 32 mmol L−1 during the next 2 h). During hyperglycaemic clamp at 8 mmol L−1, the areas under the Δinsulin curve (AUCΔinsulin , mean ± SEM) from 0 to 10 min (first phase) were not different: 1007 ± 235 vs. 1059 ± 261 pmol L−1 × 10 min (with and without glibenclamide, P = 0.81). However, glibenclamide led to a significantly larger increase in AUCΔinsulin from 30 to 120 min (second phase): 16 087 ± 4489 vs. 7107 ± 1533 pmol L−1 × 90 min (with and without glibenclamide respectively, P < 0.03). The same was true for AUCΔC‐peptide: no difference from 0 to 10 min but a significantly higher AUCΔC‐peptide from 30 to 120 min on the glibenclamide day (P < 0.01). The M/I ratio (mean glucose infusion rate divided by mean plasma insulin concentration) from 60 to 120 min, a measure of insulin sensitivity, did not change: 0.26 ± 0.05 vs. 0.22 ± 0.03 μmol kg−1 min−1 pmol L−1 (with and without glibenclamide, P = 0.64). During hyperglycaemic clamp at 32 mmol L−1, the AUCΔinsulin from 120 to 130 min (first phase) was not different on both study days: 2411 ± 640 vs. 3193 ± 866 pmol L−1 × 10 min (with and without glibenclamide, P = 0.29). AUCΔinsulin from 150 to 240 min (second phase) also showed no difference: 59 623 ± 8735 vs. 77389 ± 15161 pmol L−1 × 90 min (with and without glibenclamide, P = 0.24). AUCΔC‐peptide from 120 to 130 min and from 150 to 240 min were slightly lower on the glibenclamide study day (both P < 0.04). The M/I ratio from 180 to 240 min did not change: 0.24 ± 0.04 vs. 0.30 ± 0.07 μmol kg−1 min−1 pmol L−1 (with and without glibenclamide, P = 0.25). In conclusion, glibenclamide increases second‐phase insulin secretion only at a submaximally stimulating blood glucose level without enhancement of first‐phase insulin release and has no additive effect on insulin secretion at maximally stimulating blood glucose levels. Glibenclamide did not change insulin sensitivity in this acute experiment.
Effects of low‐dose l‐arginine on insulin‐mediated vasodilatation and insulin sensitivity
Authors: WASCHER T. C. , GRAIER W. F. , DITTRICH P. , HUSSAIN M. A. , BAHADORI B. , WALLNER S. , TOPLAK H.
Published: November 2003

The present study was carried out to evaluate the effect of a low‐dose intravenous supplementation of l‐arginine on insulin‐mediated vasodilatation and insulin sensitivity. The study was performed in healthy subjects (n = 7) and patients with obesity (n = 9) and non‐insulin‐dependent diabetes mellitus (NIDDM) (n = 9). Insulin‐mediated vasodilatation was measured by venous occlusion plethysmography during the insulin suppression test, evaluating insulin sensitivity. Experiments were performed twice in each subject in the presence or absence of a concomitant infusion of l‐arginine (0.52 mg kg−1 min−1). l‐Arginine restored the impaired insulin‐mediated vasodilatation observed in obesity (22.4 ± 4.1%, P < 0.01 vs. without l‐arginine) and NIDDM (20.3 ± 3.2%, P < 0.01 vs. without l‐arginine). In healthy subjects, no effect on insulin mediated‐vasodilatation was observed (24.8 ± 3.1% vs. 21.4 ± 3.1%). Insulin sensitivity was improved significantly (P < 0.001) in all three groups by infusion of l‐arginine. No effect of l‐arginine was observed on insulin, insulin‐like growth factor I (IGF‐I), free fatty acids (FFAs) or C‐peptide levels during the insulin suppression test. Our data indicate that defective insulin‐mediated vasodilatation in obesity and NIDDM can be normalized by intravenous l‐arginine. Furthermore, l‐arginine improves insulin sensitivity in obese patients and NIDDM patients as well as in healthy subjects, indicating a possible mechanism that is different from the restoration of insulin‐mediated vasodilatation.
Somatostatin receptor subtype gene expression in human endocrine gastroentero‐pancreatic tumours
Authors: JAÏS P. , TERRIS B. , RUSZNIEWSKI P. , LeROMANCER M. , REYL‐DESMARS F. , VISSUZAINE C. , CADIOT G. , MIGNON M. , LEWIN M. J. M.
Published: November 2003

Somatostatin and its analogues are now of current use in the management of endocrine gastroentero‐pancreatic (GEP) tumours for the purpose of inhibiting hormone hypersecretion, carrying scintigraphy imaging and attempting to slow down tumour growth. Recent molecular studies have revealed the existence of up to five membrane somatostatin receptor subtypes termed SSTR1–5. However, whether or not scintigraphy imaging and tumour characteristics are correlated with specific subtype(s) remains unclear. SSTR1–5 messenger RNA (mRNA) transcripts were investigated in 38 endocrine GEP tumours (32 islet cell tumours, six carcinoid) using reverse transcriptase polymerase chain reaction (RT‐PCR), and their distribution was analysed with respect to tumour characteristics and scintigraphy imaging. SSTR2, SSTR5 and SSTR4 were detected in most cases of endocrine GEP tumours (92%, 84%, and 82% respectively), but SSTR1 and SSTR3 were less frequently observed (66% and 50% respectively). No clear‐cut correlation was found between tumour characteristics and subtype mRNA distribution. Moreover, no differences in mRNA subtype distribution were found between the 17 tumours detected by scintigraphy and the four tumours not detected by this method. Somatostatin receptor mRNA subtypes are widely expressed in endocrine GEP tumours, but their distribution is not correlated with tumour characteristics or scintigraphy positivity.
Multiple biochemical effects in the pathogenesis of alcoholic fatty liver
Authors: EATON S. , RECORD C. O. , BARTLETT K.
Published: November 2003

The pathogenesis of alcoholic fatty liver is unknown, but several causes have been proposed based on biochemical findings. These include the metabolism of alcohol leading to a shift in the cytosolic [NAD+]/[NADH] ratio to reduction, which in turn causes a direct inhibition of β‐oxidation and enhanced triacylglycerol formation via the [glycerol‐3‐phosphate]/[dihydroxyacetone phosphate] ratio. There are also chronic effects of ethanol on hepatic enzyme activities. Thus, increased activity of phosphatidate phosphohydrolase, an increased amount of fatty acid binding protein, decreased secretion of very low‐density lipoprotein and impairment of the respiratory chain as a result of decreased protein synthesis or decreased amounts of ubiquinone could all lead to fat accumulation and steatosis. The interplay of each of these with nutritional and genetic factors would then lead to the heterogeneity of the severity and characteristics of the steatosis observed in human alcoholics.
Viruses and cancers: possible role of hepatitis C virus
Authors: FERRI C. , LA CIVITA L. , ZIGNEGO A. L. , PASERO G.
Published: November 2003

Oncogenesis is a multifactorial process in which environmental, genetic and infectious factors are variably involved. A possible role of specific viruses has been suggested in at least 15% of human cancers. Hepatitis C virus (HCV), which is both hepato‐ and lymphotropic, is responsible for various liver disorders, i.e. chronic hepatitis, cirrhosis and hepatocellular carcinoma, as well as for a constellation of extrahepatic immune‐mediated manifestations, among which is mixed cryoglobulinaemia. This is a systemic disorder secondary to a chronic, benign B‐lymphocyte proliferation, which in some subjects may evolve to a malignant non‐Hodgkin's lymphoma (NHL). Interestingly, recent studies reported the appearance of malignant B‐cell neoplasias in patients with type C chronic hepatitis; moreover, in a significant number (from 22% to 50%) of ‘idiopathic’ NHLs, the presence of HCV infection has been demonstrated. The presence of a geographical etherogeneity in the prevalence of HCV‐positive NHL suggests that other co‐factors, i.e. genetic and environmental, could be involved in the lymphomagenesis. HCV may exert its oncogenic potential in two different directions, leading to liver cancer or B‐cell lymphoma.
Stress‐induced blood pressure measurements predict left ventricular mass over three years among borderline hypertensive men
Authors: GEORGIADES A. , LEMNE C. , DE FAIRE U. , LINDVALL K. , FREDRIKSON M.
Published: November 2003

Exaggerated cardiovascular reactivity has been implicated in the development of left ventricular hypertrophy. The aim of the present study was to investigate the predictive value of casual clinic, 24‐h ambulatory blood pressure and stress‐induced blood pressure measurements in the laboratory for left ventricular structures over a 3‐year period in a group of middle‐aged borderline hypertensive men. The stress test included a pretask resting period and two tasks, mental arithmetic and isometric muscle contraction. Left ventricular wall thickness was assessed by M‐mode echocardiography. All stress‐induced blood pressure levels and reactivity measures as well as ambulatory systolic blood pressure and mean arterial pressure levels were significantly correlated with left ventricular mass index (LVMI) 3 years later (r = 0.31–0.50), whereas there were no significant correlations between casual clinic or resting BP measurement and LVMI. A stepwise multiple regression analysis with LVMI at the 3‐year follow‐up as the dependent variable was applied. Baseline LVMI was entered as a forced variable and explained 24% of the variance in LVMI. Mean arterial blood pressure reactivity in the laboratory was the strongest additional independent variable, and added 15% to the prediction of LVMI 3 years later. Using a median split approach, the borderline hypertensive group was divided into high and low BP reactors. High and low BP reactors did not differ at initial baseline, but at the 3‐year follow‐up the high reactive group had significantly larger LVMI than the low reactive group. Results from the present study suggest that stress‐induced BP reactivity measurements predict the development of LVMI better than casual or resting BP measurements. Thus, measuring BP during standardized stress tests could be a method used to identify borderline hypertensive individuals at increased risk of developing left ventricular hypertrophy.
Human uterine smooth muscle exhibits a very low phosphocreatine/ATP ratio as assessed by in vitro and in vivo measurements
Authors: STEINGRÍMSDÓTTIR T. , ERICSSON A. , FRANCK A. , WALDENSTRÖM A. , ULMSTEN U. , RONQUIST G.
Published: November 2003

The purpose of the study was to investigate by in vitro and in vivo methods the phosphocreatine (PCr)/ATP ratio as an expression of the energy metabolic state of human myometrium in comparison with striated skeletal muscle. The contents of PCr and adenylates in biopsies of uterine smooth muscle and m. rectus abdominis from seven term pregnant women were determined in vitro and compared with results obtained in vivo by phosphorus magnetic resonance spectroscopy (31P‐MRS) in the uterus and m. gastrocnemius of eight non‐pregnant women. The PCr/ATP ratio in the striated skeletal muscle was about three times higher than that of the myometrium. The results of the in vitro biopsy part of the study and the in vivo 31P‐MRS part conformed with each other. In the biopsies both PCr and ATP concentrations were significantly lower in the myometrium than in the rectus muscle, but the difference for PCr was more pronounced, accounting for the significantly lower PCr/ATP ratio in the uterine smooth muscle. The energy metabolic pattern of uterine smooth muscle differs from that of striated skeletal muscle regarding the contents of high‐energy phosphocompounds and the PCr/ATP ratio. This in vivo finding is the first report on human smooth muscle using 31P‐MRS.
Ocular and systemic reactivity to isoprenaline in patients with insulin‐dependent diabetes mellitus
Authors: SCHMETTERER L. , FINDL O. , STRENN K. , FASCHING P. , ZANASCHKA G. , EICHLER H.‐G. , WOLZT M.
Published: November 2003

There is experimental evidence of decreased β‐adrenergic myocardial sensitivity in patients with insulin‐dependent diabetes mellitus (IDDM). In the present study we hypothesized that the ocular response to isoprenaline, as a consequence of increased arterial vessel rigidity, might also be blunted in patients with IDDM. We therefore compared the correlation between systemic pulse pressure amplitude (PPA) and fundus pulsation amplitude (FPA) during intravenous isoprenaline administration in 11 otherwise healthy IDDM patients and 11 healthy control subjects. Ocular fundus pulsations were measured by a recently developed laser interferometric method. Isoprenaline increased PPA in both study groups in a dose‐dependent way, but the response was significantly less in IDDM patients (at 0.8 μg min−1: + 38% in control subjects, + 27% in IDDM patients, P < 0.05 between groups). Moreover, a dose‐dependent increase in FPA was observed, which again was more pronounced in healthy subjects (at 0.8 μg min−1: + 45% in controls, + 17% in IDDM patients, P < 0.005 between groups). The regression line between PPA and FPA was very close to the 45° line in healthy subjects, whereas it was significantly flattened in IDDM patients. In conclusion, linear regression between PPA and FPA during isoprenaline suggests arterial stiffening in patients with IDDM. Hence, comparison of systemic PPA and FPA during isoprenaline provocation may be a useful method of estimating changes in arterial capacitance in patients with diabetes mellitus.
Effects of dietary fat saturation on eicosanoid production, platelet aggregation and blood pressure
Authors: LAHOZ C. , ALONSO R. , ORDOVÁS J. M. , LÓPEZ‐FARRÉ A. , DE OYA M. , MATA P.
Published: November 2003

The effects of dietary fat saturation on eicosanoid urinary excretion, platelet aggregation (PA) and blood pressure (BP) were studied in 42 healthy subjects. They consumed four consecutive diets differing in their fat saturation [saturated (SFA); monounsaturated (MUFA); polyunsaturated n‐6 (PUFA n‐6); and polyunsaturated n‐6/n‐3, (PUFA n‐3)]. Each diet period lasted 5 weeks. There were no differences in 24‐h 2,3‐dinor‐6‐keto‐prostaglandin F1α excretion among dietary periods. A significant effect was noted regarding the excretion of 11‐dehydro‐thromboxane B2 (P < 0.0001). During the PUFA n‐6 phase the excretion was significantly higher than during SFA and MUFA periods. Dietary fatty acid composition had a significant effect on ADP (1 μmol L−1) and collagen (2 mg L−1) induced PA. Dietary fat also had a significant effect on systolic and diastolic blood pressure (P < 0.0001). Both were significantly higher during the SFA period than during the other three periods. Our findings suggest that changes in dietary fatty acids may have mild, but significant, effects on eicosanoid production, platelet aggregation and blood pressure.
Both plasma and renal endothelin‐1 participate in the acute cardiovascular response to exercise
Authors: NERI SERNERI G. G. , CECIONI I. , MIGLIORINI A. , VANNI S. , GALANTI G. , MODESTI P. A.
Published: November 2003

Plasma endothelin (ET‐1) and renal endothelin are two distinct functional systems involved in maintaining blood volume. To investigate whether plasma and renal ET‐1 participate in the cardiovascular response to exercise‐induced hypovolaemia, we studied changes in plasma and urinary ET‐1 in healthy non‐professional athletes after 2 h of jogging performed both without and with drinking isotonic fluids. After the run, which caused a 13% plasma volume (PV) reduction, plasma and renal ET‐1 (+117% and +118%) increased significantly (all P < 0.01). Fluid loss restitution during the run significantly attenuated either the PV contraction (−1.2%) and plasma and renal ET‐1 increase (+2 and +3%). At multiple regression analysis changes in AVP plasma concentration, and not in PRA or PV per se, were significantly related to ET‐1 changes both in plasma and urine. The present findings indicate that both plasma and renal ET‐1 participate in the cardiovascular response to hypovolaemia induced by long‐lasting, dynamic exercise.
Elevated plasma levels of reduced homocysteine in common variable immunodeficiency — a marker of enhanced oxidative stress
Authors: AUKRUST P. , BERGE R. K. , MÜLLER F. , UELAND P. M. , SVARDAL A. M. , FRØLAND S. S.
Published: November 2003

Based on previous studies from our group, we hypothesized that enhanced oxidative stress in association with a persistent immune activation may be important in both the immunopathogenesis and certain clinical manifestations in a subgroup of patients with common variable immunodeficiency (CVI). To explore this hypothesis further, we examined plasma levels of lipid peroxidation, antioxidant vitamins and redox status of various thiol species in 20 CVI patients and 16 healthy control subjects. We found significantly higher malondialdehyde (MDA) levels in plasma from CVI patients than in healthy control subjects. Furthermore, in a subgroup of CVI patients characterized by persistent immune activation in vivo (CVIHyper), we found significantly decreased levels of vitamin E and β‐carotene. In the CVI patients, there was a significant inverse correlation between MDA levels and levels of vitamin E and β‐carotene. Finally, we found a marked elevation in plasma levels of reduced homocysteine in the CVI group, but no corresponding rise in plasma levels of total homocysteine. In the CVI group, the high plasma levels of reduced homocysteine were significantly correlated with enhanced lipid peroxidation and low levels of vitamin E. The results of the present study further support a role for enhanced oxidative stress in the immunopathogenesis of CVI. Furthermore, our finding of markedly elevated plasma levels of reduced homocysteine in CVI patients without simultaneous elevation of other homocysteine species suggests that this disturbance in homocysteine metabolism may be related to enhanced oxidative stress.
Glycaemic control and in vivo non‐oxidative Maillard reaction: urinary excretion of pyrraline in diabetes patients
Authors: PORTERO‐OTÍN M. , PAMPLONA R. , BELLMUNT M. J. , BERGUA M. , PRAT J.
Published: November 2003

The presence of pyrraline in human urine has recently been described. Using reversed‐phase high‐performance liquid chromatography, we measured urinary pyrraline in 45 insulin‐treated diabetic patients with preserved renal function and in 30 age‐ and sex‐matched healthy subjects. The relationship between urinary pyrraline and metabolic control parameters in the diabetic population (glycaemia, fructosamine, haemoglobin Alc, and 1‐year mean haemoglobin A1c) was evaluated. The mean urinary level of pyrraline in diabetic patients with poor glycaemic control (HbA1c > 9.5%) was higher than that in healthy subjects (1.12 ± 0.35 vs. 0.75 ± 0.2 μmol mmol−1 creatinine, P < 0.04), whereas in patients with good to moderate glycaemic control (HbA1c < 9.5) it was slightly but not significantly higher than in healthy subjects (0.80 ± 0.3 μmol mmol−1 creatinine vs. 0.75 ± 0.2 μmol mmol−1 creatinine). There is a significant correlation between urinary pyrraline level and glycaemia (P < 0.008), haemoglobin A1c (P < 0.01) and 1‐year mean haemoglobin A1c values (P < 0.007), but not with fructosamine. The results of the present work prove, for the first time, that glycaemic status influences circulating levels of advanced Maillard reaction products.
Effects of the angiotensin‐converting enzyme inhibitor enalapril on blood haematopoietic progenitors and Acetyl‐N‐Ser‐Asp‐Lys‐Pro concentrations
Authors: COMTE L. , LORGEOT V. , VOLKOV L. , ALLEGRAUD A. , ALDIGIER J.‐C. , PRALORAN V.
Published: November 2003

Acetyl‐N‐Ser‐Asp‐Lys‐Pro (AcSDKP) is a physiological inhibitor of the proliferation of haematopoietic stem cells. In 12 healthy volunteers treated with the angiotensin‐converting enzyme (ACE) inhibitor enalapril (20 mg day−1 for 15 days), we studied plasma and urinary AcSDKP levels, the in vitro degradation of AcSDKP by plasma ACE and the numbers of circulating haematopoietic progenitors (granulocyte‐monocytic colony forming unit: CFU‐GM; burst forming unit‐erythroid: BFU‐E; and mixed colony forming unit: CFU‐mixed). During treatment, plasma and urinary AcSDKP concentrations increased 2‐ to 5‐fold, degradation of AcSDKP was reduced, and CFU‐mixed significantly increased by 100% while BFU‐E and CFU‐GM significantly decreased by 16% and 26%, respectively. These results indicate that ACE inhibitors may be of value during chemotherapy or radiotherapy, warranting further study.
Nitric oxide concentration in the gas phase of the gastrointestinal tract in man
Authors: KASTNER J. , PFEFFEL F. , RAJEK A. , PEZAWAS T. , HIESMAYR M. , EICHLER H.‐G.
Published: November 2003

Nitric oxide (NO) has been implicated in various aspects of physiological regulation in the gastrointestinal tract. Hence, measurement of luminal NO concentrations is of interest for studying physiological and pathophysiological alterations in NO generation; however, at present, no reliable measurement techniques are available. Here we describe novel approaches for measurement of NO concentrations directly in the gas phase of the stomach and colon in healthy subjects and patients. Studies were conducted in young healthy volunteers (n = 13), intensive care patients (n = 8) and patients undergoing gastroscopy (n = 8) or colonoscopy (n = 8). NO concentrations were measured by chemolumininescence detection in air obtained through a nasogastric tube, after inflation into the stomach of a defined volume of air, or directly in the air suctioned from the endoscope. The mean NO concentration obtained from the stomach of healthy volunteers studied under baseline conditions was 18.0 ± 2.8 (SEM) p.p.m. Day‐to‐day reproducibility of NO measurements was high. Tube feeding with a nitrite‐ and nitrate‐free feeding solution left gastric NO concentrations unchanged, but standardized bicycle exercise caused an ≈30% decrease in NO levels. NO concentrations in intensive care patients were ≈2 log cycles lower than in healthy volunteers. NO levels in the colon were similar to those in the stomach. We have described two readily applicable techniques for direct, uncontaminated measurement of NO concentrations in the lumen of the gastrointestinal tract. Our finding of a striking reduction in gastric NO concentrations in intensive care patients requires further study.
Oxidative stress induced by bloodless limb surgery on humans
Authors: KARG E. , NÉMETH I. , VIRÁG G. , MÉSZÁROS T. , BODA D. , PINTÉR S.
Published: November 2003

Measure of oxidative stress were studied in blood samples from 10 patients undergoing bloodless lower limb surgery. Ischaemia induced a significant increase in plasma hypoxanthine concentration and xanthine oxidase activity both in the operated leg and in the systemic circulation. Five minutes after reperfusion, ratio of xanthine oxidase/total xanthine oxidase and dehydrogenase activities rose moderately, whereas at 20 min xanthine oxidase accounted for all xanthine oxidoreductase activity in the systemic circulation. A significant increase in blood glutathione redox ratio, enhanced oxidation of haemoglobin to methaemoglobin and rise in plasma haemoglobin concentration were present only in the operated limb. Thus, although the level of the potential free radical generators rose significantly both locally and in the systemic circulation, oxidative stress, as indicated by blood glutathione and erythrocyte injuries, remained limited to the reperfused leg.
Pro‐ and anti‐inflammatory cytokines in healthy volunteers fed various doses of fish oil for 1 year
Authors: BLOK W. L. , DESLYPERE J.‐P. , DEMACKER P. N. M. , VAN DER VEN‐JONGEKRIJG J. , HECTORS M. P. C. , VAN DER MEER J. W. M. , KATAN M. B.
Published: November 2003

Dietary supplementation with n‐3 fatty acids from fish oil alleviates inflammation in various chronic inflammatory disease states. Reductions in the production of pro‐inflammatory cytokines interleukin 1β (IL‐1β), tumour necrosis factor alpha (TNF‐α), and interleukin 6 (IL‐6) have been seen in humans after short‐term n‐3 fatty acid supplementation. We investigated long‐term effects of dietary n‐3 fatty acids on circulating cytokine concentrations and on ex vivo stimulated whole‐blood production of IL‐1β, TNF‐α and interleukin 1 receptor antagonist (IL‐1Ra), the naturally occurring antagonist of IL‐1. A total of 58 monks with a mean age of 56 years were randomized into four groups and their diets were supplemented with 0, 3, 6, or 9 g of fish oil, providing 0, 1.06, 2.13 or 3.19 g of n‐3 fatty acids per day. Subjects received equal amounts of saturated fatty acids, vitamin E and cholesterol. Compliance was excellent and erythrocyte fatty acid profiles closely reflected the amounts of n‐3 fatty acids ingested. In the group receiving 9 g of fish oil per day, no influence of n‐3 fatty acids on circulating cytokine concentrations was observed relative to placebo. Endotoxin‐stimulated whole‐blood cytokine production was measured at 26 and 52 weeks after the start and at 4, 8 and 26 weeks after cessation of supplementation. In all groups, the production of IL‐1β and IL‐1Ra was higher during supplementation than afterwards. However, no differences in cytokine production were noted between the placebo group and the various treatment groups at any point in time. Our results suggest that long‐term supplementation of fish oil does not affect ex vivo cytokine production in man.
Neurotransmitters in cerebrospinal fluid reflect pathological activity
Authors: STOVER J. F. , PLEINES U. E. , MORGANTI‐KOSSMANN M. C. , KOSSMANN T. , LOWITZSCH K. , KEMPSKI O. S.
Published: November 2003

The excitatory transmitters glutamate and aspartate become toxic whenever their extracellular levels are increased because of neuronal, glial and endothelial impairment. Taurine, a volume‐regulating amino acid, is released upon excitotoxin‐induced cell swelling. Our aim was to investigate if glutamate and aspartate in cerebrospinal fluid (CSF) reveal neuropathology in neurological patients, and if taurine unmasks glutamate‐mediated toxicity. Glutamate and aspartate are doubled in viral meningitis, acute multiple sclerosis (MS) and myelopathy compared with control subjects and patients with peripheral facial nerve palsy. These levels do not coincide with a disturbed blood–brain barrier, as estimated by the albumin ratio, are independent of their precursors (glutamine, asparagine) and are not associated with cell lysis. Taurine is significantly increased in meninigitis, acute MS, and myelopathy, suggesting glutamate‐mediated toxicity. Analysis of transmitters in lumbar CSF can be used to identify patients with cerebral and spinal pathology who might benefit from specific receptor‐modulating agents.
Correlates of plasma total homocysteine in patients with hyperlipidaemia
Authors: TONSTAD S.
Published: November 2003

The study sought to define the relation of plasma total homocysteine to biological and clinical variables and to serum vitamin concentrations in patients with primary hyperlipidaemia. Fasting plasma total homocysteine was measured in 219 men and 159 women; vitamin concentrations were available for about 60% of the sample. Men had significantly higher plasma total homocysteine than women [median (25th, 75th percentiles) 9.4 (8.2, 11.5) μmol L−1 vs. 8.5 (7.0, 10.2) μmol L−1; P = 0.0001]. Plasma total homocysteine was lower in women taking lipid‐lowering drugs than in women who were not taking drugs. Serum folate and vitamin B12 concentrations were normal for all but one and four subjects respectively. Correlations (P ≤ 0.06) were found between plasma total homocysteine and age, triglyceride concentration in women, uric acid concentration in men, serum folate, vitamin B12 and creatinine concentrations. In multiple regression analysis, the association between plasma total homocysteine and sex and between plasma total homocysteine and use of lipid‐lowering drugs disappeared when creatinine concentration was entered into the analysis. This study shows that plasma total homocysteine is related to vitamin concentrations within the normal range, suggesting that plasma total homocysteine may be modifiable by diet in hyperlipidaemic subjects with normal vitamin nutritition. Sex‐related differences appear to be related to men's higher creatinine concentration. Whether lipid‐lowering drugs interact with total homocysteine concentration requires further study.
Oxidative autoaggression by phagocytes in human peritonitis
Authors: BILLING A. G. , JOCHUM M. , FRÖHLICH D. , CHERONIS J. C. , FRITZ H.
Published: November 2003

In 60 abdominal exudates from patients with the diagnosis of either acute or persistent (chronic) peritonitis, indicators of phagocyte‐derived oxidative systems (myeloperoxidase, chemiluminescence) and proteases (elastase) were measured. These exudates reveal a picture of maximal inflammatory activation. Both types of exudates (30 each) showed a significant influx of inflammatory cells, with the mean leucocyte count being 73 000 μL and 32 000 μL−1 respectively. Local myeloperoxidase concentrations were approximately 1000‐fold greater than that of normal plasma. Spontaneous and elicitable chemiluminescence—indicators of phagocyte respiratory burst activity—were dramatically increased. In addition, levels of extracellularly released elastase (from neutrophils) were found to be up to about 1000‐fold that of normal plasma values. Although most of the elastase detected in the exudates was complexed with α1‐proteinase inhibitor (α1PI), enzymatically active elastase could be measured in approximately 60% of the samples being investigated. As there was an excess of immunoreactive α1PI in these exudates, the free elastase activity implies that much of the α1PI was inactive, presumably subjected to oxidative destruction. Moreover, a trypsin‐inhibitory activity to antigen ratio below 1 (mean = 0.81) in 75% of the purulent exudates indicated also partial proteolytic degradation of α1PI. In contrast, 16 clear exudates (no bacteria, white cell count below 500 μL−1) taken from the non‐infected peritoneal cavity of patients undergoing intra‐abdominal surgery revealed a similar permeability increase of the peritoneum but did not show relevant oxidative and proteolytic activity or destruction of α1PI compared with purulent specimens. Thus, only the inflammatory process of peritonitis appears to result in an overwhelming local phagocytic activity that initiates and maintains protease inhibitor consumption and/or inactivation. The tremendous oxidative potential found in purulent exudates may cause destruction in a wide variety of defence systems.
Granulocyte colony‐stimulating factor enhances protection by anti‐K1 capsular IgM antibody in murine Escherichia coli sepsis
Authors: HUSTINX W. , BENAISSA‐TROUW B. , VAN KESSEL K. , KUENEN J. , TAVARES L. , KRAAIJEVELD K. , VERHOEF J. , HOEPELMAN A.
Published: November 2003

Combined prophylactic treatment with recombinant murine granulocyte colony‐stimulating factor (G‐CSF) and a suboptimal dose of anti‐K1 capsular IgM monoclonal antibody (MAb) significantly enhanced survival in an experimental mouse Escherichia coli O7:K1 peritonitis model compared with untreated animals (67% vs. 11% survival; P < 0.001) and with either treatment alone (67 vs. 29% and 27% survival, respectively; P < 0.01), which suggests synergism between these agents. Enhanced survival by combined treatment was associated with increased neutrophil counts in blood and peritoneal lavage fluid, lower systemic and higher levels of local tumour necrosis factor (TNF) and lower bacterial counts in blood cultures. Mouse neutrophils treated with G‐CSF but not infected with E. coli showed enhanced phagocytic and respiratory burst capacity, down‐regulation of L‐selectin receptors and enhanced expression of Fc RII‐III receptors but not of complement receptors.
Corrected QT interval in relation to the severity of diabetic autonomic neuropathy
Authors: TENTOLOURIS N. , KATSILAMBROS N. , PAPAZACHOS G. , PAPADOGIANNIS D. , LINOS A. , STAMBOULIS E. , PAPAGEORGIOU K.
Published: November 2003

The aim of this study was to investigate to what extent the existence of objective signs of diabetic autonomic neuropathy affects the corrected QT interval (QTc) in diabetic subjects. A total of 105 diabetic subjects (type 1, n = 53; type 2, n = 52) as well as 40 matched (by age and sex) control subjects were studied. All subjects underwent the battery of five Ewing tests. Autonomic neuropathy was diagnosed if two of the five tests were abnormal. In addition, the result of each test was considered as normal (grade = 0), borderline (grade = 1) or abnormal (grade = 2), and on the basis of the sum of the scores we calculated a total score for autonomic neuropathy. The QTc interval was measured at rest, and a value > 440 ms was considered abnormal. The QTc interval was significantly more prolonged in diabetic persons with autonomic neuropathy than in those without neutopathy and in control subjects: 408.4 ± 24.2 ms vs. 394.6 ± 27.9 ms and 393.6 ± 25.5 ms respectively (P = 0.001). Furthermore, multivariate analysis controlling for age, sex, systolic and diastolic blood pressure, body mass index (BMI), waist–hip ratio (WHR), smoking, type and duration of diabetes, type of treatment, HBA1c and total score of autonomic neuropathy eliminated the role of all these factors as potential confounders except for the total score of autonomic neuropathy, which was found to affect QTc interval independently and significantly (P = 0.012). In summary, the present study confirmed the well‐known relation between autonomic neuropathy and QTc interval; in addition, it showed that QTc prolongation is associated with major degrees of autonomic neuropathy.
Can reduction in hypertriglyceridaemia slow progression of microalbuminuria in patients with non‐insulin‐dependent diabetes mellitus?
Authors: SMULDERS Y. M. , VAN EEDEN A. E. , STEHOUWER C. D. A. , WEIJERS R. N. M. , SLAATS E. H. , SILBERBUSCH J.
Published: November 2003

The objective of this study was to investigate whether reduction in hypertriglyceridaemia is associated with a slower rate of progression of microalbuminuria in patients with non‐insulin‐dependent diabetes mellitus (NIDDM). Fifteen normotensive NIDDM patients with hypertriglyceridaemia (> 2.5 mmol L−1) and microalbuminuria were randomly selected to receive either placebo (eight patients) or gemfibrozil 600 mg b.i.d. (seven patients). Progression of microalbuminuria was assessed during a 12‐month follow‐up period with measurements, consisting of blood tests and triplicate 24‐h urine collections, at 1, 3, 6, 9 and 12 months. All but one patient in the treatment group showed a favourable response (≥ 20% reduction) of hypertriglyceridaemia to gemfibrozil. One patient in the placebo group showed a spontaneous reduction in triglyceride levels. Progression of microalbuminuria was lower, although not statistically significantly so, in the treatment group (36%) than in the placebo group (65%). In the group with ≥ 20% reduction in triglyceride levels, progression of MA was significantly lower than in the group with stable or increasing triglyceride levels (+1%, range −56% to +49% vs. +97%, range −35% to +202% respectively) (P = 0.03). Continued follow‐up data of patients switching from placebo to gemfibrozil after the trial further support the role of serum triglyceride reduction in stabilizing albumin excretion. In conclusion, the results indicate that, in microalbuminuric NIDDM patients, effective treatment of dyslipidaemia could be associated with stabilization of urinary albumin excretion.
Autonomic dysfunction and upper digestive functional disorders in untreated adult coeliac disease
Authors: USAI P. , USAI SATTA P. , LAI M. , CORDA M. G. , PIRAS E. , CALCARA C. , BOY M. F. , MORELLI A. , BALESTRIERI A. , BASSOTTI G.
Published: November 2003

There is recent evidence that upper‐gut motor abnormalities may be present in coeliac disease. However, to date, the pathophysiological mechanisms responsible for the above have not been explored. The purpose of the present study was to investigate upper‐gut motor activity in coeliac disease and explore the role played by the autonomic nervous system in motility disturbances. Thirty untreated adult coeliac patients were recruited into the study. Oesophageal manometry and cardiovascular autonomic tests were performed in all patients; oesophageal pH‐metry was carried out in 20 patients, gastrointestinal manometry in eight and scintigraphic gastric emptying in 13. Oesophageal motor abnormalities were detected in about 50% of patients, pH‐metry was abnormal in 30% of them, and up to 75% of coeliac patients displayed gastrointestinal motility alterations. Delayed gastric emptying was documented in about 50% of patients and was correlated with manometric post‐prandial hypomotility. Autonomic tests were positive in 45% of patients as a group, and reached pathological score in 19% of them. Autonomic score correlated significantly with the percentage of bi‐peaked waves and with the number of fasting intestinal clusters. This study confirms that upper‐gut motor abnormalities are frequently present in adult coeliac disease. Extrinsec autonomic neuropathy may play a role, although other pathophysiological mechanisms are likely to occur.
Fat ingestion is associated with increased levels of apoC‐III‐ and apoE‐B‐containing lipoprotein particles in humans
Authors: DALLONGEVILLE J. , BAUGÉ E. , LEBEL P. , FRUCHART J.‐C.
Published: November 2003

Apolipoprotein (apo) C‐III and apoE have a major influence on post‐prandial apoB‐containing lipoprotein metabolism. The goal of the present study was to compare the post‐prandial changes in particles containing apoB and apoC‐III and those containing apoB and apoE. Twenty subjects consumed a fatty meal (1 g of fat kg−1). Human lipoprotein particles were measured by enzyme‐linked immunosorbent assay (ELISA) using combinations of anti‐apoC‐III, ‐apoE and ‐apoB. Post‐prandial lipaemia was associated with an increase in LpC‐III:B (+ 100%) and LpE:B (+ 55%; P < 0.05), which occurred 4.07 ± 1.2 and 4.7 ± 0.8 h after the meal respectively (P < 0.05). Gel filtration chromatography showed that fasting plasma LpC‐III:B and LpE:B eluted in two fractions consisting of large and smaller sized particles; 3 h after the meal, LpC‐III:B and LpE:B increased in the very low‐density lipoprotein (VLDL) + intermediate‐density lipoprotein (IDL) fraction; at 6 h, LpC‐III:B and LpE:B decreased in VLDL and LpE:B increased moderately in the low‐density lipoprotein (LDL) size range; at 10 h, both concentrations of lipoprotein particles returned to fasting levels. In conclusion, apoC‐III‐B‐containing and apoE‐B‐containing lipoproteins have different post‐prandial metabolic fates. These differences may result in different atherogenic potential.
A hyperinsulinaemic, sequentially eu‐ and hypoglycaemic clamp test to characterize autonomous insulin secretion in patients with insulinoma
Authors: NAUCK M. A. , BAUM F. , SEIDENSTICKER F. , RØDER M. , DINESEN B. , CREUTZFELDT W.
Published: November 2003

To better characterize autonomous insulin secretory behaviour in insulinoma patients and to establish diagnostic criteria with high accuracy, hyperinsulinaemic, sequentially eu‐ and hypoglycaemic clamp tests were performed in insulinoma patients and control subjects. Ten patients with insulinoma (benign in nine, histologically proven in nine) and 10 patients with suspected episodes of hypoglycaemia, in whom thorough clinical evaluation excluded an insulinoma, were examined. Five insulinoma patients were restudied after successful extirpation of the tumour. Suppression of C‐peptide during low‐dose [2 pmol kg–1 min–1 (20 mU kg–1h–1) for 90 min, plasma insulin approximately 120 pmol L–1 (20 mU L–1)] and high‐dose [8 pmol kg–1 h–1 (80 mU kg–1 h–1) for 90 min, plasma insulin approximately 450 pmol L–1 (75 mU L–1)] insulin infusion under euglycaemic conditions [plasma glucose 4.4–5.0 mmol L–1 (80–90 mg dL–1)]) and during high‐dose insulin infusion under hypoglycaemic conditions [glucose 2–2.2 mmol L–1 (40–45 mg dL–1)] was evaluated by radioimmunoassay (RIA). Euglycaemic hyperinsulinaemia suppressed C‐peptide in control subjects (P < 0.0001), whereas in insulinoma patients apparently irregular changes in C‐peptide concentrations (with spontaneous or paradoxical increments, P = 0.0006 vs. controls) were observed. The combination of hyperinsulinaemia and controlled hypoglycaemia led to a nearly complete suppression of C‐peptide in normal subjects (from basal, 0.76 ± 0.08–0.06 ± 0.01 nmol L–1; maximum observed value 0.10 nmol L–1), which was more pronounced than at the point of discontinuation of prolonged fasting (> 48 h; 0.26 ± 0.16 nmol L–1; P = 0.005). In insulinoma patients, C‐peptide remained elevated under all conditions (P = 0.51 vs. prolonged fasting). All these findings were reversible after successful surgical removal of the insulinoma. Insulinoma patients could be identified as abnormal by (a) non‐suppression of C‐peptide even under hyperinsulinaemic/hypoglycaemic conditions (10 out of 10 patients) and (b) irregular increments in C‐peptide under conditions that led to at least partial suppression in all normal subjects (9 out of 10 patients) and/or by an apparent shift to the left of insulin secretion relative to glucose concentrations (7 out of 10 patients). Controlled exposure to hyperinsulinaemic/hypoglycaemic conditions can help to characterize autonomous secretion in insulinoma patients and may be used as a diagnostic procedure when conventional methods yield equivocal results.
Cocaine administration enhances platelet reactivity to subendothelial components: studies in a pig model
Authors: Zurbano M. J. , Heras M. , Rigol M. , Roig E. , Epelde F. , Miranda F. , Sanz G. , Escolar G. , Ordinas A.
Published: November 2003

Myocardial infarction in cocaine abusers may be related to a direct platelet‐activating effect. We analysed this possibility in an experimental model. Studies were carried out in eight normal, anaesthetized pigs with a weight of 30.7 ± 3.7 kg. Blood samples were withdrawn before and 20 min after i.v. administration of cocaine (10 mg kg−1; at 1 mg kg−1 every 2 min). Modifications in platelet responses to arachidonic acid (AA; 1.4 mmol L−1), ADP (1–4 μM), synthetic thromboxane endoperoxide analogue (U46619; 1 μM), collagen (2.5–5 μg mL−1), adrenaline (10 μM) and ristocetin (0.8–1 mg mL−1) were tested by conventional aggregometry. Changes in the capacity of platelets to form aggregates on damaged subendothelium were assessed by means of an ex vivo perfusion system in which blood was circulated for 10 min at 800 s−1, a shear rate similar to that found in normal coronary arteries. The interaction of platelets with perfused denuded arterial segments was morphometrically quantified and expressed as a percentage of damaged vessel surface covered by platelets (%CS). Cocaine administration did not influence platelet aggregation patterns in pigs. However, there was a significant increase in the interaction of pig platelets with subendothelial structures after cocaine infusion (%CS = 40 ± 17% vs. 27 ± 16% baseline; mean ± SD; P < 0.01). Cocaine administration in this animal model increases the reactivity of platelets exposed to subendothelium. These results support the concept that the administration of cocaine to pigs has a prothrombotic effect by facilitating the interaction of platelets with damaged arteries.