bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibitory effect of vitamins C and E on the oxygen free radical production in human polymorphonuclear leucocytes
Authors: HERBACZYŃSKA‐CEDRO K. , WARTANOWICZ M. , PANCZENKO‐KRESOWSKA B. , CEDRO K. , KLOSIEWICZ‐WASEK B. , WA̧SEK W.
Published: March 2008

Abstract Beneficial effects of dietary supplementation with antioxidant vitamins are attributed mainly to the influence upon lipid metabolism, endothelial and vascular functions. Their effect upon leucocyte oxygen free radical producing capacity has not been investigated. In 13 healthy volunteers we examined the influence of oral supplementation with vitamins C and E (aa 600 mg per day for 14 days) upon leucocyte oxygen free radical production estimated by lucigeninamplified chemiluminescence in isolated leucocytes stimulated with arachidonic acid. After supplementation with vitamins, significant increase in serum content of ascorbic acid and tocopherol was concomitant with significant (P < 0·001) decrease of leucocyte chemiluminescent response (mean 63·2 + 23·0 SD, % of initial values) and lowering of serum lipid peroxides (P < 0·05). These findings suggest that suppression of leucocyte capacity to produce oxygen free radicals as shown in this study, may contribute to vasoprotective action of vitamins C and E.
Smoking attenuates the vasoconstrictor response to noradrenaline in type I diabetic patients and normal subjects: possible relevance to diabetic nephropathy
Authors: BODMER C. W. , VALENTINE D. T. , MASSON E. A. , SAVAGE M. W. , LAKE D. , WILLIAMS G.
Published: March 2008

Abstract Exaggerated vascular reactivity has been implicated in the pathogenesis of diabetic nephropathy, and several studies suggest that smoking accelerates its progression. We therefore assessed the vasoactive effects of smoking by comparing noradrenaline‐induced vasoconstriction in dorsal hand‐veins between smoking and non‐smoking groups of Type I diabetic patients with and without microalbuminuria and in non‐diabetic subjects. Smokers had a significantly higher dose causing 50% vasoconstriction (reduced sensitivity to noradrenaline) in all three groups: microalbuminuric diabetic smokers vs. non‐smokers, 20·2(4·6) (SEM) vs. 6·6(2·3) ng min‐1 (P = 0·02); normoalbuminuric, 76·9(29·4) vs. 22·8(9·1) ng min‐1 (P = 0·03); non‐diabetic subjects, 97·8(30·0) vs. 38·0(12·8) ng min‐1 (P = 0·01). Both microalbuminuric diabetic groups showed significantly greater sensitivity to noradrenaline‐induced vasoconstriction than the other smoking and non‐smoking groups, respectively (P<0·01).

Vasoconstrictor responses to noradrenaline are attenuated in smokers, possibly due to α‐adrenoceptor down‐regulation. Smoking could increase urinary albumin losses and accelerate renal damage through catecholamine surges which raise systemic and, perhaps, intraglomerular blood pressure. This hypothesis deserves further consideration.
Enhancement of cyclosporin A induced hepato‐ and nephrotoxicity by glutathione depletion
Authors: INSELMANN G. , LAWERENZ H. U. , NELLESSEN U. , HEIDEMANN H. T.
Published: March 2008

Abstract The role of glutathione in cyclosporin A (cyclosporin) hepato‐ and nephrotoxicity has not been clarified yet. The hypothesis that a glutathione deficit enhances the hepato‐ and nephrotoxicity of cyclosporin was tested in an animal model. Glutathione depletion was achieved by administration of diethyl maleate (DEM). Adult Sprague Dawley rats were divided into four groups (A–D; n≥ 8) and treated for 8 d as follows: group A, glucose 5% (0·4 ml kg‐1, i.p.) + 3 h later olive oil (0·5 ml kg‐1, oral); group B, DEM (0·4 ml kg‐1, i.p.) + 3 h later olive oil (0·5 ml kg‐1, oral); group C, glucose 5% (0·4 ml kg‐1, i.p.) + 3 h later cyclosporin (50 mg kg‐1, oral); group D, DEM (0·4 ml kg‐1, i.p.) + 3 h later cyclosporin (50 mg kg‐1, oral). Cyclosporin alone increased bilirubin concentration from 1·0 ± 0·6 μmol l‐1 to 8·4 ± 1·9 μmol l‐1 (P < 0·05) without changing transaminases. In glutathione depleted rats cyclosporin caused a further elevation of serum bilirubin up to 23·4 ± 5·5 μmol l‐1. This was accompanied by a 50% increase of serum glutamic oxaloacetic transaminase (GOT). Cyclosporin alone significantly decreased creatinine clearance to 50% of controls (P < 0·05). Cyclosporin treatment following glutathione depletion resulted in a further decline of creatinine clearance to 22% of controls. DEM had no effect on kidney or liver function. In conclusion glutathione depletion increases the susceptibility to cyclosporin‐induced liver and kidney injury. The results support the hypothesis that sufficient cellular glutathione concentrations may be important to prevent cyclosporin‐induced hepato‐ and nephrotoxicity.
Distribution of hepatitis B virus DNA sequences in different peripheral blood mononuclear cell subsets in HBs antigen‐positive and negative patients
Authors: CALMUS Y. , MARCELLIN P. , BEAURAIN G. , CHATENOUD L. , BRÉCHOT C.
Published: March 2008

Abstract. Hepatitis B virus (HBV) DNA sequences have been detected in leucocytes from HBV‐infected individuals. The aim of this study was to assess the specificity of HBV for a special leucocyte subset in nine healthy chronic HBV carriers, nine HBs antigen‐positive patients with chronic active hepatitis, 16 HBs antigen‐negative haemophiliacs with HBc and/or HBs antibodies, and 10 patients with HBV‐related systemic necrotizing vasculitis. HBV‐DNA sequences were found by Southern blot hybridization in the leucocytes of 15 out of the 44 (34%) patients. The prevalence was not significantly different between the four groups. HBV‐DNA was found in the CD4+ cells (9/11) as well as in the CD8+ cells (4/11), B cells (4/12) and monocytes (2/12). In conclusion, leucocytes, and particularly CD4+ lymphocytes, are frequently infected by HBV in patients with HBV serum markers.
Plasma homocysteine in relation to serum cobalamin and blood folate in a psychogeriatric population
Authors: NILSSON K. , GUSTAFSON L. , FÄLDT R. , ANDERSSON A. , HULTBERG B.
Published: March 2008

Abstract Plasma homocysteine, serum cobalamin and blood folate were analysed in 296 consecutive patients referred to a psychogeriatric department for diagnosis of mental disease. Plasma homocysteine correlated with positive significance with age and serum creatinine, and with negative significance with serum cobalamin and blood folate. Approximately 35–40% of the patients with low serum cobalamin (<150 pmol l‐1) or low blood folates (<150 nmol l‐1) exhibited normal values of plasma homocysteine (<19·9 μmol l‐1). Possibly, these patients do not have a deficiency of the vitamins in the tissue. At least 7·5% of the patients with serum cobalamin levels (>150 pmol l‐1) showed an inexplicably increased level of plasma homocysteine. These patients might have a deficiency of tissue cobalamin despite the normal serum cobalamin levels. The effect of cobalamin supplementation for 7–10 days on plasma homocysteine was tested in 62 patients with different levels of serum cobalamins. We found the most pronounced decrease of plasma homocysteine in the patients with lowest serum cobalamin levels and in the patients with highest plasma homocysteine, indicating that the percentage decrease of the initial concentration of plasma homocysteine could reflect the degree of cobalamin deficiency. Folate supplementation for 7–10 days reduced plasma homocysteine not only in patients with folate deficiency but also in those with a normal folate status, and even in patients with cobalamin deficiency. The latter patients further reduced their plasma homocysteine after additional cobalamin treatment. The findings in this study support the view that, in elderly patients with co‐existing organic brain disease, cobalamin substitution should be started when serum cobalamin concentrations are below 200 pmol l‐1 and plasma homocysteine is elevated, to prevent further organic lesions related to cobalamin deficiency.
Contribution of glycaemic control, endogenous lipoproteins and cholesteryl ester transfer protein to accelerated cholesteryl ester transfer in IDDM
Authors: RITTER M. C. , BAGDADE J. D.
Published: March 2008

Abstract In an earlier study we demonstrated that the transfer of cholesteryl ester (CET) estimated as the net mass of CE lost from HDL to the apoB‐containing lipoproteins (VLDL + LDL) during incubation of plasma is accelerated in normolipidaemic patients with insulin‐dependent diabetes mellitus (IDDM). Recombination experiments with isolated lipoprotein fractions employing this same mass transfer assay indicated that this disturbance resulted from dysfunction of VLDL and not from changes in the activity of CE transfer protein (CETP).

In this study, we sought first to determine whether CET estimated with an isotopic method that measures the transfer of radiolabelled CE from exogenous HDL from non‐diabetic controls to endogenous VLDL + LDL was also increased in IDDM and, if so, the extent to which this disturbance was affected by glycaemic control, VLDL and CETP. As observed with the mass transfer assay, the rate of transfer of the HDL‐CE label to VLDL + LDL was also significantly accelerated in IDDM plasma (IDDM: k = 0·256±0·07; control: k = 0·092±0·05; mean±SD; P < 0·001). Fasting glucose and fructosamine correlated with both isotopic transfer (k) (r= 0·54, P= 0·009; r= 0·57, P= 0·005, respectively) and the mass of CE transferred at 2 h (r= 0·55, P= 0·006; r= 0·59, P= 0·004, respectively). Recombination experiments revealed that isotopic CET was accelerated when: (a) IDDM VLDL were combined with controls HDL and d > 1·21 fractions; and (b) IDDM d > 1·21 plasma fractions containing CETP were combined with controls VLDL + LDL and HDL. While CETP concentrations in a subset of the study group were higher in the diabetic than in the non‐diabetic controls, the difference was not statistically significant (IDDM 2·25±0·97 vs. control 1·58±0·58 μg ml‐1; mean±SD; P<0·1). These findings indicate that dysfunction of VLDL and increased CETP concentrations both contribute to the pathological acceleration of isotopic transfer in IDDM plasma and that the magnitude of this proatherogenic defect correlates closely with glycaemic control.
Influence of age on cerebral potentials evoked by oesophageal balloon distension in humans
Authors: WEUSTEN B. L. A. M. , LAM H. G. Th. , AKKERMANS L. M. A. , BERGE‐HENEGOUWEN G. P. VAN , SMOUT A. J. P. M.
Published: March 2008

Abstract The recording of viscerosensory cerebral evoked potentials is a new field in the research on gastrointestinal perception. The aim of our study was to assess the relationships between age and peak amplitudes and latencies of cerebral potentials evoked by balloon distension of the human oesophagus. In 16 healthy volunteers (aged 21–59 years), cerebral evoked potentials were recorded from a midline scalp electrode, using a series of 50 rapid balloon inflations with 13 ml of air. Peak to peak amplitudes (N1‐P1, P1‐N2) and peak latencies (N1, P1, N2) were assessed. Inverse correlations were found between age and N1‐P1 amplitude (P < 0·05), and between age and P1‐N2 amplitudes (P < 0·05). N1 and P1 latencies were significantly longer in elderly patients (N1: P < 0·05; P1: P < 0·05). Amplitudes and peak latencies of cerebral potentials evoked by balloon distension of the oesophagus are age‐dependent. In cerebral evoked potential studies, patients and healthy controls should be age‐matched.
Minimal model analyses of insulin sensitivity and glucose‐dependent glucose disposal in black and white Americans: a study of persons at risk for type 2 diabetes
Authors: OSEI K. , COTTRELL D. A.
Published: March 2008

Abstract. We have examined the impact of race and positive family history of type 2 diabetes on glucose/insulin dynamics and the two components of glucose disposal in healthy, first‐degree relatives of black and white American patients with type 2 diabetes mellitus who are at a greater risk from the disease and their healthy control subjects. Seventeen black and 15 white relatives were studied. Twenty‐two black people and 24 white people, without family history of type 2 diabetes, served as healthy control subjects. Standard oral glucose tolerance test (OGTT) and tolbutamide‐modified frequent sampling intravenous glucose tolerance (FSIGT) tests were performed in each subject. Insulin sensitivity index (SI) and glucose effectiveness (SG) were calculated using the MINI‐MOD method described by Bergman et al. Mean fasting and post‐stimulation serum glucose levels were not significantly different in the black and white relatives. However, mean serum insulin responses to oral and/or intravenous stimulation were significantly greater in the blacks than whites, irrespective of positive family history of diabetes. The mean SI was significantly (P < 0·02) lower (52%) in the black (3·67±0·56) than the white [7·50±1·93 times 10‐4 min‐1 (mUl)‐1] relatives. Comparing the healthy controls, the mean SI was significantly (P < 0·02) lower (51%) in black than white controls (4·84±0·78 vs. 9·71±1·27 times 10min‐1(mUl)‐1]. Mean SG and KG were greater (P < ·05) in the blacks than whites, irrespective of family history of diabetes. In summary, the present study demonstrates that non‐diabetic black people manifest insulin resistant and hyperinsulinaemia, irrespective of family history of diabetes, when compared to white people. We speculate that these metabolic changes could play a potential role in the higher prevalence of type 2 diabetes in the black Americans.
The fragile X syndrome: implications of molecular genetics for the clinical syndrome
Authors: ROUSSEAU F.
Published: March 2008

Abstract. The fragile X syndrome of mental retardation is one of the most common genetic diseases. Characterization of the mutations involved has greatly improved our knowledge of the transmission of fragile X syndrome and new DNA‐based diagnostics tools significantly outperform cytogenetic testing both for establishing the diagnosis and for determining carrier status. Fragile X mutations consist of an expansion of a CGG trinucleotide repeat localized in a gene (FMR‐1) that is abnormally methylated in all affected individuals. They are classified as premutations (asymptomatic) and full mutations (associated with the disease). Several different DNA analysis protocols are used for fragile X genotyping but only a few have been tested on large samples of individuals. There are several clinical indications for direct DNA genotyping for fragile X including mental retardation, learning disability or hyperactivity in children with or without a family history of mental retardation, the establishment of carrier diagnosis in fragile X families and prenatal screening of children from carrier women.
Proteolytic inactivation of alpha‐1‐antitrypsin by human neutrophils: involvement of multiple and interlinked cell responses to phagocytosable targets
Authors: OTTONELLO L. , DAPINO P. , SCIROCCO M. , DALLEGRI F. , SACCHETTI C.
Published: March 2008

Abstract. Neutrophil polymorphonuclear leukocytes (PMN) can inactivate the PMN‐elastase inhibitor alpha‐1‐antitrypsin (A1AT) proteolytically, by using metalloproteinases normally stored as zymogens in myeloperoxidase (MPO)‐negative granules. Supernatants from opsonized zymosan (OPZ)‐triggered human PMN cleaved and inactivated human AlAT through a process inhibitable by metal‐chelators, suggesting that the interaction of PMN with OPZ leads to the extracellular availability of active metalloenzymes. During OPZ‐triggering, PMN used approximately 80% of the generated hydrogen peroxide (H2O2) to produce HOCl by means of the MPO pathway, while the remainder was catabolized by PMN themselves. No H2O2 was available as free compound in the extracellular environment and hydroxyl (·OH) or ·OH‐like radicals were not generated. The selective deletion of single components of the HOCl‐generating MPO pathway resulted in the generation of PMN supernatants free of active metalloenzymes but rich of the corresponding zymogens. Similar results were obtained by replacing normal PMN with cells from a patient with hereditary MPO deficiency. No evidence was obtained for the intervention or contribution of ·OH‐like radicals, serine‐proteinases and oxidized glutathione in the transformation of the zymogens into enzymes able to inactivate AlAT. On concluding. PMN undergoing phagocytosis release MPO in amount sufficient to handle the extracellular pool of the generated H2O2 entirely, leading to the generation of equimolar amounts of HOCl. In turn, HOCl or a similar compound derived from it interacts with concomitantly released metallozymogens, switching on their AlAT inactivating potential without the apparent contribution of other PMN‐derived molecules. As HOCl and its derivatives are well‐known to oxidize and inactivate AlAT, the herein shown ability of PMN to transform short‐living HOCl into long‐acting and AlAT‐inactivating enzymatic systems suggest a central role for the HOCl‐generating MPO pathway in the PMN‐mediated impairment of lung anti‐elastase defenses.
Circulating somatostatin‐28 is not a physiologic regulator of gastric acid production in man
Authors: HILDEBRAND P. , ENSINCK J. W. , BUETTIKER J. , DREWE J. , BURCKHARDT B. , GYR K. , BEGLINGER C.
Published: March 2008

Abstract. Studies were designed to establish the acid inhibitory potency and plasma kinetics of somatostatin‐28 (S‐28) in humans and to determine whether the amount of S‐28 released into the circulation after a meal is sufficient to regulate gastric acid secretion. A liquid meal induced a significant increase of S‐28 (P < 0·01) whereas S‐14 levels did not change. Postprandial S‐28 concentrations were then mimicked by exogenous infusions and tested on basal and pentagastrin‐stimulated gastric acid secretion. Expressed in terms of circulating plasma concentrations measured by specific radioimmunoassays, S‐14 was 10 times more potent than S‐28 in inhibiting gastric acid production. The plasma half‐life of S‐28 (1·86 min) was longer than that of S‐14 (1·00 min) due to a slower plasma clearance rate. S‐28 did neither affect basal and stimulated gastric acid secretion nor postprandial intragastric acidity.

These studies suggest that postprandial plasma concentrations of S‐28 are unlikely to regulate gastric acid secretion in man. They also show that S‐28 is several times less potent than S‐14 with respect to inhibition of gastric acid output.
Platelet glycoprotein IIb‐IIIa and size are increased in acute myocardial infarction
Authors: GILES H. , SMITH R. E. A. , MARTIN J. F.
Published: March 2008

Abstract. Platelet aggregation, which plays an important role in acute myocardial infarction (AMI), is mediated by fibrinogen binding to the platelet membrane glycoprotein (GP)IIb‐IIIa (CD41). This study measured the relative number of GPIIb‐IIIa complexes on platelets from patients immediately following AMI (n= 14) compared with those from controls (n= 14). Flow cytometry was used to demonstrate that there were, on average, 20% more GPIIb‐IIIa complexes on platelets after AMI compared with controls. Platelet size was also 7% greater in AMI and it is known that larger platelets are more reactive. Since platelet size and protein content are determined at thrombopoiesis the majority of these platelets must have been circulating prior to AMI. Larger platelets, with more GPIIb‐IIIa may, therefore, be causally related to AMI.
Cholecystokinin is a physiological regulator of gastric acid secretion in man
Authors: BURCKHARDT B. , DELCO F. , ENSINCK J. W. , MEIER R. , BAUERFEIND P. , AUFDERHAAR U. , KETTERER S. , GYR K. , BEGLINGER C.
Published: March 2008

Abstract. CCK8 is a poor stimulant of gastric acid secretion in vivo, but is equipotent to gastrin‐17 (G17) in in vitro systems. To further evaluate the role of cholecystokinin (CCK) in regulating acid output in humans, dose‐response curves were constructed to CCK8 or G17 (6·4–800 pmol kg‐1 per h) with and without a specific CCK‐A receptor antagonist (loxiglumide). During loxiglumide infusion, G17‐stimulated acid output was unchanged, whereas CCK8‐stimulated secretion increased significantly. Gastric somatostatin‐14 release increased fivefold with CCK8 alone, but was blocked with loxiglumide administration. These data suggest that CCK8 directly stimulates acid secretion by binding to a CCK‐B/gastrin receptor on parietal cells, but at the same time inhibits acid responses by stimulating gastric somatostatin release to a CCK‐A receptor‐mediated pathway. To test which action of CCK is relevant under physiological circumstances, the effect of loxiglumide on fasting and post‐prandial acidity was measured through continuous pH‐metry. After eating, gastrin levels increased fourfold compared to controls with concomitant increases in acid secretion. These results suggest that post cibum, CCK is an inhibitor of acid secretion by regulating gastrin through local somatostatin; they support the hypothesis that CCK acts as an enterogastrone.
The in vivo effect of interleukin‐1β on urea synthesis is mediated by glucocorticoids in rats
Authors: HEINDORFF H. , ALMDAL T. , VILSTRUP H.
Published: March 2008

Abstract. Interleukin‐1β has been proposed as one mediator of parts of the catabolic response following surgery. However, it is not known whether such an effect is due to interleukin‐1β itself or the associated changes in glucocorticoids.

The effect of interleukin‐1β on urea synthesis was investigated in rats given a high (10 μg kg‐1) and a low dose (0·1 μg kg‐1) of recombinant interleukin‐1β (NOVO, Denmark) 3 h prior to determination of the rate of urea synthesis in vivo. Urea synthesis increased dose‐dependently after the low dose from 4·0±0·3 (control) to 6·3±0·3 (P<0·01), and after the high dose to 7·7±0·3 μmol (min·100 gBW)‐1 (P<0·01). The blood concentration of amino acids fell during interleukin‐1β treatment, so the effect on urea synthesis was not due solely to increased proteolysis, but was exerted predominantly in the liver.

Pharmacological glucocorticoid receptor blockade (hormone analogue RU486, Roussel–Uclaf, Paris, France) given 1 h prior to the interleukin treatment, completely abolished the interleukin‐1β induced increases in urea synthesis. The study demonstrates that interleukin‐1β stimulates urea synthesis in vivo, and that the major part of the effect depends on glucocorticoid action.
β‐adrenergic priming of rats in vivo modulates the effect of β‐agonist in vitro on surfactant phospholipid metabolism of isolated lungs
Authors: BERNHARD W. , MÜLLER B. , WICHERT P. VON
Published: March 2008

Abstract. To evaluate the effects of multiple β‐adrenergic stimulations on pulmonary surfactant phospholipids, perfused lungs from β‐adrenergic primed and non‐primed rats were challenged with the β‐agonist terbutaline in vitro. Cell‐free lung lavage, lavagable alveolar cells and lung tissue were analysed for phospholipid content and incorporation of precursors. In lung lavage, terbutaline in vitro doubled the incorporation of 14C‐choline and 3H‐palmitate into total phosphatidylcholine (PC) and of 3H‐palmitate into phosphatidylglycerol (PG). β‐adrenergic priming in vivo prior to terbutaline in vitro lowered the increase of precursor incorporation. For lavagable cells, terbutaline in vitro increased the incorporation of 3H‐palmitate into PC. Priming in vivo reduced this effect and diminished the specific 3H‐choline incorporation into lavagable cell PC below control level. For lung tissue, priming increased the amounts of PC and disaturated PC (DSPC) whereas terbutaline in vitro decreased DSPC in both primed and non‐primed lungs. Terbutaline in vitro slightly increased the incorporation of 14C‐choline and 3H‐palmitate into PC and DSPC in non‐primed but not in primed lungs. β‐adrenergic blockade by ICI 118.551 prevented all effects but generally increased 3H‐palmitate incorporation into the phospholipids and, in lavagable cells, the amount of PC. We conclude that long‐term β‐adrenergic treatment may alter the metabolism of pulmonary surfactant phospholipids by increasing tissue PC and DSPC and by decreasing the secretion of newly‐synthesized PC.
Effects of lithium on bone resorption in cultured foetal rat long‐bones
Authors: PEPERSACK T. , CORVILAIN J. , BERGMANN P.
Published: March 2008

Abstract. Increased serum calcium has been observed in manic depressive patients treated with lithium (Li), and one of the mechanisms increasing serum calcium could be a sensitizing effect of Li on bone resorption. In a previous study, however, Li has been found slightly to inhibit PTH‐stimulated resorption in cultured foetal rat long‐bones. In this work, we extended the study of the effects of Li on bone resorption in culture when resorption of foetal rat long‐bones was stimulated by factors other than PTH. Li 3 mM had no effect on basal resorption, a slight and inconsistent inhibitory effect on PTH stimulated bone resorption, a moderate and inconstant inhibitory effect on prostaglandin E2 (PGE2) stimulated resorption, and did not significantly affect the enhancement of resorption by interleukin 1 (ILI). The more constant effect of Li was a nearly complete inhibition of the resorption response to 1,25‐dihydroxycholecalciferol (1,25(OH)2D3). This study confirms that Li has no stimulatory effect on bone resorption by itself, nor a sensitizing action on the stimulation of resorption by several activators. Conversely, Li has a striking inhibitory effect on bone resorption stimulated by 1,25(OH)2D3.
Plasma lipids in HIV‐infected patients: a prospective study in 95 patients
Authors: CONSTANS J. , PELLEGRIN J. L. , PEUCHANT E. , DUMON M. F. , PELLEGRIN I. , SERGEANT C. , SIMONOFF M. , BROSSARD G. , BARBEAU P. , FLEURY H. , CLERC M. , LENG B. , CONRI C.
Published: March 2008

Abstract. The present study aimed to determine plasma lipid levels in 95 HIV‐infected patients divided into four groups according to the CD4 lymphocyte counts comparatively to a control group of 20 HIV‐negative normolipidaemic subjects. A relationship between lipidic abnormalities and immune or nutritional status was also investigated. The patients below 200 CD4 lymphocyte mm‐3 (groups 1 and 2) had significantly lower total cholesterol than the controls. The patients below 400 CD4 lymphocytes mm‐3 (groups 1, 2, 3) had significantly higher triglycerides and Lp(a) but lower LDL‐cholesterol than the controls. In all HIV‐positive patients, whatever their CD4 lymphocyte count, HDL‐C and apoA1 were lower than in the controls. By multivariate analysis triglycerides were positively correlated to acute opportunistic infections and to interferon‐α levels, while cholesterol was negatively correlated to TNF‐α, and LDL‐C was positively correlated to albuminaemia. The latter parameter was the only lipidic value to correlate with nutritional markers. The contamination route, or the presence of wasting, was not correlated to any lipidic disorder.
Extended duration of vertical position might impair bone metabolism
Authors: BEN‐SASSON S. A. , FINESTONE A. , MOSKOWITZ M. , MARON R. , WEINNER M. , LEICHTER I. , MARGULIES J. , STEIN P. , POPOVTZER M. , RUBINGER D. , ROUASH T. , HARRARI H. , GALUN E.
Published: March 2008

Abstract. Bone‐remodelling is markedly influenced by vectors of gravitational forces. Sleep‐deprivation, common during military training, involves a change in the normal balance between horizontal and vertical forces enacting on the skeleton. Stress fractures are likewise prevalent among army recruits. In order to investigate the impact of sleep‐deprivation on bone‐metabolism, three groups of young, healthy volunteers were selected to exercise the following: 63 h of sleeplessness (17 participants, group A); vertical sleep in a seated position for three consecutive nights (9 participants, group B); controls who slept 6 h a night horizontally (14 participants, group C). During periods of wakefulness, all participants were kept in an upright position. Twenty‐four hours' urine collection was strictly observed from two days prior to the experiment until two days after it (1 week). Changes in levels of the most characteristic bone‐metabolites, calcium and hydroxyproline indicate an increased bone‐resorption in the two experimental groups, but not in controls. The calcium excreted in the fasting urine peaked significantly at 72 h after the beginning of the experiment (+ 170% in group A; +68% in group B, relative to the basal level). Qualitatively, similar results were obtained with hydroxyproline. On an individual basis, approximately 40% of the participants in either group responded by exceeding urinary‐calcium elevation. A comparison of pre‐test bone‐density between responders and non‐responders, reveals a significantly lower bone‐density (‐ 5%) in calcium and hydroxyproline excretors. These results suggest a pre‐disposition to bone‐resorption associated with responsiveness to changes in the balance between gravitational forces.
Nitric oxide reduces hydrogen peroxide production from human polymorphonuclear neutrophils
Authors: FORSLUND T. , SUNDQVIST T.
Published: March 2008

Abstract. Nitric oxide has been reported to affect both adhesion and respiratory burst of neutrophils. This indicates a possible role of nitric oxide in regulation of acute inflammatory responses. Release of oxygen metabolites from neutrophils can be measured using luminol‐enhanced chemiluminescence and this method can detect both extracellularly and intracellu‐larly released oxygen metabolites. Neutrophils treated with nitroprusside and activated with FMLP, type I collagen or PMA decreased their extracellular release of oxygen metabolites, while their intracellular release was almost unaffected. The effect of nitroprusside was mediated by nitric oxide since treatment with cyanide had the opposite effect. N‐ethylmaleimide treatment decreased both extra‐ and intracellular release of oxygen metabolites. This indicates that nitric oxide affects membrane‐bound NADPH‐oxidase either indirectly or directly, and not a cytosol factor of the oxidase as earlier shown for N‐ethylmaleimide. In conclusion, extracellular nitric oxide attenuates extracellularly released oxygen metabolites from activated neutrophils in an inflammatory response.
The effect of dietary salt on insulin sensitivity
Authors: FLISER D. , FODE P. , ARNOLD U. , NOWICKI M. , KOHL B. , RITZ E.
Published: March 2008

Abstract. Acute reduction of salt intake causes an increase in serum lipid and insulin levels in healthy volunteers and patients with essential hypertension, suggesting induction of insulin resistance by salt restriction. Direct measurements of insulin sensitivity using the euglycaemic clamp showed no significant change after 7 days of salt restriction. Our previous study showed a time dependent course of dyslipidae‐mia after institution of a low salt diet. We therefore assessed insulin sensitivity (M‐value) under euglycaemic conditions (clamp technique) at discrete time points using a parallel group design. Two groups of healthy males were examined on high (200 mmold‐1) and low (20 mmold‐1) salt intake. One group (n— 7, 25 ± 3 years, BMI 22.4 ±2.1 kg m‐2) received high and low salt diet in random order each for 7 days. The other group (n= 7, 26 ± 3 years, 22.1 ± 1.9 kg m‐2) received the respective diet in random order for 3 days. A significantly (P < 0.01) different mean M‐value was noted in the group receiving the diets for 3 days, i.e. after low salt intake it was 7.4 ± 1.2mg kg‐1 min‐1 and after high salt intake 8.6± 1.1 mg kg‐1 min‐1. In contrast, the mean M‐value was similar after low and high salt periods in the group of individuals who had been studied after 7 days on either salt take (7.8 ± 1.8 on low salt vs. 7.6 ± 1.3 mg kg‐1 min‐1 on high salt). There were no differences in baseline mean serum glucose and potassium levels on either salt intake, whereas baseline mean serum insulin concentrations were significantly (P < 0.05) higher on low salt intake as compared with high salt intake in the group on diets for 3 days and for 7 days, respectively. Mean plasma renin activity, angiotensin II and nor‐adrenaline levels were higher after low salt than after high salt intake in both groups of volunteers. The data suggest that modulation of dietary salt intake can influence insulin sensitivity in healthy volunteers. The change in insulin sensitivity is, however, an evanescent phenomenon as previously also shown for dyslipidaemia. Extrapolations from acute effects of severe salt restriction on glucose and lipid metabolism to long‐term consequences of moderate low salt diet in the therapy of hypertension are therefore not warranted.
Vascular responses to 17β‐oestradiol in postmenopausal women
Authors: RIEDEL M. , OELTERMANN A. , MÜGGE A. , CREUTZIG A. , RAFFLENBEUL W. , LICHTLEN P.
Published: March 2008

Abstract. The vascular responses to 17β‐oestradiol were examined in 23 postmenopausal women (59 ± 7 years [mean ± SD]) using a placebo‐controlled double‐blind crossover design. All women received 1 mg 17β‐oestradiol or placebo (P) sublingually on consecutive days in random order. Axial diameters and blood flow rates of the left common femoral arteries were determined before and 60–80 min after application of verum or placebo as well as 10–30 min after 10 mg isosorbide dinitrate (ISDN) with a quantitative duplex ultrasound technique. Oestradiol induced a vasodilation of femoral arteries (+6.4±4.1% of basal, P < 0.001 vs. basal and P), the vessel diameter was unchanged with placebo (+0.7 ± 2.1%). The blood flow rate increased significantly after oestradiol application (+30 ± 28%, P < 0.05 vs. basal and P), but not after placebo (+11 ±21%). Mean blood pressure and heart rate remained constant with both drugs. Despite its vasodilatory effect, ISDN significantly reduced the arterial blood flow after pretreatment with oestradiol and placebo, probably through cardiac preload reduction. In conclusion, 17β‐oestradiol alters the vascular tone of systemic arteries resulting in a vasodilation and increase of blood flow. We suggest that these direct vascular actions may contribute to the preventive properties of oestrogens on cardiovascular diseases in postmenopausal women.
Clinical evaluation of total serum calcium in primary hyperparathyroidism and the risk of death after surgery
Authors: HEDBÄCK G. , ODÉN A.
Published: March 2008

Abstract. This study aims to understand the behaviour and clinical value of total serum calcium in untreated primary hyperparathyroidism, to identify the significant relationship between pre‐operative total serum calcium and the risk of death after surgery, and to consider the issue of when to operate. The risk of death after surgery was studied as dependent on pre‐operative serum calcium levels in a series of 896 patients followed up for mean 12.9 years (SD 6.1) after surgery. The predictive power of pre‐operative peak calcium levels was stronger than that of mean calcium levels. It was found that an increase of peak serum calcium from 2.60 mmolL‐1 to 2.90 in one patient meant a death risk increase, with 38% still 5 years after surgery. The marginal risk increase per mmolL‐1 was found to be higher below the peak serum calcium level of 2.90 mmolL‐1 than above that level. The variation of total serum calcium before surgery was found to be substantial and the occurrence of transient high serum calcium levels was not unusual. Therefore, conservative surveillance with yearly total serum calcium estimations seems insufficient. Rather, early surgery, when serum calcium levels are not more than moderately increased, appears to be the most favourable alternative.
Bone mineral density and its relationship to skin colour in Caucasian females
Authors: MAY H. , MURPHY S. , KHAW K.‐T.
Published: March 2008

Abstract. Low bone mineral density (BMD) is associated with a high risk of osteoporosis and fracture. While women with darker skin, such as women of American African origin, are reputed to have lower risk osteoporosis and fractures compared with women with fair skin such as Caucasian women, with Oriental women having intermediate levels of risk, the reasons for these differences are not clear. We examined the relationship between BMD and skin colour in a population based study of 2005 Caucasian women with a mean age of 58–1 years, resident in Cambridge and categorized into fair, medium and dark complexions by self‐report. There was no difference between the three categories of skin colour with regard to body size or life‐style characteristics. Women with self‐reported fair skin had lowest BMD values, women with self‐reported dark skin had highest BMD values, and women with self‐reported medium skin colour had intermediate values at all sites. These differences were significant at the trochanter and Ward's triangle of the hip (P values of 0.01 and 0.03, respectively). These associations were independent of age and weight. The associations remained after stratifying for smoking habit and years since menopause. In a cohort of Caucasian women resident at latitude 52d̀ North, fair‐skinned women have lower BMD values than darker‐skinned women. This association between skin colour and BMD may reflect sunlight exposure times and underlying vitamin D status.
Effect of genetic risk load defined by HLA‐DQB1 polymorphism on clinical characteristics of ID DM in children
Authors: VEIJOLA R. , KNIP M. , REIJONEN H. , VAHASALO P. , PUUKKA R. , IIONEN J.
Published: March 2008

Abstract. Clinical and autoimmune characteristics of 150 diabetic children of mean age 7.8 years (SD 4.1 years) were recorded at clinical manifestation and during the first 2 years of IDDM in order to investigate whether subjects with high risk HLA‐DQB1 genotypes differ from those without these risk markers. When comparing subjects with the DQB 1*0302/0201, DQBl *0302/x, DQBl *0201/x, or other DQB1 genotypes (x = no protective allele), no differences were found in the age of the subjects at diagnosis, the duration of hyperglycaemic symptoms, or the length of clinical remission. The frequency of islet cell antibodies (ICA) and quantitative serum levels of these antibodies were of the same magnitude in all four groups. During the initial 2 years of IDDM serum C‐peptide concentrations were observed to be inversely related to the degree of genetic risk (P < 0.001 in two‐way analysis of variance for repeated measures), the lowest C‐peptide levels being observed in the group of DQB 1*0302/0201 hetero‐zygotes (P < 0.001 vs. DQBl *0201/x; P < 0.01 vs. DQBl *0302/x; P= 0.05 vs. others). On the other hand, the subjects with the DQB 1 *0201 genotype had the highest serum C‐peptide concentrations, the levels being even higher than those of the patients carrying neutral or protective DQB1 genotypes (P < 0.01). These subjects also had lower daily insulin doses and blood glycated haemoglobin A1 (HbA1) levels over the initial 2 years of the disease when compared with the DQB 1 *0302/0201 heterozygotes (P < 0.05 and P < 0.01, respectively). We conclude that the DQB 1 *0302/0201 heterozygous individuals with the greatest genetic risk of IDDM lack the capacity for recovery of β‐cell function commonly seen in other subjects after starting exogenous insulin treatment. Our results also suggest that the DQBl *0201/x genotype is associated with a milder form of the disease, since these subjects were characterized by a transient recovery of β‐cell function accompanied by lower requirement of exogenous insulin and better metabolic control over the initial 2 years of IDDM.
Gastrointestinal motor and secretory responses to cholinergic stimulation in humans. Differential modulation by muscarinic and cholecystokinin receptor blockade
Authors: KATSCHINSKI M. , STEINICKE C. , REINSHAGEN M. , DAHMEN G. , BEGLINGER C. , ARNOLD R. , ADLER G.
Published: March 2008

Abstract. The present study investigated how a cholinergic agonist modifies interdigestive motility and secretion of the upper gastrointestinal tract and how muscarinic and cholecystokinin receptor blockade interfere with this direct cholinergic stimulation. In eight healthy volunteers, gastrointestinal motor and secretory responses to bethanechol (12.5, 25, and 50 μg kg‐1 h‐1) with and without a background of atropine (5 μg kg‐1 h‐1) or loxiglumide (10 mg kg‐1 h‐1) were studied. Stepdoses of bethanechol caused a parallel stimulation of antroduodenal motility and gastropancreatic secretion (P < 0.01) without inducing a fed pattern. However, duration of phase I was shortened (P < 0.05). Only high doses of bethanechol enhanced gastrin (P < 0.05), cholecystokinin (P < 0.05), and pancreatic polypeptide (P < 0.01) release. Atropine completely antagonized motor and secretory responses to cholinergic stimulation. Loxiglumide left cholinergically stimulated motility and pancreatic enzyme secretion unaltered. With co‐infusion of bethanechol and loxiglumide, PP release dropped by 63% (P < 0.01); gastric acid output, gastrin and CCK release increased by 56%, 16%, and 25%, respectively (P < 0.05). We conclude that stimulation by a cholinergic agonist preserves the interdigestive pattern. Low dose muscarinic receptor blockade abolishes cholinergic stimulation over the full dose range. Inhibition of somatostatin release would explain stimulation of gastrin release and gastric acid secretion with co‐infusion of bethanechol and loxiglumide. Endogenous CCK appears to interact with direct cholinergic stimulation at the pancreatic PP cell and the gastric D‐cell but not at pancreatic acinar and antroduodenal smooth muscle cells.
Relationship between fractional calcium absorption and gastric emptying
Authors: WISHART J. M. , HOROWITZ M. , MORRIS H. A. , NEED A. G. , RUSSO A. , JONES K. L. , SUN W. M. , NORDIN B. E. C.
Published: March 2008

Abstract. The relationship between calcium absorption and gastric emptying and the precision of measurement of fractional calcium absorption using a single isotope technique were evaluated in 14 normal postmenopausal women (age range 61–72 years). On two occasions separated by between 5 and 15 days, each subject was given 250 mL water containing 0.2 MBq of 45Ca in 20 mg of calcium carrier as the chloride, 20 mg kg‐1 paracetamol and 9 MBq of 99mTc sulphur colloid. Venous blood samples were taken at ‐2, 15, 30, 45, 60, 90, 120, 150 and 180 min after consumption of the drink, and gastric emptying (GE) was monitored with a gamma camera. Fractional calcium absorption in the first hour (α6) was calculated from the blood samples obtained at 15, 30, 45, 60, 90 and 120 min. An absorption rate was also derived from the 60 min sample using only a calibration curve (α1). There were close correlations between radiocalcium absorption on the two study days (r= 0.89, P < 0.001 for both α1 and α6) and between α1 and α6 (r= 0.93, P < 0.001). Plasma paracetamol concentrations at 15 min were directly related to the early phase of GE (r= 0.42, P < 0.05). In contrast, calcium absorption was inversely related to GE (r— 0.45, P < 0.05). We conclude that radiocalcium absorption is not greatly influenced by gastric emptying rate and that the single blood sample procedure has similar precision to the six‐blood sample test.
G‐protein mutations in human pituitary adrenocorticotrophic hormone‐secreting adenomas
Authors: WILLIAMSON E. A. , INCE P. G. , HARRISON D. , KENDALL‐TAYLOR P. , HARRIS P. E.
Published: March 2008

Abstract. Activating mutations of Gsα (gsp) and Gi2α (gip) have been described in various endocrine neo‐plastic conditions. The objective of this study was to assess the prevalence of gsp and gip mutations in human adrenocorticotrophin hormone‐secreting pituitary adenomas. Adrenocorticotrophin hormone production and secretion by pituitary corticotroph cells is under stimulatory control by corticotrophin‐releasing factor, acting via the production of cyclic AMP. Interference with this regulatory pathway as a result of G‐protein dysfunction could lead to disordered corticotroph cell function and growth. We have studied 32 corticotroph adenomas for the presence of gsp and gip mutations using site‐directed oligonucleo‐tide hybridization of polymerase chain reaction‐amplified DNA. G‐protein gene mutations were identified in three (9%) tumours: gsp mutations were demonstrated in two tumours at codon 227, and a gip mutation was identified in one tumour at codon 179. We did not observe a correlation between tumour phenotype and the presence of G‐protein gene mutations. We conclude that G‐protein gene mutations are an uncommon abnormality in corticotroph adenomas.
Screening for germline mutations of the p53 gene in familial breast cancer patients
Authors: PATEL U. A. , PERRY M. , CRANE‐ROBINSON C.
Published: March 2008

Abstract. The constitutive DNA from members of four families showing predisposition to breast cancer was amplified by PCR in the region of exons 5, 6, 7 and 8 of the p53 proto‐oncogene. Single‐strand conformation polymorphism (SSCP) gels were used to compare patient DNA with mutant and wild‐type control samples. No cases of anomalous mobility were observed in samples from the susceptible families. The lack of inherited mutations was confirmed for exons 5 and 7 by solid‐phase DNA sequencing. The results lend further support to the view that inherited mutations in p53 alleles are not a significant contributor to breast cancer predisposition and it is not, therefore, clinically worthwhile to screen predisposed or potentially predisposed families for germline mutations in the p53 gene.
Phenotypic and immunoregulatory analysis of intestinal T‐cells in patients with inflammatory bowel disease: evaluation of an in vitro model
Authors: NIESSNER M. , VOLK B. A.
Published: March 2008

Abstract. Although a disturbed immune response to constituents of the gut mucosa has been implicated in the pathogenesis of inflammatory bowel disease, the mechanisms are still unclear. Intestinal T‐cells derived from gut biopsies were propagated in vitro as single and co‐cultures under different experimental conditions prior to flow cytometry. Intestinal T‐cell lines from inflamed mucosa (n= 69) showed a significant (P < 0.001) decrease in CD4+ T‐cells compared to T‐cells from normal (n= 49) and uninflamed (n= 29) tissue specimens. Co‐culturing of inflamed and uninflamed mucosa led to a normalization of CD4+ T‐cells in cultures derived from inflamed mucosa. Analysis of supernatants revealed a significantly (P< 0.001) increased secretion of IL‐ 4 under co‐culture conditions. Moreover, stimulation of cultures derived from inflamed mucosa with rIL‐4 led to a significant (P< 0.001) increase in CD4+ T‐cells, whereas anti‐IL‐4 antibodies or IFN‐γ supplementation of T‐cells derived from uninflamed mucosa significantly (P < 0.001) reduced the CD4+ subset. Treatment with IFN‐γ and anti‐IL‐4 antibodies did not affect the phenotype of T‐cells derived from inflamed mucosa. These data suggest that IL‐4 might play a key role in the intestinal immune response. Furthermore, this in vitro system allows the investigation of mucosal immune mechanisms in more detail under standardized conditions.
Effect of insulin treatment on serum lipoprotein(a) in non‐insulin‐dependent diabetes
Authors: KUUSI T. , YKI‐JÄRVINEN H. , KAUPPINEN‐MAKELIN R. , JAUHIAINEN M. , EHNHOLM C. , KAUPPILAy M. , SEPPÄLÄ P. , VIIKARI J. , KUJANSUU E. , RAJALA S. , LAHTI J. , NISKANEN L. , MARJANEN T. , SALO S. , RYYSY L. , TULOKAS T. , TASKINEN M.‐R.
Published: March 2008

Abstract. In order to evaluate whether Lp(a), a lipoprotein that is potentially thrombogenic and atherogenic, is a potential risk factor for CAD in non‐insulin‐dependent diabetes (NIDDM), we compared the Lp(a) and its distribution in 145 NIDDM patients with that in 94 healthy control subjects. Furthermore, we studied the effect of insulin treatment on serum Lp(a) in 108 patients with NIDDM. Male and female NIDDM patients had similar Lp(a) concentrations to healthy controls (median value 167 mg L‐1, range 15–1550 mg L‐1 vs. 157 mg L‐1, range 15–919 mg L‐1, NS and 92, range 15–1190 mg L‐1 vs. 103 mg L‐1, range 15–842 mg L‐1, NS). Also, the cumulative distribution of Lp(a) did not differ between the NIDDM patients and healthy subjects. Insulin treatment increased Lp(a) in diabetics with a Lp(a) concentration of less than 300 mg ‐1L, but this effect was not related to the concomitant improvement in metabolic control (mean change (±SEM) of HbA1c from 9.80±0.15 to 8.00±0.12; P < 0.001). In subjects with elevated Lp(a) concentrations (>300 mg L‐1) the Lp(a) concentration was unaffected by insulin, despite a similar improvement in glycaemic control. These results suggest that insulin may modulate the concentration of Lp(a).