bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypersensitivity to ADP of platelets from diabetic rats associated with enhanced fibrinogen binding
Authors: WINOCOUR P. D. , PERRY D. W. , KINLOUGH‐RATHBONE R. L.
Published: March 2008

Abstract. Platelets from diabetic humans and animals are hypersensitive to ADP. The hypersensitivity to ADP of platelets from diabetic rats occurs independently of activation of the arachidonate pathway or release of dense granule contents. During platelet aggregation by ADP, fibrinogen binds to its receptor on platelets. We examined if the hypersensitivity to ADP of platelets from diabetic rats is associated with enhanced early binding of fibrinogen to its receptor on these platelets. Fibrinogen association with platelets from rats with spontaneous or streptozotocin‐induced diabetes was significantly greater 10 s or 1 min after addition of ADP (10μm) than with platelets from their corresponding control rats. Since enhanced fibrinogen association occurred with platelets from insulin‐treated rats with spontaneous diabetes, and from rats with streptozotocin‐induced diabetes that did not receive insulin, the enhanced fibrinogen binding is likely due to the diabetic state rather than to the administration of insulin or the mechanism responsible for the diabetes. Therefore, enhanced early fibrinogen association with platelets from diabetic rats is associated with their hypersensitivity to ADP.
Vasoactive intestinal polypeptide (VIP) and peptide histidine methionine (PHM) in human penile corpus cavernosum tissue and circumflex veins: localization and in vitro effects
Authors: KIRKEBY H. J. , FAHRENKRUG J. , HOLMQUIST F. , OTTESEN B.
Published: March 2008

Abstract. Localization and functional effects of vasoactive intestinal polypeptide (VIP) and peptide histidine methionine (PHM), two peptides derived from a common precursor molecule, were investigated in isolated preparations from human penile corpus cavernosum (CC) and circumflex vein (CV). VIP‐ and PHM‐immunoreactivity (IR) was demonstrated in both CC and CV. The concentrations of VIP‐IR and PHM‐IR in CC tissue were 54.4PM15.3, and 42.0 PM7.5 pmol g‐1 wet weight respectively with a VIP/PHM ratio of 1.5PM0.4 (meanPMSEM). The corresponding values for CV tissues were 28.0 PM7.7 and 9.6 PM2.6 pmol g‐1 wet weight with a VIP/PHM ratio of 3.1PM0.4. CC and CV displayed VIP‐ and PHM‐IR confined to nerve fibres in close relation to bundles of smooth muscle cells and blood vessels in both tissues. In vitro, VIP and PHM had no effects in unstimulated tissue preparations. Both peptides concentration‐dependently (10‐9‐10‐6 m) relaxed CC and CV preparations precontracted with 3 times 10‐6 m noradrenaline. In CC the maximum relaxant effect of VIP and PHM was 22PM 11 % and 9 PM 9% and in CV the corresponding values were 82 PM 8% and 93 PM3% respectively. The present study supports the hypothesis of VIP and PHM as neurotransmitters and/or neuromodulators in the nervous control of penile erection.
Sodium‐lithium countertransport kinetics in normal and hypertensive human pregnancy
Authors: RUTHERFORD P. A. , THOMAS T. H. , MACPHAIL S. , WILKINSONg R.
Published: March 2008

Abstract. Erythrocyte sodium‐lithium countertransport activity is increased in a subgroup of patients with essential hypertension but activity also rises temporarily during normal pregnancy. It is not known if the mechanism of raised activity is the same in both of these situations. Standard sodium‐lithium counter‐transport activity and its kinetic characteristics (sodium affinity and maximum velocity) were measured in 15 women with a normal pregnancy. The mechanism of raised sodium‐lithium countertransport activity was an increase in maximum velocity. There was no change in sodium affinity. This contrasts with essential hypertension where the mechanism is increased sodium affinity.

Sodium‐lithium countertransport activity was also measured in 14 primigravidae whose pregnancies were complicated by hypertension, and mean activity was not significantly higher than in normal pregnancy. However, six women had increased sodium affinity suggestive of essential hypertension and a different underlying mechanism of hypertension to those with normal sodium affinity. Prospective measurement of sodium‐lithium countertransport kinetics may lead to a better understanding of the pathophysiology of hypertension in pregnancy.
Skin blood cell flux in insulin‐dependent diabetic subjects in relation to retinopathy or incipient nephropathy
Authors: HOUBEN A. J. H. M. , SCHAPER N. C. , SLAAF D. W. , TANGELDER G. J. , KRUSEMAN A. C. NIEUWENHUIJZEN
Published: March 2008

Abstract. We studied the relationship of retinal and/or renal microvascular complications and duration of disease with altered finger skin microcirculation in insulin‐dependent diabetic (IDDM) subjects. Short‐term and long‐term IDDM subjects without complications or with proliferative retinopathy or incipient nephropathy were investigated with laser‐Doppler fluxmetry. An increased resting flux in skin microcirculation was found in short‐term (median: 34 perfusion units, PU) and uncomplicated long‐term IDDM subjects (25 PU) as compared with age‐matched healthy controls (18 PU), which suggests a generalized dilatation of the microcirculation throughout the body. In long‐term IDDM subjects with retinopathy we also observed an increased resting flux (37 PU), but in subjects with incipient nephropathy resting flux was decreased (17 PU) relative to the other diabetic subjects, to a level not different from the healthy control group. Post‐occlusive hyperaemic peak flux was decreased in patients with incipient nephropathy relative to the other diabetic patients, which suggests a defect in maximal arteriolar vasodilatation. No differences were found between the groups in the veno‐arteriolar reflex during venous occlusion. In conclusion, IDDM patients demonstrated increased red blood cell flux. However, with the occurrence of incipient nephropathy the resting flux and the maximal post‐occlusive vasodilatation decreased, which suggests that development of nephropathic changes in diabetes is representative of a more generalized alteration of microvascular flow regulation. Local neuro‐genic microvascular control appears to be unaffected in these patients.
Plasma homocysteine before and after methionine loading with regard to age, gender, and menopausal status
Authors: ANDERSSON A. , BRATTSTRÖM L. , ISRAELSSON B. , ISAKSSON A. , HAMFELT A. , HULTBERG B.
Published: March 2008

Abstract. Homocysteine is a probably atherogenic amino acid, the fasting and post‐methionine load serum concentrations of which have been reported to be much lower in premenopausal women than in men and postmenopausal women. This difference has been proposed to explain the reduced proneness of premenopausal women to vascular disease. We measured both free and total plasma homocysteine concentrations both fasting and postmethionine load, in 169 healthy subjects. Twelve subjects (7%) had distinctly abnormal plasma homocysteine values. Among the remaining 157 subjects, neither fasting nor post‐load values of free or total homocysteine were lower in premenopausal women (n= 46) than in men of similar age (n= 41) or postmenopausal women (n= 37). Fasting but not post‐load values were lower in postmenopausal women than in men of similar age (n= 33), and lower among the women as a whole (n= 83) than among the men (n= 74). In men, fasting values increased with age, and paralleled age‐related decreases in the concentrations of homocysteine metabolism cofactors (serum vitamin B12, blood folate, and plasma pyridoxal 5‐phosphate). Both in men and in women, fasting total plasma homocysteine values were significantly and negatively correlated to serum vitamin B12 and blood folate concentrations. Whether the small differences in plasma homocysteine values between the present men and women may be a contributory factor vis‐à‐vis their different proneness to vascular disease has yet to be settled.
Evaluation of mechanisms behind elevated energy expenditure in cancer patients with solid tumours
Authors: HYLTANDER A. , KÖRNER U. , LUNDHOLM K. G.
Published: March 2008

Abstract. The aim of this study was to demonstrate significant factors behind elevated resting energy expenditure in weight‐losing cancer patients. There tore, weight‐losing cancer patients (n= 60), with normal liver and kidney function tests, were randomized to receive one of four drug treatments for 5 days: (a) Propranolol 80 mg × 2 (β‐adreneceptor blockade); (b) Indomethacin 50 mg × 2 (prostaglandin synthesis inhibition); (c) Morphine 5 mg × 3 (pain reliet) or (d) Placebo x 2. A reterence group of healthy well‐nourished individuals were examined outside the formal randomization protocol and they received Propranolol 80 mg × 2. The cancer patients were randomized by a computer based algorithm stratifying for measured resting energy expenditure (REE), body composition, biochemical tests, previous therapy, tumour type and tumour stage. Resting energy expenditure was measured by indirect calorimetry in the morning after an overnight fast betore and after drug treatment. β‐blockade reduced REE significantly in cancer patients from 1416 ± 95 kcal day‐1 to 1160 ± 63 kcal day‐1 (P <0.02) and from 1472 ± 69 vs. 1398 ± 62 kcal day‐1, (P <0.01) in the well‐nourished reterence individuals. The reduction found in cancer patients (10%) was significantly larger than that in the group of reterence patients (5%), (P <0.01). Indomethacin, morphine or placebo did not induce any significant alteration in energy expenditure in our cancer patients. Propranolol treatment was associated with a significant reduction in plasma concentrations of free fatty acids (FFA), but not in plasma glycerol. Our results support the suggestion that adrenergic factors are the most important mediators behind elevated resting energy expenditure in weight‐losing cancer patients. Such factors were more important than inflammation and cytokine production related to prostaglandin dependent pathways.
11β‐hydroxysteroid dehydrogenase isoforms and their implications for blood pressure regulation
Authors: SECKL J. R.
Published: March 2008

Abstract.11β‐hydroxy steroid dehydrogenase (11 β‐HSD) catalyzes the reversible conversion of physiological glucocorticoids (cortisol, corticosterone) to inactive products. The enzyme thus protects non‐selective renal mineralocorticoid receptors from circulating glucocorticoids (ensuring aldosterone‐selectivityin vivo), excludes maternal glucocorticoids from the foetal circulation and modulates glucocorticoid access to glucocorticoid receptors in other tissues. 11β‐HSD has been purified from rat liver, antisera raised, a cDNA isolated and its human homologue cloned. However, it is difficult to reconcile all of the actions of 11β‐HSD with a single enzyme. Here data are reviewed that demonstrate not only molecular heterogeneity of the ‘liver‐type’ 11β‐HSD, but also the existence of a novel high affinity isoform in the placenta and perhaps distal nephron. These data are discussed in the light of their potential physiological and pathological importance, with particular reference to the pathogenesis of hypertension.
No evidence for feedback inhibition of hepatic apolipoprotein B (apo B) production after extracorporeal low density lipoprotein precipitation as determined by [I‐13C]leucine infusion in normal volunteers
Authors: ARENDS J. , BIER D. M. , SCHÄFER G. , ARMSTRONG V. W. , THIERY J. , SEIDEL D. , SCHAUDER P.
Published: March 2008

Abstract. To determine the impact of an acute reduction of the circulating mass of apolipoprotein B (apo B) on apo B metabolism we studied six healthy male volunteers before (day 0), 1 day after (day 2), and 7 days after (day 8) an LDL apheresis treatment which reduced apo B mass by 59%. Appearance of newly synthesized apo B in plasma VLDL and LDL was studied using a primed‐constant infusion of [I‐13C]‐leucine. VLDL apo B pool size and fractional VLDL apo B production rate calculated using a one‐compartment model were similar on all 3 study days. Absolute VLDL apo B production was not statistically different throughout the study (19.7±12.3, 19.5 ± 7.5, 29.1 ± 17.7 mg kg‐1 day‐1). LDL apo B fractional production rate was increased on day 2 (0.38 ± 0.17, 0.68±0.08, 0.37±0.06 pools day‐1on days 0, 2, and 8; P<0.01). Absolute LDL apo B production, however, remained constant throughout the study (10.8 ± 3.3, 11.0±1.9, 10.8 ± 3.1 mg kg‐1 day‐1). We conclude that in healthy male volunteers acute reduction of the circulating apo B mass by LDL apheresis does not affect apo B metabolism significantly.
Angiotensin converting enzyme activity in the serum, lung and kidney of diabetic rats
Authors: ERMAN A. , DYK D. J. VAN , CHEN‐GAL B. , GILER I. D. S. , ROSENFELD J. B. , BONER G.
Published: March 2008

Abstract. Diabetes Mellitus in its early stages, is associated with kidney enlargement and increased glomerular filtration rate in humans and in rats. The present study was designed to clarify the direct effect of diabetes on serum and tissue angiotensin converting enzyme (ACE) activity in streptozotocin‐induced diabetic rats. Serum ACE activity, as determined using a radiometric assay, was significantly increased in the diabetic rats (n= 15) 14 days after induction of diabetes (670 ± 31 vs. 506±14 nmol ml‐1 min‐1). Lung ACE activity, but not renal, was significantly elevated at 7 and 14 days by 29 and 46%, respectively. Plasma renin activity in the diabetic rats was decreased at 7 and 14 days by 41 and 78%, respectively. Incubations of lung slices in the presence of glucose at different concentrations did not affect in‐vitro release of the enzyme. Administration of insulin (8 units kg‐1) to diabetic rats (n= 6) on the 4th day for 11 days reduced ACE activity to values below control. Thus, serum and lung ACE activity is increased in the diabetic rat and reduced upon insulin treatment.
Dietary saturated fatty acids increase cholesterol synthesis and fecal steroid excretion in healthy men and women
Authors: GLATZ J. F. C. , KATAN M. B.
Published: March 2008

Abstract. In a strictly controlled 6‐week trial with 47 healthy volunteers we have determined the effect of replacement of polyunsaturated by saturated fatty acids on the fecal steroid excretion and on the rate of whole body cholesterol synthesis, as measured both by the sterol balance method and by the concentration of the cholesterol precursor lathosterol in serum. Subjects were fed mixed natural diets, of which the total fat content was kept constant at 45% energy. Consumption of polyunsaturated fatty acids, mainly linoleic acid, was 21 % energy for the first 3‐week period (P: S ratio 1.9), and 5% of energy (P: S ratio 0.2) for the next 3‐week period, or vice versa. Cholesterol intake as determined by analysis of duplicate diets was 41 mg MJ‐1 (about 500 mg day‐1) during both periods. Feces were collected for 5 days at the end of both periods. The steroid composition of the feces was not affected by the change of diets. The fecal excretion of neutral steroids was significantly higher on the low P: S high‐saturated‐fat (2.25 ± 0.68 mmol day‐1) than on the high P:S high‐linoleic‐acid diet (2.00 ± 0.69 mmol day‐1; P < 0.01). The excretion of bile acids was similar (0.77 ± 0.40 and 0.79 ± 0.41 mmol day‐1, respectively). The cholesterol balance and the rate of cholesterol synthesis were higher during the low P:S (1.86 ± 0.83 mmol day‐1) than during the high P:S period (1.55 ± 0.85 mmol day‐1; P < 0.01). The ratio of lathosterol to cholesterol in serum was 0.86 ± 0.33 μmol mmol‐1 on the high‐and 1.07 ± 0.39 μmol mmol‐1 on the low P: S diet (P < 0.01). Thus, both the balance and the cholesterol precursor method suggested that saturated fatty acids stimulate whole‐body cholesterol synthesis.
Peripheral macro‐and microcirculation in short‐term insulin‐dependent diabetes mellitus: the role of prostaglandins in early haemodynamic changes
Authors: HOUBEN A. J. H. M. , KRUSEMAN A. C. NIEUWENHUIJZEN , BOUHOUCH E. , SLAAF D. W. , SCHAPER N. C.
Published: March 2008

Abstract. To determine whether vasodilator prostaglandins are involved in the peripheral hyperperfusion observed in patients with short‐term insulin‐dependent diabetes mellitus (IDDM), forearm and skin blood flow were studied before and after cyclooxygenase inhibition. Skin nutritive (CBV: capillary bloodcell velocity) and thermoregulatory (LDF: laserDoppler fluxmetry), and forearm (muscle) blood flow (FBF) were measured before and after 500 mg acetylsalicylic acid (ASA) infused intravenously in 14 short‐term IDDM patients and 22 healthy control subjects. In the IDDM patients, baseline LDF (median: 27 (19–35); interquartile range) vs. 17 (15–23) pu) and FBF (3.4 (2.5–4.1) vs. 2.6 (2.2–2.9) ml 100 ml‐1 min‐1) were increased, while CBV (0.70 (0.40–1.33) vs. 069 (0.41–0.96) mm s‐1) was unchanged compared to healthy controls. ASA infusion had similar effects on baseline CBV, LDF, and FBF in patients and controls. In eight of the control subjects the role of prostaglandins in the regulation of basal peripheral blood flow was studied before and after ASA and placebo infusion. The changes in baseline CBV, LDF, and FBF were similar after ASA and placebo infusion in healthy controls. In conclusion, in short‐term IDDM patients, increased skin thermoregulatory and forearm (muscle) blood flow are probably not related to vasodilator prostaglandins. Furthermore, prostaglandins are not likely to be involved in regulating basal peripheral blood flow in healthy man.
Reversible translocation of glycoprotein Ib in plasmin‐treated platelets: consequences for platelet function
Authors: LU H. , SORIA C. , SORIA J. , ROMEUF C. DE , PERROT J.‐Y. , TENZA D. , GARCIA I. , CAEN J. P. , CRAMER E. MARTIN
Published: March 2008

Abstract. Understanding the effect of fibrinolysis on platelet function is of clinical importance. Plasmin is recognized to affect platelet adhesive function by reducing the interaction of platelet glycoprotein (GP) lb with von Willebrand factor (vWF) bound to the subendothelium. This platelet function is commonly explored in vitro by the ristocetin‐induced agglutination test. Our previous study demonstrated a plasmin‐induced redistribution of GP Ib molecules from the platelet surface to the linings of the surface‐connected canalicular system (SCCS), a critical mechanism for understanding plasmin‐induced GP Ib dysfunction. Here, we demonstrate that neutralization of plasmin by its inhibitors, aprotinin or tripeptide Val‐Phe‐Lys‐CH2CI, permits a time dependent recovery (within 30 min) of ristocetin‐induced agglutination in the platelets which were stimulated by plasmin at < 1 CUml‐1. This functional recovery was accompanied with a restoration of a normal amount of GP Ib on the platelet surface, as measured by the binding of both monoclonal anti‐GP Ib antibody SZ 2 and 125I‐labelled vWF to the platelets. Cytochalasin D did not inhibit this recovery, suggesting that this process may be due to passive actin depolymerization. These findings were further confirmed by immunoelectron microscopic study. Utilizing the platelets pre‐labelled with anti‐GP Jb antibody prior to plasmin stimulation, it was demonstrated that the observed recovery is due to a reverse translocation from the SCCS to the plasma membrane of the same GP Ib molecules which were present initially at the cell surface. It is concluded that plasmin‐induced GP Ib dysfunction can be reversed by plasmin neutralization and GP Ib reverse translocation plays an important role in the restoration of platelet interaction with vWF.
Ursodeoxycholic acid improves ethinyl estradiol–induced cholestasis in the rat
Authors: JACQUEMIN E. , DUMONT M. , MALLET A. , ERLINGER S.
Published: March 2008

Abstract. The effect of oral chronic administration of ursodeoxycholic acid has been examined in rats with cholestasis induced by ethinyl estradiol. Ursodeoxycholic acid at the dose of 25 mg kg‐1 per day during 4 days, did not improve the decrease in basal bile flow and bile acid secretion induced by ethinyl estradiol alone. In contrast, when ursodeoxycholic acid was given at the same dose during 10 days, basal bile flow was significantly improved and basal bile acid secretion was restored to control values. When ursodeoxycholic acid was given at the dose of 500 mg kg‐1 per day, basal bile flow and bile acid output were not further improved. However, bile flow and bile acid output under taurocholate infusion were restored to control values. Bile of rats treated with ursodeoxycholic acid was enriched with this bile acid. These results show a significant improvement of ethinyl estradiol‐induced cholestasis in rats after chronic administration of ursodeoxycholic acid and support the use of this bile acid in intrahepatic cholestasis in man.
Changes in Iipoprotein(a), LDL‐cholesterol and apolipoprotein B in homozygous familial hypercholesterolaemic patients treated with dextran sulfate LDL‐apheresis
Authors: LASUNCIÓN M. A. , TERUEL J. L. , ALVAREZ J. J. , CARRERO P. , ORTUÑO J. , GÓMEZ‐CORONADO D.
Published: March 2008

Abstract. We evaluated the effect of periodical treatment with LDL‐apheresis by adsorption to dextran sulfate (Liposorber LA‐15) on several aspects related to LDL and Lipoprotein(a) metabolisms, in three homozygous familial hypercholesterolaemic patients with LDL receptor deficiency. The dextran sulfate columns retained apolipoprotein B‐containing particles with high affinity and capacity, in such a way that the treatment of a volume of plasma equivalent to three times the patient plasma volume resulted in an 85% decrease of circulating LDL‐cholesterol and Lipoprotein(a). The continuous treatment with LDL‐apheresis was highly beneficial for these patients since an average plasma concentration lower than 200 mg dl‐′ for LDL‐cholesterol, and lower than 25 mg dl‐′ for Lipoprotein(a) could be achieved by treating the patients once a week. After each apheresis treatment, plasma concentrations of these metabolites progressively returned to the pretreatment, steady‐state, levels. The analysis of the rates of return allowed us to estimate the fractional catabolic rates. FCRs of LDL‐cholesterol were 0–052, 0.049 and 0.047 pools day‐1, and those of apolipoprotein B, 0.065, 0.045 and 0.050 pools day‐1 in the three subjects, respectively. These values are much lower than those in normolipidaemic individuals as observed by others, and are in accordance with the LDL‐receptor deficiency condition of our patients. Two of them had highly elevated Lipo‐protein(a) plasma concentrations, and their FCRs of Lipoprotein(a) were calculated to be 0.112 and 0.066 pools day‐1. These values were significantly higher than the respective FCR of LDL‐cholesterol and apolipoprotein B, which demonstrates that Lipopro‐tein(a) and LDL were not metabolically homogeneous in these patients. Values of ‐kt for Lipoprotein(a), LDL‐cholesterol and apolipoprotein B correlated during the first days inmediately after each apheresis session, suggesting that production of Lipoprotein(a) in these individuals was associated to that of apolipoprotein B. It is proposed that elevated Lipoprotein(a) plasma levels in familial hypercholesterolaemia are mainly a consequence of a high production rate rather than decreased fractional catabolic rate.
The effects of hydrocortisone on in vitro lymphocyte proliferation and interleukin‐2 and ‐4 production in corticosteroid sensitive and resistant subjects
Authors: CHIKANZA I. C. , PANAYI G. S.
Published: March 2008

Abstract. Corticosteroids (CS) are potent immunosup‐pressive and anti‐inflammatory agents which are frequently used to treat a number of conditions such as rheumatoid arthritis (RA), asthma, and renal allograft rejection. Patients taking corticosteroids can be divided into ‘steroid‐sensitive’ (SS) and ‘resistant’ (SR) groups on clinical and laboratory criteria. Corticosteroid ‘resistance’ has been extensively documented in asthma and renal allografting. The underlying mechanisms are unknown. Using the inhibition by hydro‐cortisone of concanavalin‐A induced lymphocyte proliferation in vitro, we have divided rheumatoid arthritis patients (RA) and normal controls (HC) into SS and SR groups. The SS and SR phenotypes were stable over several months in RA and HC subjects. Inhibition of Con‐A induced production of interleukin‐2 and ‐4 by corticosteroids in vitro correlated with the in vitro defined SS and SR phenotype. When highly purified T‐cells were stimulated via the CD3 and CD28 receptor pathways, corticosteroids did not inhibit cell proliferation in SS and ST subjects. It may be concluded that the SS and SR phenomenon is a stable intrinsic property of the individual which is dependent primarily on the inhibitory effects of corticosteroids on accessory cell function and only secondarily on T‐cell function. This is a novel observation for the inhibitory effects of corticosteroids on T‐lymphocytes.
Non‐insulin dependent diabetes mellitus: defects in insulin secretion
Authors: WOLFFENBUTTEL B. H. R. , HAEFTEN T. W. VAN
Published: March 2008

Abstract. NIDDM is a heterogeneous disorder, characterized by defects in insulin secretion as well as in insulin action. Several pathophysiological mechanisms are involved in the development of disturbances in insulin secretion. One of the histological features of islets of NIDDM patients is the deposition of amyloid‐like material. Accumulation of amyloid over many years can lead to slowly progressive disruption of islet architecture and possibly to some of the abnormalities in insulin secretion, as found in NIDDM patients. Loss of pulsatility is the earliest detectable abnormality of insulin secretion in the disease, either as a specific early defect or as a disturbance caused by minimally elevated blood glucose levels. Although it has been shown that maximum insulin release is decreased by 50% in NIDDM, the B‐cell sensitivity to glucose appears to be normal. Coregulatory factors such as prostaglandins do not play a major role in the derangements of insulin secretion in NIDDM. An imbalance between stimulatory and inhibitory endorphins, or in sympathetic tone may be of more importance. Hyperglycaemia by itself has a deleterious effect on insulin release, and may perpetuate the disturbances of insulin secretion.
Vasoactive peptides in Bartter's syndrome
Authors: STAHL M. M. S. , VAARA I. , HEDNER P. , EKMAN R.
Published: March 2008

Abstract. Patients with Bartter's syndrome exhibit an increased vascular resistance to the pressor effects of angiotensin II and noradrenaline. Further, an increased production of vasodilating renal prosta‐glandins, perhaps mediating the vascular unresponsi‐veness, has been hypothesized in this syndrome based on high urinary prostaglandins. To determine whether different peptides might contribute to blood pressure control in this syndrome, the basal immunoreactive plasma levels of an array of vasoactive peptides and catecholamines were analysed in six patients with Bartter's syndrome. Among the vasoconstrictors analyzed, the mean plasma levels of noradrenaline (NA), adrenaline (A) and neuropeptide Y‐like immunoreac‐tivity (NPY‐LI) were significantly increased as compared to healthy subjects (P= 0.030, 0.046 and 0.001, respectively). The plasma level of the vasodilator substance P (SP‐LI) was also higher in these patients (P = 0.057).

These results indicate that in Bartter's syndrome the vasoconstrictive effect of catecholamines and angiotensin II may be enhanced by concomitant NPY release. Whether a release of the vasodilator substance P is an independent mechanism or represents a reflex response to the increased secretion of angiotensin II, catecholamines and/or NPY remains to be established. However, the significance of these biochemical findings for blood pressure maintenance in Bartter's syndrome remains to be settled.
Fc‐Gamma receptor III shedding by polymorphonucIear cells in primary Sjögren's syndrome
Authors: LAMOUR A. , SOUBRANE C. , ICHEN M. , PENNEC Y. L. , KHAYAT D. , YOUINOU P.
Published: March 2008

Abstract. A sandwich enzyme‐linked immunosorbent assay was developed to assess Fc‐gamma receptor III (FcγRIII), based on a combination of two non‐competing monoclonal antibodies. This receptor was detectable in the serum of eight out of 23 patients with primary Sjögren's syndrome and two out of 23 normal controls. The proportion of FcγRIII‐carrying polymorphonuclear (PMN) cells was lower (P < 0.05) in the patients with cell‐free FcγRIII (90·4 ± 7.5%) than in the remainder (84.8 ± 8.3%). The PMN cell functions were evaluated and the diminished adherence (71.7, geometric mean) and chemotaxis (1.23) paralleled the FcγRIII release. The relative inefficiency of PMN cells in SS might be due to phagocytosis of immune complexes.
Increased human erythrocyte sodium‐Iithium countertransport in hyperlipidaemic patients may indicate increased membrane lipid fluidity
Authors: DOWD A. , THOMAS T.H. , WILKINSON R.
Published: March 2008

Abstract. Erythrocyte sodium‐lithium countertransport (SLC) activity, membrane fluidity, plasma trigly‐ceride and cholesterol were measured in hyperlipidaemic patients and normal subjects. Fluidity was assessed by the fluorescence anisotropy (inversely related to fluidity) of the probes 1,6‐diphenyl‐1,3,5‐hexatriene (DPH) and 1,4‐trimethylammonium‐3,5‐hexatriene (TMA‐DPH). In a second group of patients the maximum velocity (Vmax) and external sodium affinity constant (km) of SLC was also measured.

In the first group of patients, SLC activity was increased compared with the controls (0.279 ± 0.019 vs. 0.213 ± 0.013, P= 0.006) as was membrane fluidity in the deep hydrophobic regions (DPH anisotropy 0.211 ± 0.0007 vs. 0.215 ± 0.0011, P= 0.007). There was a strong correlation between SLC and DPH anisotropy (Rs= ‐0.72, P= < 0.001) which was due to the correlation between Vmax and DPH anisotropy (Rs=‐0.90, P= < 0.001).

Increases in Vmax of SLC in hyperlipidaemic patients may be due to differences in lipid organisation in the deep hydrophobic regions of the membrane which may affect the turnover rate of the transporter.
Very long chain n‐3 and n‐6 polyunsaturated fatty acids inhibit proliferation of human T‐lymphocytes in vitro
Authors: SØYLAND E. , NENSETER M. S. , BRAATHEN L. , DREVON C. A.
Published: March 2008

Abstract. The effect of marine n‐3 polyunsaturated fatty acids on proliferation of human T‐cells in vitro was compared to other polyunsaturated, monounsa‐turated and saturated fatty acids. Monoenes and saturated fatty acids had little effect on T‐cell proliferation. Eicosapentaenoic acid and docosahexaenoic acid exerted a strong dose‐dependent inhibitory effect on proliferation of mitogen‐ or antigen‐stimulated T‐cells, similar to that observed for arachidonic acid. Sixty μM of albumin‐bound eicosapentaenoic acid or arachidonic acid promoted 25–40% inhibition of proliferation of T‐cells stimulated with mitogen, whereas the same concentration of albumin‐bound docosahexaenoic acid promoted 60% inhibition. When epidermal cells (Langerhans cells) were used as antigen‐presenting cells, 100 μM of albumin‐bound eicosapentaenoic acid or arachidonic acid caused 40% inhibition on T‐cell proliferation. Low density lipo‐protein (LDL), isolated after four months of dietary intake of fish oil or corn oil, inhibited mitogen‐stimulated T‐cell proliferation in a dose‐dependent manner. Fish oil‐ and corn oil‐enriched LDL showed similar ability to inhibit T‐cell proliferation. Epidermal cells preincubated with docosahexaenoic acid, and extensively washed before adding purified T‐cells and antigen, resulted in a strong inhibition of T‐cell proliferation, whereas preincubation of purified T‐cells with docosahexaenoic acid did not cause any inhibitory effect. Cyclooxygenase and lipoxygenase inhibitors (indomethacin, acetylsalicyclic acid, nordi‐hydroguaertic acid) did not affect the antiproliferative effect of eicosapentaenoic acid and arachidonic acid, neither did the antioxidants butylated hydroxytoluene or alpha‐tocopherol. Eicosanoids, (PCE2, PGE3, LTB4, LTB5 and lipoxin A or lipoxin B) added directly to mitogen‐stimulated peripheral blood mononuclear cells (PBMC) did not influence T‐cell proliferation significantly. Decreased viability was observed when mitogen‐stimulated lymphocytes were cultured with essential polyunsaturated fatty acids, whereas the viability of unstimulated lymphocytes was hardly influenced by the same fatty acids. We conclude that; (a) pharmacological albumin‐bound concentrations of the highly unsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid promote a strong antiproliferative effect on mitogen‐ and antigen‐stimulated human T‐cells: (b) docosahexaenoic acid can suppress accessory cell function and consequently suppress T‐cell activation; (c) physiologic concentration of LDL particles rich in n‐3 and n‐6 fatty acids, both promote a dose‐dependent antiproliferative effect on mitogen‐stimulated PBMC; (d) the inhibition is independent of eicosanoid metabolites: and (e) lipid peroxidation seems unlikely to be responsible for the antiproliferative effect.
Decreased expression of the platelet‐derived growth factor β‐receptor in fibroblasts from a patient with Werner's syndrome
Authors: MORI S. , KAWANO M. , KANZAKI T. , MORISAKI N. , SAITO Y. , YOSHIDA S.
Published: March 2008

Abstract. The study of Werner's syndrome, a premature ageing syndrome, may provide insight into the processes of natural ageing. We investigated the reason for the reduced growth potential of fibroblasts in Werner's syndrome which is considered to be similar to that of fibroblasts in normal senescence. The responses to different isoforms of platelet‐derived growth factor (PDGF) of fibroblasts from a patient with Werner's syndrome (W‐cells) and from a normal subject (control cells) were assessed by [3H]thymidine incorporation assay, a 125I‐PDGF‐AB binding experiment, and Northern blot analysis with a PDGF β‐receptor specific cDNA probe. PDGF‐stimulated increase in [3H]thymidine incorporation in W‐cells was much lower than that in control cells, especially with PDGF‐AB and ‐BB as mitogens. The specific binding of 125I‐PDGF‐AB to W‐cells was correspondingly lower than that to control cells. Furthermore, Northern blot analysis demonstrated a decreased basal level, and lack of PDGF‐AB‐induced up‐regulation of the PDGF β‐receptor transcript in W‐cells. Decreased expression of the PDGF β‐receptor due to decrease in its synthesis may be a causative factor of the decreased mitogenic response of W‐cells to PDGF.
Cerebral trauma and alcohol abuse
Authors: RÖNTY H. , AHONEN A. , TOLONEN U. , HEIKKILÄ J. , NIEMELÄ O.
Published: March 2008

Abstract. We report results of clinical examinations, computed tomography, quantitative electroencepha‐lography (QEEG), and cerebral blood flow measurements performed on a series of 56 consecutive brain injury patients including 15 alcohol abusers and 41 non‐alcoholic subjects. Greater volumes of intra‐cranial haemorrhage were noted in the alcoholics for a similar severity of injury and local brain atrophy became more pronounced in them during a follow‐up of 1 year. After this time, the third ventricle width, distance between frontal horns, the sum of lateral ventricle dimensions and cortical sulci were all markedly larger in the alcoholics. The QEEG results also indicated a weaker improvement in the alcoholics. The cerebral blood flow at the site of the injury was initially slow in the alcoholics when compared to the contrala‐teral region of the other hemisphere, although these differences disappeared during the follow‐up. Permanent occupational disability was also found to be associated with pretraumatic alcohol abuse.

The findings indicate that ethanol abuse is not only commonly associated with cerebral trauma but is also a risk factor for a more severe brain damage following the injury.
Alternative splicing of human G6PD messenger RNA in K562 cells but not in cultured erythroblasts
Authors: CAPPELLINI M. D. , TAVAZZI D. , MONTEMUROS F. MARTINEZ DI , SAMPIETRO M. , GAVIRAGHI A. , CARANDINI D. , FIORELLI G.
Published: March 2008

Abstract. The biochemical properties of glucose‐6‐phosphate dehydrogenase (G6PD) vary in different tissues, and different protein isoforms of the enzyme have been described. Alternative splicing of G6PD intron VII has been detected in transformed lympho‐blasts, granulocytes and spermatocytes; the function of this mRNA species is still unknown. We developed a PCR for detecting alternatively spliced G6PD mRNA in K562 and in erythroblasts at different stage of maturation obtained from human peripheral BFU‐E in order to evaluate a possible physiological role during erythroid maturation. Trace events of alternative splicing of G6PD intron VII sequences were observed in K562 cells but not in BFU‐E‐derived erythroid precursors; we consider this phenoemenon a non‐functional activity in the cells analysed.
Effects of acute respiratory acidosis on water and electrolyte transport in the human ileum
Authors: EHERER A.J. , PETRITSCH W. , BERGER J. , HINTERLEITNER T. , CHARNEY A. N. , KREJS G.J.
Published: March 2008

Abstract. Animal experiments have shown that acute respiratory acidosis stimulates water, Na and C1 absorption and HCO3 secretion in the ileum. The aim of this study was to investigate whether the human ileum also responds to changes in systemic acid‐base balance. Seven healthy volunteers (mean age 24, range 21–29 years) underwent segmental ilea perfusion using a multi‐lumen tube assembly with a proximal occluding balloon. A 30 cm test segment was perfused under steady state conditions with a plasma‐like electrolyte solution containing PEG as a non‐absorb‐able volume marker. After a control period, respiratory acidosis (blood pCO2 56.2 mmHg, pH 7.29 and [HCO3] 26.4 mmol 1‐1) was induced by CO2‐breathing over a period of 50 min. Acute respiratory acidosis stimulated net HCO3 secretion in patients secreting HCO3 and reduced absorption in patients exhibiting net HCO3 absorption. These changes were immediate and appeared to be at least partly reversible. Net water, Na, K and CI movement were not affected. The data suggest that HCO3 transport in the human ileum responds to acute respiratory acidosis.
Immunologic and viral markers in the circulation of anti‐HIV negative heroin addicts
Authors: DALEKOS G. N. , MANOUSSAKIS M. N. , ZERVOU E. , TSIANOS E. V. , MOUTSOPOULOS H. M.
Published: March 2008

Abstract. To assess the degree of immune system activation associated with addiction or hepatotropic viruses infection, we examined 60 HIV‐negative heroin addicts for the presence of hepatitis B virus (HBV) infection markers, hepatitis C virus antibodies (anti‐HCV), various auto‐antibodies, and serum levels of soluble interleukin‐2 receptors (sIL‐2R). In addition, 28 anti‐HCV positive patients comprising the disease control group, were also examined. Our results demonstrated a high prevalence of anti‐HCV antibodies (61.7% and 90% with 1st and 2nd generation ELISA, respectively). Eighty‐seven percent (87Yi) of the addicts positive for anti‐HCV by the latter and 92.8% of the disease control patients, were also positive with 2nd generation recombinant immuno‐blot assay (RIBA‐II). In 88.9% of anti‐HCV positive addicts, antibody to C22–3 was the predominant (anti‐C33c in 81.5%). Antibodies to C33c and C22–3 polypeptides were also more frequent in disease control group (92.8% and 85.7%, respectively). Anti‐HCV antibodies were associated with increased transaminases (ALT or AST, P<0.05), as well as with longer duration of addiction (P<0.005). HBV infection markers (HBsAg, anti‐HBc only and anti‐HBs) were also present in the addicts (5%, 28.3% and 26.7%, respectively). Rheumatoid factors (RF) were detected in 36.7%, antinuclear antibodies (ANA) in 11.7%, antibodies (IgG and/or IgM) against cardiolipin (anti‐CL) and double stranded DNA (anti‐ds DNA) in 20% and 50%, respectively. RF, ANA, anti‐CL and anti‐dsDNA antibodies were also detected in the disease control group (32.10/, 89.3%, 28.5% and 28.5% respectively). Auto‐antibodies of at least one specificity, were found in 83.3% of addicts independently of anti‐HCV antibodies, HBV infection markers, increased ALT or AST levels, and the duration of addiction. They were, on the other hand, associated in addicts with antibodies to the C22–3 polypeptide of HCV (P = 0.0001) and with both of the predominant antibodies (anti‐C33c and anti‐C22–3) of the HCV (P<0.01 and P<0.05 respectively) in the disease control group. Thirty‐nine addicts (65%) and 50% of the disease control patients were found to have increased levels of sIL‐2R. In contrast to the disease control group, serum sIL‐2R levels of addicts were associated with RF (P<0.05), anti‐dsDNA (P< 0.0005) and total auto‐antibodies (P=0.0005), while there was a slight negative correlation with the duration of addiction (r= ‐0.26, P<0.05). However, sIL‐2R levels, were not associated with HBV and HCV infection markers in both groups. We conclude that intravenous heroin addiction appears to be associated with an increased prevalence of HCV and non‐organ specific auto‐antibodies. The latter may be driven by C22–3 and C33c polypeptides of HCV. Increased sIL‐2R levels attest to a cellular immune activation in addicts, which is slightly correlated with shorter duration of addiction, independently of HCV or HBV, but in association with auto‐antibodies production.
Lipoprotein lipase activity in muscle tissue influenced by fatness, fat distribution and insulin in obese females
Authors: RICHELSEN B. , PEDERSEN S. B. , MØLLER‐PEDERSEN T. , SCHMITZ O. , MØLLER N. , BØRGLUM J. D.
Published: March 2008

Abstract. Obesity is associated with dyslipidaemia and increased morbidity and mortality from premature atherosclerosis and diabetes mellitus. Particularly, hypertriglyceridaemia is a characteristic finding in patients with obesity. In addition, the elevated levels of triglycerides may be an important risk factor for development of the obesity‐related complications. Lipoprotein lipase activity in skeletal muscle tissue (mLPL) has previously been found to be an important factor regulating the concentration of serum triglycerides. To describe the relationship between mLPL, triglycerides and fatness/fat distribution in more detail we have investigated these parameters under basal conditions and during insulin stimulation in 20 obese females. During hyperinsulinaemia (204 μU ml‐1) for 4 h the mLPL activity decreased from 528 ± 52 nmol FFA g‐1 to 412 ± 44 (P< 0.001). Basal mLPL was negatively correlated with serum triglycerides (r= ‐0.48, P<0.05) and positively correlated with HDL‐cholesterol (r = 0–58, P<0.01). Employing multiple variance analysis it was found that both BMI and WHR were negatively correlated to mLPL, however, the impaired lipid profile (high triglyceride, low HDL‐cholesterol, high FFA) could only be related to BMI and not to WHR in these obese females. However, reduced insulin‐action (insulin resistance) was closely related to abdominal fatness determined by WHR both in relation to the insulin‐effect on mLPL as well as for the insulin‐effect on whole‐body glucose metabolism (clamp‐study). A tendency to a positive correlation was observed between the impaired insulin‐stimulated glucose disposal and the reduced insulin‐effect on mLPL (r = 0.41, P = 0.08) indicating that mLPL might be an indicator of muscle insulin sensitivity. In conclusion, reduced mLPL activity seems to play a role for the increased triglyceride levels associated with obesity and the mLPL activity seems to be negatively influenced by both total fatness and abdominal fatness. Finally, mLPL is an insulin sensitive enzyme where short‐term insulin infusion inhibits the enzyme activity.
Bile concentration promotes nucleation of cholesterol monohydrate crystals by increasing the cholesterol concentration in the vesicles
Authors: ERPECUM K. J. VAN , STOLK M. F. J. , BROEK A. M. W. C. VAN DEN , RENOOIJβ W. , HEIJNING B. J. M. VAN DE , HENEGOUWEN G. P. VAN BERGE
Published: March 2008

Abstract. Cholesterol in bile is solubilized in mixed micelles and cholesterol‐phospholipid vesicles. Biliary cholesterol supersaturation and increased concentration of bile in the gallbladder promotes nucleation of cholesterol monohydrate crystals and gallstone formation, possibly by creating unstable vesicles with a high cholesterol/phospholipid ratio. In the present study super‐saturated and unsaturated biles (cholesterol saturation index (CSI) 1.4 and 0.8 respectively) were prepared with concentrations typical of gallbladder and more dilute hepatic bile (total lipid concentration (TLCo) 10 and 2.5 g dl‐1 respectively). The distribution of cholesterol between vesicles and micelles, and vesicular cholesterol/phospholipid ratio were studied using ultracentrifugation and gel‐permeation chromatography. The nucleation time of cholesterol crystals was determined in whole model bile, and in the vesicular and micellar peak fractions. Increased CSI and bile dilution led to an increased proportion of cholesterol solubilized in vesicles. The concentration of bile did not influence vesicular cholesterol/phospholipid ratio. The vesicular cholesterol/ phospholipid ratio found in gel‐permeation chromatography experiments was similar at high and low CSI, whereas the ratio was significantly higher in supersaturated than in unsaturated biles in ultracentrifugation studies. Nucleation of cholesterol crystals from whole model bile was more rapid at the higher bile concentration and higher cholesterol saturation. Nucleation time in whole model bile correlated significantly with nucleation time in the corresponding vesicular peak fraction obtained by gel‐permeation chromatography (r = 0,58: P< 0.01) and with the cholesterol concentration in this vesicular peak (r= ‐0.77; P<0.002) but not with vesicular peak cholesterol/phospholipid ratio. Highest vesicular peak cholesterol concentrations and shortest nucleation times were found for concentrated supersaturated biles, whereas vesicular cholesterol/phospholipid ratio was not different from dilute or unsaturated biles. The present study indicates that increased concentration of bile promotes nucleation of cholesterol crystals by increasing the concentration of cholesterol in the vesicular peak rather than by changing its cholesterol/phospholipid ratio.
On the relationships between mineral metabolism, obesity and fat distribution
Authors: LIND L. , LITHELL H. , HVARFNER A. , POLLARE T. , LJUNGHALL S.
Published: March 2008

Abstract. Alterations in calcium metabolism have been associated with cardiovascular risk factors. An altered binding of calcium to plasma proteins and raised levels of parathyroid hormone (PTH) have been described in morbid obesity. In the present study, indices of mineral metabolism were related to obesity (body mass index, BMI) and fat distribution (waist to hip ratio, w/h) in 194 subjects with a wide range of BMI and w/h. The ratio of total serum calcium to plasma ionized calcium (Ca2+) was found to be significantly correlated to both BMI (r = 0.20, P<0.02) and w/h (r = 0.22, P<0.005). Serum phosphate was also correlated to both of the indices of obesity in an inverse way (r= ‐0.24, P< 0.0008 for BMI and r= ‐0.33, P< 0.0001 for wl h). These relationships were still significant when the influences of age, sex and serum creatinine were included in the multiple regression analysis. This kind of analysis also disclosed that w/h was superior to BMI as a determinant of serum phosphate and the total calcium/Ca2+ ratio in serum. PTH was not significantly correlated to any of the indices of obesity.

In conclusion, fat distribution rather than obesity per se was found to be associated with an altered mineral metabolism.