bluuebunny/crossref_metadata_2025 huggingface dataset:
Nephrotoxicity of cyclosporin A in humans: effects on glomerular filtration and tubular reabsorption rates
Authors: DIEPERINK H. , LEYSSAC P. P. , KEMP E. , STARKLINT H. , FRANDSEN N. E. , TVEDE N. , MØLLER J. , FREDERIKSEN P. BUCHLER , ROSSING N.
Published: March 2008

Abstract. The contention that cyclosporin A (CyA) nephrotoxicity may be due to renal afferent arteriolar constriction was inferred from rat studies showing CyA to increase renal vascular resistance, to reduce glomerular filtration rate (GFR) and delivery of tubular fluid from the end of the proximal tubule to the loop of Henle (Vprox), and to increase proximal fractional reabsorption. In order to test whether the mechanism of human CyA nephrotoxicity is similar to its rat analogue, and whether CyA treatment causes prolonged renal malfunction after drug withdrawal, renal function was investigated with clearance techniques including lithium clearance (CLi) as a measure of Vprox. The subjects were patients (n= 11) with previously normal renal function, given CyA in the treatment of ocular manifestation of extrarenal disease, or bone‐marrow transplant recipients. Nine out of these eleven patients were investigated before and during CyA treatment: GFR (P<0·05) and Vprox (P<0·005) decreased while proximal fractional reabsorption increased (P<0·01). In six patients investigated before CyA was given, and re‐examined a mean of 273 days (range 84–384 days) after CyA withdrawal, CLi was reduced (P<0·05) while mean GFR was not significantly lowered (0·5>P > 0·2). In one of these six patients GFR was reduced to a subnormal value of 26 ml min‐1 (1·73m2 body surface)‐1. In conclusion, human and rat CyA nephrotoxicity have the same pattern of renal functional deterioration. Cyclosporin A nephrotoxicity was evident in patients investigated a mean of 9 months after CyA withdrawal.
Regional variation in high‐density lipoprotein binding to human adipocyte plasma membranes of massively obese subjects
Authors: SALTER A. M. , FONGx BESSIE S. , JIMENEZ J. , ROTSTEIN LORNE , ANGEL A.
Published: March 2008

Abstract. Obesity is associated with significant changes in cholesterol and lipoprotein metabolism. High density lipoprotein (HDL) cholesterol is often reduced and adipose tissue cholesterol stores are increased in obese individuals. This prompted a study on the binding of HLD fractions (HDL2 and HDL3) to adipocyte plasma membranes obtained from massively obese subjects (BMI > 37 kg m‐2) undergoing gastroplasty. Regional variation in HDL binding to these adipocyte plasma membranes was demonstrated. Membranes derived from the abdominal subcutaneous depot exhibited similar binding affinity (Kd) but higher binding capacity (Bmax) for HDL2 and HDL3 than that from the omental depot. There was significant inter‐individual variation in Bmax but the amount of HDL2 or HDL3 bound to the two depots of the same individual was positively correlated (HDL2, r= 0·66, P < 0·05; HDL3, r= 0·88, P < 0·01). While HDL2 binding showed a higher affinity (lower Kd) than HDL3, a significant positive correlation existed between HDL2 and HDL3 binding to the same adipocyte membranes (r= 0·89, P < 0·01). A significant inverse correlation (P < 0·05) was also observed between HDL2 and HDL3 binding to adipocyte membranes and plasma HDL‐cholesterol concentration. These results suggest that adipose tissue is an important site of HDL metabolism and the subcutaneous fat depot may play a proportionally more significant role due to its higher HDL binding capacity. It is further suggested that increased HDL binding and metabolism by the expanded adipose tissue mass may contribute to reduced plasma HDL‐cholesterol levels frequently associated with obesity.
Effects of vitamin E therapy on ethanol‐induced changes in platelet aggregation, thromboxane formation, factor VIII levels and serum lipids
Authors: HILLBOM M. , MUURONEN A. , NEIMAN J. , BJÖRK G. , EGBERG N. , KANGASAHO M.
Published: March 2008

Abstract. A transient increase in platelet thromboxane formation has been observed in non‐alcoholics during acute ethanol intoxication and in alcoholics shortly after ethanol withdrawal. Whether these effects are related to the generation of free radicals and lipid peroxidation was investigated by using vitamin E as a free radical scavenger and inhibitor of lipid peroxide formation. The results demonstrate that a high dose of vitamin E (1800 IU) taken daily by non‐alcoholic men slightly (P < 0·05) decreases aggregation‐associated platelet thromboxane formation during ethanol oxidation. Likewise, vitamin E prevents the ethanol‐induced increase (P < 0·01) in factor VIII coagulant activity. These observations suggest that the enhancement of platelet thromboxane formation and factor VIII coagulant activity by acute ethanol ingestion may be related to stimulated lipid peroxidation. By contrast, similar effects of vitamin E were not found in alcoholics shortly after ethanol withdrawal suggesting other mechanisms for their platelet hyperreactivity.
Haematological and hormonal responses to dynamic exercise in patients with chronic airway obstruction
Authors: GIMENEZ M. , MOHAN‐KUMAR T. , HUMBERT J.‐C. , TALANCE NICOLE DE , TEBOUL M. , PONZy J. L. , POLU J. M.
Published: March 2008

Abstract. The influence of exercise on hormonal and total white blood cells (WBC), lymphopcytes (L). Granulocytes (GR), and platelet (P) count responses was studied in: twenty‐five patients with chronic airway obstruction (CAO, 47 pL 1·8 years, ±x pL SEM) and thirteen normal subjects (N, 36 pL 2·6 years). They performed a submaximal (40 W) and a maximal exercise (±VO2max). Arterial blood samples were taken at rest, 40 W, and ±VO2max. [H+], PaCO2, PaO2 haematocrit (Hct), [Hb], P, total platelet volume (TPV), WBC, GR, L, and total red blood cells (RBC) were measured. At rest, WBC, GR, P and TPV were higher in CAO patients, whilst PaO2 and cortisol were lower. At 40 W, when compared to values obtained at rest, WBC, GR, L, P and TPV were increased in both groups; WBC, GR, P and TPV were higher in CAO patients. ±VO2max of CAO patients represented 54% of that of controls. At ±VO2max, Hct, [Hb] and RBC were approximately 10% higher than at rest in both groups, whilst changes were more significant in normals for WBC (CAO = 55%, N = 76%), lymphocytes (CAO = 83%, N = 105%), GR, (CAO = 37%; N = 51%), platelets (CAO = 23%, N = 29%), TPV (CAO = 25·4%, N = 35%), [H+] (CAO = 43%, N = 38%) and ACTH (CAO = 82%, N = 139%). PaO2 and cortisol did not differ between groups. PaCO2 and platelets however, were higher in the CAO group. Ambient temperature, age and degree of bronchial obstruction at rest, as well as haemoconcentration, PaO2, acidosis and cortisol during exercise do not seem to be responsible for the higher WBC and platelet values observed in patients.
Collagen metabolism in normal and complicated pregnancy: changes in the aminoterminal propeptide of type III procollagen in serum
Authors: RISTELI LEILA , PUISTOLA ULLA , HOHTARI HANNELE , KAUPPILA ANTTI , RISTELI JUHA
Published: March 2008

Abstract. The turnover of type III collagen, a major constituent of the myometrium and the uterine cervix, during pregnancy was evaluated by monitoring serum antigens related to the aminoterminal propeptide of type III procollagen. Their concentration increased markedly towards term in most uncomplicated pregnancies, while their size distribution throughout the pregnancy resembled that seen in the sera of normal healthy persons. In some patients, however, the level remained low, indicating interindividual variation in the release into serum and metabolism of the propeptide. There were no distinct changes during or immediately after vaginal delivery. Values exceeding the reference range for uncomplicated pregnancies were found during weeks 28–37 in patients with pre‐eclampsia, essential hypertension, intrahepatic cholestasis of pregnancy or twin pregnancy. Thus, pregnancy should be taken into account when evaluating results of the serum assay for the aminopropeptide and the use of this assay as an indicator of pregnancy complications warrants further study.
Increased DNA synthesis in adipocytes and capillary endothelium in rat adipose tissue during overfeeding
Authors: SYPNIEWSKA GRAZYNA , BJÖRNTORP P.
Published: March 2008

Abstract. Adult male rats were subjected to overfeeding with a high‐fat, high‐sugar diet for 3 and 7 days resulting in a moderate expansion of adipose tissue depots by an increase in fat‐cell size. Seventeen hours and 7 days after injection of a pulse of labelled thymidine, specific activity of DNA was examined in different cellular fractions obtained from the epididymal and perirenal adipose tissues after collagenase liberation and separation procedures. A slow increase of formation of new adipocytes occured after 3 and 7 days of overfeeding, most pronounced in cells from perirenal adipose tissue. Capillary endothelium and cells in the stromal fraction showed a rapid synthesis and turn‐over. Overfeeding induced an increased formation of new capillary endothelial cells after 7 days of overfeeding, again most pronounced in perirenal cells. It was concluded that new fat cells are formed at a slow rate early during overfeeding. Capillary endothelium in adipose tissue has a high rate of turnover, and its synthesis is increased further by overfeeding. New adipocytes precede, and possibly stimulate, the formation of new capillaries. Formation of new cells in the remaining stromal‐vascular cells is probably occurring at different rates among different types of cells.
Insulin deficiency and insulin resistance in Type 2 (non‐insulin‐dependent) diabetes: quantitative contributions of pancreatic and peripheral responses to glucose homeostasis
Authors: NESHER R. , CASA L. DELLA , LITVIN Y. , SINAI J. , RIO G. DEL , PEVSNER BELLA , WAX Y. , CERASI E.
Published: March 2008

Abstract. A non‐steady state dose‐response study was designed to quantitate peripheral sensitivity to insulin and pancreatic responsiveness to glucose, and to assess their relative contribution to glucose intolerance in Type 2 diabetes (Type 2 DM, non‐insulin‐dependent). Eleven lean and eleven obese patients with mild diabetes (fasting plasma glucose, FPG, 10·3 pL 1·0 and 9·4 pL 0·6 mmol l‐1, respectively) were examined; twenty‐six lean and twelve weight‐matched obese subjects served as controls. Pancreatic response was measured by sequential injection of 0·1, 0·3 and 0·9 g kg‐1 glucose; peripheral sensitivity to insulin was determined from the rate of clearance (Kgluc) of 0·3 g glucose injected sequentially together with 25, 50 and 100 mU insulin kg‐1 or with 0, 12·5 and 50 mU kg‐1, under somatostatin infusion. The mean dose‐response curve describing glucose‐induced insulin release showed increased maximal capacity to secrete insulin in obese controls, while the responses of lean as well as obese Type 2 DM were reduced by more than 80%. The mean dose‐response curves relating plasma exogenous insulin levels to Kgluc were similar in lean diabetics and lean controls. The curves of both obese controls and obese diabetics were shifted to the right, demonstrating similar insulin resistance. In four lean controls, sensitivity to insulin was tested also during a hyperglycemic clamp set at 10·3 pL 0·6 mmol l‐1. Hyperglycemia reduced the Kgluc at all insulin levels. Individual dose‐response curves were transformed to single weighted numerical pancreatic responsiveness scores [PRS], and peripheral sensitivity scores [PSS]. Pancreatic responsiveness scores were significantly higher in controls than in diabetics (nine‐fold differences in both the obese and lean groups). Pancreatic responsiveness scores distinguished well between diabetics and non‐diabetics (84% of the cases), while PSS did not. When the odds for disease of a subject with a given PRS and PSS was estimated by multiple logistic analysis, only PRS determined significantly the differentiation of Type 2 DM from controls: 90% of diabetics could be correctly classified with this method. We conclude that decreased responsiveness of the beta cell to glucose is predominantly responsible for the abnormal glucose metabolism in Type 2 DM. Insulin resistance is unlikely to be the primary factor leading to glucose intolerance, since normal beta cells can cope with insulin resistance by increasing adequately the hormone production.
Effect of 16, 16‐dimethyl prostaglandin E2 on small intestinal mucosa in suckling rats
Authors: KOELZ H. R. , LENTZE M. J. , MÜLLER O. M. , HALTER F.
Published: March 2008

Abstract. Suckling rats were treated every 8 h by intragastric instillation of 16, 16‐dimethyl prostaglandin E2 (PG) in a dose of 25 μg kg‐1 (PG25), or 100 μg kg‐1 (PG1OO), or saline from postnatal day 7–11. PG increased small intestinal villus length and crypt depth, most markedly in the duodenum, leading to a mucosal height of 543 ± 24 μm after saline, 670 ± 26 μm after PG25 and 823 ± 40 μm after PG100. In the proximal small bowel, PG1OO raised the mean activities of sucrase by 439%, maltase by 98%, trehalase by 584%, lactase by 58% and alkaline phosphatase by 76%. In the distal small intestine, only sucrase and trehalase activities were stimulated whereas other enzymes were depressed. PG25 caused similar but less pronounced changes of enzyme activities. Eight hours after both the last PG25 and the last PG1OO dose, plasma gastrin and corticosterone levels were decreased while thyroxine remained unchanged. The effect of a single dose of 100 μg kg‐1 PG or saline was also tested on 5‐ and 11‐day‐old rats; they were killed 16 h after PG administration. An increase in villus length occurred along the entire small intestine of rats treated on day 5, and also in the ileum of rats treated on day 11. In the proximal intestine, maltase and trehalase were stimulated after early and late treatment and, in addition, sucrase and lactase after late treatment. Serum corticosterone levels were found to be significantly higher 2–6 h after PG1OO than in the controls and then decreased gradually. We conclude that administration of PG to suckling rats induces maturation of the small intestine and could, in part, be attributed to corticosterone release.
Comparison of serum cardiac specific troponin‐I with creatine kinase, creatine kinase‐MB isoenzyme, tropomyosin, myoglobin and C‐reactive protein release in marathon runners: cardiac or skeletal muscle trauma?
Authors: CUMMINS P. , YOUNG A. , AUCKLAND M. L. , MICHIE C. A. , STONE P. C. W. , SHEPSTONE B. J.
Published: March 2008

Abstract. Problems arise in distinguishing skeletal from cardiac muscle trauma on the basis of serum enzyme tests following severe muscle exercise. The contributions of cardiac and skeletal sources have been assessed in eleven marathon runners by measuring pre‐and post‐race serum levels of cardiac‐specific myofibrillar troponin‐I together with total creatine kinase, creatine kinase‐MB isoenzyme, myoglobin, myofibrillar tropomyosin and C‐reactive protein. Total creatine kinase, creatine kinase‐MB isoenzyme, tropomyosin and myoglobin were significantly elevated above prerace levels in all runners between 1 h and 128 h post‐race. Neither mean cardiac troponin‐I nor C‐reactive protein was elevated post‐race. Nine out of sixty‐three samples fulfilled conventional positive criteria for cardiac muscle damage on the basis of combined creatine kinase and creatine kinase‐MB isoenzyme levels. Six runners had one or more positive samples. No samples had levels above twice the upper normal limit for either cardiac troponin‐I or C‐reactive protein. Correlation analysis of levels in each sample indicated skeletal and not cardiac muscle as the source of raised serum protein.
Formation of prostaglandins and leukotrienes by human lung tissue in vitro after activation by the calcium ionophore A23187
Authors: ZIJLSTRA F. J. , NAAKTGEBOREN M. , MONS H. , VINCENT J. E.
Published: March 2008

Abstract. The formation of metabolites of arachidonic acid by the cyclo‐oxygenase and lipoxygenase pathways were determined in human lung tissue, obtained from surgery. In this measurement the chopped tissue was incubated with the calcium ionophore A23187. Formation of metabolites from [1‐14C] arachidonic acid was also determined. The metabolites were extracted, separated by HPLC and identified by measurement of the absorption spectrum at 280 nm, radioactivity, biological activity and by radioimmunoassay.

6‐keto‐prostaglandin F1α (6‐ketoPGF1α), the metabolite of prostacyclin, is the cyclo‐oxygenase product present in the highest amount (400±49 ng g‐1), followed by PGD2 (162±59 ng g‐1) thromboxane B2 (102 ± 32 ng g‐1) PGE2 (104 ± 46 ng g‐1) and PGF2α (58 ± 26 ng g‐1). The amounts of the lipoxygenase products are: leukotriene B4 (LTB4), 163 ± 100 ng g‐1; LTC4, 63±31 ng g‐1 and LTE4 121±34 ng g‐1. From [1‐14C] arachidonic acid higher amounts of the cyclooxygenase than of the lipoxygenase products were formed, with the exception of PGE2.

The effects of several of these substances on the contraction of human small airway smooth muscle were measured. The contractions, induced by equivalent amounts of LTC4 and a synthetic analogue of thromboxane T x A2 were approximately one hundred times those induced by PGD2, PGF2α and histamine.

These results suggest that thromboxane A2 and LTC4 are the most important arachidonic acid metabolites that induce bronchoconstriction in the human lung.
Identification and characterization of α1‐ and β2‐adrenergic receptors in human liver
Authors: BEVILACQUA M. , VAGO T. , NORBIATO G. , CHEBAT E. , BALDI G. , MERONI R. , REGALIA E.
Published: March 2008

Abstract. Adrenergic receptors were identified in healthy human hepatic tissue from thirty‐nine subjects undergoing elective abdominal surgery by using the specific α1‐antagonist [3H]‐prazosin and the beta adrenergic antagonist [3H]‐dihydroalprenolol ([3H]‐DHA). [3H]‐prazosin binding to plasma membranes was rapid, of high affinity, saturable and stereospecific with a maximal binding capacity (Bmax) of 74·1±5·5 fmol mg‐1 of protein. The displacement curve for (–)‐norepinephrine was better explained by a one‐site binding and after addition of GTP 0·1 mM the curve was not right‐shifted, suggesting the majority of alpha receptors in healthy human liver are of the α1 subtype and not linked to a GTP‐binding protein. 3H‐DHA binding to liver plasma membranes was also rapid, of high affinity, saturable and stereospecific with a Bmax 96·5±10·3 fmol mg‐1 of protein of receptors. Computer aided analysis of the displacement curve of ICI 118,551, a subtype selective β2‐antagonist (IC50=62±2 nM), indicated a one‐site binding, thus, showing that beta adrenergic receptors are of the β2 subtype. The displacement curve of 3H‐DHA for (–)‐isoproterenol was right shifted by GTP indicating that beta 2 adrenergic receptors are linked to a GTP‐binding protein in human liver. These results indicate that α1‐ and β2‐receptors co‐exist in human liver but only β2‐receptors are linked to a GTP‐binding protein.
Abnormal Na+‐K+ ATPase kinetics in a subset of essential hypertensive patients
Authors: SIERRA A. DE LA , COCA A. , AGUILERA M. T. , URBANO A.
Published: March 2008

Abstract We have performed a kinetic analysis of the interaction of Na+‐K+ ATPase with internal Na+ in erythrocytes of 30 normotensive controls and 72 essential hypertensive patients. Neither the maximal rate of ouabain‐sensitive sodium efflux (Vmax) nor the internal Na+ content required for half‐maximal stimulation (K50%) were significantly different between normotensive and hypertensive patients. Nevertheless, using the 95% confidence limits of the K50% in the normotensive group as a cut‐off point, 13 (18·06%) essential hypertensive patients exhibited increased values of this parameter (29·16 ± 4·31 mmol l‐1 cells) revealing decreased affinity of Na+‐K+ ATPase for internal Na+ (Pump‐hypertensives). The Vmax was also higher in the Pump‘—’ subset (14·08 ± 4·85 mmol (1 cells h)‐1 vs. 6·92 ± 1·80; P = 0·0002) and 10 of these 13 hypertensives exhibited a Vmax above the upper end limit of 10·5 mmol (1 cells h)‐1, suggesting a compensatory effect. No differences were observed between the Pump ‘—’ subset and the remaining 59 hypertensives without Na+‐K+ pump abnormality when basal erythrocyte Na+ content and clinical parameters of hypertension were examined. Decreased apparent affinity of Na+‐K+ pump for internal Na+ present in 9–27% of essential hypertensives may be implicated in pathogenetic mechanisms of hypertension.
Alpha‐ and gamma‐interferon (IFNα, IFNγ) but not interleukin‐1 (IL‐1) modulate synthesis and secretion of β2‐microglobulin by hepatocytes
Authors: RAMADORI G. , MITSCH A. , RIEDER H. , BÜSCHENFELDE K.‐H. MEYER ZUM
Published: March 2008

Abstract Soluble serum β‐microglobulin has been thought to result from membrane shedding by activated T‐lymphocytes. This hypothesis could explain the increase of β2‐microglobulin serum levels during virally induced mononucleosis, but not elevated levels as observed in other virally induced and in malignant diseases. In this paper we demonstrate that β2‐microglobulin is a true secretory protein, and that its synthesis in hepatocytes is modulated by IFNs but not by IL‐1. While the 45000 MW HLA antigen can be found only in cell lysates, β2‐microglobulin is shown to be secreted also into the culture medium like other secretory proteins (e.g. albumin‐factor B‐complement C3). Furthermore, interferon alpha (IFNα) as well as interferon gamma (IFNγ) directly stimulate, in a dose‐and time‐dependent manner, β2‐microglobulin synthesis by human hepatoma cells (Mz‐Hep‐1 and PLC/PRF5) and murine hepatocyte primary cultures. The increase of β2‐microglobulin production induced by interferons is demonstrated at both the protein and the RNA level, indicating that interferon acts at a pretranslational level. The interferon effect on β2‐microglobulin synthesis is specific since synthesis of secretory proteins like complement C3 or albumin, and of a structural protein like actin, remains unchanged. In contrast to IFN, IL‐1, the main mediator of acute phase response, does not change β2‐M biosynthesis rate. These data indicate that (i) β2‐microglobulin is a secretory protein, (ii) IFNs but not IL‐1 can mediate increased β2‐M serum levels, and (iii) the liver may be its primary source.
Increased sensitivity to pressor hormones in central diabetes insipidus
Authors: WILLIAMS T. D. M. , LAYCOCK J. F. , LIGHTMAN S. L. , GUY R. L.
Published: March 2008

Abstract Pressor sensitivities to infusions of arginine vasopressin (AVP), noradrenaline (NA) and angiotensin II (AII), as well as cardiovascular responses to head‐up tilt, were assessed in subjects with central diabetes insipidus (CDI) and compared with those in normal control subjects. During incremental i.v. infusions of AVP at 0·2–5·0 pmol min‐1kg‐1, mean arterial blood pressure (MABP) rose progressively in CDI subjects only and the rise was significantly greater than that which occurred in control subjects during their final infusion. The pressor effects of incremental i.v. infusions of NA and AII were greater, and the bradycardia associated with NA was more pronounced, in CDI subjects than in controls. Whole body tilt from supine to 45° head‐up was associated with increased heart rate and an insignificant rise in MABP in both groups, although a rise in plasma AVP occurred in control subjects only. These results demonstrate that subjects with CDI are more sensitive than control subjects to the pressor effects of NA and AII, and also develop sensitivity to the pressor effects of AVP. Their cardiovascular responses to head‐up tilt remain intact. Presumably the increased vascular sensitivity to NA and AII in subjects with CDI is sufficient to compensate for their lack of AVP response during head‐up tilt.
Role of atrial natriuretic factor, cyclic GMP and the renin–aldosterone system in acute volume regulation of healthy human subjects
Authors: GERBES A. L. , ARENDT R. M. , GERZER R. , SCHNIZER W. , JÜNGST D. , PAUMGARTNER G. , WERNZE H.
Published: March 2008

Abstract The role of the atrial natriuretic factor (ANF), its second messenger cyclic guanosine monophosphate (cGMP), and the counteracting reninaldosterone system in acute volume regulation was investigated in 25 healthy human subjects. Central volume stimulation by 1‐h head‐out water immersion (WI) into a thermoneutral water‐bath increased plasma levels of ANF (mean ± SEM) from 6·0 ± 0·6 to 13·6 ± 2·6 fmol ml‐1. This was paralleled by a rise of plasma cGMP levels from 1·9 ± 0·2 to 2·8 ± 0·4 pmol ml‐1, and an increase of urinary cGMP excretion from 340 ± 64 to 692 ± 103 pmol min‐1. Water immersion reduced plasma aldosterone concentration (PAC) from 13·0 ± 1·7 to 6·5 ± 0·8 ng 100 ml‐1and plasma renin activity (PRA) from 5·3 ± 0·9 to 2·4 ± 0·3 ng AI ml‐1h‐1. Volume stimulation markedly increased diuresis and natriuresis. Whereas the plasma cGMP increase correlated with plasma ANF stimulation, neither ANF nor PRA or PAC correlated with basal or stimulated renal parameters. Water immersioninduced changes in natriuresis and urinary cGMP excretion were correlated. These data suggest a role of ANF and cGMP in acute volume regulation of healthy human subjects.
Characterization of a heparin‐like activity released in dogs during deep hypothermia
Authors: CORNILLON B. , MAZZORANA M. , DUREAU G. , BELLEVILLE J.
Published: March 2008

Abstract In a previous paper, we demonstrated that deep hypothermia in dogs provokes a release of a heparin‐like factor. In the present study, we investigated some properties of this anticoagulant activity and compared it with exogenous heparin activity. The endogenous anticoagulant inhibited factors IIa and Xa; it was hydrolysed by heparinase and was AT III dependent. However, it differed from heparin in so far as it was adsorbed on cation exchange gel at neutral pH, its inhibition was decreased in the presence of neuraminidase, and it could not be neutralized with Polybrene or protamine. A release of heparan sulphate is suggested but remains to be demonstrated.
Decreased insulin sensitivity and muscle enzyme activity in elderly subjects
Authors: KRUSZYNSKA Y. T. , PETRANYI G. , ALBERTI K. G. M. M.
Published: March 2008

Abstract Skeletal muscle glycogen deposition, and the activation of muscle glycogen synthase and pyruvate dehydrogenase during a hyerinsulinaemic euglycaemic clamp have been measured in six young and six elderly males matched for body mass index, physical activity and diet. Clamp glucose requirement (insulin, 0·1 U kg‐1 h‐1) was significantly lower in the older subjects (8·0 ± 0·4 mg kg‐1 min‐1) than in younger subjects (10·5 ± 0·6 mg kg‐1 min‐1, P < 0·02). Although the older subjects had a 6·5% decrease in lean body mass, clamp glucose requirement expressed per unit of lean body mass was also significantly decreased in the older subjects (10·2 ± 0·5 vs. 12·4 ± 0·6 mg kg‐1 min‐1, P < 0·05). The increase in muscle glycogen with the clamp was decreased by 33% in the older subjects (elderly: 13·1 ± 1·3 mg g‐1 protein, young: 19·6 ± 2·2 mg g‐1 protein; P < 0·05), and was strongly correlated with clamp glucose requirement (r= 0·72, P < 0·01). Glucose‐6‐phosphate independent glycogen synthase activity increased significantly between fasting and the end of the clamps in both groups (P < 0·001), but was lower at the end of the clamp in the older subjects (P < 0·05). Glycogen synthase activity at the end of the clamp correlated with both clamp glucose requirement (r= 0·83, P < 0·01) and muscle glycogen deposition (r= 0·73, P < 0·01). Skeletal muscle pyruvate dehydrogenase activity increased significantly between fasting and end of clamp in the young subjects (P < 0·05) but not in the elderly males. Pyruvate dehydrogenase activity at the end of the clamp, however, did not differ between the two groups and was not related to clamp glucose requirement. Thus the impaired glucose handling of the elderly may be related to decreased insulin action on muscle and muscle enzymes.
Oxyntomodulin: a potential hormone from the distal gut. Pharmacokinetics and effects on gastric acid and insulin secretion in man
Authors: SCHJOLDAGER B. T. G. , BALDISSERA F. G. A. , MORTENSEN P. E. , HOLST J. J. , CHRISTIANSEN J.
Published: March 2008

Abstract Synthetic oxyntomodulin, a predicted product of the glucagon gene, which is produced in the human lower intestinal mucosa, was infused in doses of 100 and 400 ng kg‐1 h‐1 into six volunteers to study its pharmacokinetics and effects on pentagastrin‐stimulated gastric acid secretion (100 ng kg‐1 h‐1). The concentration of oxyntomodulin in plasma measured with a cross‐reacting glucagon assay increased from 37 ± 5 to 106 ± 17 and 301 ± 40 pmol l‐1, respectively. The metabolic clearance rate was 5·2 ± 0·7 ml kg‐1 min‐1 and the half‐life in plasma was 12 ± 1 min. Oxyntomodulin reduced the pentagastrin‐stimulated acid secretion by 20 ± 9% during the low‐rate infusion (P < 0·05) and by 76 ± 10% during the high‐rate infusion (P < 0·05). In accordance with the homology with glucagon, there was a small, significant rise in plasma concentrations of insulin and insulin C‐peptide during oxyntomodulin infusion. Oxyntomodulin may therefore be included among the potential incretins and enterogastrones in man.
The effect of ageing on human platelet sensitivity to serotonin
Authors: GLEERUP G. , WINTHER K.
Published: March 2008

Abstract Twelve healthy young volunteers (mean age 21, range 18–27 years) and 12 elderly people (mean age 77, range 72–86 years) were tested regarding platelet aggregation induced by adrenaline, ADP and serotonin. The serum levels of thromboxane B2 (TXB2) and serum 6‐keto‐PGF1α and the plasma level of adrenaline and cyclic AMP (cAMP) were also measured. Platelet aggregation induced by adrenaline and ADP increased significantly in the elderly compared with the young group (P < 0·05 and P < 0·02, respectively). There was a substantial and highly significant increase in the response of platelets from elderly people to serotonin (P < 0·01). No alteration was observed in the serum level of TXB2 or 6‐keto‐PGF1α. Plasma adrenaline increased in the old group, but plasma cAMP was unaffected. As serotonin is known to amplify adrenaline‐ and ADR‐induced platelet aggregation, the considerable increase in platelet sensitivity to serotonin could be an important factor in the increased adrenaline and ADP‐induced platelet aggregability of elderly people.
Asparaginase‐induced derangements of glutamine metabolism: the pathogenetic basis for some drug‐related side‐effects
Authors: OLLENSCHLÄGER G. , ROTH E. , LINKESCH W. , JANSEN S. , SIMMEL A. , MÖDDER B.
Published: March 2008

Abstract Several side‐effects of asparaginase therapy have been said to be a consequence of the glutaminase activity of Escherichia coli asparaginase, especially the deleterious influence on the liver function. We report here the drug‐induced impairments of asparagine and glutamine metabolism in correlation to concentrations changes of plasma proteins, synthesized in the liver, in patients with acute lymphatic leukaemia. One hour after asparaginase application, plasma glutamine decreased to 5% (0–39%: median, range) of the initial values, with a subsequent rise to concentrations slightly lower than those prior to therapy. During the 14 days of drug application the fasting plasma concentrations of glutamine fell to a median of 63% of the pre‐therapeutic levels, indicating a depletion of the glutamine pools. Two days after the end of asparaginase application, in one patient the glutamine concentrations increased to the pre‐therapeutic range. Plasma concentrations of fibrinogen and antithrombin III decreased to 46% and 56%, respectively, of the initial values, with a slight increase 2 days after the end of therapy. The changes of plasma protein concentrations followed the course of plasma glutamine and asparagine. From that we deduce that the hepatic synthesis of the plasma proteins might be influenced by asparagine and glutamine depletion as a consequence of the therapy with E. coli asparaginase.
Synthesis and secretion of α2‐macroglobulin by human hepatocytes in culture
Authors: PETERSEN C. MUNCK , CHRISTIANSEN B. S. , HEICKENDORFF L. , INGERSLEV J.
Published: March 2008

Abstract Hepatocytes were isolated by application of the two‐step collagenase perfusion technique to pieces of human liver. The cells were incubated in serum‐free medium or 10% FCS‐medium supplemented with insulin, glucagon and dexamethason, and kept in culture for more than 2 weeks. Seventy‐five per cent of the medium was changed regularly and assayed for α2‐macroglobulin (α2‐M), pregnancy zone protein, α1‐antitrypsin and albumin by means of ELISA. Significant amounts of α2‐macroglobulin were present in all cultures. During incubation, α2‐M accumulated in the medium and the quantity of α2‐M released from the cells by far exceeded protein associated with hepatocytes prior to incubation. In 24 h 106hepatocytes secreted 160·5 ± 82·2 ng of α2‐M (mean ± SD, n= 5). Cell‐associated, as well as secreted α2‐M appeared to be on native form, as determined by immunoisolates from lysed cells and culture supernatants. Pregnancy zone protein was only detected in about 50% of the cultures and its rate of secretion was less than 2 ng 24 h–1per 106cells. In contrast, culture medium contained considerable quantities of α1‐antitrypsin and albumin. In 24 h, 106hepatocytes released > 2 μg α1‐antitrypsin and > 5 μg albumin. The present study suggests the hepatocyte to be of major importance for the synthesis of intravascular α2‐M.
Prevalence of hypercalcaemia in a health survey: a 14‐year follow‐up study of serum calcium values
Authors: PALMÉR M. , JAKOBSSON S. , ÅKERSTRÖM G. , LJUNGHALL S.
Published: March 2008

Abstract. Among 16 401 subjects attending two health screenings, in 1969 and 1971, 176 showed hypercalcaemia on both occasions, i.e. serum calcium values above 2·60 mmol l‐1. The prevalence of hypercalcaemia increased in women with advancing age and occurred in close to 3% of those above the age of 60, whilst in men it was found in less than 0·7% in all age groups. The mean serum calcium concentration in women above the age of 50 was significantly higher than in men. This observation could at least partly explain why hyperparathyroidism (HPT) is more often diagnosed in females. Only nine persons were initially referred for neck exploration. Most of the others were not even notified of the biochemical disturbance and thus it was possible to study the serum calcium values in an unattended cohort until follow‐up after 14 years. In the hypercalcaemic patients there was little or no increase in serum calcium during these years. In no patient did the serum calcium level rise above 3·0 mmol l‐1. Altogether, 24 patients from the initial cohort were subsequently operated on for primary HPT but there were only two further cases of verified HPT, which developed during the follow‐up period, in those who had been clearly normocalcaemic at the health surveys. In conclusion, hypercalcaemia, presumably caused by primary HPT, is common but apparently develops slowly and with little risk of a progressive rise of serum calcium concentrations.
Red blood cell sodium and potassium fluxes in psoriatic patients
Authors: SEMPLICINI A. , MOZZATO M. G. , RIGON E. , PAROLIN O. , SAMÀ B. , PADOVAN S. , DEGAN P. , PESERICO A. , PESSINA A. C.
Published: March 2008

Abstract. Psoriasis might be a widespread membrane disorder. Therefore, the red blood cell sodium, potassium and lithium outward fluxes (through Na‐K‐ATPase, Na‐K‐Cl co‐transport, Li‐Na countertransport and passive permeability), as well as the Na and K content, were studied in 31 psoriatic patients and 23 normal controls. A significant increase in intracellular potassium content, in the maximal velocity of the Na‐K ATPase and of Na‐K‐Cl co‐transport as well as in the outward passive permeability for Na were found in the psoriatic patients compared with controls. On the contrary, no differences were observed in sodium content, Li‐Na countertransport and passive potassium permeability between the two groups. These results are compatible with a selective increase in inward, as well as outward, membrane permeability to sodium, which is compensated for by increased activity of the Na‐K pump, and of the outward Na‐K‐Cl co‐transport with a secondarily increased erythrocyte potassium content. They indicate that the red blood cell might be a useful model for the study of membrane transport in psoriatics.
Role of the adrenal cortex in the natriuresis associated with vasopressin infusion
Authors: DREW P. J. T. , MONSON J. P. , HOLLY J. M. P. , GOODWIN F. J. , WILLIAMS T. D. M.
Published: March 2008

Abstract. We have compared the effects of a 48‐h continuous infusion of arginine vasopressin (AVP) given to four subjects (one subject studied twice) with that given to four patients lacking adrenocortical function and maintained on fixed doses of mineralocorticoid and glucocorticoid replacement therapy. Both patients and normal subjects were subjected to dietary salt and water restriction during the period of the infusion, and all participants were in balance on a low sodium diet at the start of the infusion period. Infusion of vasopressin in normal subjects was associated with an increase in fractional excretion of sodium by the kidney, which continued during the day after the infusion was stopped. The infusion was also associated with a fall in plasma aldosterone as well as falls in whole blood packed cell volume, plasma renin activity and plasma noradrenaline. Infusion of vasopressin in patients lacking adrenocortical function was associated with a smaller increase in fractional excretion of sodium by the kidney in comparison with that seen in normal subjects, and the increase in sodium excretion was confined to the period of the infusion. Mineralocorticoid activity was maintained constant during the infusion, although a fall in whole blood packed cell volume, plasma renin activity and plasma noradrenaline were noted, in similarity to the study made in normal subjects. We conclude that changes in mineralocorticoid activity are the main factors contributing to the increase in renal sodium excretion seen during, and after, the continuous infusion of vasopressin in salt‐ and water‐restricted man.
Tamm Horsfall glycoprotein in diabetes mellitus: abnormal chemical composition and colloid stability
Authors: RAMBAUSEK M. , DULAWA J. , JANN K. , RITZ E.
Published: March 2008

Abstract. Tamm Horsfall glycoprotein (THP) was isolated, using sodium chloride precipitation technique, from 24‐h urine of 19 non‐proteinuric insulin‐dependent diabetics and 19 matched controls. Tamm Horsfall glycoprotein was pure, as judged by PAGE electrophoresis, by Ouchterlony double diffusion against anti‐THP or anti‐albumin antibodies, and by isoelectric focusing. Content of carbohydrates (gaschromatography), amino acids or amino sugars (AA‐analyser), N‐acetylneuraminic acid (thiobarbituric acid method) and lysyl‐bound glucose (furosine method) were determined and showed the following abnormalities: THP of diabetics had significantly higher glucose content (d: 2·55±0·66 g 100 g‐1 THP; CO: 0·99±0·23; P<0·05) and increased lysyl‐bound glucose, but diminished N‐acetyl‐neuraminic acid content (3·54±0·25 vs. 4·96±0·15; P<0·01) with no significant differences of amino acids or amino sugars. Low N‐acetyl‐neuraminic acid content was paralleled by reduced surface charge density of THP, as revealed by polyelectrolyte titration. No abnormality of the protein core was revealed by amino acid analysis and by probing reactivity to seven different monoclonal antibodies to human THP. Altered colloid stability, i.e. greater precipitation of THP of diabetic patients, was demonstrated by laser nephelometry. The data are consistent with abnormal post‐translational modification of THP in diabetes.
Measures of fat distribution as determinants of serum lipids in healthy volunteers consuming a uniform standardized diet
Authors: SEIDELL J. C. , MENSINK R. P. , KATAN MARTIJN B.
Published: March 2008

Abstract. The relation was investigated between body fat topology and serum lipoproteins in healthy, non‐obese men and women. Twenty‐four men and 24 women consumed a standardized affluent diet for 17 days. Serum was obtained after 14 and 17 days. Regression coefficients of lipids and lipoproteins with age, body mass index, measures of fat distribution, and estimates of fat areas at a cross‐section of the body at the level of the umbilicus, were calculated. Waist‐to‐thigh circumference ratio proved to be the strongest correlate of serum lipids compared with other measures of fat distribution. Upon multiple regression analysis, the waist‐to‐thigh ratio proved to be a stronger predictor of total cholesterol, LDL‐cholesterol and triglyceride levels in men than either age or body mass index. In women this was only true for HDL3‐cholesterol. In addition, no significant relations were observed any more of age and body mass index with these serum lipids, with the exception of age for IDL‐cholesterol in men. Estimates of intra‐abdominal fat area showed in general a stronger correlation with serum lipids than estimates of subcutaneous fat area. It is concluded that, in non‐obese subjects, fat distribution is a stronger determinant of serum lipids than either body mass index or age.
Platelet serotonin content and plasma tryptophan in peri‐ and postmenopausal women: variations with plasma oestrogen levels and depressive symptoms
Authors: GUICHENEY P. , LÉGER D. , BARRAT J. , TRÉVOUX R. , LIGNIÈRES B. DE , ROQUES P. , GARNIER J. P. , BOYER P. , GRENIER J. , DREUX C. , MEYER P.
Published: March 2008

Abstract. Platelet serotonin content was measured by high pressure liquid chromatography in 56 peri and postmenopausal women, in order to study variations of this parameter with hormonal status and depressive mood symptoms. Clinical symptoms were assessed by a self‐report depression symptom scale (CES‐D of NIMH). Thirty‐eight women with a score of 16 or more were considered as presenting depressive symptoms (mean score ± SD = 28·8 ± 10·5), while the others formed the control group (n= 18, score = 4·4 ± 4·2). Platelet serotonin contents were significantly lower in the ‘depressed’ group (0·302 ± 0·010 vs. 0·366 ± 0·020 nmol 10‐8 platelets, x̄+ SEM, P< 0·001 by Mann‐Whitney U‐test). In ‘depressed’ women who had been treated for one or more depressive episodes, platelet 5‐HT contents (0·283 ± 0·023, n= 18, P<0·01) were significantly lower with respect to controls. In patients without previous episodes of depression, serotonin expressed in nmol 10‐8 platelets did not differ significantly from controls but serotonin expressed in nmol ml‐1 of blood was slightly lower than control values (0·890 ± 0·085, n= 20 vs. 1·088 ± 0·090 nmol ml‐1, n= 18, P<0·02). Platelet serotonin content was positively correlated to plasma oestrone and oestradiol concentrations among the control group but not in the ‘depressed’ group. Luteinizing hormone and FSH determination in women with plasma oestradiol < 50 ng l‐1 showed lower LH values in ‘depressed’ than in ‘non‐depressed’ women (19·6 ± 2·2, n= 23 vs. 26·1 ± 1·9 mIU ml‐1, n= 9, x̄± SEM, P<0·01). Variations in platelet 5‐HT content did not appear to be secondary to alteration of plasma‐free and total tryptophan since no modifications of these parameters were detected either with depressive symptoms or with plasma oestrogen concentrations.
Arginine vasopressin dissociates the diuresis and natriuresis due to atrial natriuretic factor in man
Authors: McMURRAY J. , FORSLING MARY L. , STRUTHERS ALLAN D.
Published: March 2008

Abstract. The possible interaction between arginine vasopressin (AVP) and atrial natriuretic factor (ANF) in the control of urinary sodium and water excretion was investigated in man. Nine healthy male volunteers undergoing stable maximal water diuresis were studied on four separate occasions. Atrial natriuretic factor 15 pmol kg‐1 min‐1 or placebo (P) was concomitantly administered against a background infusion of either AVP 0·003 pmol kg‐1 min‐1 or P; thus the combinations P + P, AVP + P, P + ANF and AVP + ANF were studied. Atrial natriuretic factor caused a significant increase in sodium excretion (UNaV) [+ 56%], urinary flow rate (V) [+ 17%] and free water clearance (CH2O) [+ 23%]; creatinine clearance (Ccr) did not change. Arginine vasopressin reduced V (‐ 58%) and CH2O (‐ 68%) but did not alter UNaV or Ccr. On the AVP + ANF study day, UNaV increased (+ 64%) as with P + ANF, but V (‐ 44%) and CH2O (‐ 52%) continued to decrease below baseline levels; analysis of variance showed this antidiuresis reflected the prevalent effect of AVP rather than any specific interaction. These results show that AVP is able to dissociate the natriuretic and diuretic effects of ANF.
Natriuretic factors and lithium clearance in patients with the syndrome of inappropriate antidiuretic hormone (SIADH)
Authors: GROSS P. , LANG R. , KETTELER M. , HAUSMANN C. , RASCHER W. , RITZ E. , FAVRE H.
Published: March 2008

Abstract. Because the syndrome of inappropriate antidiuretic hormone (SIADH) is a state of disturbed body fluid volume regulation and altered sodium balance we sought to determine if recently described volume regulatory factors were stimulated in SIADH. We measured atrial natriuretic peptide (ANP), endogenous digitalis‐like natriuretic factor (EDNF) and urinary free dopamine in SIADH (n= 27). We also determined fractional clearance of lithium (FCLi). The data obtained in SIADH were compared with similar measurements performed in sodium retaining hyponatremias, such as those of heart failure (n= 26), liver cirrhosis (n= 19) and volume contraction (n= 28). We observed: ANP was 19.5 ± 2.7 μM/ml in SIADH; it was significantly lower than ANP in cardiac failure, but no different from ANP in volume contraction. Urinary free dopamine was 2.2 ± 0.8 μM/24 h in SIADH; this was significantly higher than in volume contraction and liver cirrhosis. EDNF (259 ± 42 nM/24 h) and FCLi (21.4 ± 2%) were both numerically higher in SIADH than in other hyponatremic disorders; however, the differences did not achieve significance. In conclusion, our observations did not establish a specific role of ANP in chronic stable SIADH. As to the importance of EDNF, dopamine and proximal tubular fluid reabsorption (FCLi) additional work using acute volume changes may demonstrate their participation in the renal sodium handling of SIADH more clearly than our study did.
Cerebrospinal fluid alpha‐1‐antitrypsin alpha‐1‐antitrypsin‐elastase complex levels in meningitis
Authors: HOFFMAN H. DU P. , DONALD P. R. , HANEKOM C. , BEER F. C. DE
Published: March 2008

Abstract. Alpha‐1‐antitrypsin (A‐1‐AT) and A‐1‐AT‐elastase complex levels in cerebrospinal fluid have been evaluated in 11 children with viral meningitis (VM), 14 with bacterial meningitis (BM), 10 with tuberculous meningitis (TBM) and 10 investigated for, but found not to have meningitis (NM). A‐1‐AT concentrations in the NM group were lower than in the BM group (P=0.0002) and the TBM group (P=0.0005) but did not differ from the concentrations in VM; those in the VM group were lower than in the BM group (P=0.0001) and the TBM group (P=0.003) but no difference was found between the BM and TBM groups. A‐1‐AT‐elastase complex concentrations in CSF were lower in the NM group than the BM group (P=0.0001) or the TBM group (P=0.0089), however those in the BM group were significantly higher than in the TBM group (P=0.0001). A significant correlation existed in CSF between the protein concentrations and neutrophil counts as well as the A‐1‐AT and A‐1‐AT‐elastase complex concentrations.