bluuebunny/crossref_metadata_2025 huggingface dataset:
Bufuralol metabolism in human liver: a sensitive probe for the debrisoquine‐type polymorphism of drug oxidation
Authors: MINDER ELISABETH I. , MEIER PETER J. , MÜLLER HEINZ K. , MINDER CHRISTOPH , MEYER URS A.
Published: March 2008

Abstract. The genetically controlled polymorphism causing decreased metabolism of debrisoquine is closely related to that of the metabolism of bufuralol and numerous other drugs and has important clinical consequences. A sensitive in vitro assay was developed which quantifies the production of 1′‐hydroxy‐bufuralol (carbinol) from bufuralol in human liver microsomes. Initial formation rates of carbinol suggested Michaelis‐Menten kinetics with an apparent KM of 61 and 171 μmol l‐1 and Vmax of 3·2 and 5·8 nmol mg‐1 microsomal protein h‐1 in two human liver samples. The Vmax in microsomes of thirty‐two liver samples was 4·2 ± 1·0 (SD) nmol carbinol mg‐1 protein h‐1. Metabolism of debrisoquine in vivo, as expressed by the ‘metabolic ratio’ of debrisoquine over 4‐OH debrisoquine correlated (r= ‐0·65, P < 0·01; n= 18) with carbinol production rate in microsomes in vitro. Microsomes of one individual identified as poor metabolizer of debrisoquine in vivo showed reduction of carbinol formation to 1·97 nmol mg‐ h‐1. Mixing his microsomes with those of an extensive metabolizer resulted in additive formation of carbinol excluding mediation of the defect by a soluble inhibitor.

These data support the concept of a primary defect in microsomal oxidation of bufuralol. The described assay offers a sensitive tool to investigate the molecular mechanism of the ‘debrisoquine polymorphism’.
Abnormal plasma lipoprotein composition in hypercholesterolaemic patients induces platelet activation
Authors: VIENER AVI , BROOK J. GERALD , AVIRAM MICHAEL
Published: March 2008

Abstract. Increased platelet activation has been shown to be a feature of patients with familial hypercholesterolaemia. Plasma lipoprotein concentration and composition were studied in eleven male patients with familial hypercholesterolaemia and in ten agematched healthy controls. Increased levels of cholesterol were found in very‐low‐ and low‐density lipoproteins (53 and 275%, respectively), whereas in high‐density lipoprotein, both cholesterol and apolipoprotein A‐I were decreased by 21 and 26%, respectively. On incubation of gel‐filtered platelets derived from normolipidaemic controls with identical concentrations of lipoproteins derived from either nomolipidaemic controls or hypercholesterolaemic patients very‐low‐ and low‐density lipoproteins from the patients caused significantly greater thrombin‐induced platelet aggregation (P < 0·01). High‐density lipoprotein from normal subjects reduced platelet release by 22%, whereas the patients' high‐density lipoprotein had no significant effect on platelet release. Lipoprotein‐deficient plasma from both groups augmented platelet function to a similar extent. Lipoprotein composition has an important effect on platelet function in vitro. The abnormal lipid and protein composition of the lipoproteins derived from hypercholesterolaemic patients appears to be the cause of platelet hyperactivity observed in these patients.
An erythrocyte transketolase isoenzyme pattern associated with the Wernicke‐Korsakoff syndrome
Authors: NIXON PETER F. , KACZMAREK M. JAN , TATE JILL , KERR RAY A. , PRICE JOHN
Published: March 2008

Abstract. Two techniques were used to seek variants of human erythrocyte transketolase and to test for any association of the Wernicke‐Korsakoff syndrome, a thiamin‐deficiency disease, with a particular variant of this thiamin‐dependent enzyme. Apparent Km values for the cofactor thiamin diphosphate were similar for patients and controls. However, isoelectric focussing separated erythrocyte transketolase into different isoenzymes characterized by pI values in the range 6·6–9·2. Six distinct patterns of isoenzymes were found in thirty‐six healthy control subjects. The isoenzyme pattern for thirty‐nine out of forty‐two patients suffering from the Wernicke‐Korsakoff syndrome was identical to a pattern found in only eight of thirty‐six control subjects, a highly significant association (P < 0·001). This association suggests that a variant transketolase and thiamin deficiency together contribute to the pathogenesis of the brain damage of the Wernicke‐Korsakoff syndrome by some mechanism independent of apparent Km values for thiamin diphosphate.
Early released lipid‐soluble cardiodepressant factor and elevated oestrogenic substances in human septic shock
Authors: BENASSAYAG CLAUDINE , CHRISTEFF NÉVÉNA , AUCLAIR MARIE‐CLAUDE , VERNIMMEN CATHERINE , CARLI‐VIELLE CLAIRE , NUNEZ EMMANUEL , CARLI ALAIN
Published: March 2008

Abstract. A cardiodepressant factor (CDF) able to decrease contractile activity of cultured rat heart cells was determined to be located in the lipid‐soluble fraction of sera from men in septic shock. This heat‐stable CDF has a molecular weight under 1000. Repeated fractionations of sera gave evidence of an oestrone‐like chromatographic behaviour.

Oestrone, oestradiol and cortisol were immunologically quantified in two groups (recovery and death) of men in septic shock. All of them were elevated in sera from patients with shock. Highest levels of oestrone 4330 pmol l‐1 (SEM pL 851, n= 15), oestradiol 1030 pmol l‐1 (SEM pL 220, n= 15) and cortisol 1096 pmol l‐1 (SEM pL 94, n= 15), were found in patients who failed to recover from shock. However, oestrone levels were the most striking, especially in the male.

This study gives evidence for a polarity relationship between the CDF and oestrone, but natural oestrone does not appear to be a direct CDF. Moreover, this study shows that radioimmunoassay of oestrone could be an important index evaluating the severeness of septic shock.
Increased platelet sensitivity and thromboxane B2 formation in type‐II hyperlipoproteinaemic patients
Authors: TREMOLI ELENA , MADERNA PAOLA , COLLI SUSANNA , MORAZZONI GABRIELE , SIRTORI MARINA , SIRTORI CESARE R.
Published: March 2008

Abstract. Platelet aggregation induced by collagen, ADP and epinephrine, was monitored in 150 type‐II patients (115 type IIA and 35 type IIB) and compared with a reference group of normolipidaemic controls; in addition, malondialdehyde formation and thromboxane B2 were examined in a subsample of the type‐IIA patients. Threshold aggregatory concentrations were significantly lower in the whole group of type‐II patients for all three aggregating agents; no difference in terms of aggregatory response was detected between platelets from type‐IIA and ‐IIB patients. Only 56% of type‐II patients, however, exceeded the 95th percentile of the threshold aggregatory concentrations in controls. The formation of malondialdehyde in platelet‐rich plasma stimulated with thrombin and collagen, was significantly higher in platelets from type‐IIA patients. The production of thromboxane B2 by platelets, from endogenous arachidonic acid in type‐IIA patients, was significantly higher and exceeded the highest level found in controls.
Effect of sustained portal‐systemic shunting on glycolytic and citric‐acid cycle intermediates in the rat brain
Authors: HINDFELT BENGT
Published: March 2008

Abstract. The effect of portacaval (PC) shunting on brain glycogen, glucose, glycolytic and citric‐acid cycle intermediates was analysed in rats shunted for 3, 8 and 16 weeks. Portal‐systemic shunting was accompanied by a progressive fall in brain glucose which was reduced to about half of control after 16 weeks of shunting (P<0·05). Glycogen remained unchanged. Glucose‐6‐phosphate and fructose‐1,6‐diphosphate were significantly (P<0·05) increased and decreased, respectively, which may indicate some inhibition of phosphofructokinase. These changes in brain glucose content and glycolysis may be additive to any further metabolic perturbation and provide one tentative mechanism of sensitization of the brain in liver failure.
Studies of the influence of immunological and serological factors from patients with cholestasis due to alcoholic or viral hepatitis on biliary function in the rat
Authors: MARBET U. A. , SHEFER S. , LEEVY C. M.
Published: March 2008

Abstract. Studies were undertaken to (a) determine if cholestasis in alcoholic or viral hepatitis is related to immunologic hyperreactivity as suggested for cholestasis due to type‐II drug‐induced hepatitis, and (b) evaluate possible mechanisms involved in lymphokine‐induced cholestasis. Results indicate that a cholestatic factor exists in alcoholic and acute viral hepatitis. Supernatants of lymphocytes from patients with alcoholic hepatitis stimulated by an extract of alcoholic hyalin evoked a 28%pL7·3 SEM reduction in rat bile flow (P<0·03). Supernatants of lymphocytes from patients with acute viral hepatitis activated by liver‐specific protein caused a reduction in rat bile flow of 24%pL5·9 SEM (P<0·03). A decrease in bile flow also occurred following injections of sera from patients with alcoholic or acute viral hepatitis. In contrast, injection of supernatants of non‐stimulated lymphocytes or those from chronic active hepatitis or healthy subjects did not produce a significant change in bile flow. Supernatants of stimulated lymphocytes from tuberculin‐sensitized guinea pigs caused a similar decrease in rat bile flow and reduced excretion of human secretory immunoglobulin A (IgA). Despite reductions in rat bile flow there were no alterations in liver morphology, liver plasma membrane Na‐K‐ATPase activity, microsomal cholesterol‐7α‐hydroxylase activity or low‐dose indocyanine green clearance during the period of observation.
Influence of fasting on lipolytic response to adrenergic agonists and on adrenergic receptors in subcutaneous adipocytes
Authors: ÖSTMAN JAN , ARNER PETER , KIMURA HIROSHI , WAHRENBERG HANS , ENGFELDT PETER
Published: March 2008

Abstract. The influence of 1 week's total fasting on the lipolytic effect of adrenergic agonists and on the binding of adrenergic antagonists was examined in isolated adipocytes of subcutaneous specimens removed from the hypogastric and the femoral sites in seventeen obese women. In the femoral adipocytes the lipolytic sensitivity to isopropyl noradrenaline decreased 30‐fold (P<0·01) during fasting. The specific binding of the radioligands (–)‐[3H]‐dihydroalprenolol and (–)‐[125I]‐cyanopindolol decreased significantly during fasting, essentially owing to a reduction in the receptor density. In adipocytes from the hypogastric region no such changes were found. For both tissue regions fasting induced a right‐ward shift in the dose–response curve for the inhibitory effect of the α2 agonist, clonidine, on theophylline‐induced lipolysis, corresponding to a 10‐fold decrease in sensitivity. There was also a significant decrease of about 20% in the α2‐adrenoceptor density, as estimated with the radioligand [3H]‐yohimbine. The results suggest that the regulation of the lipid mobilization in man by the sympathetic nervous system during fasting occurs not only through an increase in the level of circulating noradrenaline but also through changes in the adrenergic receptor density of the adipocytes.
Exogenous factors influencing the human erythrocyte sodium–lithium countertransport system
Authors: BEUCKELMANN DIRK , ERDMANN ERLAND
Published: March 2008

Abstract. It has recently been found that the Na+–Li+ countertransport across the human erythrocyte membrane is increased in patients with essential hypertension. We investigated the influence of hypokalaemia, oral contraceptives, diabetes mellitus and essential hypertension on the activity of this transport system.

Normal values for the maximal Na+–Li+ transport rate were 0·25pL0·08 mmol l‐1 h‐1 (males, n= 18) and 0·23pL0·06 (females, n= 14). We found elevated values in women taking oral contraceptives (0·34pL0·07, n= 10, P<0·001), in patients with chronic hypokalaemia due to diuretic or laxative abuse (0·41pL0·16, n= 13, P<0·005) and in those with essential hypertension (0·32pL0·08, n= 24, P<0·001) (all data meanpLSD).

Thus our results with hypertensive patients support the findings of other investigators. However, oral contraceptives and drug‐induced hypokalaemia greatly modify this system, indicating a regulation of the Na+–Li+ countertransport by hormones. Thus the transport rate does not seem to be an appropriate test for the diagnosis of essential hypertension.
Abnormal intestinal motility in diabetics with the gastroparesis syndrome
Authors: CAMILLERI MICHAEL , MALAGELADA JUAN‐R.
Published: March 2008

Abstract. Gastroparesis syndrome is a recognized complication of longstanding diabetes mellitus and is attributed to reduced gastric contractility due to ‘autovagotomy’. However, motor abnormalities associated with this syndrome may not be limited to the stomach. To test this hypothesis we have studied the fasting and fed manometric profiles of the proximal small intestine of fourteen patients with the clinical diagnosis of gastroparesis. Abnormal intestinal manometric patterns were observed in twelve out of the fourteen patients. In four patients there was reduced duodenojejunal phasic pressure activity, whereas in nine there were non‐propagated long bursts of powerful contractions. Furthermore, while the majority of patients (eleven out of fourteen) exhibited the expected reduction in antral pressure activity and gastric phase III, a small subgroup of three patients exhibited a peculiar continuous 3 min‐1 antral contractile activity.

Our findings show that the small intestine is frequently affected in patients with diabetic gastroparesis, and that the motility disorder both in the stomach and the small bowel is not invariably of a ‘paretic’ type. The occurrence of incoordinated intestinal long bursts and continuous antral activity suggests that disturbed sympathetic innervation participates in the aetiopathogenesis of their upper‐gut dysfunction.
Iodine‐induced thyrotoxicosis: analysis of eighty‐five consecutive cases
Authors: LEGER AUBÈNE F. , MASSIN JEAN P. , LAURENT MARIE F. , VINCENS MONIQUE , AURIOL MICHÈLE , HELAL OURKIA B. , CHOMETTE GUY , SAVOIE JEAN C.
Published: March 2008

Abstract. Iodine‐induced thyrotoxicosis was documented in eighty‐five cases. Eighty per cent occur in apparently normal thyroid glands; 60% among them occur in males. Amiodarone accounted for 50% of iodine‐induced thyrotoxicosis. Mean thyroid hormone levels at diagnosis were: FT1: 21·7 (normal mean: 7·5, arbitrary units); T3: 4·53 nmol l‐1 (normal: 2·30 nmol l‐1). Mean 131I‐ 24‐h uptake was 3·5% (normal range in France 25–45%) and was activated by exogenous TSH (mean 27%). The spontaneous cure in non‐treated cases was observed within an average 6 months. A phase of biological hypothyroidism (mean FT1: 3·7, T3: 1·23 nmol l‐1, TSH: 9·6 μU ml‐1 (normal TSH range: 1–7 μU ml‐1)) preceded the return to euthyroidism. Intrathyroid iodine content measured by X‐ray fluorescence was high, then fell gradually. Thyroid tissue study showed a large quantity of intrathyroid iodine and the overiodination of thyroglobulin. Histological and electron microscopic studies are reported. Prednisone and in some cases propylthiouracile were found to be effective.
Erythrocyte membrane sialic acids in primary and secondary hypertension in man and rat
Authors: REZNIKOVA M. B. , ADLER A. M. , POSTNOV YU. V.
Published: March 2008

Abstract. Sialic acids of erythrocyte membranes (erythrocyte ‘ghosts’) and blood plasma were studied in patients with essential or chronic renal hypertension, and in spontaneously hypertensive rats (SHR). The total content of sialic acids in erythrocyte membranes (determined by thiobarbituric‐acid assay) was around 100 μmol/g protein in both the hypertensive patients and controls, there being no difference between the three groups. Similarly total sialic‐acid content of plasma did not differ between the hypertensive patients and controls, being around 2 mmol/l. Although total membrane sialic acid was unchanged, the sialic‐acid content of glycolipids extracted from erythrocyte membranes was 17% greater (P < 0·001) in patients with essential hypertension than in renal hypertensive patients and controls (22·1 ± 0·5 μmol/g protein v. 18·2 ± 0·8 and 18·9 ± 0·8, respectively). Sialic acid in plasma glycolipid did not differ between the patient groups. The animal study revealed no differences between total—or glycolipid—sialic‐acid content in plasma and erythrocyte membrane in SHR and normotensive rats. The finding of an increase in the sialic‐acid content of erythrocyte membrane glycolipid in essential hypertension is in agreement with recent studies demonstrating structural abnormalities in hydrophobic regions of erythrocyte membrane, and is considered a manifestation of membrane glycolipid alteration in primary hypertension.
Effects of plasma infusion on plasma lipids, apoproteins and plasma enzyme activities in familial lecithin: cholesterol acyltransferase deficiency
Authors: MURAYAMA N. , ASANO Y. , KATO K. , SAKAMOTO Y. , HOSODA S. , YAMADA N. , KODAMA T. , MURASE T. , AKANUMA Y.
Published: March 2008

Abstract. The siblings presented here are the third family found in Japan with familial LCAT deficiency. Their post‐heparin plasma lipoprotein lipase and hepatic triglyceride lipase activities were measured selectively by an immunochemical method. Plasma triglyceride levels were elevated, and post‐heparin plasma lipoprotein lipase was decreased only in a patient with nephropathy, while hepatic triglyceride lipase activities were within reference limits in both patients. The plasma concentrations of apo A‐I, apo A‐II, and apo B were reduced in both patients. On the other hand, the plasma concentration of apo E was markedly increased. Enzyme replacement therapy by plasma transfusion in the propositus resulted in marked improvement of deranged compositions of triglyceride‐rich lipoproteins. Also, improvement of the plasma apo E concentration was demonstrated, while the improvement of post‐heparin lipase did not occur. These results suggest that LCAT may play an important physiological role in triglyceride metabolism as well as in cholesterol metabolism.
Effect of short‐term treatment with bezafibrate and fenofibrate on biliary lipid metabolism in patients with hyperlipoproteinaemia
Authors: BERGMANN KLAUS VON , LEISS OTTMAR
Published: March 2008

Abstract. Sixteen patients with different types of hyperlipoproteinaemia were treated with the clofibrate analogues, bezafibrate or fenofibrate. Serum lipids and lipid composition of gallbladder bile were measured before and after 3–4 weeks of treatment. Both bezafibrate and fenofibrate reduced serum lipids effectively but increased the lithogenic index of bile from 1·11 to 1·47 and 1·25 to 1·80 (P < 0·01), respectively, by increasing molar percent of cholesterol and decreasing molar percent of bile acids. Measurements of biliary lipid secretion in three patients before and after bezafibrate administration revealed a marked and significant increase in cholesterol secretion (from 119 to 166, from 58 to 128, and from 149 to 172 μmol h‐1, respectively; P < 0·05) without altering bile acid and phospholipid output. These results indicate that bezafibrate and fenofibrate exhibit the same effect on biliary lipid metabolism as clofibrate and might therefore induce cholesterol gallstone disease.
Effect of long‐term starvation on acetate and ketone body metabolism in obese patients
Authors: SEUFERT C. D. , MEWES W. , SOELING H. D.
Published: March 2008

Abstract. The turnover of ketone bodies and acetate was evaluated as well from the disappearance rate of (3‐14C)acetoacetate or (1‐14C)acetate respectively as from the conversion of FFA into these metabolites in normal weight and obese overnight‐fasted and in obese long‐term starved patients. The disappearance rate of (1‐14C)oleate was the same in all three groups.

Long‐term starvation enhanced ketone body turnover almost 10‐fold, whereas the disappearance rate for ketone bodies decreased from 0·035 to 0·015 min‐1. Under the same circumstances the turnover of acetate was about 1 μmol g‐1 min‐1 accounting for about 5% of FFA turnover.

Long‐term starvation decreased the conversion of (1‐14C)oleate into triglycerides by almost 50% and increased the (2‐C)‐(4‐C)/(1‐C) ratio of radioactivity in ketone bodies. The reincorporation of radioactivity from the (1‐C)position of (1‐14C)oleate into the ((2‐C)‐(n‐C)) position of FFA, which is a measure of the reutilization of acetyl‐CoA for FFA synthesis decreased significantly during long‐term starvation.
Stimulation of peritoneal synthesis of vasoactive prostaglandins during peritonitis in patients on continuous ambulatory peritoneal dialysis
Authors: STEINHAUER H. B. , GÜNTER B. , SCHOLLMEYER P.
Published: March 2008

Abstract. The peritoneal generation of arachidonic acid metabolites was studied in eight patients with end‐stage renal disease undergoing continuous ambulatory peritoneal dialysis (CAPD) during infection‐free periods and during bacterial peritonitis. The prostacyclin metabolite 6‐keto‐PGF1α was found to be the major prostanoid generated by human peritoneal mesothelium (1090 ng(6h)‐1, SEM 86, n= 8) followed by lesser amounts of PGE2 (142 ng (6 h)‐1, SEM 26, n= 8), PGF2α (162ng(6h)‐1, SEM 27, n= 8) and TXB2 (59 ng (6 h)‐1, SEM 5, n= 8). During peritonitis a significant increase of all prostaglandins and TXB2 occurred (P < 0·001). The ratio of the vasodilating prostaglandins and their metabolites (PGE2 and 6‐keto‐PGF1α) to the vasoconstrictors and their metabolites (PGF2α and TXB2) increased from 6·6 to 10·5 during peritoneal inflammation. Augmented peritoneal clearances of creatinin and urea and increased losses of proteins during peritonitis as well as the enhanced peritoneal generation of prostanoids were reduced to basal values by adequated antibiotic therapy.

The present results suggest that the increased peritoneal blood flow during peritonitis, probably responsible for the observed changes of peritoneal transport properties, may be induced by a change in the ratio of vasoactive prostaglandins generated by peritoneal mesothelial cells.
Effect of dazoxiben, a thromboxane synthetase inhibitor on skin‐blood flow following cold challenge in patients with Raynaud's phenomenon
Authors: TINDALL H. , TOOKE J. E. , MENYS V. C. , MARTIN M. F. R. , DAVIES J. A.
Published: March 2008

Abstract. The effects of dazoxiben on finger‐blood flow in response to cold challenge were studied in normal subjects and patients with Raynaud's phenomenon. In normal subjects concentrations of TXB2 and 6‐oxo‐PGF1α were measured in blood taken from dorsal hand veins following cold challenge. In a parallel multicentre study we examined the effects of dazoxiben on finger temperature and capillary blood cell velocity in patients with Raynaud's phenomenon. Dazoxiben did not affect finger arterial inflow at rest or during cold challenge in patients or controls. However in both groups, recovery was quicker after cold challenge on dazoxiben treatment. In patients median flow was 5 ml (100‐1 ml) min‐1 (range 1–10) v. 2 (0·5–15), P lt; 0·05 dazoxiben v. placebo at 15 min after cold challenge. However, in normal subjects this did not prove to be statistically significant. In normal subjects there was a fall in TXB2 concentrations and relative rise in 6‐oxo‐PGF1α following dazoxiben treatment indicating redirection of prostaglandin endoperoxides towards synthesis of PGIi. Comparison of the sum‐total output of each eicosanoid following treatment with dazoxiben revealed a 65% reduction in TXB2 concentrations (P < 0·025 compared with placebo) and a 40% increase in 6‐oxo‐PGF1α concentrations (P < 0·05 compared with placebo). However a simultaneous increase in concentrations of FPA indicated generation of thrombin, probably at the needle tip. Long‐term treatment with dazoxiben resulted in no significant change in finger‐skin temperature or capillary blood cell velocity, duration, or severity of attacks of Raynaud's phenomenon.
Adrenergic regulation of lipolysis in abdominal adipocytes of obese subjects during caloric restriction: reversal of catecholamine action caused by relief of endogenous inhibition
Authors: KATHER H. , WIELAND E. , FISCHER B. , WIRTH A. , SCHLIERF G.
Published: March 2008

Abstract. The effects of adrenaline, noradrenaline, and of the α2‐ and β‐selective agonists clonidine and isoproterenol were studied in fifteen obese subjects before and after 4 weeks of caloric restriction (300 cal day‐1). Basal glycerol release averaged 1·4 μmol (106 cells)‐1 (180 min)‐1 before starvation and 2·8 μmol (106 cells)‐1 (180 min)‐1 during starvation (P≤ 0·1). Before starvation adrenaline and noradrenaline caused a 2–3‐fold increase of glycerol release. This lipolytic effect disappeared during starvation. An inhibitory effect of adrenaline was observed instead which was maximal at an adrenaline concentration of 1 μmol 1‐1 (P≤ 0·05). The dose‐response relationships of the α2 and β‐selective agents clonidine and isoproterenol were not appreciably changed by caloric restriction.

The increase of basal lipolytic rate and the reversal of adrenaline action seen during caloric restriction could be mimicked by removal of endogenous adenosine using adenosine deaminase (1·6 μg ml‐1). In addition, inclusion of N6‐phenylisopropyladenosine (1 μmol 1‐1) into the medium reverted the adrenaline‐induced inhibition seen during caloric restriction.

The results suggest that local modulators such as adenosine are of primary importance for the apparent change of responsiveness to adrenaline and noradrenaline seen during starvation of human fat cells in vitro.
Effect of renal function on renal responsiveness to parathyroid hormone in primary hyperparathyroidism and chronic renal failure
Authors: LEWIN I. G. , HENDY G. N. , PAPAPOULOS S. E. , TOMLINSON S. , O'RIORDAN J. L. H.
Published: March 2008

Abstract. The effect of renal function on the cyclic AMP (cAMP) response to exogenous parathyroid hormone (PTH) was examined in patients with chronic renal failure (n= 22) and primary hyperparathyroidism (n= 19). In the patients with chronic renal failure there was marked resistance to the effect of exogenous PTH. In primary hyperparathyroidism the cAMP responses were variable; most of the patients with an abnormally small response having impaired renal function. After parathyroidectomy, responsiveness improved to varying degrees. In three patients repeatedly tested up to several months after parathyroidectomy, the recovery of responsiveness was a gradual process which began within days but did not, however, return to normal. Thus, there was an irreversible component to the resistance to PTH in these patients. A strong negative correlation between plasma creatinine and the cAMP response to PTH (P < 0·001) was found in a group of patients, some with treated primary hyperparathyroidism and some with chronic renal failure. Thus, renal impairment is an important, but probably not the sole, contributory factor involved in the irreversible resistance to the action of PTH in hyperparathyroidism.
Variation in serum Type III procollagen peptide with age in healthy subjects and its comparative value in the assessment of disease activity in children and adults with chronic active hepatitis*
Authors: TRIVEDI PREMILA , CHEESEMAN PAUL , PORTMANN BERNARD , HEGARTY JOHN , MOWAT ALEX P.
Published: March 2008

Abstract. To determine the comparative value of serum Type III procollagen peptide (PIIIP) in paedia‐tric and adult liver disease we have measured PIIIP in 201 healthy subjects (aged 1 day–77 years) and twenty‐one children and five adults with chronic active hepatitis (CAH). Healthy children had significantly higher PIIIP levels than adults (P < 0·001), with highest values of 298 ± 88 ng ml‐1 (s.d.) in the neonatal period. PIIIP fell to 30·9 ± 7·0 by 1 year, 19·1 ± 4·5 by 3 years and rose significantly (P < 0·01) at puberty. Adult levels (8·3 ± 3·2) occurred by 16 years of age. Serum PIIIP levels were significantly elevated (P < 0·001) in adults when they had biochemical and histological evidence of active liver disease but were consistently within the normal range for age in 70% of children with similar hepatic pathology. The minor elevations in PIIIP in the other children were unrelated to clinical, biochemical or histological evidence of active liver disease. While raised PIIIP may be a non‐invasive marker of liver disease activity in adults, its value in childrens' disorders appears to be limited by the high levels of PIIIP which occur during growth.
Insulin in vivo increases the in vitro fall of plasma potassium concentration in human venous blood
Authors: KALSHEKER N. A. , HALES C. N.
Published: March 2008

Abstract. Venous blood taken from fasting subjects at rest and incubated in vitro at room temperature for 120 min showed a mean fall in the plasma potassium concentration of 0·13 mmol 1‐1 (SEM 0·08, n= 6). Blood obtained 15 min after the intravenous administration of insulin (0·67 nmol kg‐1 body weight) and incubated under the same conditions showed a significantly greater fall in the mean plasma potassium concentration of 0·33 mmol l1 (SEM 0·09, P < 0·05, n= 6). The addition of insulin (up to 33 nmol l‐1) to blood taken from fasting subjects did not induce the phenomenon. The transfer of plasma from pre‐insulin blood samples to blood cells obtained 15 min after insulin administration and vice versa indicated that the fall in plasma potassium concentration was a property of the 15 min post‐insulin blood cells, presumably erythrocytes, rather than the plasma. The ouabain‐suppressible component of 86Rb+ influx in erythrocytes obtained 15 min after the administration of insulin was virtually doubled compared to erythrocytes obtained before insulin suggesting increased activity of the sodium pump of erythrocytes.
Concentrative transport of purine nucleosides in brush border vesicles of the rat kidney
Authors: HIR M. LE , DUBACH U. C.
Published: March 2008

Abstract. Nephrotoxicity has been reported in humans and in animals during treatment with nucleosides. We described recently a Na+ gradient‐dependent concentrative transport of adenosine in brush border vesicles isolated from the cortex of the rat kidney. The results of the present study suggest that that transport is shared by other purine nucleosides. The transport of adenosine is inhibited by several purines at micromolar concentrations. The transports of deoxyadenosine, of inosine and of guanosine are concentrative in the presence of a Na+ gradient and they are inhibited by adenosine. We conclude that there exists a concentrative system for reabsorption of various purine nucleosides in the proximal tubule. The transport of nucleosides is non‐concentrative in all other cell types studied so far. The concentrative capacity of the transport of nucleosides in the kidney might explain the particular sensitivity of that organ during treatment with nucleosides.
Is the renal kallikrein system relevant to sodium sensitivity in patients with essential hypertension
Authors: KOOLEN M. I. , DAHA M. R. , BRUMMELEN P. VAN
Published: March 2008

Abstract. In twenty‐five outpatients with essential hypertension, the relevance of renal kallikrein excretion for inter‐individual differences in the blood pressure response to changes in dietary sodium intake was investigated. The patients were studied during 2 weeks of high (300 mmol) and 2 weeks of low (50–100 mmol) sodium intake. In addition there were two control periods of normal sodium intake, one lasting 4 weeks at the beginning and one lasting 2 weeks at the end of the study. Blood pressure, body weight and 24 h urinary sodium and kallikrein excretion were measured at the end of all periods. At the end of the first control period, 1 mg furosemide per kg body weight was administered intravenously, and the urinary excretion of kallikrein and sodium were measured 30 and 120 min later. The difference in mean arterial pressure (A MAP) between high and low sodium intake ranged from + 18 to ‐ 8 mmHg. The eight patients with a A MAP greater than 10 mmHg were regarded as salt‐sensitive. They were older and had a higher initial blood pressure than salt‐insensitive patients. For all patients, urinary kallikrein excretion at the end of the low sodium period (123(SEM 20·3) μg 24 h‐1) was significantly higher than at the end of the first control period (96(SEM 16·3) μg 24 h‐1, P < 0·01) and at the end of the high sodium period (96(SEM 23·7) μg 24‐1, P < 0·01). When compared with salt‐insensitive patients, salt‐sensitives had lower levels of urinary kallikrein excretion and a blunted kallikrein response to dietary sodium restriction and furosemide. No relationships between sodium sensitivity and either urinary kallikrein excretion or the differences in urinary kallikrein excretion between the periods of different sodium intake were found. The data indicate that renal kallikrein is not an important determinant of sodium sensitivity in essential hypertension.
Effect of sympathetic stimulation and intrarenal alpha‐blockade on the secretion of renin by the human kidney
Authors: LEEUW P. W. DE , BOS R. DE , ES P. N. VAN , BIRKENHÄGER W. H.
Published: March 2008

Abstract. This study was initiated to explore the possible involvement of renal alpha‐adrenoceptors in the regulation of active and inactive renin. In fifteen hypertensive patients who proved not to have vascular abnormalities on diagnostic renal arteriography, blood samples were collected simultaneously from the renal artery and vein before and during an intrarenal infusion of either saline (n= 5), or the alpha‐1 blocker doxazosin (n= 5) or the non‐selective alpha‐blocker phentolamine (n= 5). Subsequently, responses of renal blood flow and renin secretion were assessed following 3 min of handgrip exercise. In none of the experiments secretion of inactive renin could be detected. Release of active renin increased from 580 (SEM 170) to 650 (SEM 220) μU min‐1 (100 g)‐1 during infusion of doxazosin (P < 0·05)and from 760(SEM 100)to 1000 (SEM 340) μU min‐1 (100 g)‐1 during infusion of phentolamine (P < 0·01). Saline infusion had no effect on secretion of active renin. While handgrip exercise had no significant effect on active renin secretion in the saline and in the doxazosin group, it enhanced secretion from 1000 (SEM 340) to 1280 (SEM 390) μU min‐1 (100 g)‐1 in the phentolamine group (P < 0·01).

The results indicate that mainly alpha‐2 adrenoceptors exert an inhibitory effect on release of active renin, although alpha‐1 receptors participate to some degree. There is no evidence that the kidney secretes inactive renin.
Bioavailability, gastrointestinal transit, solubilization and faecal excretion of ursodeoxycholic acid in man
Authors: PARQUET M. , METMAN E. H. , RAIZMAN A. , RAMBAUD J. C. , BERTHAUX N. , INFANTE R.
Published: March 2008

Abstract. The bioavailability of ursodeoxycholic acid (UDCA), a cholesterolic gallstone dissolving agent, has been analysed in seven healthy human volunteers. After absorption of a capsule containing a 500 mg dose, the time course of plasma concentrations of the drug presented a double peak profile over a 240 min period. In order to explain this result, a second group of five subjects bearing a four‐way jejunal catheter fitted with an occluding balloon, received an oral dose of 250, 500 or 750 mg of the drug. Simultaneous analyses of plasma UDCA concentrations and jejunal UDCA contents were carried out.

UDCA is poorly soluble in the gastro‐duodeno‐jejunal contents of fasted subjects since 21–50% of the ingested doses were recovered in solid form. The profile of plasma concentration paralleled the amount of soluble UDCA present in intestinal lumen. When jejunal contents were infused below the balloon a second plasma peak appeared in cases corresponding to ingestion of higher doses of UDCA. In conclusion, pharmacological doses of UDCA are not readily soluble in the stomach and intestine of a healthy fasting man. In consequence, the bioavailability of the drug varies with its progressive solubilization in the gastrointestinal tract. The present results suggest that repeated daily doses of UDCA should improve its bioavailability in treated gallstone patients.
Age related changes of platelet prostacyclin receptors in humans
Authors: MODESTI P. A. , FORTINI A. , ABBATE R. , GENSINI G. F.
Published: March 2008

Abstract. Platelet receptors for PGI2 were investigated in eighteen healthy volunteers divided in two classes of age: nine were 18–40 years old and nine were 41–65 years old.

PGI2 platelet receptors were found to decrease significantly with age; the young subjects had 106 ± 16 (mean ± SD) high affinity receptors/platelet and 3509 ± 529 low affinity receptors/platelet whereas the old subjects had 86 ± 14 high affinity receptors/platelet (P<0·02) and 2471 ± 640 low affinity receptors/platelet (P<0·005). The cumulated data from all the subjects yielded a significant negative correlation with age(r= ‐0·71, P< 0·001 for the high affinity class and r=‐0·65, P<0·01 for the low affinity class). The affinity of receptor sites for the ligand did not statistically change with aging (P<0·30 and P<0·90 respectively for high and low affinity receptors).
Evidence for a Na‐K‐ATPase‐inhibitor in erythrocytes of patients with essential hypertension
Authors: WALTER U. , MÜLLER S.
Published: March 2008

Abstract. ATPase activities were determined in haemolysed and dialysed erythrocytes and in haemoglobin‐free membranes of twenty patients with essential hypertension and twenty normotetisive controls. Ouabain‐sensitive ATPase (Na‐K‐ATPase) activity of haemolysate but not that of membranes was decreased in hypertensives whereas ouabain‐insensitive ATPase (Mg‐ATPase + some residual Ca‐ATPase) activity was increased in both enzyme preparations when measurements were performed in the absence of Ca2+‐chelating substances. In haemolysed erythrocytes ouabain‐sensitivity as a percentage of total ATPase activity was a good discriminator between both groups and may be a possible marker for essential hypertension. The decreased activity of Na‐K‐ATPase in haemolysate is apparently due to a non dialysable inhibitor of Na‐K‐ATPase which is either tightly bound to the erythrocyte membrane or dissolved in the cytoplasm. Following haemolysis with subsequent centrifugation the Na‐K‐ATPase inhibitor is removed, at least in part, and thus differences in Na‐K‐ATPase activity demonstrable in haemolysed and dialysed erythrocytes are no longer apparent in haemoglobin‐free membranes.
Phosphocreatine content and intracellular pH of calf muscle measured by phosphorus NMR spectroscopy in occlusive arterial disease of the legs
Authors: KELLER U. , OBERHÄNSLI R. , HUBER P. , WIDMER L. K. , AUE W. P. , HASSINK R. I. , MULLER S. , SEELIG J.
Published: March 2008

Abstract. Energy metabolism of calf muscle was assessed non‐invasively by phosphorus (31P) NMR spectroscopy in eleven patients with symptomatic arterial occlusion and in seven matched controls. Phosphocreatine (PCr) content and pH values decreased during non‐ischaemic foot exercise to lower values in severely afflicted patients but in all patients, as a group, they were not significantly decreased compared to controls. In contrast, recovery from ischaemic exercise (arterial occlusion by a tourniquet) demonstrated significant differences between patients and controls. Intracellular pH and PCr recovered more slowly in patients than in controls; PCr recovery proceeded exponentially with a recovery half‐time of 203 ± 74 s in patients compared to 36±7 ± 5±5 s in controls (P<0±02). Phosphocreatine (PCr) recovery after ischaemic exercise correlated significantly with the degree of arterial stenoses as assessed by Doppler ultrasound (r= 0±739, P= 0±019) and by angiography (r= 0±885, P= 0±005), suggesting that the degree of large vessel stenoses limits the postischaemic increase in mitochondrial oxidative phosphorylation. Reactive blood flow after ischaemia failed to correlate with PCr recovery or with the degree of arterial stenoses. Phosphorus (31P) NMR spectroscopy provides, therefore, quantitative parameters of muscle energy metabolism in patients with peripheral arterial occlusions.
Dispositions of di‐ and mono‐(2‐ethylhexyl) phthalate in newborn infants subjected to exchange transfusions
Authors: SJÖBERG P. , BONDESSON U. , SEDIN G. , GUSTAFSSON J.
Published: March 2008

Abstract. The dispositions of the plasticizer di‐(2‐ethylhexyl) phthalate (DEHP) and its primary metabolite mono‐(2‐ethylhexyl) phthalate (MEHP) were studied in newborn infants subjected to exchange transfusions. During a single exchange transfusion the amounts of DEHP and MEHP infused ranged from 0±8‐3±3 and 0±05‐0±20 mg kg‐1 body weight, respectively. There were indications that about 30% of the infused DEHP originated from parts of the transfusion set other than the blood bag. Approximately 30% of the infused amount of DEHP was withdrawn during the course of each transfusion. Immediately after the transfusions the plasma levels of DEHP ranged between 5±8 and 19±6 μg ml‐1, and subsequently they declined rapidly. This decline, probably reflecting distribution of DEHP within the body, was followed by a slower elimination phase. The half‐life of this phase was approximately 10 h. The maximal plasma levels of MEHP were about 5 μg ml‐1. In one pre‐term infant the elimination of MEHP was slower than its formation, whereas in one full‐term newborn the formation appeared to be rate‐limiting for the elimination.
A study of the structural heterogeneity of low‐density lipoproteins in two patients homozygous for familial hypercholesterolaemia, one of phenotype E2/2
Authors: LUC G. , CHAPMAN M. J. , GENNES J.‐L. DE , TURPIN G.
Published: March 2008

Abstract The structural heterogeneity of the low‐density lipoproteins (d 1·019—1·063 g ml‐1) in two female patients homozygous for familial hypercholesterolaemia, one of phenotype E2/2, has been evaluated using a new ultracentrifugal density gradient procedure. The mass distribution, chemical composition, particle size and heterogeneity, hydrated density and apolipoprotein content of 16 LDL subfractions were determined. By gradient gel electrophoresis, the lighter LDL subfractions (d 1·016—1·037 g ml‐1) displayed a single particle species which progressively diminished in size from 24·8 to 22·0 nm with increase in density. By contrast, subfractions of higher density (d> 1·037 g ml‐1) exhibited two LDL particle species of distinct size; one component decreased in size from 21·8 to 20·4 nm with increase in density, while the second maintained an essentially constant diameter (between 22·5 and 23·5 nm) across these LDL subfractions. Immunoblotting with anti‐apo‐B100 of LDL subspecies separated by gradient gel electrophoresis showed all particles to contain apo‐B100. However, dot‐blots and immunoblotting with a monoclonal antibody to lipo‐protein (a) (Lp(a)) revealed that the LDL particle subspecies of greatest diameter (22·5—23·5 nm) present in the denser subfractions (d> 1·037 g ml‐1) also contained the Lp(a) antigen. These findings, taken together with the high plasma Lp(a) levels (> 60 mg dl‐1) in our patients, raise the possibility that Lp(a) may contribute in a significant manner to the atherogenic process in homozygous familial hypercholesterolaemia.
Trans‐ and paracellular calcium transport across the colonic mucosa after short‐ and long‐term treatment with 1,25‐dihydroxyvitamin D3
Authors: KARBACH U. , RUMMEL W.
Published: March 2008

Abstract The electrical parameters and the unidirectional fluxes of 45Ca and 3H‐mannitol were measured in preparations of rat colon descendens freed from the muscularis externa and mounted in a modified Ussing‐chamber. Two criteria were used to differentiate between changes in the trans‐ and the paracellular calcium transport after treatment with 1,25(OH)2D3: (a) the fluxes of the simultaneously measured 3H‐mannitol as a paracellular marker; (b) the 45Ca fluxes in preparations with clamped potentials. After a short‐time (6 h) pretreatment by s.c. administration of 1,25(OH)2D3 (250 ng kg‐1) in normal rats the mucosa (m) to serosa (s) 45Ca flux under short circuit conditions increased about 65%, whereas the electrical parameters and the 3H‐mannitol fluxes remained unchanged. In clamped epithelia the PD‐independent m to s 45Ca flux was increased, whereas the PD‐dependent flux remained unchanged. In contrast, after long‐time (4 days) induction by 1,25(OH)2D3 (a) the m to s 45Ca flux increased under short circuit conditions by about 100% and the m to s 3H‐mannitol flux increased by 50%, (b) PD and Isc decreased by more than 60%, whereas tissue resistance was the same, (c) in clamped epithelia the calculated PD‐independent, transcellular m to s 45Ca‐flux was 2·4 times and the PD‐dependent, paracellular 45Ca‐flux was 1·9 times higher than in controls, whereas the s to m 45Ca flux remained unchanged. On the basis of the relevant references the following conclusions were drawn: (a) after short‐time exposure to 1,25(OH)2D3 only the PD‐dependent, transcellular m to s calcium transport is increased; this is probably due to a liponomic effect of 1,25(OH)2D3 at the brush border membrane. (b) After long‐time induction the PD‐dependent, paracellular m to s transport of calcium and mannitol is increased additionally. It is hypothesized that a solvent drag effect might be responsible for the increased paracellular calcium flux after long‐time treatment with 1,25(OH)2D3. It is concluded that long‐term treatment with 1,25(OH)2D3 stimulates paracellular m to s movement of other solutes than that of calcium.
Combined treatment with cholestyramine and nicotinic acid in heterozygous familial hypercholesterolaemia: effects on biliary lipid composition
Authors: ANGELIN B. , ERIKSSON M. , EINARSSON K.
Published: March 2008

Abstract In ten patients with heterozygous familial hypercholesterolaemia, combination therapy with cholestyramine and nicotinic acid was instituted for a minimum of 2 months. During therapy, plasma low‐density lipoprotein levels were reduced by 32%, and low‐density lipoprotein to high‐density lipoprotein ratios by 40%. The cholesterol saturation of fasting gall‐bladder bile was reduced by 33% during treatment. We conclude that long‐term combination therapy with cholestyramine and nicotinic acid is practically feasible in heterozygous familial hypercholesterolaemia, normalizes plasma cholesterol and low‐density lipoprotein levels in many patients, and does not result in unwanted side‐effects on biliary lipids. It should therefore be considered as the therapy of choice in this condition.