bluuebunny/crossref_metadata_2025 huggingface dataset:
Skeletal muscle and whole body protein turnover in cardiac cachexia: influence of branched‐chain amino acid administration
Authors: MORRISON W. L. , GIBSON J. N. A. , RENNIE M. J.
Published: March 2008

Abstract. Muscle protein wasting commonly accompanies severe heart failure. The mechanism of this socalled cardiac cachexia has been investigated in eight patients with an average body weight decrement of 19%, whose results have been compared with those from 11 healthy control subjects. Exchanges of tyrosine and 3‐methylhistidine across leg tissue were used as specific indicators of net protein balance and myofibrillar protein breakdown, respectively. Whole body protein turnover was measured using a stable isotope labelling technique with L‐[l‐13C] leucine as tracer. In patients with cardiac cachexia there were greater values, relative to those values in normal control subjects, of leg efflux of tyrosine (‐ 8·1±0·6 nmol 100 ml leg tissue‐1 min‐1 vs. ‐4·2±0·3 nmol 100 ml‐1 min‐1 (P < 0·01) and of 3‐methylhistidine (‐0·8±0·1 nmol 100 ml leg tissue‐1 min‐1 vs. ‐0·1±0·02 nmol 100 ml‐1 min‐1 (P < 0·005), mean±SEM). The results suggest that in patients with cardiac cachexia the state of net negative protein balance across leg tissue is associated with an increased rate of myofibrillar protein breakdown. In cardiac cachexia, neither efflux of tyrsoine (‐ 8·4±0·7 nmol 100 ml leg tissue‐1 min‐1) nor of 3‐methylhistidine (‐ 1·0±0·2 nmol 100 ml leg tissue‐1 min‐1) were significantly altered by branched‐chain amino acid (BCAA) infusion to plasma concentrations of 1300±14 μmol ml‐1, i.e., four times normal plasma values (282±11 μmol ml‐1). Similarly, in normal subjects, effluxes of tyrosine (‐ 3·7±0·5 nmol 100 ml‐1 min‐1) were unaltered by BCAA administration. Nevertheless, BCAA infusion caused a net retention of total amino and amide nitrogen in leg tissue of cachectic patients, but not in that of normal control subjects. The results suggest that BCAA have no acute effect on muscle protein synthesis or breakdown in normal subjects or in cardiac patients with muscle wasting, but may promote increases in the intracellular pool of amino acid nitrogen, which may have beneficial longer term effects. In cardiac cachexia, differences from normal in the components of the leucine plasma flux (determined by stable isotope labelling techniques) suggested that there was a depression in whole body leucine flux (protein breakdown), leucine oxidation and protein synthesis compared with normal [79±24 ±mol kg‐1 h‐1 vs. 133±27 μmol kg‐1 h‐1 (P < 0·0001) (mean±SD), 25±20 vs. 40±10 mol kg‐1 h‐1 (P < 0·0001), and 54±7 vs. 89±20 μmol kg‐1 h‐1 (P < 0·0001), respectively]. These results suggest that although there is an overall depression of whole body protein turnover, in cardiac cachexia, this is associated with elevations of myofibrillar protein breakdown from skeletal muscle in the leg.
Pharmacological control of the human gastric histamine H2 receptor by famotidine: comparison with H1, H2 and H3 receptor agonists and antagonists
Authors: GESPACH C. , FAGOt D. , EMAMI S.
Published: March 2008

Abstract. Histamine 0–1 μM‐0.1 mM increased adenylate cyclase activity five‐ to ten‐fold in human fundic membranes, with a potency Ka = 3 μM. The histamine dose‐response curve was mimicked by the H3 receptor agonist (R) α‐MeHA, but at 100 times lower potency, Ka = 0.3 mM. Histamine‐induced adenylate cyclase activation was abolished by H2, H1 and H3 receptor antagonists, according to the following order of potency IC50: famotidine (0.3 μM) > triprolidine (0.1 mM) thioperamide (2 mM), respectively. Famotidine has no action on membrane components activating the adenylate cyclase system, including the Gs subunit of the enzyme stimulated by forskolin and cell surface receptors sensitive to isoproterenol (β2‐type), PGE2 and VIP. The Schild plot was linear for famotidine (P<0.01), with a regression coefficient r= 0.678. The slope of the regression line was 0.64 and differs from unity. Accordingly, famotidine showed a slow onset of inhibition and dissociation from the H2 receptor in human cancerous HGT‐1 cells. The results demonstrate that famotidine is a potent and selective H2 receptor antagonist with uncompetitive actions in human gastric mucosa. Consequently, famotidine might be a suitable drug with long‐lasting actions in the treatment of Zollinger‐Ellison syndrome. The results also confirm and extend the previous observations that (R) α‐MeHA and thioperamide are two selective ligands at histamine H3 receptor sites. In the human gastric mucosa, these drugs are respectively 330 and 6700 times less potent than histamine and famotidine on the adenylate cyclase system. The possible involvement of histamine H3 receptors in the regulation of gastric secretion is proposed.
New form of dual porphyria: coexistent acute intermittent porphyria and porphyria cutanea tarda*
Authors: DOSS M. O.
Published: March 2008

Abstract. A previously unrecognized form of dual porphyria has been identified in four patients. One male and one female with acute symptoms were diagnosed as having acute intermittent porphyria (AIP), and two males with cutaneous and acute symptoms were diagnosed as having porphyria cutanea tarda (PCT). Biochemically, the excretion of haem precursors showed a complex constellation, with signs characteristic of both AIP and PCT. In one male, a clinical course with both overt PCT and acute manifestations of AIP was observed. Enzyme studies of haem biosynthesis in erythrocytes revealed a dual deficiency, with decreased activity of both porphobilinogen deaminase, as seen in AIP, and uroporphyrinogen decarboxylase, as seen in PCT. A family study showed that the two disorders do not consistently segregate together.

These findings suggest that the dual porphyria reflects a double heterozygous condition of coexistent AIP and PCT genes in the same subject.
High plasma levels of a ouabain‐like factor in normal pregnancy and in pre‐eclampsia*
Authors: DELVA P. , CAPRA C. , DEGAN M. , MINUZ P. , COVI G. , MILAN L. , STEELE A. , LECHI A.
Published: March 2008

Abstract. Recent reports have described high levels of one or more substances which cross‐react with digoxin antibodies in the serum of women with pre‐eclampsia. We measured plasma ouabain‐like activity and intra‐erythrocyte sodium and potassium concentrations, in addition to performing routine hypertensive laboratory tests, in 13 normotensive non‐pregnant subjects, 15 normotensive pregnant women and 16 pre‐eclamptic women (gestational age: 33–36 weeks). Plasma ouabain‐like activity, measured as plasma‐induced variations in ouabain binding to human erythrocytes, proved significantly higher in both groups of pregnant subjects as compared to normotensive non‐pregnant women, and a significant difference was also found between pre‐eclamptic and normotensive pregnant women, the former exhibiting higher plasma ouabain‐like activity. No differences in intracellúlar sodium and potassium levels were detected among the three groups studied. Though there is reason to believe that the high plasma levels found both in normal and hypertensive pregnancy may depend on placental production, we are not in a position to define with any degree of certainty what the mechanism or mechanisms are that regulate ouabain‐like factor production.
Electromagnetically generated extracorporeal shock waves for gallstone lithotripsy: in vitro experiments and clinical relevance
Authors: STARITZ M. , RAMBOW A. , MILDENBERGER P. , GOEBEL M. , SCHERFE Th. , GROSSE A. , JUNGINGER Th. , HOHENFELLNER R. , THELEN M. , BÜSCHENFELDE K.‐H. MEYER ZUM
Published: March 2008

Abstract. First generation shock wave sources have been proved to disintegrate gallstones effectively, but they require the immersion of the patient's body in a tank of water. A recently developed second generation shock wave source (Siemens‐Lithostar, Erlangen, FRG) generates shock waves electromagnetically. It presents several novel features. In particular the waterbath can be omitted and due to lower shock wave pressure general anaesthesia is not required. In vitro studies showed that 36 out of 38 gallstones (11–30 mm in diameter) could be disintegrated. Two concrements resisting lithotripsy were pure white cholesterol stones.

Independent of shape, size, and composition (cholesterol or pigment) the maximum diameter of remaining fragments after lithotripsy was between 1 and 8 mm. For sufficient disintegration precise focusing (±1 cm) of the stones and maximum power of the shock wave generator were required.
Myocardial (iso)enzyme activities, DNA concentration and nuclear polyploidy in hearts of patients operated upon for congenital heart disease, and in normal and hypertrophic adult human hearts at autopsy
Authors: LAARSE A. VAN DER , HOLLAAR L. , VLIEGEN H. W. , EGAS J. M. , DIJKSHOORN N. J. , CORNELISSE C. J. , BOGERS A. J. J. C. , QUAEGEBEUR J. M.
Published: March 2008

Abstract. To investigate biochemical characteristics of hypertrophic myocardium of young and adult humans, we analysed myocardial biopsies obtained from 28 mainly young patients undergoing cardiac surgery for congenital heart disease and 41 autopsied hearts from 18 adult normal and 23 hypertrophic human subjects. Myocardial activities of the enzymes creatine kinase and lactate dehydrogenase were independent of age during childhood, but decreased significantly with hypertrophy at adult age. Myocyte nuclei showed increased polyploidization during childhood which was progressive with age, and in the adult stage polyploidization was correlated with heart weight. Nevertheless myocardial DNA concentration fell under both conditions, which is to be ascribed to the ‘diluting’ effect of myocyte hypertrophy.

Before an age of 8 years DNA concentration in the child heart material studied has reached the value found in adult nonhypertrophic hearts, although at that time polyploidization of myocyte nuclei in child hearts was only half the value found in adult nonhypertrophic hearts. Biochemical measurement of DNA concentration in peroperatively taken myocardial biopsies may contribute to the in vivo diagnosis of ventricular hypertrophy in quantitative terms, in combination with radiology, echocardiography and histology.
Relationships of plasma lipoprotein concentrations to unbound, albumin‐bound and sex hormone‐binding globulin‐bound fractions of gonadal steroids in men
Authors: NANJEE M. N. , RAJPUT‐WILLIAMS J. , SAMUEL L. , WOOTTON R. , MILLER N. E.
Published: March 2008

Abstract. Most epidemiologic studies of plasma lipoproteins and gonadal steroids have measured total hormone concentrations only. Gonadal steroids are transported in plasma in unbound, albumin‐bound and sex hormone‐binding globulin (SHBG)‐bound forms, only the first two of which are biologically active. In the present study the associations of plasma lipoproteins with the different fractions of testosterone, oestradiol and 5α‐dihydrotestosterone (5αDHT) were explored by multiple regression in 70 men aged 52–67 years (mean, 59 years). The principal finding was that the distribution of cholesterol between the two major subclasses of high density lipoprotein (HDL) was correlated with the concentrations of unbound and albumin‐bound oestradiol, but not with SHBG‐bound oestradiol or any fraction of testosterone or 5αDHT. These associations were independent of plasma triglyceride. Apoproteins A‐I and A‐II were not correlated with any hormone fraction. Thus, in middle‐aged/elderly men HDL subclasses appear to be influenced by circulating estrogenic activity, but not by androgenic activity, through a mechanism that is unrelated to triglyceride transport or HDL apoprotein metabolism.
Effects of a bolus dose of atrial natriuretic factor in young and elderly volunteers
Authors: HEIM J.‐M. , GOTTMANN K. , WEIL J. , STROM T. M. , GERZER R.
Published: March 2008

Abstract. We assessed the haemodynamic and renal effects as well as the effects on plasma cGMP levels of a small i.v. dose (33 μg) of human atrial natriuretic factor (99–126; hANF) in two age groups of healthy volunteers. Binding properties of platelet ANF receptors were also measured. The elderly (four males, eight females, mean age 52.3 years) showed increased haemodynamic (decrease in blood pressure) and renal responses (diuresis, natriuresis, calciuresis) as well as greater increases in plasma cGMP levels and urinary cGMP excretion than the young subjects (four males, 12 females, mean age 26 years). Binding capacities and affinities of platelet ANF receptors were identical in both groups.

These data indicate that the sensitivity to ANF increases with age and that this increased sensitivity is reflected in the reactivity of plasma cGMP levels but not in the properties of platelet ANF receptors. The data may be important for the therapeutic use of ANF, for the understanding of the physiological regulation of ANF action and may underline the necessity of using age‐matched control subjects for clinical studies on the possible therapeutic effectiveness of ANF.
Renal responsiveness to synthetic human parathyroid hormone 1–38 in healthy subjects
Authors: ROELEN D. L. , FRÖLICH M. , PAPAPOULOS S. E.
Published: March 2008

Abstract. Renal responsiveness to synthetic human parathyroid hormone (HPTH) 1–38 was examined in seven healthy volunteers. Each subject received three different doses (35 μg, 17.5 μg, 8.75 μg) as bolus intravenous injections. Rapid, transient, dose‐dependent decreases in diastolic blood pressure and increases in heart rate were observed, as reported previously in animal studies, suggesting an acute vasodilatory effect of the hormone. The extracellular cyclic AMP responses were brisk and dose‐dependent in the group as a whole as well as in the individual subjects. In contrast, the phosphaturic responses, though statistically significant with all three doses, were of a lesser magnitude and showed an individual variability. Nearly maximal decreases in TmP/GFR were found even after the lowest dose with minimal increases in cyclic AMP in some subjects. The injections of HPTH 1–38 also induced a dose‐dependent natriuresis which was accompanied by an increase in excreted calcium. It seems that under these experimental conditions the sodium‐dependent renal calcium transport cannot be compensated by the effects of the hormone on the distal tubule. HPTH 1–38 can be safely and predictably used for the assessment of renal responsiveness to PTH in routine clinical practice.
Changes of immunoregulatory cells induced by acoustic stress in patients with systemic lupus erythematosus, sarcoidosis, and in healthy controls
Authors: HINRICHSEN H. , BARTH J. , FERSTL R. , KIRCH W.
Published: March 2008

Abstract. In order to determine whether the characteristically attenuated cell mobilization after physical stress in patients with systemic lupus erythematosus (SLE) or sarcoidosis is disease specific or the result of lower tolerance for such stress, SLE and sarcoidosis patients as well as healthy volunteers were subjected to an acoustic stress model, independent of physical capacity. After a 10‐min period of intermittent acoustic stress, healthy subjects showed significant increases in leucocyte and lymphocyte counts, marked relative elevations of B and T suppressor cytotoxic lymphocytes (P < 0.01), and a relative reduction in T helper lymphocytes (P < 0.01). By contrast, this degree of change was significantly less pronounced in the 14 female SLE patients studied (P < 0.01) as compared with the healthy controls, but not in the 12 sarcoidosis patients tested. No dependence was found between the severity of disease or administration of corticosteroid therapy and cell mobilization. It is yet to be determined whether the attenuated response of SLE patients to stress is a consequence of pathophysiological mechanisms or plays an aetiopathogenic role in the course of the disease.
Oestrogen‐induced changes in lipoprotein metabolism: role in prevention of atherosclerosis in the cholesterol‐fed rabbit
Authors: HENRIKSSON P. , STAMBERGER MONIKA , ERIKSSON M. , RUDLING M. , DICZFALUSY U. , BERGLUND L. , ANGELIN B.
Published: March 2008

Abstract. Administration of moderate pharmacological doses of oestrogen to cholesterol‐fed rabbits for 12 weeks resulted in a dramatically retarded development of arterial lesions as compared to non‐oestrogen‐treated, cholesterol‐fed rabbits (7% vs. 47% aortal involvement). Oestrogen treatment was associated with a retarded increase in plasma cholesterol, and five times higher high density lipoprotein (HDL) to very low density lipoprotein (VLDL) cholesterol ratio. Expression of hepatic lipoprotein receptor activity, as detected by heparin‐releasable binding of 125I‐hyper‐cholesterolaemic VLDL, was heavily suppressed by cholesterol feeding. Administration of oestrogen modulated this reponse and resulted in higher receptor expression. In accordance, oestrogen treatment resulted in a less prominent reduction of 125I‐hypercholesterolaemic VLDL clearance in the cholesterol‐fed rabbits. VLDL from both groups of cholesterol‐fed animals stimulated cholesteryl ester synthesis in cultured macrophages to the same extent. Thus, in rabbits under a dietary cholesterol load, oestrogen counteracted hepatic lipoprotein receptor suppression, reduced plasma VLDL‐ and increased plasma HDL‐cholesterol levels, and to a large extent abolished the development of atherosclerosis.
Lipoprotein lipase with a defect in lipid interface recognition in a case with type I hyperlipidaemia
Authors: KOBAYASHI J. , SHIRAI K. , SAITO Y. , YOSHIDA S.
Published: March 2008

Abstract. Defective lipoprotein lipase (LpL) was found in the postheparin plasma (PHP) of a patient with severe hypertriglyceridaemia. The patient was a 14‐year‐old girl with a maximum plasma triglyceride (TG) level of 3600 mg d‐1 who had been suffering from recurrent pancreatitis. The patient's LpL purified from the PHP by heparin‐Sepharose and phenyl‐Sepharose chromatographies hydrolysed tributryrin, but not triolein emulsified with Triton X‐100 and phosphatidylcholine (PC), or in chylomicrons, whereas normal LpL hydrolysed these substrates. Moreover, unlike normal LpL, LpL from the patient did not associate with VLDL, as shown by Sepharose 4B column chromatography. The patient's LpL hydrolysed triolein emulsified with lysophospholipid at a normal rate in the presence of apolipoprotein CII. These findings suggest that this patient has LpL with a normal catalytic site for tributyrin but with a defect in lipid interface recognition resulting in loss of ability to recognize VLDL or chylomicrons, but not of triolein emulsified with lysophospholipid.
Metabolic effects of biosynthetic human proinsulin in type 2 diabetes mellitus
Authors: KLAUSER R. , PRAGER R. , WATSCHINGER B. , SCHERNTHANER G.
Published: March 2008

Abstract. Due to a longer plasma half‐life and half‐time of action on glucose metabolism biosynthetic human proinsulin was thought to be an alternative to long‐acting insulin preparations. To test this hypothesis we studied 23 type 2 diabetic patients who could no longer be treated sufficiently with oral hypoglycaemic agents. After an initial 1 week phase during which all patients received protamine bound insulin twice daily, the patients either continued on NPH insulin (Group A, n= 11) or were randomly switched to human proinsulin (Group B, n= 12). Glucose profiles and peripheral and hepatic insulin sensitivity (euglycaemic clamp: 120 mU m‐2 min‐1) were measured at the end of the initial period (Time 1) and 1 week later (Time 2).

The insulin‐mediated glucose disposal (RD) was not changed after either treatment (group A: 176±18 vs. 192±19 mg m‐2 min‐1; group B: 175 ± 15 vs.174±12 mg m‐2 min‐1 for times 1 and 2, respectively, NS). Suppression of hepatic glucose output (HGO) was complete in both groups at both times. Fasting blood glucose levels (FBG) and basal HGO were equally low at times 1 and 2 (group A: FBG 118 vs. 123 mg dl‐1, BHGO 81 vs. 79 mg m‐2 min‐1; group B: FBG 118 vs. 106 mg dl‐1, BHGO 87 vs. 84 mg m‐2 min‐1; NS). Mean blood glucose levels (MBG) were unchanged in the group receiving NPH insulin (164 vs. 162 mg dl‐1; NS) but improved in group B (182 vs. 142 mg dl‐1; P < 0.001). Blood glucose levels were lower in group B, expecially during the afternoon (from 12.00 to 19.00 h). Insulin requirement was the same in group A at times 1 and 2; in group B the proinsulin dosage was reduced significantly to 33 U day‐1 at time 2 as compared to an insulin dose of 41 U day‐1 at time 1 (P < 0.01). In summary, equal metabolic control can be achieved with proinsulin compared to protamine bound insulin with a lower dose on a unit base for proinsulin. Peripheral and hepatic insulin sensitivity remain unchanged during proinsulin therapy compared to NPH insulin treatment.
Pharmacological control of the human gastric histamine H2 receptor by famotidine:comparison with H1, H2 and H3 receptor agonists and antagonists
Authors: GESPACH C. , FAGOT D. , EMAMI S.
Published: March 2008

Abstract. Histamine 0–1 µM‐0.1 mM increased adenylate cyclase activity five‐ to ten‐fold in human fundic membranes, with a potency Ka = 3 µM. The histamine dose‐response curve was mimicked by the H3 receptor agonist (R) α‐MeHA, but at 100 times lower potency, Ka = 0.3 mM. Histamine‐induced adenylate cyclase activation was abolished by H2, H1 and H3 receptor antagonists, according to the following order of potency IC50:famotidine (0.3 µM) > triprolidine (0.1 mM) thioperamide (2 mM), respectively. Famotidine has no action on membrane components activating the adenylate cyclase system, including the Gs subunit of the enzyme stimulated by forskolin and cell surface receptors sensitive to isoproterenol (β2‐type), PGE2 and VIP. The Schild plot was linear for famotidine (P < 0.01), with a regression coefficient r= 0.678. The slope of the regression line was 0.64 and differs from unity. Accordingly, famotidine showed a slow onset of inhibition and dissociation from the H2 receptor in human cancerous HGT‐1 cells. The results demonstrate that famotidine is a potent and selective H2 receptor antagonist with uncompetitive actions in human gastric mucosa. Consequently, famotidine might be a suitable drug with long‐lasting actions in the treatment of Zollinger‐Ellison syndrome. The results also confirm and extend the previous observations that (R) α‐MeHA and thioperamide are two selective ligands at histamine H3 receptor sites. In the human gastric mucosa, these drugs are respectively 330 and 6700 times less potent than histamine and famotidine on the adenylate cyclase system. The possible involvement of histamine H3 receptors in the regulation of gastric secretion is proposed.
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.
Effect of a soluble bacterial carbohydrate fraction on the viscosity of intestinal contents in healthy subjects and patients with Crohn's disease
Authors: HAZENBERG M. P. , PENNOCK‐SCHRöDER A. M. , WENSINCK F. , MERWE J. P. VAN DE
Published: March 2008

Abstract. Supernatants of faecal suspensions from patients with Crohn's disease (CD) showed much lower viscosity than those from healthy subjects. Material responsible for the viscosity could be precipitated with ethanol. Gel filtration indicated that the viscosity was not due to the glycoprotein fraction but to a fraction with higher molecular weight and relatively high contents of muramic acid suggesting a bacterial origin. The concentration and viscosity of this fraction are less in faeces from patients with CD than in that of healthy subjects.
High plasma levels of a ouabain‐like factor in normal pregnancy and in pre‐eclampsia*
Authors: DELVA P. , CAPRA C. , DEGAN M. , MINUZ P. , COVI G. , MILAN L. , STEELE A. , LECHI A.
Published: March 2008

Abstract. Recent reports have described high levels of one or more substances which cross‐react with digoxin antibodies in the serum of women with pre‐eclampsia. We measured plasma ouabain‐like activity and intra‐erythrocyte sodium and potassium concentrations, in addition to performing routine hypertensive laboratory tests, in 13 normotensive non‐pregnant subjects, 15 normotensive pregnant women and 16 pre‐eclamptic women (gestational age:33–36 weeks). Plasma ouabain‐like activity, measured as plasma‐induced variations in ouabain binding to human erythrocytes, proved significantly higher in both groups of pregnant subjects as compared to normotensive non‐pregnant women, and a significant difference was also found between pre‐eclamptic and normotensive pregnant women, the former exhibiting higher plasma ouabain‐like activity. No differences in intracellúlar sodium and potassium levels were detected among the three groups studied. Though there is reason to believe that the high plasma levels found both in normal and hypertensive pregnancy may depend on placental production, we are not in a position to define with any degree of certainty what the mechanism or mechanisms are that regulate ouabain‐like factor production.
Therapeutic strategies in the management of endocrine GEP tumours
Authors: ARNOLD R.
Published: March 2008

Abstract. The therapeutic principles in the management of endocrine gastroenteropancreatic (GEP) tumours include surgical extirpation of the primary tumour in the absence of metastases and medical control of symptoms in the preoperative phase. In the presence of metastases only palliative procedures are available. Tumour growth might be controlled by surgical procedures as debulking of tumour masses, medically by chemotherapy and more recently by new developments as a long‐acting somatostatin analogue (SMS 201–995) and α‐interferon. Their efficacy is currently evaluated in prospective studies. In contrast to inhibition of growth symptoms derived from excessive hormone production by GEP tumours can be well controlled. SMS 201–995 effectively prevents or at least improves flush and diarrhoea in the carcinoid syndrome, disabling diarrhoea in the Verner‐Morrison syndrome and migratory erythema in the glucago‐noma syndrome. SMS acts by inhibition of hormone release from the tumour and by a direct mechanism at the site of the target cell via SMS receptors present on tumour and target cells. For control of acid hypersec‐retion in gastrinoma patients omeprazole is superior to all former and present alternatives and replaced total gastrectomy completely. A similarly effective drug to prevent hypoglycaemia due to uncontrolled insulin release from insulinomas is not available since neither SMS nor diazoxide are effective in every insulinoma patient.
Normalization of enhanced hepatic gluconeogenesis by the antiglucocorticoid RU 38486 in acutely uraemic rats
Authors: SCHAEFER R. M. , RIEGEL W. , STEPHAN E. , KELLER H. , HÖRL W. H. , HEIDLAND A.
Published: March 2008

Abstract. Hepatic amino acid uptake, urea and glucose production are increased in acute uraemia. It has been shown that this metabolic pattern is mediated by glucocorticoids. Accordingly, the administration of the antiglucocorticoid RU 38486 to acutely uraemic rats resulted in a reduction of serum urea‐N and glucose levels. To clarify whether this effect is due to a reduction in hepatic gluconeogenesis we examined the effect of the antiglucocorticoid RU 38486 on urea and glucose formation in isolated hepatocytes from sham‐operated (SHAM) and bilaterally nephrectomized (BNX) rats receiving RU 38486 or the vehicle only. Hepatic glucose production in BNX rats was considerably increased from Na‐pyruvate (+ 79%), alanine (+ 174%), glutamine (+158%), and serine (+ 87%) compared with SHAM animals. Concomitantly, hepatic urea formation was also enhanced from amino acid substrates in acutely uraemic rats. When uraemic animals were treated with RU 38486, glucose production from amino acids and Na‐pyruvate was reduced to the range of SHAM animals or even lower. This effect could not be demonstrated in SHAM‐operated controls. A comparable decrement in hepatic urea production was observed in BNX rats treated with the antiglucocorticoid. Thus, glucocorticoids appear to play a key role in the abnormal hepatic urea and glucose production of acutely uraemic rats.
Relationship between plasma levels of components of the fibrinolytic system and acute‐phase reactants in patients with uterine malignancies
Authors: KIRCHHEIMER J. C. , KOULBL H. , TATRA G. , BINDER B. R.
Published: March 2008

Abstract. Plasma samples from 17 patients with endo‐metrial cancer and from 52 patients with cervical carcinoma were determined with respect to their levels of components of the fibrinolytic system (tissue‐type plasminogen activator antigen, urokinase‐type plasmi‐nogen activator antigen, plasminogen activator inhibitor activity) and related to the observed alterations of three acute‐phase reactants (C‐reactive protein, coeru‐loplasmin, α‐1‐antitrypsin). As shown previously, uterine malignancies, especially at later stages, exhibited significant increases in plasma levels of urokinase‐type plasminogen activator antigen as compared to an age‐matched control group. In contrast, tissue‐type plasminogen activator antigen and plasminogen activator inhibitor activity remained unchanged. Determination of the acute‐phase reactants revealed significant changes in the case of C‐reactive protein and coeruloplasmin in later tumour stages. However, the increase in urokinase‐type plasminogen activator antigen did not correlate with the increase of either C‐reactive protein or coeruloplasmin plasma level. These data indicate that the increase in plasma urokinase‐type plasminogen activator antigen in patients with uterine malignancies does not follow the pattern of common acute‐phase reactants, like C‐reactive protein or coeruloplasmin.
Accelerated atherogenesis occurs following platelet destruction and increases in megakaryocyte size and DNA content
Authors: KRISTENSEN S. DALBY , ROBERTS K. M. , KISHK Y. T. , MARTIN J. F.
Published: March 2008

Abstract. Platelets and megakaryocytes have a role in atherogenesis. In this study the effect of platelet destruction, caused by injection of serum containing anti‐platelet antibodies, on the development of ather‐oma and on megakaryocyte size and DNA content was studied in rabbits on a high cholesterol diet. Seven days after destruction of the circulating platelets a significant (150% and 300% in two separate studies) increase in the area of alheroma in the aorta was demonstrated. Histological examination revealed that large quantities of extracellular lipid and connective tissue were present in these plaques. The acceleration of atherogenesis in this model was found to be preceded by a significant increase in megakaryocyte size and in the frequency of megakaryocytes with a high DNA content. Platelets derived from large, high ploidy megakaryocytes may be of importance for the development of the atherosclerotic lesion. Neither the endothelial permeability as assessed by injection of Evans blue nor the prostacyclin production by the aorta of animals injected with anti‐platelet scrum were significantly different from the aortas of control animals.
Reduction of lymphocytic β‐adrenoceptor level in chronic alcoholics and rapid reversal after ethanol withdrawal
Authors: MÄKI T. , HEIKKONEN E. , HÄRKÖNEN T. , KONTULA K. , HÄRKÖNEN M. , YLIKAHRI R.
Published: March 2008

Abstract. Plasma catecholamine levels, lymphocytic β‐adrenoceptor densities and lymphocytic cAMP production were studied in 10 male subjects attending a withdrawal clinic after prolonged alcohol abuse. On admission the mean β‐adrenoceptor density was 29 ± 9 fmol mg‐1 protein (about 60% of the mean level of healthy control subjects, P < 0.002). The following day a significant elevation of the β‐adrenoceptor level up to 46±19 fmol mg‐1 protein (P<0.05) took place. This was accompanied by a parallel activation of the β‐adrenoceptor‐mediated cAMP production of the lymphocytes. No major changes in β‐adrenoceptor levels or cAMP production took place during the next 7 days. Plasma catecholamine levels were elevated at arrival and decreased steadily during the withdrawal period.

In conclusion, chronic alcoholism is associated with a reduction of lymphocytic β‐adrenoceptor density and functioning, which is followed by a rapid reversal during abrupt ethanol withdrawal. Thus an accelerated responsiveness to catecholamines may occur during the first ethanol‐free day of chronic alcoholics.
Inhibitory effects of pertussis toxin on the cAMP generating system in human mononuclear leucocytes
Authors: GRIESE M. , GRIESE S. , REINHARDT D.
Published: March 2008

Abstract. In a previous investigation of children infected with pertussis during the first week of paroxysmal stage, we found a 50–75% reduction of the isoprenaline (IPN)‐induced cAMP response in peripheral MN leucocytes. In order to characterize these findings further, intact human MN leucocytes from healthy adults were treated with PT in vitro. Basal, as well as prostaglandin E1‐stimulated cAMP levels were decreased by PT in a dose‐dependent fashion over a range of 0.01 to 1000 ng ml‐1 to about 65% of control levels. Stimulation of PT‐pretreated cells (100 ng ml‐1, 90 min, 37 C) showed significantly reduced IPN and PGE1induced cAMP accumulation, indicated by a depression and shift of the dose response curves to the right. In contrast, cAMP generation was unchanged by forskolin, a diterpene that is believed to directly stimulate adenylyl cyclase. The anti‐allergic drug ketotifen had no direct effects on basal, IPN or PGE1‐ induced cAMP responses; however the inhibitory actions of PT pretreatment on cAMP levels were diminished (basal and isoprenaline‐stimulated) or reversed (PGE1‐stimulated).

To further locate the site of impaired cAMP responses, β‐adrenoceptor binding, as well as displacement characteristics of the receptor, were estimated by 1251‐cyanopindolol binding to a plasma membrane fraction pretreated with or without PT. No differences in β‐adrenoceptor number or in the affinities of the binding sites could be detected. These data are in close agreement with the findings on MN leucocytes from pertussis‐infected children and support the notion of PT‐induced impaired signal transduction in the cAMP generating system in human MN leucocytes.
Cholesterol synthesis in patients with glutathione deficiency
Authors: GUSTAFSSON J. , CARLSSON B. , LARSSON A.
Published: March 2008

Abstract. 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase catalyses the rate‐limiting step in cholesterol synthesis. Glutathione (GSH) has been postulated to be an important activator of HMG‐CoA reductase in vivo.

HMG‐CoA reductase activity was assayed in cultured fibroblasts from healthy children. Solubilized enzyme preparations were prepared by ultracentrifu‐gation after freezing and thawing of fibroblasts. Such treatment increased the relative enzyme activity markedly. Enzymological assay conditions were established. Addition of GSH stimulated the reaction, whereas there was inhibition after addition of glutathione disulphide (GSSG). The inhibitory effect of GSSG could be reversed by the addition of excess GSH.

Fibroblast preparations, deficient in GSH, were obtained from children with glutathione synthetase deficiency or from normal subjects after the growth of fibroblasts in the presence of buthionine sulphoximine. Solubilized enzyme preparations from GSH‐deficient fibroblasts had HMG‐CoA reductase activities lower than or comparable with those of control preparations.

The results indicate only some reduction in the capacity for cholesterol synthesis in subjects with glutathione deficiency.

The existence of additional activation mechanisms in vivo, alternative to GSH, for thiol‐dependent modulation of HMG‐CoA reductase activity seems likely.,
Arachidonic acid absorption in human jejunum in organ culture: effects of ethanol
Authors: BARROS H. , CHEN Q. , FLORÉN C.‐H. , NILSSON Å.
Published: March 2008

Abstract. Human jejunal tissue obtained by peroral biopsy was cultured in control medium and in medium containing 100 mmol 1‐1 ethanol. Subsequently, the incorporation and metabolism of [3H]‐arachidonic and [14C]‐linoleic acid were evaluated. Of the two fatty acids a significantly higher amount of [3H]–arachidonic acid was incorporated into phospholipids and more [14C]–linoleic acid was incorporated into triacylglycer–ols. This preferential distribution of the labelled fatty acids was not affected by ethanol, but when ethanol was present in the tissue culture medium, there was a significant decrease in the incorporation of both fatty acids into tissue phospholipids. The study thus shows that ethanol in moderate concentrations can affect human jejunal absorption and metabolism of poly–enoic fatty acids, contributing to a decrease in the amount of eicosanoid precursors available in jejunal tissue.
Preservation of the porcine pancreas with HTK and Euro‐Collins solution: studies in a reperfusion system
Authors: LEONHARDT U. , BARTHEL M. , TYTKO A. , DRÖGE M. , SIEGEL E. G. , NEBENDAHL K. , KÖHLER H. , CREUTZFELDT W.
Published: March 2008

Abstract. The present study compares the preservation of the porcine pancreas by the standard Euro‐Collins solution or the cardioplegic histidine‐trypto‐phan‐ketoglutarate solution (HTK). The explanted pancreas was stored at 4°C for 6 and 24 h respectively, following which organ quality was assessed in a reperfusion chamber measuring physiological and biomedical parameters. After 6 h ischaemia, the amount of lactate was significantly lower when HTK was used for protection. Other parameters like insulin release, amylase release, vascular resistance and oxygen consumption of the pancreas did not indicate a significant difference. Protection with HTK significantly improved pancreas preservation after 24 h ischaemia: lactate content in the reperfusate was lower (HTK: 64.0±7.2μmol 50 ml‐1
n= 8, v. EC: 114.2pM1–7 μmol 50 ml‐1, n= 6), the arteriovenous flow rate was higher (HTK: 5.7pM0.91 ml min‐1 v. EC: 3.0pM0.26 ml min‐1), and the pancreatic oxygen consumption was increased (HTK: 2.15pM0.22 μl O2 min‐1 g‐1 v. 0.47pM0.08 μl O2 min‐1 g‐1). We conclude that pancreas preservation can be improved in vitro by protection with HTK solution.
Increased high‐density lipoprotein cholesterol concentration in alcoholics is related to low cholesteryl ester transfer protein activity
Authors: SAVOLAINEN M. J. , HANNUKSELA M. , SEPPÄNEN S. , KERVINEN K. , KESÄNIEMI Y. A.
Published: March 2008

Abstract. Cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl esters from HDL to apo B‐containing lipoproteins. Since alcoholics have high HDL cholesterol and low LDL cholesterol levels, a defect in cholesteryl ester transfer could be responsible for the alcohol‐induced alteration in cholesterol distribution between lipoproteins. To test this hypothesis, we compared CETP activity in plasma from 30 alcoholics without severe liver damage and 16 control subjects.

Plasma CETP activity was 28% lower in the alcoholics compared with the controls (P < 0.001), while the teetotallers among the latter had slightly higher CETP activity than those who consumed alcohol in moderation. CETP activity increased slowly after ethanol withdrawal, but did not reach the control level within the 7‐day observation period. A positive correlation was observed between plasma CETP activity and the LDL cholesterol/HDL cholesterol ratio (r= 0.480, P < 0.002), whereas CETP activity showed a negative correlation with HDL cholesterol level (r= ‐0.467, P < 0.001).

The results indicate that defective transfer of cholesteryl esters from HDL to LDL contributes to the high HDL cholesterol levels in alcoholics.
Interferon‐γ reverses the stimulation of collagen but not fibronectin gene expression by transforming growth factor‐β in normal human fibroblasts
Authors: VARGA J. , OLSEN A. , HERHAL J. , CONSTANTINE G. , ROSENBLOOM J. , JIMENEZ S. A.
Published: March 2008

Abstract. It has recently become apparent that several cytokines and growth factors are capable of modulating fibroblast proliferation and biosynthetic activity. To understand the role of these factors in connective tissue regulation, we examined the effects of the simultaneous addition of interferon‐γ (IFN‐γ) and transforming growth factor‐β (TGF‐β) on normal human dermal fibroblast collagen and fibronectin production. In addition, in vitro transcription rates and steady‐state mRNA levels for these molecules were determined by nuclear run‐off assays and Northern and dot‐blot hybridization using specific human cDNA probes. Treatment of cultures with TGF‐β caused stimulation of collagen and fibronectin production. Addition of IFN‐γ to the TGF‐γ‐treated cultures abrogated the stimulatory effects of TGF‐γ on collagen production in a dose‐dependent manner and resulted in a net inhibition of collagen production. In contrast, the increase in fibronectin synthesis induced by TGF‐γ was augmented further by IFN‐γ. These changes in collagen and fibronectin production were accompanied by parallel changes in the steady‐state mRNA levels for these proteins. The effects of TGF‐γ plus IFN‐γ on fibronectin gene expression appeared to be mediated entirely by transcriptional mechanisms, whereas the effects on collagen gene expression resulted from a combination of transcriptional and post‐transcriptional events.
Peripheral and hepatic insulin sensitivity in healthy elderly human subjects
Authors: BROUGHTON D.L. , JAMES O.W.F. , ALBERTI K.G.M.M. , TAYLOR R.
Published: March 2008

Abstract. Insulin resistance has been reported in normal ageing but discrepancies between such studies may be related to compounding factors such as body composition and exercise patterns. We employed a two‐step hyperinsulinaemic euglycaemic clamp to assess peripheral and hepatic tissue insulin sensitivity and glucose recycling in 13 elderly (E) and 14 young (Y) healthy subjects controlling for the above factors. There was no difference in basal hepatic glucose production (E: 2±36 ± 0±06, Y: 2±47 ± 0±1 mg kg–1 min–1; P= 0±4). At step 1 (insulin infusion 15mUkg–1 h–1) glucose turnover was similar (E: 2±65 ± 0±13, Y: 2±88 ± 0±22 mg kg–1 min–1; P= 0±4) but hepatic glucose production was lower in the elderly group (0±20 ± 0±16 vs 0±64 ± 0±10 mg kg–1 min–1; P= 0±03). At step 2 (insulin infusion 50 mU kg–1 h–1) glucose turnover was similar (E: 7±60 ± 0±24, Y: 8±05 ± 0±34 mg kg–1 min–1; P= 0±3) and hepatic glucose production was equal but negative (E: –1±35 ± 0±18, Y: ‐1±34 ± 0±22 mg kg–1 min–1; P= 0±9). Glucose recycling did not differ between the groups at any stage. Similar serum insulin levels were achieved in both groups at each step. Decreased glucose tolerance was confirmed in E with a higher 2 h blood glucose after an OGTT (5±3 ± 0±4 vs 4±1 ± 0±3 mmol l–1; P= 0±03) but incremental insulin response was similar (E: 3236 ± 289, Y: 3586 ± 463 mU l–1 min–1; P= 0±5). We conclude that changes in hepatic tissue insulin sensitivity do not cause the deterioration in glucose tolerance observed with age. A small reduction in both peripheral tissue insulin sensitivity and late insulin secretion may be responsible.
Spinal and forearm bone mass in relation to ageing and menopause in healthy Italian women
Authors: ORTOLANI S. , TREVISAN C. , BIANCHI M.L. , CARACENI M.P. , ULIVIERI F.M. , GANDOLINI G. , MONTESANO A. , POLLI E.E.
Published: March 2008

Abstract. Most studies concerning bone status have been performed in Nordic and Anglo‐Saxon countries and few data are available on southern European populations.

We performed a cross‐sectional study on spine and forearm bone mass in 234 healthy Italian women and related the results to age and time since menopause.

Forearm bone mass does not decline in premenopausal age, whereas, as far as the spine is concerned, a significant reduction appears 3 years before the mean age of menopause; in both cases, the occurrence of menopause accounted for an accelerated phase of bone loss. In postmenopausal women both spine and forearm bone mass show a stronger correlation with years since menopause than with age. According to a linear exponential model, the rate of spinal bone loss per year since menopause is around 4% in the first 3 years which slows down to around 2% in the 5th year; the corresponding rates of forearm bone loss are 2% and 1.3%, respectively.
High‐dose intravenous glutathione in man. Pharmacokinetics and effects on cyst(e)ine in plasma and urine
Authors: AEBI S. , ASSERETO R. , LAUTERBURG B.H.
Published: March 2008

Abstract. Parenteral glutathione has therapeutic potential for targeted delivery of cysteine equivalents. Thus, high doses of reduced glutathione (GSH) protect from the nephrotoxic and urotoxic effects of cisplatinum and oxazaphosphorines. In order to elucidate the underlying mechanisms the kinetics and the effect of glutathione on plasma and urine sulphydryls were studied in 10 healthy volunteers. Following the intravenous infusion of 2 g m–2 of glutathione the concentration of total glutathione in plasma increased from 17±5 ± 13±4 μmol l‐1 (mean ± SD) to 823 ± 326 μmol l–1. The volume of distribution of exogenous glutathione was 176 ± 107 ml kg–1 and the elimination rate constant was 0±063 ± 0±027 min–1 corresponding to a half‐life of 14±1 ± 9±2 min. Cysteine in plasma increased from 8±9 ± 3±5 μmol l–1 to 114 ± 45 μmol l–1 after the infusion.In spite of the increase in cysteine, the plasma concentration of total cyst(e)ine (i.e.cysteine, cystine, and mixed disulphides) decreased, suggesting an increased uptake of cysteine from plasma into cells. Urinary excretion of glutathione and of cyst(e)ine was increased 300‐fold and 10‐fold, respectively, in the 90 min following the infusion. The present data suggest that the concentration of sulphydryls in the urinary tract and, more importantly, the intracellular availability of cysteine increase markedly following parenteral glutathione. The high intracellular concentration of cysteine may protect against cisplatinum and oxazaphosphorine toxicity either directly or indirectly by supporting the synthesis of glutathione.