bluuebunny/crossref_metadata_2025 huggingface dataset:
Post‐prandial lipoprotein metabolism in nephrotic syndrome
Authors: WARWICK G. L. , PACKARD C. J. , STEWART J. P. , WATSON T. D. G. , BURNS L. , BOULTON‐JONES J. M. , SHEPHERD J.
Published: March 2008

Abstract.Post‐prandial lipaemia was investigated in a group of nine subjects with nephrotic syndrome by following the concentrations of triglyceride and retinyl palmitate in the d< 1.006 g ml‐1fraction of plasma after a standard oral fat load containing vitamin A. Lipoprotein lipase and hepatic triglyceride lipase activities were measured in post‐heparin plasma. Subjects with other renal disease but insignificant protein‐uria acted as controls. The time course of the lipaemic response was similar in both groups although individual patients demonstrated a prolonged lipaemia. Overall, there were no significant differences in the rise in triglyceride at 6 h (nephrotic—median 2.53 mmol 1‐1; range 0.87–4.76 vs. control 1.88; 0.38–4.12,p= 0.34), the peak concentration of retinyl palmitate (nephrotic 0.87 mg dl‐1; 0.27–2.16 vs. control 0.65; 0.24–1.89,P= 0.97) or the areas under the curve from 0.24 h for triglyceride (nephrotic 10.5 mmol. h l‐1; 2.9–43.6 vs. control 9.7; 4.3–27.0,P=l.0) or retinyl palmitate (5.5 mg.h dl‐1; 1.0–23.4 vs. 4.3; 1.5–12.4,P= 0.7). At baseline, the particles in the d < 1.006 g ml‐1fraction of plasma from nephrotic subjects had a higher free cholesterol: phospholipid ratio but this difference was no longer apparent 6 h after the test meal. There were no differences in total heparin‐releasable lipase, lipoprotein lipase or hepatic triglyceride lipase activities between the two groups. These data suggest that impaired clearance of chylomicrons is not a major contributor to nephrotic hyperlipidae‐mia in man.
Uptake of chylomicron remnant retinyl esters in human leukocytes in vivo
Authors: SKREDE B. , BLOMHOFF R. , MÆLANDSMO G. M. , OSE L. , MYKLEBOST O. , NORUM K. R.
Published: March 2008

Abstract. Retinoids have been successfully used in the treatment of some forms of leukaemia, suggesting that such cells have an efficient uptake mechanism for circulating retinoids. Therefore, we have studied the uptake of lipoprotein‐associated retinyl esters in human leukocytes in vivo. After an oral load of 100 μmol retinyl palmitate (30000 retinol equivalents) per square meter given to healthy adults, the concentration of retinoids in circulating leukocytes was determined. A peak was measured after 5 h, which coincided with a peak of retinyl esters in plasma.

To test whether low‐density lipoprotein receptors are necessary for the postprandial uptake of retinoids, we studied retinoid uptake in leukocytes from two patients homozygous for familial hypercholesterolae‐mia. After an oral load of retinoids we found that leukocytes from these patients took up at least as much retinoid as leukocytes in normal individuals, suggesting that uptake of chylomicron remnant retinyl esters may proceed independent of the low‐density lipoprotein receptor. The expression of mRNA for the low density lipoprotein receptor‐related protein, which is a putative chylomicron remnant receptor, was similar in leukocytes from a patient homozygous for familial hypercholesterolaemia and normal individuals.

Six hours after vitamin A administration, recovery of unesterified retinol was 71% in normal leukocytes, however, only 9% unesterified retinol was recovered in leukocytes from the two patients with familial hypercholesterolaemia. Thus, the apparent rate of retinyl ester hydrolysis was markedly reduced in leukocytes from these patients, indicating different intracellular traffic of chylomicron remnants in normal individuals and patients homozygous for familial hypercholesterolaemia.
Glucagon‐like peptide‐1 cells in the gastrointestinal tract and pancreas of rat, pig and man
Authors: EISSELE R. , GÖKE R. , WILLEMER S. , HARTHUS H.‐P. , VERMEER H. , ARNOLD R. , GÖKE B.
Published: March 2008

Abstract. A highly specific monoclonal antibody directed against the C‐terminal part of glucagon‐like peptide‐1 (GLP‐1) was raised to immunohistochemi‐cally evaluate the distribution of GLP‐1 containing cells in the entire gastrointestinal tract including pancreas of rat, pig and man. In the pancreas GLP‐1 ‐immunoreactive cells were found variously shaped and predominantly located in the periphery of the islets. Ultrastructurally, GLP‐1 was co‐localized with gluca‐gon in the α‐granula of A‐cells and was mainly restricted to the electrondense core. In the intestine open type cells reaching the lumen via a slender apical process were stained with the GLP‐1 antibody. They occurred in all parts of the crypts but predominantly in the basal portion. The density of GLP‐1 immuno‐reactive cells varied between species in a characteristic order: rat > pig > man. In pig and human gut a large number of cells occurred in the distal jejunum and ileum. A continuous increase of cell densities was found from the proximal to the distal colon resulting in highest numbers in the rectum. In rats the highest cell density occurred in the ileum. Again, a continuous increase of GLP‐1‐positive cell numbers was evident from the proximal to the distal portion of small and large bowel. GLP‐1 was partly co‐localized with PYY. The GLP‐1 positive cells appeared electronmicrosco‐pically as L‐cells with the typical large granula. This morphological data indicates that GLP‐1‐releasing cells in the small intestine are appropriately positioned in the distal part to sense and respond to the presence of nutrients that have escaped the absorptive surface of the upper small intestine.
Intrinsic hepatic clearance of indocyanine green in the pig: Dependence on plasma protein concentration
Authors: OTT P. , KEIDING S. , BASS L.
Published: March 2008

Abstract. Intrinsic hepatic clearance (K) of indocyanine green (ICG) is used as a quantitative measure of liver function. ICG is tightly bound to plasma proteins. The purpose of this study was to examine the effect of changes of plasma protein concentration on K. in anaesthetized pigs with intact hepatic circulation. In addition, an attempt was made to evaluate the corresponding changes of the unbound intrinsic clearance of ICG. The plasma protein concentration was changed by exchange of plasma with either dextran‐70 or donor pig plasma. Plasma albumin concentration was measured in a peripheral artery and changes of the concentrations of other plasma proteins were assumed to parallel those of albumin. ICG was given as a constant infusion and K was calculated from peripheral artery and hepatic vein concentrations of ICG according to the sinusoidal perfusion model. One experimental series comprised 3 measurement periods: From Period 1 to Period 2 (eight animals) albumin concentration was decreased by 36.6 ± 6.5% (Mean±SD). This was associated with an increase of K of 32.8 ±28.8% (P= 0.004). From Period 2 to 3 (five animals) albumin was increased by 13.2 ± 3.2% and K decreased by 18.5 ± 8.3% (P= 0.03). In the second experimental series (eight animals), albumin concentration was increased by 21.6± 10.3% and K decreased by 20.3± 8.1% (P= 0.001). For both series, changes in albumin concentration were associated with oppositely directed changes of K in 20 out of 21 comparisons (P < 0.001). Thus K depends not only on hepatocyte function but also on plasma protein concentration. This finding should affect interpretation of K when used as a liver function test. Changes of the unbound intrinsic clearance of ICG were examined indirectly by means of the K · a product (a: albumin concentration). According to the overall evaluation of the data the unbound intrinsic clearance of ICG was not affected by the changes in plasma protein concentration, but the results were internally inconsistent, apparently due to a time‐dependency of the K · a product. We suggest this to be due to a slow but steady decrease of the ‘background’ K. After correction for the average decrease of K of 0.102% per min our data were in accordance with the hypothesis that the unbound clearance of K was enhanced by the binding protein(s) of ICG.
Effects of cholestyramine and acipimox on subf ractions of plasma low density lipoprotein. Studies in normolipidaemic and hypercholesterolaemic subjects
Authors: GRIFFIN B. A. , CASLAKE M. J. , GAW A. , YIP B. , PACKARD C. J. , SHEPHERD J.
Published: March 2008

Abstract. Two independent studies were designed to investigate the separate and combined effects of acipimox and cholestyramine on plasma low density lipoprotein subfractions. In the first study, normolipidaemic subjects were given cholestyramine (16 g day‐1, 4 weeks), followed, after an 8‐week wash‐out period, by acipimox (750mg day‐1, 4 weeks). In the second study, moderately hypercholesterolaemic subjects were prescribed acipimox (1250mg day‐1, 10 weeks), followed by acipimox in combination with low dose cholestyramine (12g day‐1) for a further 10 weeks. In the normal subjects, cholestyramine decreased total LDL mass (density (d)= 1.019–1.063g ml‐1) by selectively reducing the largest, least dense LDL‐I(d 1.025–1.034 gml‐1, P < 0.05) and LDL‐II (d 1.034–1.044 g ml‐1, P<0.005) subfractions. The small, dense LDL‐III (d 1.044–1060 g ml‐1) showed a variable response to the resin. In the same subjects acipimox produced no overall change in total LDL mass but showed a tendency to redistribute LDL towards LDL‐I (+10%) and LDL‐II (+10%) in a manner related to the changes in plasma triglyceride (TG) (TG vs. LDL‐III r= 0.75, P <0.05). In the hypercholesterolaemic subjects acipimox induced a substantial redistribution of LDL subfractions (LDL‐1 + 84%P <0.05; LDL‐III‐50%) without affecting total LDL mass. The addition of cholestyramine produced a significant decrease in total LDL mass which was again confined to the LDL‐I (‐28%) and LDL‐II (‐23%) subfractions. These consistent and complementary changes in discrete LDL subfractions may, in part, explain the hypolipidaemic potency of acipimox in combination with low dose cholestyramine. In view of the association between LDL subfrac‐tion profile and coronary heart disease risk, this particular combination of drugs may represent an effective regimen for the modification of an athero‐genic lipoprotein phenotype.
Human macrophages modulate the phenotype of cultured rabbit aortic smooth muscle cells through secretion of platelet‐derived growth factor
Authors: MORISAKI N. , KOYAMA N. , KAWANO M. , MORI S. , UMEMIYA K. , KOSHIKAWA T. , SAITO Y. , YOSHIDA S.
Published: March 2008

Abstract. Phenotypic change of aortic smooth muscle cells (SMC) is a key step for their abnormal proliferation in atheromatous lesions. In this study modulation of the growth properties of SMC by macrophages was investigated to clarify the mechanism regulating the SMC phenotype. Cultured rabbit SMC preincu‐bated with either macrophages derived from human peripheral monocytes, or conditioned medium from macrophages grew faster than control SMC in the absence of either macrophages or conditioned medium. SMC preincubated with purified platelet‐derived growth factor (PDGF) also grew faster than control SMC in the absence of PDGF, and their rapid growth was maintained for at least two passages. SMC preincubated with conditioned medium of macrophages plus anti‐PDGF antibody did not grow faster than control SMC. Furthermore SMC preincubated with PDGF acquired the ability to secrete some mitogen, which differed from PDGF. These results suggest that macrophages modulate the phenotype of SMC by a mechanism mediated by PDGF. As a result the SMC grow faster and at the same time secrete some mitogen probably distinct from PDGF in an autocrine manner.
Determinants of coronary effects of atrial natriuretic factor in dogs
Authors: ERTL G. , BAUER B. , GAUDRON P. , KOLB M. , KOCHSIEK K.
Published: March 2008

Abstract. The direct vascular action of atrial natriuretic factor (ANF) is unclear. In coronary vasculature, vasodilation has been reported as well as vasoconstric‐tion. Doses of ANF, baseline plasma ANF levels and interference with the renin‐angiotensin system might account for the controversy. We tried to further analyse determinants of the effect of ANF on coronary blood flow in anaesthetized dogs. The chest was opened and the left anterior descending coronary artery cannulated and perfused at constant normal (= 76 ±5 mmHg, n= 10) or reduced (= 37 ± 3 mmHg, n= 10) pressure from the femoral arteries. At normal coronary perfusion pressure, ANF (1 ng kg‐1 i.c.) reduced coronary flow from 30.7 ± 4.2 to 26.9 ± 4.0 ml min‐1 (P<0.05). This effect was no longer significant at reduced coronary perfusion pressure (4.9 ± 0.8 vs. 4.6 ± 0.7 ml min‐1). ANF (1 ng kg‐1 i.c.) reduced coronary blood flow in correlation with baseline plasma ANF levels (r= 0.77, P< 0.001). However the large variability of the constrictor effect of ANF in the rather small range of baseline plasma ANF, weakens the importance of this result and suggests other additional determinants. ANF (100 ng kg‐1 i.e.) significantly increased coronary blood flow by 16–23% (P<0.05). In a second series of experiments, the converting enzyme inhibitor captopril (0.25 mg kg‐1 i.c. followed by 0.25 mg kg‐1 h‐1, i.c., n= 8) and the angiotensin II receptor blocker saralasin (1 μg kg‐1 min‐1, i.c., n=9) significantly reduced the coronary dilator effect of ANF while coronary flow was similar after repeated injections in control animals (n= 6). Thus, lower doses (1 ng kg‐1 i.c.) of ANF may induce coronary constriction. The occurrence and extent of coronary constriction is variable and depends to some extent on baseline ANF levels. Higher doses of ANF (100 ng kg‐1 i.c.) consistently induce coronary dilatation which results at least in part from interference with the renin‐angiotensin system.
Reappraisal of the role of insulin on sodium handling by the kidney: effect of intrarenal insulin infusion in the dog
Authors: BRIFFEUIL P. , THU T. HUYNH , KOLANOWSKI J.
Published: March 2008

Abstract. Since several studies suggest that increased insulin levels may induce antinatriuresis, the present work was undertaken to determine whether a physiological increase in insulin levels in blood perfusing the kidney may exert direct effect on kidney function, and more specifically on sodium reabsorption. To this end, insulin was infused directly into one renal artery of 10 anaesthetized dogs at the rate of 4 mU min‐1 for a period of 90 min. The contralateral kidney was infused with saline alone, to provide reference values. Insulin level in the renal vein of the insulin‐infused kidney went up from 1.4±0.9 before to 30.6±71 μU ml‐1 after 90 min of insulin perfusion. There was no significant effect on renal plasma flow, glomerular filtration rate and renal uptake of substrates or oxygen between ipsi‐ and contralateral kidney. The fractional excretion of sodium was likewise unaffected, since it averaged at the end of insulin infusion 0.41±0.11 % vs. 0.50 ± 0.14% for the contralateral saline infused kidney. Even if one may assume that the baseline low insulin concentrations promote tubular sodium reabsorption, the results of the present study suggest that a moderate hyperinsulinaemia is without any additional effect on renal sodium handling.
Graves' immunoglobulins and cytokines stimulate the expression of intercellular adhesion molecule‐1 (ICAM‐1) in cultured Graves' orbital fibroblasts
Authors: HEUFELDER A. E. , BAHN R. S.
Published: March 2008

Abstract. Intercellular adhesion molecule‐1 (ICAM‐1) and lymphocyte function‐asociated antigen‐1 (LFA‐1) are cell surface adhesion receptors that bind to one another and promote a variety of effector/target cell interactions in tissues affected by inflammatory or immune processes. Local infiltration of the thyroid gland and the retro‐ocular space by mononuclear cells is a hallmark of Graves' disease and Graves' ophthal‐mopathy (GO). Thus, we studied the role of these adhesion receptors in the interaction of inflammatory cells with retro‐ocular fibroblasts (OF) derived from patients undergoing transantral decompression for severe GO, and from normal individuals. Confluent OF‐monolayers were incubated with various cytokines or protein‐A affinity‐purified IgGs prepared from sera of patients with severe GO, Hashimoto's thyroiditis (HT), rheumatoid arthritis (RA) and normal individuals. As determined by immunocytochemistry and immunoprecipitation using a monoclonal anti‐ICAM‐1 antibody, interleukin‐1 ‐alpha (I L‐1a), tumour necrosis factor‐alpha (TNFa) and interferon‐gamma (IFNg) strongly enhanced surface expression of ICAM‐1 in both GO‐ and normal OF. By contrast, Graves' IgGs stimulated ICAM‐l expression only in GO‐, but not in normal OF. No effect was observed in either cell type with interleukin‐2, transforming growth factor‐beta, or IgGs from patients with HT, RA and normal individuals. Using phorbol ester‐activated, 51Cr‐labelled peripheral blood mononuclear cells (PBMCs) in a cell adhesion assay, we demonstrated potent adhesive activity of ICAM‐1 in GO‐OF pretreated with IL‐1a, TNFa, IFNg or Graves' IgGs, while all other compounds did not affect PBMC adhesion to GO‐OF. In other studies, PBMCs or GOOF were pre‐incubated (following stimulation with cytokines or Graves' IgGs) with monoclonal antibodies against ICAM‐1 or LFA‐1‐alpha. While PBMC‐adherence was only partially inhibited by anti‐ICAM‐1 antibody, anti‐LFA‐1‐alpha almost completely blocked cell attachment. In conclusion, inflammatory cytokines and Graves' IgGs are potent modulators of ICAM‐1/LFA‐1‐mediated interactions between immunocompetent cells and GO‐OF. These mechanisms likely play a role in the localization of the inflammatory infiltrate within the orbit and may affect antigen presentation and maintenance of the chronic immune process in GO.
Normal lipoprotein(a) concentrations and apolipoprotein(a) isoforms in patients with insulin‐dependent diabetes mellitus
Authors: KLAUSEN I.C. , SCHMIDT E. BERG , LERVANG H. H. , GERDES L. U. , DITZEL J. , FAERGEMAN O.
Published: March 2008

Abstract. Lipoprotein(a) [Lp(a)] is an LDL particle in which apoliporotein B‐100 is attached to a large plasminogen‐like protein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined phenotypes differing in molecular weight, to which Lp(a) concentrations in plasma are inversely correlated, and plasma Lp(a) concentrations above 20–30 mg dl‐1 are an independant risk factor for ischaemic heart disease (IHD).

To investigate whether Lp(a) could be important for the high cardiovascular mortality rate in patients with insulin dependent diabetes mellitus (IDDM), we determined Lp(a) concentrations and phenotypes in a group of 108 men (median age 32 years) with IDDM without nephropathy. A group of 40‐year‐old men (n= 466) served as controls. The median Lp(a) concentration was 7.4 mg dl‐1, [95% CI 4.9 to 11.7] in the diabetic patients and 6.3 mg dl‐1 [95% CI 5.2 to 7.0] in controls. The Lp(a) concentration exceeded 30 mg dl‐1 in 22% of IDDM patients and in 20% of controls (P= 013). Moreover, the distribution of apo(a) phenotypes did not differ between patients and control.

Lp(a) levels and apo(a) phenotypes are thus apparently the same in IDDM patients without nephropathy and controls. These findings do not exclude the possibility that Lp(a) may be increased in patients with nephropathy in whom coronary artery disease frequently co‐exist or that Lp(a) in a given concentration is more atherogenic in IDDM patients than in persons without IDDM.
Increased GPIIB/IIIA expression and altered DNA‐ploidy pattern in megakaryocytes of diabetic BB‐rats
Authors: TSCHÖPE D. , SCHWIPPERT B. , SCHETTLER B. , KIESEL U. , ROTHE H. , ROESEN P. , GRIES F. A.
Published: March 2008

Abstract. Hyperactive platelets contribute to angio‐pathic complications in diabetes mellitus. It is unclear whether the increased platelet function is a primary pathogenetic factor in diabetes or follows vascular injury. Increased platelet size and numbers of glyco‐protein receptors on diabetic platelets suggest that thrombopoiesis is altered in diabetes mellitus. For further support of this hypothesis we studied whether megakaryocytes are changed with regard to the DNA‐ploidy pattern and the GPIIB/IIIA expression in 10 acute diabetic (AD) and 24 insulin treated diabetic (ITD) BB rats in comparison with 22 diabetes resistant (ND) BB rats. In the AD group megakaryocyte size (P=0.035) and the modal DNA‐ploidy distribution dropped (P=0.0001) concomitant with increased TNF‐alpha activity (P=0.001). GPIIB/IIIA expression and the peripheral platelet status were unchanged. After 4 weeks of insulin substitution metabolic parameters (glucose, cholesterol, triglycer‐ides) were lowered, but remained still elevated. As compared to the AD group the modal DNA‐ploidy pattern reversed, but the relative percentage of 64n megakaryocytes increased 2.3‐fold and GPIIB/IIIA expression increased 1.6‐fold. Simultaneously, the peripheral platelet count and size increased. From these results we conclude that alterations of the megakaryocyte compartment occur at early onset of diabetes. These changes could reflect a response to increased systemic cytokine production during inflammatory islet cell destruction. The peripheral platelet thrombotic potency increased with insulin treatment. This was associated with an increase of 64n‐megakary‐ocytes with upregulated GPIIB/IIIA expression and could reflect a mitogenic effect of insulin upon the endomitotic cycle of the megakaryocytes.
Severe type III hyperlipoproteinemia associated with unusual apolipoprotein E1 phenotype and & epsilon;1/lsquo;null genotype‡
Authors: FEUSSNER G. , FUNKE H. , WENG W. , ASSMANN G. , LACKNER K. J. , ZIEGLER R.
Published: March 2008

Abstract. A 60‐year‐old white male (KH) was diagnosed to suffer from severe type III hyperlipoproteinemia (HLP) and premature cardiovascular disease. Biochemical analysis revealed an unusual apolipoprotein (apo) E phenotype and genotype. All clinical characteristics of type III HLP were present in the patient. His very low density lipoprotein (VLDL) cholesterol to plasma triglyceride (TG) ratio was elevated at 0.97 without therapy which is unusually high (normal ratio about 0.18). By contrast his plasma apo E level was only moderately elevated (6.8 mg dl‐1). The patient's apo E migrated in the apo El position on isoelectric focusing gels. Chemical modification with cysteamine and treatment with neuraminidase confirmed the presence of two cysteine residues in the patient's apo E and a normal sialylation pattern. Pedigree analysis suggested that the patient was a compound heterozygote with one apo ε l allele and another allele whose product did not appear in the plasma compartment (‘null’ allele). Direct sequencing of polymerase chain reaction (PCR) amplified segments of the apo E gene as well as restriction fragment length polymorphism (RFLP) analysis with the endo‐nuclease Taq I identified an adenosine for guanosine (G←A) exchange in the second base of codon 127 that is predictive for an Asp for Gly substitution in the encoded apo E amino acid sequence. This mutation is the structural basis for the apo E l isoform identified upon isoelectric focusing. Five other family members are also carriers of the mutant apo εl allele. Two of those were hyperlipidemic and exhibited biochemical characteristics of type III HLP. A second mutation, a deletion of a G in codon 31, is predictive for a reading frameshift that encodes for a premature stop in codon 60. Our inability to identify the product of a second apo E allele in the plasma of the patient and two other members of the KH family corresponds with the heterozygous presence of this mutation in the affected individuals. Both relatives (like the index case) had an increased VLDL cholesterol to plasma TG ratio, which indicates the presence of cholesterol‐enriched VLDL particles. We propose that the single base deletion in the apo E gene which is the cause of a nonfunctional ‘null’ allele in addition to a probably dominant apo El (Gly127→Asp, Arg158→Cys) variant of late or incomplete penetrance are the primary genetic defects in this kindred leading to severe dysbetalipoproteinemia.
Pancreatic and pituitary hormonal responses to insulin‐induced hypoglycaemia during muscarinic cholinergic blockade in man
Authors: FISHER B. M. , HEPBURN D. A. , FRIER B. M. , MORTON J. J. , BEASTALLD G. H. , GRAY C. E. , BUCHANAN K. D.
Published: March 2008

Abstract. To investigate the role of muscarinic cholinergic mechanisms in mediating the pancreatic and pituitary hormonal responses to hypoglycaemia, six normal subjects were studied during acute insulin‐induced hypoglycaemia under control conditions, and during blockade with intravenous atropine. During atropine blockade the response of pancreatic polypep‐tide was suppressed while the maximum response of plasma glucagon was significantly higher. The increment in plasma vasopressin was also increased significantly during cholinergic blockade. During blockade with atropine the responses of plasma prolactin was reduced, with a slight but significant reduction in the growth hormone response, and although a similar maximum response of plasma ACTH was achieved, this rise was delayed. These results implicate involvement of a cholinergic muscarinic inhibitory and stimulatory mechanisms in regulating the responses of pancreatic and pituitary hormones to hypoglycaemia.
Experimental variations in renovascular resistance in normal man as detected by means of ultrasound
Authors: BARDELLI M. , JENSEN G. , VOLKMANN R. , CAIDAHL K. , AURELL M.
Published: March 2008

Abstract. The pulsatility index (PI) of blood flow velocities has been reported to vary with changes in peripheral vascular resistance. Since blood flow velocities can easily be detected with the Echo‐Color‐Doppler technique in interlobar arteries of normally positioned kidneys, we tried in six healthy volunteers to estimate pharmacological induced variations in renal plasma flow (RPF) and renovascular resistance (RVR) by means of PI measurements.

In this study no significant correlation between the absolute values of PI and RVR was found. In order to correct PI for different blood pressure‐inputs to the renal artery, PI was divided by the pulsatility of the systemic arterial pressure, i.e. the ‘blood pressure index’ [BPI = (SAD‐DAP)/MAP)], resulting in the ‘velocity blood‐pressure index’ (VBI = PI/BPI), which was significantly correlated with RVR (r=0.54, P<0.01). The pharmacological induced changes of RPF and RVR (ΔRPF, ΔRVR) were also correlated to the respective changes of PI and VBI (ΔPI, ΔVBI), with the highest significance when ΔVBI was plotted against ARVR (r = 0.83, P<0.0001). VBI, i.e. the pulsatility index of blood flow velocities as corrected for the pulsatility of the driving force, may be a tool for non‐invasive assessment of changes in RVR and thereby of importance for the diagnosis and follow‐up of renovascular diseases.
Relationship of insulin clearance and secretion to insulin sensitivity in non‐diabetic Mexican Americans
Authors: HAFFNER S. M. , STERN M. P. , WATANABE R. M. , BERGMAN R. N.
Published: March 2008

Abstract. The antecedents of type II diabetes, while still controversial, are thought to involve decreased insulin sensitivity and compensatory hypersecretion of insulin. Mexican Americans have a three‐fold excess risk of type II diabetes and non‐diabetic Mexican Americans are characterized by hyperinsulinaemia and insulin resistance. Few data exist, however, on whether there are defects in insulin secretion and/or clearance in this population. We examined insulin sensitivity, secretion and clearance using combined insulin and C‐peptide measurements analysed by the minimal model technique of Bergman and colleagues in 10 non‐obese, normoglycaemic Mexican Americans and 11 age, sex and obesity‐matched non‐Hispanic whites. Mexican Americans had significantly decreased insulin sensitivity (S1 4.06 s. 7.56, P= 0.017), higher first phase insulin secretion (1.03 nM vs. 0.72 nM) and decreased insulin clearance (0.099 vs. 0.161) than non‐Hispanic whites. Thus, normal Mexican Americans have higher rather than lower insulin secretion suggesting that lower insulin sensitivity may be an early defect in this ethnic group. In addition, they have reduced insulin clearance. Moreover, insulin sensitivity and insulin clearance were positively correlated. We thus speculate that decreased insulin clearance may represent a further autoregulatory mechanism in addition to increased insulin secretion to compensate for decreased insulin sensitivity.
Determinants of fasting plasma triglyceride levels: metabolism of hepatic and intestinal lipoproteins
Authors: CORTNER J. A. , LE N.‐A. , COATES P. M. , BENNETT M. J. , CRYER D. R.
Published: March 2008

Abstract. The contribution of the kinetics of exogen‐eous and endogenous lipoproteins in determining the level of triglyceride in fasting plasma was assessed in a group of 19 normolipidaemic and hypertriglyceridae‐mic subjects. From data derived during a 9‐h infusion of [15N]‐glycine, we have assessed very low density lipoprotein apolipoprotein B production, and from data analysed by kinetic modelling obtained following ingestion of retinol and triolein, we have assessed chylomicron and chylomicron remnant clearance in a group of 19 normolipidaemic and hypertriglyceridae‐mic subjects. A strong positive correlation was observed between the fasting plasma triglyceride level and the reciprocal of the apolipoprotein B fractional synthetic rate (r= 0.83, P<0.01). A positive correlation was also found with the rate of clearance of chylomicron remnants (Sf 20–400; r= 0.87, P<0.01) and of chylomicrons (Sf400; r= 0.69, P < 0.01). No correlation was found between the fasting plasma triglyceride level and either of the plasma post‐heparin lipolytic activities. Multivariate analysis revealed that 95% of the variance in triglyceride levels could be explained by the apolipoprotein B fractional synthetic rate and the chylomicron remnant clearance rate. The strong correlation between chylomicron remnant clearance, a measure of exogenous lipid metabolism, and fasting (hence, endogenous) plasma triglyceride levels suggests that remnants of chylomicrons and very low density lipoproteins share some common components of the removal process.
Plasma apolipoprotein A‐IV metabolism in patients with chronic renal disease
Authors: DIEPLINGER H. , LOBENTANZ E.‐M. , KÖNIG P. , GRAF H. , SANDHOLZER C. , MATTHYS E. , ROSSENEU M. , UTERMANN G.
Published: March 2008

Abstract. The plasma concentration and distribution of apolipoprotein A‐IV were investigated in normo‐triglyceridaemic patients with end‐stage renal disease and compared with those in a sex‐ and age‐matched control group with normal renal function. A three‐fold elevated plasma mean concentration of apolipoprotein A‐IV was found in patients with end‐stage renal disease treated by haemo‐ or peritoneal dialysis (58.5±18.9 mg dl‐1 or 50.5±12.2 mg dl‐1, respectively) compared with the controls (18.3 ± 6.4 mg dl‐1). The plasma distribution of apolipoprotein A‐IV was studied in patients treated by haemodialysis and in controls by gel permeation chromatography. In the haemodialysis group, 40.3% of the apolipoprotein A‐IV was found to be associated with the fraction of high density lipoproteins, whereas the rest (59.7%) was not associated with lipoproteins. This distribution was significantly different from that in the control group (24.8% vs. 75.2%, 0.01 < P<0.05).

The elevated plasma concentrations of apolipoprotein A‐IV in the patients are not related to triglyceride levels and therefore are unlikely to result from an impaired catabolism of triglyceride‐rich lipoproteins. The accumulation of apolipoprotein A‐IV in high density lipoproteins from patients with end‐stage renal disease might reflect the impaired reversed cholesterol transport mechanisms which are believed to be a major cause of the high prevalence of atherosclerotic diseases in these patients.
Raised concentrations of the carboxy terminal propeptide of type IV (basement membrane) procollagen (NC1) in serum and urine of patients with glomerulonephritis
Authors: KELLER F. , SER Y. LYREAL , SCHUPPAN D.
Published: March 2008

Abstract. Type IV collagen is a major component of the glomerular and tubular basement membrane. We used a specific radioimmunoassay to determine (mean ± SD) the concentration of carboxy terminal non‐collagenous fragment (NCI) of type IV procollagen in the serum (normal 6.0± 1.2 ng ml‐1) and urine (normal 1.5 ± 2.0 ng ml‐1)of 142 patients with various kidney diseases. The 15 patients with active glomerulonephritis displayed (anova, Scheffé test) significantly elevated NCI values in their serum (14 ± 8.2 ng ml‐1) as compared with the 32 patients with chronic interstitial nephritis (7.8 ± 30 ng ml‐1), the 17 patients with various other chronic kidney diseases (8.1±2.4 ng ml‐1) and the 23 ambulatory kidney transplant patients (9.1 ± 1.7 ng ml‐1). The highest serum NCI concentrations were found in nine patients with mem‐branoproliferative glomerulonephritis (16± 9.4 ng ml‐1). Sequential serum NCI concentrations in the one patient with active Goodpasture's syndrome were marginally elevated (< 11 ng ml‐1). Serum NCI did not increase with acute interstitial rejection episodes in six kidney transplant patients. The highest urinary NCI concentrations were found in seven patients with minimal change glomerulonephritis (7.5 ± 3.2 ng ml‐1). No correlation was found between serum NCI and serum creatinine, NCI and creatinine clearance, or renal NCI clearance and creatinine clearance. There was a significant correlation between serum NCI and proteinuria. Serum and urinary NCI concentrations were elevated independently from renal function, thus indicating intrinsic renal disease. We conclude that serum and urinary NCI may be useful parameters for distinguishing active damage to the glomerular and tubular basement membrane from other kidney diseases.
lnterleukin‐8 and neutrophil activation in acute pancreatitis
Authors: GROSS V. , ANDREESEN R. , LESER H.‐G. , CESKA M. , LIEHL E. , LAUSEN M. , FARTHMANN E. H. , SCHÖLMERICH J.
Published: March 2008

Abstract. It has been suggested that leucocytes play an important role in the pathogenesis of complicated pancreatitis. Indeed, increased plasma concentrations of neutrophil elastase as a marker of neutrophil activation could be detected in patients with a severe course of the disease. Recently, interleukin‐8 (IL‐8) has been described as a novel neutrophil activating peptide. To determine the role of IL‐8 in acute pancreatitis we measured its serum concentrations by a specific enzyme‐linked immunosorbent assay in 10 patients with acute pancreatitis daily during the first week of hospitalization. IL‐8 levels were compared with plasma concentrations of neutrophil elastase and the clinical course of the disease. Three of the patients had uncomplicated pancreatitis, while seven showed various extrapancreatic complications. Patients with complicated pancreatitis had statistically significant (P<0.05) higher mean values of IL‐8 (121 ±41 pg ml‐1 vs. 13 ± 6 pg ml‐1, mean ± SEM) and neutrophil elastase (547 ± 35 ng ml‐1 vs. 250±20 ng ml‐1) than patients with uncomplicated disease. There was a positive correlation (r= 0.52, P < 0.0001) between IL‐8 and neutrophil elastase in the lower concentration range of IL‐8 (< 100 pg ml‐1). At IL‐8 levels > 100 pg ml‐1 neutrophil elastase was always greatly elevated; however, under these conditions the relationship between IL‐8 and elastase was no longer linear. No measurable IL‐8 concentrations were found when plasma elastase was < 200 ng ml‐1. During follow‐up, initially elevated IL‐8 concentrations decreased in correlation with clinical improvement. In conclusion, the results suggest that IL‐8 contributes to initial neutrophil activation during acute pancreatitis. IL‐8 seems thus to be a factor involved in the pathogenesis of complicated pancreatitis.
Increase of glomerular filtration rate and renal plasma flow by insulin‐like growth factor‐1 during euglycaemic clamping in anaesthetized rats
Authors: BAUMANN U. , EISENHAUER T. , HARTMANN H.
Published: March 2008

Abstract. Renal function was studied in anaesthetized rats receiving i.v. infusions of recombinant human insulin‐like growth factor‐I (IGF‐I) under euglycaemic clamp conditions. IGF‐I increased glomerular filtration rate up to 35% and renal plasma flow up to 100%, this increase being dose dependent with half‐maximal stimulation at serum IGF‐I concentrations of about 24 pmol ml‐1. Renal vascular resistance was reduced up to 50%, filtration fraction decreased up to 30% and urine flow increased up to three fold while arterial blood pressure was unchanged. Renal haemodynamics were affected at serum IGF‐I concentrations that did not stimulate total body glucose disposal during euglycaemic clamping. IGF‐I seemed to regulate renal function through IGF‐I receptors apparently independent of acute changes of glucose metabolism.
Hyperhomocysteinaemia in stroke: prevalence, cause, and relationships to type of stroke and stroke risk factors
Authors: BRATTSTRÖM L. , LINDGREN A. , ISRAELSSON B. , MALINOW M. R. , NORRVING B. , UPSON B. , HAMFELT A.
Published: March 2008

Abstract. Moderate hyperhomocysteinaemia is a frequent finding in atherothrombotic cerebrovascular disease. This study confirms and extends this observation. Hyperhomocysteinaemia was present in 57 of 142 survivors with stroke (40%) and in four of 66 controls (6%). Plasma homocysteine concentrations were increased not only in carotid artery disease or lacunar stroke but also in haemorrhagic or embolic strokes. Homocysteine values were unrelated to the presence of hypertension, smoking, or hypercholester‐olaemia, or to the concentrations of blood glucose, glycosylated haemoglobin, and plasma fibrinogen. Multiple regression analysis of the patient data showed that about 40% of the variation in plasma homocysteine concentrations could be predicted by the values for the homocysteine metabolism cofactors, blood folate and plasma pyridoxal 5‐phosphate and by renal function as reflected in the values for serum creatinine. In patients, urine excretion of homocysteine per unit creatinine was significantly increased and strongly correlated both to the plasma homocysteine concentration and to the values for blood folate, plasma pyridoxal 5‐phosphate, and serum vitamin B12. We conclude that moderate hyperhomocysteinaemia is frequently present in cases of stroke, is independent of other stroke risk factors or the type of stroke, and is partly related to renal function and the concentrations of homocysteine metabolism cofactors.
Clinical pharmacokinetic studies of a human haemopoietic growth factor, GM‐CSF
Authors: HOVGAARD D. , MORTENSEN B. T. , SCHIFTER S. , NISSEN N. I.
Published: March 2008

Abstract. The pharmacokinetics of glycosylated recombinant human granulocyte‐macrophage colony‐stimulating factor (rhGM‐CSF) was studied following intravenous (i.v.) and subcutaneous (s.c.) bolus injection of rhGM‐CSF, 8 μg kg‐1 employing a sensitive radioimmunoassay. After a single i.v. bolus injection, an initial high serum level of rhGM‐CSF was observed, followed by a rapid decrease that occurred in two phases with a half‐life (t1/2) α of 20.0PM 5 min and at1/2 β of 68.3PM 8 min. Following s.c. bolus injection the absorption was more prolonged. Peak serum concentrations did not occur until about 15–20 h, and were followed by a more protracted elimination than by the i.v. route.

In all patients the single rhGM‐CSF injection led to an increase in peripheral white blood cells (WBC), after a temporary drop of 2–5 h duration. The increase in WBC was of longer duration after s.c. than after i.v. bolus treatment. Since the subcutaneous administration leads to prolonged serum concentration of rhGM‐CSF and prolonged increase in peripheral WBC, it seems preferable to i.v. bolus injection, and as effective as continuous i.v. infusion.
Transport of L‐leucine hydroxy analogue and L‐lactate in human small intestinal brush border membrane vesicles
Authors: FRIEDRICH M. , MURER H. , STERCHI† E. , BERGER E. G.
Published: March 2008

Abstract. Nitrogen load can be reduced by substituting dietary protein intake with keto or hydroxy analogues of amino acids. To investigate their intestinal absorption, human jejunal brush border membrane vesicles were used to measure uptake of L‐leucine hydroxy analogue (L‐LHA) and L‐lactate. Uptake assays were performed under voltage‐clamped conditions in the presence of valinomycin and K+ inside and outside. Both inward directed H+‐ and Na+‐gradients stimulated uptake of both substrates. The H+‐gradient was the major driving force and led to an increased rate of L‐LHA or L‐lactate transport. The proton ionophore FCCP abolished the H+‐gradient‐driven but not the Na+‐gradient‐driven uptakes of both substrates. The H+‐gradient‐driven uptake of both substrates was trans‐stimulated by L‐LHA, D‐LHA, L‐valine hydroxy analogue or L‐lactate, respectively. In the presence of a Na+‐gradient the uptake of tracer L‐lactate was trans‐stimulated only after preloading the vesicles with L‐lactate but not by L‐LHA.

It can be concluded that the H+‐gradient‐driven transport of L‐ or D‐hydroxy analogues of branched chain amino acids and L‐lactate across the human intestinal brush border membrane is mediated by the same carrier.
The regulation of megakaryocyte polyploidization and its implications for coronary artery occlusion
Authors: ERUSALIMSKY J. D. , MARTIN J. F.
Published: March 2008

Abstract. Polyploidization is a distinctive feature of megakaryocyte differentiation. The physiological meaning and the regulation of this process are obscure. Megakaryocyte ploidy varies in normal biology and in disease. Here we review the evidence suggesting that ploidy changes may have a role in the determination of platelet reactivity and in the aetiology of coronary artery occlusion. We also present a hypothesis that may serve as a framework to explore the regulation of megakaryocyte polyploidization at the molecular level and also may provide a rational basis to explain the occurrence of ploidy changes in ischaemic heart disease.
Dose‐response study of atrial natriuretic peptide bolus injection in healthy man
Authors: EISKJER H. , PEDERSEN E. B.
Published: March 2008

Abstract. The effects of human atrial natriuretic peptide (ANP) on glomerular filtration rate (GFR), renal plasma flow (RPF), urinary flow rate, urinary sodium excretion, tubular function estimated by lithium clearance, and plasma levels of sodium and water homeostatic hormones were studied in a dose‐response study with 50 healthy subjects. Placebo or ANP 0.5, 1.0, 1.5, or 2.0 μg kg‐1bwt was given as an intravenous bolus injection to five different groups. GFR rose after ANP, whereas no immediate change in RPF was observed. Significant increases with no distinct additional effect of ANP doses higher than 1.0 μg kg‐1were detected in filtration fraction, urinary flow rate and urinary excretion rate of sodium. Both proximal and distal fractional reabsorption of sodium was reduced and the effect seemed to flatten out at doses higher than 1 0 μg kg ‐1. Dose‐dependent increases in cyclic guano‐sine monophosphate in urine and plasma were found after ANP bolus injection, and the rise in both was correlated with the increase in urinary sodium excretion. ANP caused a dose‐dependent decrease in blood pressure and an increase in pulse rate. Plasma concentrations of angiotensin II and arginine vasopressin did not change after ANP.

In summary, we found that ANP bolus injection caused a natriuresis and diuresis in healthy man with a threshold at a dose of 1.0 μg kg‐1. No distinct further renal effects were observed with higher doses despite dose‐dependent increases in urinary cGMP excretion and plasma cGMP. Inhibition of both proximal and distal tubular fractional sodium reabsorption by ANP contributed to the natriuretic effect. The correlation between the rise in cGMP and the increase in urinary sodium excretion is concordant with cGMP being a secondary messenger for ANP in man.
Lymphatic clearance of synovial fluid in conscious pigs: the aminoterminal propeptide of type III procollagen
Authors: JENSEN L. T. , HENRIKSEN J. H. , OLESEN H. P. , RISTELI J. , LORENZEN Ib.
Published: March 2008

Abstract. The aminoterminal propeptide of type III procollagen (PIIINP) in serum is employed as a direct marker of fibrillogenesis. The balance between local fibrillogenesis and serum PIIINP is governed by the transport and possible degradation en route from tissue to circulation. In conscious pigs, we investigated the transport of PIIINP from the knee cavity into the circulation after intra‐articular injection of radiola‐belled PIIINP followed by sequential sampling of thoracic duct lymph, serum and urine. Clearance from the joint space was evaluated by external detection of 131I‐HSA, used as co‐tracer. Lymph samples were gel filtrated to assess possible lymphatic degradation of the intact PIIINP. 125I‐PIIINP and 131I‐HSA were found in thoracic duct lymph within 20 min of the intra‐articular injection. Both isotopes had a biphasic appearance, with the first peak after 60 min and a larger peak after 150 min. During the 6 h observational period 18% of the injected PIIINP was found in the lymph. Gel chromatography of lymph showed the fast formation of a small fraction with a lower MW than that of PIIINP, which suggests that some degradation of PIIINP may occur through the lymphatics. The half‐life of the joint clearance of HSA by bulk flow was assessed to be 8.3 h. The clearance of PIIINP from the joint was estimated to be equal to that of HSA, which indicates that PIIINP leaves the joint space by bulk flow as has been proposed for HSA. Whereas the fractional amount of PIIINP in lymph and blood was lower than that of HSA, in urine the fractional amount of PIIINP was substantially higher than that of HSA. This may be the outcome of a more rapid irreversible degradation of PIIINP than of HSA.

We conclude that I) PIIINP is cleared from the joint space by bulk flow; 2) degradation of PIIINP en route to the circulation cannot be excluded, but is less than 10%, and 3) after disappearing from the joint, PIIINP is distributed in body compartments in a ratio different from that of HSA. Our observations suggest that serum PIIINP may be used as a marker of fibrillogenesis in normal organisms.
Decreased sensitivity to adenosine in platelets from patients with familial hypercholesterolaemia—a change reversed by cholestyramine treatment
Authors: GASSER J. A. , COOPER M. B. , TAN K. C. B. , SAGGERSON E. D. , BETTERIDGE D. J.
Published: March 2008

Abstract. Platelet‐rich plasma was obtained from patients with untreated heterozygous familial hypercholesterolaemia (FH), from FH patients treated with cholestyramine and from control subjects. Responsiveness of platelets to the aggregation inhibitors adenosine, its analogue N‐ethylcarboxamidoadeno‐sine (NECA) and prostaglandin 12 was decreased in FH. Patients on cholestyramine therapy showed normal responsiveness to adenosine and NECA. There were only minor changes in the binding of [3H]NECA to high‐affinity binding sites on platelet membranes from untreated FH or cholestyramine‐treated FH patients. The initial rate of cyclic AMP formation in response to a high concentration of NECA was severely decreased in platelets from FH patients. By contrast, the rate of cyclic AMP formation in response to forskolin or a high concentration of prostaglandin 12 was unchanged. These data point to a defect in the coupling of the platelet A2 adenosine receptor to adenylyl cyclase in untreated FH patients.