bluuebunny/crossref_metadata_2025 huggingface dataset:
High blood pressure and insulin resistance: influence of ethnic background
Authors: FERRANNINI E. , HAFFNER S.M. , STERN M.P. , MITCHELL B.D. , NATALI A. , HAZUDA H.P. , PATTERSON J.K.
Published: March 2008

Abstract. Hyperinsulinaemia links non‐insulin dependent diabetes (NIDDM), obesity, and hypertension, each an insulin‐resistant state in its own right. Insulin resistance predicts the occurrence of NIDDM, and plays a major role in its pathogenesis. We tested the hypothesis that hyperinsulinaemia may also predict hypertension in a sample (n= 2905) of the mixed population of San Antonio, in which hyperinsulinaemia and NIDDM are more prevalent among Mexican‐Americans than non‐Hispanic whites. Whilst in the whole sample the hypertensives had significantly (P < 0.001) higher plasma insulin concentrations than the normotensives, high blood pressure was significantly (P < 0.01) more frequent among non‐Hispanic whites than Mexican‐Americans regardless of diabetes status. After adjusting for factors (age, sex, body mass, and body fat distribution) known to affect insulin levels, a direct relationship between post‐glucose plasma insulin concentrations and prevalence of hypertension was still present in both ethnic groups. In Mexican‐Americans, however, the standardized prevalence of hypertension was significantly (P < 0.001) lower at any given insulin concentration. Post‐glucose plasma glucose levels also were directly related to hypertension prevalence in both groups; again, the regression line was shifted downward and, furthermore, less steep (P < 0.02) in Mexican‐Americans, suggesting relative protection against the negative effect of hyperglycaemia on blood pressure. Dyslipidaemia (higher total cholesterol and triglyceride, and lower HDL‐cholesterol concentrations) was strongly associated with hyperinsulinaemia and blood pressure in both ethnic groups. After adjusting for plasma insulin, only hypertriglyceridaemia was associated with high blood pressure, with no inter‐ethnic difference.

We conclude that in this population hyperinsulinaemia is characteristic of hypertension but does not explain its prevalence against a divergent ethnic background. Other factors that determine high blood pressure must interact with insulin resistance to determine the prevalence rate of hypertension in the population.
The recovery of renal function in rats after release of unilateral ureteral obstruction: the effects of moderate isotonic saline loading
Authors: HARRIS K.P.G. , PURKERSON M.L. , KLAHR S.
Published: March 2008

Abstract. Following 24 h of ureteral obstruction in the rat, renal blood flow and glomerular filtration rate are markedly depressed. The effect of saline loading on post‐obstructive glomerular filtration (GFR) was studied in 15 female Sprague‐Dawley rats in the awake state, 4 h following the release of 24 h of unilateral ureteral obstruction.

Group I (n= 8) received 39 μl min ‐1of 0.9% saline only for 1 h prior to study and Group II (n= 7) received 78 μl min‐1of 0.9% saline for the whole 4 h prior to study. The Cin and CPAH of the post‐obstructed kidney were significantly reduced over control values in both groups. Saline loading (Group II) resulted in an improvement in Cin in the post‐obstructed kidney compared with group I (3.22 ± 0.14 vs.219 ± 0.14 ml/min/kg BW, P < 0.001). This was independent of any change in CPAH.

In two further groups of rats the saline loading protocol was shown to cause a rise in the excretion of urinary cGMP in the post‐obstructed kidney, but not the contralateral control kidney. In addition, administration of exogenous atriopeptin (1–24) to non‐saline loaded animals resulted in a qualitatively similar alteration in renal function to saline loading, namely a rise in Cin and an increase in excretion of cGMP by the post‐obstructed kidney, and no change in CPAH.

The results show that the decrease in GFR following release of unilateral ureteral obstruction may be improved by moderate saline loading possibly by enhancing the release of endogenous atrial peptide, and that the decline in GFR after release of ureteral obstruction is at least in part independent of renal plasma flow.
Muscle protein synthesis in patients with rheumatoid arthritis: effect of chronic corticosteroid therapy on prostaglandin F2α availability
Authors: GIBSON J. N. A. , POYSER N. L. , MORRISON W. L. , SCRIMGEOUR C. M. , RENNIE M. J.
Published: March 2008

Abstract. Using stable‐isotope techniques, we measured rates of quadriceps muscle protein synthesis in twelve women with sero‐positive rheumatoid arthritis. The results were compared to those from the normal limb of seven women with unilateral osteoarthritis of the knee. Six patients had never received corticosteroid immuno‐suppression, but the other six had taken an average of 8 mg Prednisolone per day for 9 years. Quadriceps atrophy was present in both sets of patients with rheumatoid arthritis (normal legs 444 ± 182, rheumatoid 190 ± 40, rheumatoid+steroid 300 ± 110 μg protein/μg DNA, means ± SD, both P < 0·001). Muscle protein synthesis, calculated by comparing the incorporation of 13C‐leucine into biopsy samples taken after an 8 h L‐[1‐13C] leucine infusion with the time averaged enrichment of blood α‐ketoisocaproate, was 0·056 ± 0·005% h‐1 in the patients not receiving steroids compared with 0·050 ± 0·002% h‐1 in normals (P > 0·05) indicating that muscular atrophy was primarily due to an increase in rate of muscle protein breakdown. Intra‐muscular PGE2 concentration was increased in these patients (rheumatoid 0·12 ± 0·06 ng mg‐1 tissue, normals 0·06 ± 0·03 ng mg‐1 tissue, P<0·05). Patients taking corticosteroids had a markedly depressed rate of muscle protein synthesis (0·035 ± 0·008% h‐1, P<0·05) and reduced intra‐muscular PGF2α concentration (P<0·01). We conclude that steroid therapy significantly influences the mechanism of skeletal muscle atrophy in patients with rheumatoid arthritis.
Different β‐adrenoceptor‐effector coupling in human ventricular and atrial myocardium
Authors: SCHWINGER R. H. G. , BÖHM M. , PIESKE B. , ERDMANN E.
Published: March 2008

Abstract. To examine whether the downregulation of β‐adrenoceptors is accompanied by reduced β‐adrenoceptor‐mediated effects in atrial as well as in ventricular myocardium, we investigated the β‐adrenoceptor‐effector coupling in atrial and papillary muscle strips from patients with terminal heart failure (heart transplantation because of dilated cardiomyopathy; New York Heart Association Class IV, NYHA IV) and moderate heart failure (mitral valve replacement, NYHA II‐III) and in tissue from non‐failing hearts. The isometric force of contraction induced by isoprenaline (0·001‐1 μmoll‐1) or Ca2+ 1·8–15 mmoll‐1) in atrial muscle strips and papillary muscle strips has been measured. We also examined the number of β‐adrenoceptors in both tissues by radioligand binding.

The degree of heart failure affected neither the potency (EC50: control: 0·01 (0·001‐0·082) μmoll‐1; NYHA II‐III: 0·01 (0·001‐0·125) μmoll‐1; NYHA IV: 0·01 (0·001‐0·160) μmoll‐1) nor the efficacy (NYHA IV: 7·8 ± 1·0 mN; NYHA II‐III: 6·1 ± 0·7 mN; control: 7·7 ± 0·9 mN) of the isoprenaline‐mediated increase in force of contraction in atrial muscle strips. This is in spite of a reduced number of β‐adrenoceptors in moderately (NYHA II‐III) and terminally (NYHA IV) failing atrial myocardium compared to non‐failing atrial myocardium (P<0·05). In contrast, in papillary muscle strips increasing degrees of heart failure were accompanied by a progressive reduction of the isoprenaline‐mediated increase in force of contraction (P<0·05) as well as by a progressive decrease of β‐adrenoceptors (P<0·05). In papillary muscle strips, there was a significant (P<0·05) rightward shift of the isoprenaline concentration‐response curve in failing myocardium as compared to controls. In addition, the potency of isoprenaline to increase force of contraction was lower in left ventricular myocardium compared to right atrial tissue. The Ca2+ ‐mediated maximal increase in force of contraction in atrial and papillary muscle strips was similar in non‐failing and failing myocardial tissue.

In conclusion, a surplus of β‐adrenoceptors for mediating positive inotropic effects seems to exist only in atrial but not in left ventricular human myocardium. Therefore, the efficacy of the β‐adrenoceptor‐effector coupling, at least in terms of positive inotropic effects, cannot be inferred for any tissue in the human myocardium.
Alveolar macrophage chemotaxis in fire victims with smoke inhalation and burns injury
Authors: RIYAMI B. M. S. , KINSELLA J. , POLLOK A. J. , CLARK C. , STEVENSON R. D. , REID W. H. , CAMPBELL D. , GEMMELL C. G.
Published: March 2008

Abstract. In vitro migration of alveolar macrophages was studied in 24 fire victims and 19 controls; all subjects were cigarette smokers. Unstimulated (p= 0·01) and stimulated migration towards casein‐(P= 0·01) and zymosan‐activated serum (P= 0·002) of macrophages from smoke inhalation patients (SI) (n=19) was increased when compared to control subjects (CS). Migration of alveolar macrophages from patients with burns without smoke inhalation (burns only, BO) was not increased. Patients with smoke inhalation and no burns (smoke only, SO) (n= 9) had increased migration when compared to controls but this was not statistically significant. Patients with smoke inhalation and burns (SB) (n= 10) had increased unstimulated migration (P= 0·01) and increased migration towards casein (P<0·005), ZAS (P<0·002) and F‐met‐leu‐phe (P<0·05) when compared to controls (CS). Lavage fluid from the fire victims displayed chemotactic activity towards normal human neutrophils and its analysis for the components of the complement cascade proved positive (Clq, Clr, Factor B and C33). These data suggest that activation of alveolar macrophages may contribute to the development of pathophysiological changes in patients with smoke inhalation (SI) and particularly those with smoke inhalation and burns (SB).
Hyperparathyroidism and abnormal 1,25(OH)2vitamin D3 metabolism in experimental lead intoxication
Authors: SZABO A. , MERKE J. , HÜGEL U. , MALL G. , STOEPPLER M. , RITZ E.
Published: March 2008

Abstract. Clinical evidence points to disturbed calcium metabolism in lead (Pb) intoxication. To further clarify the mechanisms involved, serum levels of 1,25(OH)2D3, receptors for 1,25(OH)2D3 as well as size and ultrastructure of parathyroid glands were examined in Wistar Kyoto rats exposed to 1% lead (Pb) acetate in drinking water for 10 weeks (short‐term study) or 0·001 – 1 % Pb acetate for 24 weeks (long‐term study). After administration of Pb for 10 weeks, bone Pb was significantly increased (641±66·9 (SD) vs. 0·648±0·39 mg kg‐1 ash in controls). Total serum calcium and ionized Ca2+ (1·15±0·031 vs. 1·25±0·03 mmol 1‐1) were significantly decreased. Renal function (Ccr) was unchanged, but urinary cAMP excretion and circulating 1,25(OH)2D3 (177±10·9 vs. 232±18·9 pmol 1‐1) were diminished. Specific binding of 1,25(OH)2D3 was increased in parathyroids (Bmax 128±4·7 vs. 108±0·6 fmol mg‐1 protein) and intestinal mucosa; Bmax failed to adequately rise in response to pretreatment with 1,25(OH)2D3 (2·10 ng day‐1 for 4 d) in Pb‐exposed animals. Receptor characteristics (sedimentation constant, KD, DNA affinity) were unchanged. Parathyroid weight was significantly increased (178·25 vs. 96·34 μg) with no change of estimated nuclear volume, cell volume or cell ultrastructure. After 24 weeks of Pb exposure, a dose‐dependent but non‐linear increase of parathyroid weight was noted between 0·001% and 1% Pb in drinking fluid.

The present study documents secondary hyperparathyroidism associated with, and presumably caused by, hypocalcaemia and low 1,25(OH)2D3 levels, in experimental Pb intoxication.
HCV infection, hepatic HLA display and composition of the mononuclear cell inflammatory infiltrate in chronic alcoholic liver disease
Authors: FRENI M. A. , AJELLO A. , RESTA M. L. , GAETA G. B. , SPADARO A. , FAVA A. , CALAPRISTI I. , ALESSI N. , FERRAÙ O.
Published: March 2008

Abstract. Viral infection may play a role in alcoholic liver disease with histological features of chronic active hepatitis (CAH). Human leucocyte antigen (HLA) hepatocellular display is supposed to allow HLA‐restricted T‐lymphocyte cytotoxicity in chronic viral hepatitis.

We studied the presence of serum anti‐hepatitis C virus (HCV) antibodies, the hepatic HLA display and the composition of the mononuclear cell infiltrate in 16 patients with alcoholic liver disease and histological features of CAH and in 11 patients with alcohol‐related degenerative changes. All patients were negative for hepatitis B virus (HBV) markers.

Anti‐HCV were tested by microplate ELISA. Class I HLA A, B, class II HLA DR, lymphocytes pan T, T helper/inducer, T suppressor/cytotoxic, B, and K NK cells were stained on liver cryostat sections by monoclonal antibodies and double indirect immunoperoxi‐dase.

Anti‐HCV were present in all the patients with features of CAH and absent in those with only degenerative changes. In livers with features of CAH the mononuclear cell infiltrate consisted largely of T lymphocytes with marked prevalence of suppressor/cytotoxic cells in periportal and lobular areas. K NK cells were rare. Class I HLA, diffusely displayed on bile duct epithelium and on sinusoidal cells, also appeared on liver cells in the areas of periportal and lobular necrosis, namely on the hepatocytes in close contact with suppressor/cytotoxic T cells. In livers with only degenerative changes class I HLA were diffusely displayed on bile duct epithelium and on sinusoidal cells but absent on the hepatocytes. In all the specimens HLA DR antigens were expressed on sinusoidal and inflammatory cells.

In alcoholic liver disease with features of CAH the presence of anti‐HCV and the close contact of T‐cytotoxic cells to hepatocytes expressing class I HLA suggest a pathogenetic role of HCV and an HLA‐restricted T‐cytotoxic mechanism of hepatocellular necrosis.
A ‘Fish‐eye disease’ familial condition with massive corneal opacities and hypoalphalipoproteinaemia: clinical, biochemical and genetic features
Authors: CLERC M. , DUMON M. F. , SESS D. , FRENEIX‐CLERC M. , MACKNESS M. , CONRI C.
Published: March 2008

Abstract. A Caucasian family of mediterranean origin comprising a patient whose parents were first cousins, his wife and their three children, and his two sisters have been studied. The patient and his two daughters were afflicted with the same corneal opacities and hypoalphalipoproteinaemia. The disease was shown to be transmitted as a non‐sex‐linked recessive trait. The corneal opacities develop at the end of the second decade of life and consist of numerous minute greyish dots in the entire corneal stroma that give the cornea a misty appearance. Vision slowly deteriorated from 40 years of age. At about 50 years of age, except in one of the two daughters who showed Marfanoid syndrome, the three patients had good general health and no symptoms of atherosclerosis. Biochemical investigations showed hypoalphalipoproteinaemia (with a faint fast‐moving HDL band on polyacrylamide gel gradient electrophoresis and small arcs of HDL2 and HDL3 of low mobility determined by agarose gel immunoelectrophoresis), low total cholesterol (3·5–4·9 mmol l‐1), slightly decreased cholesteryl ester/total cholesterol ratio (0·52–0·63), extremely low HDL cholesterol (0·20–0·21 mmol l‐1), mild hypertriglyceri‐daemia (1·94–3·80 mmol l‐1), and striking deficiency in apo A‐I and apo A‐II (0·45–0·72, 0·08–0·16 g l‐1, respectively). The esterification of HDL cholesterol was low while that of LDL and VLDL was nearly normal. Other laboratory values were normal. The HDL subspecies and major apolipoprotein isoforms have been studied to differentiate FED from Tangier disease, LCAT deficiency, as Apo A‐I, A‐II, C‐II, C‐III deficiencies and variants. The data is discussed in comparison with the other familial syndromes of lipid deposition at the corneae associated with dyslipopro‐teinaemias. Two of the three patients may be classified as having ‘Fish‐eye disease’ as the three index patients described by Carlson in 1982 [1].
PreproVIP‐derived peptides in tissue and plasma from patients with VIP‐producing tumours
Authors: RØNNOV‐JENSEN D. , GETHER U. , FAHRENKRUG J.
Published: March 2008

Abstract. To elucidate the biosynthetic processing of the precursor for vasoactive intestinal peptide (prepro‐VIP) in tumours producing VIP we have used newly developed radioimmunoassays directed against the five functional domains of the VIP precursor molecule: preproVIP 22–79, peptide histidine methionine (PHM), preproVIP 111–122, VIP and preproVIP 156–170 in combination with HPLC to identify and quantify the peptides in tumour specimen and plasma from patients with the watery diarrhoea syndrome. Elevated quantities of all the five peptides were found in the 13 tumours (nine neurogenic tumours, one pheochromocytoma, three pancreatic carcinomas) examined. The preproVIP derived peptides were expressed in non‐equimolar amounts and the relative proportion of the various peptides differed markedly from tumour to tumour. The pheochromocytoma was the only tumour type which contained large amounts of preproVIP 156–170 in comparison with the other peptides. A proportion of the VIP precursor which varied from 7% to 73% followed a pathway in which the dibasic conversion site after PHM was uncleaved as evidenced by the presence of PHV, a C‐terminally extended form of PHM. It was also found that unlike normal tissue a fraction of the C‐terminal VIP pre‐cursor peptide, preproVIP 156–170, was having its C‐terminal lysine residue removed during processing. The findings indicate that various post‐translational processing pathways of preproVIP exist. All the peptide sequences produced in the tumour tissue were secreted as evidenced by their presence in plasma in elevated concentrations. The plasma levels of preproVIP 22–79, prepro VIP 111–122 and PHV exceeded those of the remaining preproVIP‐derived peptides suggesting that determination of these peptides in patients with VIP‐secreting tumours may be better markers than VIP.
Sodium lithium counter‐transport is acutely influenced by heparin‐induced extracorporal LDL precipitation
Authors: MESSNER H. , KLEOPHAS W. , HEIN D. , GRIES F. A. , KÖBBERLING J.
Published: March 2008

Abstract. Sodium lithium countertransport may be a genetic marker for arterial hypertension and for the risk of diabetic nephropathy in type 1 diabetic patients. Since various factors seem to influence the transport velocity including serum lipid alterations, erythrocytes of seven patients with severe hyperliproteinaemia who were chronically and intermittently treated with LDL apheresis were examined before and immediately after therapy. The LDL apheresis reduced sodium lithium countertransport significantly (0.383 vs 0.269, P<0.02). Therefore, we conclude that serum lipid composition must be considered when interpreting sodium lithium countertransport velocity.
Identification of a new mutation responsible for hepatoerythropoietic porphyria
Authors: ROMANA M. , GRANDCHAMP B. , DUBART A. , AMSELEM S. , CHABRET C. , NORDMANN Y. , GOOSSENS M. , ROMEO P.‐H.
Published: March 2008

Abstract. A deficiency in the activity of uroporphyrinogen decarboxylase (URO‐D), the fifth enzyme of the haem biosynthetic pathway, is found in two hereditary diseases, familial porphyria cutanea tarda (PCT) and hepatoerythropoietic porphyria (HEP). Little is known about the genetic relationship between those two diseases and it has been postulated that HEP is the homozygous form of PCT. A URO‐D cDNA was cloned from an HEP patient and the comparison between the mutant and the wild‐type sequences showed a single base difference within the coding sequence leading to the replacement of a glutamic acid by a lysine at codon 167 of the mutant protein. This replacement produced a protein which is rapidly degraded in the presence of cell lysate. On the basis of hybridization of synthetic oligomers to amplified genomic DNA, we demonstrated that this patient is homozygous for this single base mutation. In order to look for any relationship between HEP and PCT, we tested six unrelated patients with familial PCT and could not detect the codon 167 mutation in any of them. These results indicate an heterogeneity in the mutations responsible for the PCT and HEP phenotypes.
Increased tissue concentrations of the gastrin precursor in patients treated with omeprazole
Authors: NEMETH J. , VARRO A. , BRIDSON J. , WALKER R. , DOCKRAY G. J.
Published: March 2008

Abstract. The main form of gastrin in antral mucosa, the amidated heptadecapeptide G17, is generated from an inactive precursor, progastrin, by steps involving endopeptidase cleavage and amidation. Gastrin cells are normally inhibited by gastric acid and in this study we have examined how suppression of acid by treatment with omeprazole for 6–8 weeks influences gastrin production in patients with oesophagitis. Plasma concentrations of total amidated gastrins in the fasting state increased from 18 to 43 pmol 1‐1; assays specific for G17‐immunoreactivity indicated that the plasma concentrations of this form increased from 6 to 12 pmol 1‐1. In endoscopic biopsies of antral mucosa there was no change with omeprazole treatment in the concentrations of total amidated gastrins, or their immediate precursors, the Gly‐extended gastrins. However, assays using an antibody that reacts with progastrin, together with size exclusion chromatography, indicated that tissue progastrin concentration increased 6‐fold. The data suggest a modest net increase in gastrin production with omeprazole‐treatment; because the ratio of tissue concentrations of total amidated gastrins to Gly‐extended gastrins did not change, it would seem that the amidating capacity of the gastrin cell was maintained. However, the increase in progastrin concentrations suggests a relative failure of the initial steps of post‐translational processing, and consequently that in certain circumstances endopeptidase cleavage of progastrin may be rate limiting.
Circulating inhibitor of interleukin 1 activity in patients with chronic renal diseases
Authors: RAMIĆ Z. , DIMKOVIĆ N. , DJUKANOVIĆ LJ. , LAZIĆ M. , STEPANOVIĆ S. , SIMIĆ M. , LUKIĆ M. L.
Published: March 2008

Abstract. The effects of sera derived from patients suffering from chronic renal diseases (endemic Balkan nephropathy, glomerulonephritis and pyelonephritis) on T cell proliferative response was studied. It was found that these sera contained factors which affect interleukin 1 (IL‐1) dependent events in T cell proliferative response. The factors prevent costimulatory effects of IL‐1 on T cells but do not bind to IL‐1, nor do they affect interleukin 2 (IL‐2) dependent T cell proliferation. These findings indicate that immuno‐suppression observed in some kidney disorders may be partially due to serum immunoinhibitory factors affecting IL‐1 activity.
The glucoregulatory and antilipolytic actions of insulin in abdominal obesity with normal or impaired glucose tolerance: an in vivo and in vitro study
Authors: CAVALLO‐PERIN P. , BRUNO A. , CASSADER M. , CESCO L. , GRUDEN G. , PAGANO G.
Published: March 2008

Abstract. To evaluate the effects of obesity and impaired glucose tolerance on insulin sensitivity, we performed a euglycaemic‐hyperinsulinemic clamp at about 350 pmol 1‐1, combined with 3H‐glucose infusion, in 14 obese patients, BMI 36.5 ± 1.2 and in 12 matched controls, BMI 23.9 ± 0.4. Six obese patients had normal glucose tolerance (oNGT), and eight had impaired glucose tolerance (oIGT). The ability of insulin to inhibit lipolysis in isolated adipocytes was also studied. Insulin‐mediated glucose utilization was more severely impaired in oIGT than in oNGT with respect to the controls (621 ± 51 vs. 897 ±83 vs. 1298 ± 55 μmol m‐2 min‐1, P<0.001). Plasma gly‐cerol was higher in oIGT than in oNGT and in the controls, both fasting (238 ±12 vs. 179 ± 14 vs. 112 ± 8 μmo1 1‐1, P < 0.001) and during the clamp (175 ± 21 vs. 120 ± 12 vs. 36 ± 6/μmiol1‐1, P<0.001). The correlation between glucose utilization and the percent reduction of plasma glycerol during the clamp was significant in the study group as a whole (r = 0.809, P=0.0001), and in each of the groups separately (oIGT: r = 0.929, P = 0.002; oNGT: r = 0.943, P = 0036; controls: r = 0.902, P = 0.0001). Inhibition by insulin of noradrenaline‐stimulated lipolysis in isolated adipocytes was more severely impaired in oIGT than in oNGT compared with the controls (P < 0.001). We conclude that impaired as opposed to normal glucose tolerance in obesity is associated with more severe impairment in both glucose utilization and insulin inhibition of lipolysis.
Prolonged sleep‐deprivation induced disturbed liver functions serum lipid levels, and hyperphosphatemia
Authors: ILAN Y. , MARTINOWITZ G. , ABRAMSKY O. , GLAZER G. , LAVIE P.
Published: March 2008

Abstract. Sixty‐four healthy young male volunteers were kept awake from 76 to 80 h. Blood tests conducted at the start and conclusion of the continuous sleep deprivation revealed an increase of 170% in mean SGOT, 58–5% in mean SGPT and 37–5% in mean plasma phosphorus levels. Triglyceride levels decreased by 16%, while HDL levels increased by 18% and the apoB/apoA ratio decreased by 12%. Morning plasma cortisol showed a significant increase during the experiment while evening cortisol showed a significant decrease. Morning T3 levels increased from the first to second day and decreased on the third day. There were no significant changes in other plasma electrolyte levels.
Short‐term indomethacin administration does not impair excretion of acute potassium load in humans
Authors: BUREN M. VAN , RUN H. J. M. VAN , KOOMANS H. A.
Published: March 2008

Abstract. Maintenance treatment with prostaglandin synthesis inhibitors often causes some degree of hyper‐kalemia, indicating impaired potassium (K) excretion. Hypoaldosteronism probably is a mediating factor, but it is unknown whether these drugs also impair renal K excretion directly. Indomethacin, for example, stimulates NaCl reabsorption in Henle's loop, and thus may impair K excretion by decreasing distal NaCl delivery. We therefore studied the effect of 1 day administration of indomethacin (50 mg tid) on the excretion of a single oral KC1 (1 mmol kg‐1 body weight) in six healthy volunteers taking a 40 mmol sodium diet. To allow analysis of renal sodium handling, clearance studies were performed during water loading. In this acute setting, indomethacin had no effect on plasma K, and did not decrease plasma aldosterone. However, indomethacin clearly reduced NaCl excretion. Nonetheless, the excretion of the K load was entirely normal. Excretion of the K load was accompanied by increased clearance of phosphate and uric acid, and natriuresis. Data derived from the maximal free water clearance were compatible with increased delivery to and decreased reabsorption from the diluting segment. Occurrence of these effects was not prevented by indomethacin, although overall NaCl excretion remained less than observed without indomethacin. Indomethacin reduced prostaglandin E2 excretion substantially. Apparently, in normal man indomethacin does not impair K excretion directly, even though it greatly reduces NaCl excretion. Moreover, the effects of K on renal NaCl handling, probably contributing to the excretion of a K load, are not dependent on renal prostaglandins.
Incomplete suppression of hepatic glucose production in non‐insulin dependent diabetes mellitus measured with [6,6‐2H2]glucose enriched glucose infusion during hyperinsulinaemic euglycaemic clamps
Authors: POWRIE J. K. , SMITH G. D. , HENNESSY T. R. , SHOJAEE‐MORADIE F. , KELLY J. M. , SÖNKSEN P. H. , JONES R. H.
Published: March 2008

Abstract.

We have minimized methodological errors in the isotope dilution technique by using stable isotope, [6,6‐2H2]glucose, thus avoiding the problem of contamination of tritiated glucose tracers and, by maintaining a constant plasma tracer enrichment have reduced error due to mixing transients. Using these modifications we have calculated hepatic glucose production in 20 patients with non‐insulin‐dependent diabetes mellitus during low (1 mU kg‐1 min‐1) and high (8 mU kg‐1 min‐1) dose insulin infusions. Mean fasting hepatic glucose production was 14.2 ±0.8 μnol kg‐1 min‐1. This suppressed by only 68% to 4.6&±0.8 μmol kg‐1 min‐1 during the low‐dose insulin infusion (plasma insulin 0.85 ±0.05 nmol 1‐1) and did not suppress further during the high‐dose insulin infusion (plasma insulin 14.55±0.83 nmol 1‐1). Hepatic glucose production was significantly higher than zero throughout the study.

Thus, we have found that minimization of known errors in the isotope dilution technique results in physiologically plausible and significantly positive values for hepatic glucose production indicating that the liver is resistant to insulin in patients with non‐insulin‐dependent diabetes mellitus.
Stimulation of neutrophils by insoluble immunoglobulin aggregates from synovial fluid of patients with rheumatoid arthritis
Authors: ROBINSON J. J. , WATSON F. , BUCKNALL R. C. , EDWARDS S. W.
Published: March 2008

Abstract. Insoluble immunoglobulin aggregates present in the synovial fluid of patients with rheumatoid arthritis have been examined for their ability to activate reactive oxidant and granule enzyme secretion from bloodstream neutrophils. These insoluble complexes activated luminol chemiluminescence, but did not activate O2‐, H2O2 or granule enzyme secretion and did not activate lucigenin chemiluminescence, which also measures reactive oxidant secretion. Hence, the luminol chemiluminescence detected after activation by insoluble immunoglobulin aggregates must be due to intracellularly generated reactive oxidants, i.e. produced within phagolysosomes. Because reactive oxidant and granule enzyme secretion has occurred within rheumatoid joints, other mechanisms of neutro‐phil activation must exist.
Effects of hypercholesterolemia on the nucleotide content in human blood cells
Authors: FELBEL J. M. , SIESS E. A. , ZÖLLNER N.
Published: March 2008

Abstract. In hypercholesterolemia significant changes in the nucleotide pattern of erythrocytes and lymphocytes as determined by high performance liquid chromatography were found. The decrease in ATP of lymphocytes in hypercholesterolemia from 10.4 ± 0.3 to 7.0 ± 0.4 nmol mg‐1 protein (n= 8) was associated with an increase in ADP from 2.2 ±0.2 to 4.0 ±0.2 nmol mg‐1 protein (P< 0.005). The pattern of guano. sine phosphates likewise was found to be changed in hypercholesterolemia. Akin to lymphocytes, red blood cells displayed marked changes in nucleotide levels. No such changes were observed in platelets. Cultured lymphocytes incubated with human plasma low density lipoproteins (LDL) (140 mg cholesterol dl‐1) displayed a reversible fall in ATP and an increase in ADP by about 40% and 160%, respectively, with high density lipoproteins (HDL) or very low density lipoproteins (VLDL) being essentially ineffectual. It is concluded that in hypercholesterolemia a significant change in the nucleotide pattern of blood cells is exerted by the increase in LDL. Possible pathophysio‐logical implications are discussed.
A Taql polymorphism in the human interleukin‐1β (IL‐1β) gene correlates with IL‐1β secretion in vitro
Authors: POCIOT F. , MØLVIG J. , WOGENSEN L. , WORSAAE H. , NERUP J.
Published: March 2008

Abstract. In the present study we searched for restriction fragment length polymorphisms (RFLP) in the human interleukin‐1β (IL‐lβ) gene and for correlations to monocyte (Mo) function in non‐related healthy donors and insulin‐dependent diabetic patients. We demonstrated a diallelic polymorphism with the restriction enzyme TaqI consisting of fragments of 9.4 kb and 13.4 kb. No differences in allele or genotype frequencies of this RFLP were observed between randomly selected controls and randomly selected patients with insulin‐dependent diabetes mel‐litus (IDDM). However, when analysing IDDM patients negative for HLA‐DR3 and ‐DR4, our data demonstrate that the 13.4 kb allele is more frequent in this group compared to a matched control group. The functional impact of this RFLP was studied by analysing in vitro stimulated Mo IL‐1β response. An IL‐lβ allele dosage effect on secretory capacity was observed after LPS‐stimulation: 13.4/13.4 kb homo‐zygous individuals secreted significantly more IL‐lβ than 9.4/13.4 kb heterozygous individuals, who secreted significantly more than 9.4/9.4 kb homozygous individuals. Analyses of supernatants from LPS‐sti‐mulated Mo cultures from individuals with each Taql IL‐lβ genotype revealed no differences in the mouse thymocyte co‐stimulatory assay when compared on a molar basis, indicating that the Taql polymorphism gave rise only to quantitative differences in expression levels and probably not to a mutant IL‐lβ. We conclude that the 13.4 kb allele represents an IL‐1β‘high‐secretor’ phenotype, that the observed RFLP may be a genetic susceptibility marker for IDDM in non‐DR3 and non‐DR4 individuals and that high IL‐1β secretory capacity may be a pathogenic factor for IDDM in these patients.
Bone mineral density measured by dual‐energy X‐ray absorptiometry in normal men
Authors: KROGER H. , LAITINEN K.
Published: March 2008

Abstract. A cross‐sectional study of 222 healthy Finnish men aged 20–69 years was performed to establish reference values of bone mineral density (BMD) using dual‐energy X‐ray absorptiometry (DEXA). The effects of age, and of some physical and lifestyle factors on BMD of the lumbar spine and proximal femur (femoral neck, Ward's triangle and trochanter) were investigated. The maximal mean BMD was observed at the age of 20–29 years in all the measurement sites. Except for the trochanteric area, BMD diminished along with age, the over‐all decrements being 4%, 11%, and 23% in the lumbar, femoral neck and Ward's triangle areas, respectively. BMD was in a positive relationship to weight and height in all the measurement sites. The adjusted (for age, height and weight) BMDs were higher (P <0.05) in the group of daily dietary calcium intake greater than 1200 mg as compared with the group of lowest calcium intake (< 800 mg day‐1) in the three femoral areas. Cigarette smoking or alcohol drinking had no obvious effect on BMD.
A comparison of octreotide delivered by continuous subcutaneous infusion with intermittent injection in the treatment of acromegaly
Authors: JAMES R. A. , WHITE M. C. , CHATTERJEE S. , MARCIAJ H. , KENDALL‐TAYLOR P.
Published: March 2008

Abstract. This study was undertaken to evaluate GH, IGF1 and drug levels during incremental continuous subcutaneous infusion of octreotide and compare these parameters following long‐term treatment of 300 & mug 24 h‐1 by intermittent injection in a group of acromegalic patients. Ten patients were treated by continuous subcutaneous infusion in increasing dose from 200 & mug 24 h‐1 to 1600 & mug 24 h‐1; this resulted in consistent 24‐h growth hormone suppression (<5.0 mU l‐1), and normalisation of IGF1; the optimum dose was 400 & mug 24 h‐1, the maximum dose was tolerated without any untoward effects. There was no deterioration in carbohydrate tolerance despite a marked decrease in fasting and stimulated insulin levels. After 1 year of maintenance treatment, 300 & mug 24 h‐1 by intermittent injection, patients were re‐evaluated; GH levels were not so consistently suppressed over the 24‐h period and carbohydrate tolerance had deteriorated. A sub‐group of patients with sub‐optimal GH suppression on this regimen were identified and reassessed after 6 weeks treatment with an increased dose, 600 & mug 24 h‐1 by intermittent injection; both mean GH suppression and carbohydrate tolerance improved. The dose of drug and method of administration is best adjusted for each patient to achieve optimum GH suppression, thereby minimise compensatory hyperinsuliaemia and hopefully reduce morbidity and mortality. Alterations in pituitary tumour size and acquisition of gallstones during treatment have been observed which substantiate the need to re‐evaluate these parameters on routine follow‐up of acromegalic patients on long‐term octreotide.
Correspondence between plasma mevalonic acid levels and deuterium uptake in measuring human cholesterol synthesis
Authors: JONES P. J. H. , PAPPU A. S. , ILLINGWORTH D. R. , LEITCH C. A.
Published: March 2008

Abstract. To assess the validity of two techniques capable of identifying immediate changes in human cholesterol production, plasma mevalonic acid levels and the rate of uptake of deuterium into plasma free cholesterol were compared in 5 healthy individuals over 48 h. The free‐living subjects self‐selected three meals per day prior to and during study. At t = 0, deuterium oxide was administered orally. Blood samples were collected before and every 4 h after dosing. Total cholesterol and mevalonic acid levels were determined in plasma at each timepoint. Deuterium enrichment changes in plasma free cholesterol, relative to plasma water content, were used to calculate free cholesterol fractional synthetic rates (FSR) at each timepoint. Total plasma cholesterol levels remained constant, whereas significant circadian rhythmicity was observed in both plasma mevalonic acid and deuterium uptake methods, with nadir and peak formation rates indicated at 14.00 to 16.00 h and about midnight, respectively. It is suggested that plasma mevalonic acid levels and free cholesterol deuterium uptake rate techniques are both suitable techniques for short‐term measurement of human cholesterol synthesis.
Effect of lipid A on the deformability, membrane rigidity and geometry of human adult red blood cells
Authors: PÖSCHL J. M. B. , LINDERKAMP O.
Published: March 2008

Abstract. Lipid A is responsible for the activities of endotoxin and may cause circulatory failure and haemolysis. This study evaluated the effects of different lipid A concentrations on red blood cell (RBC) deformation (rheoscope), the aspiration pressure required to aspirate RBC into 3.3 μm pipettes, the membrane shear elastic modulus (i.e. membrane rigidity) and cellular geometry (micropipette system) after 15 min of incubation. Lipid A concentrations of 10 and 100 μg ml‐1 of RBCs decreased RBC deformability by 26% and 39%, respectively. The aspiration pressure for RBCs into a 3.3 μm micropipette increased by 235% at a lipid A concentration of 10 μg ml‐1 and by 586% at a concentration of 100 μg ml‐1. The elastic shear modulus almost doubled at a lipid A concentration of 10 μg ml‐1 and tripled at 100 μg ml‐1. At a lipid A concentration of 100 μg ml‐1, 37% of RBCs showed spicules. These echinocytes were less deformable than discocytes. Mean corpuscular volume, RBC volume and surface area were not affected by lipid A. We conclude that lipid A causes marked reduction of RBC deformability due to increasing membrane rigidity.
Comparison of the effect of GIP and GLP‐1 (7–36amide) on insulin release from rat pancreatic islets
Authors: SIEGEL E. G. , SCHULZE A. , SCHMIDT W. E. , CREUTZFELDT W.
Published: March 2008

Abstract. After ingestion of glucose both GIP (gastric inhibitory polypeptide, glucose‐dependent insulino‐tropic polypeptide) and GLP‐1 (7–36amide) (glucagon‐like polypeptide‐1, 7–36amide) may play a physiological role in augmenting insulin release. Their insulinotropic effect was compared in isolated rat islets after 24‐h maintenance in tissue culture (11 mmol l‐1 glucose). Ten islets per vial were then incubated in Krebs‐Ringer‐Hepes buffer for 30 min; insulin was measured radioimmunologically. Both hormones were always compared in the same experiment. At 16.7 mmol l‐1 glucose both GIP and GLP‐l(7–36amide) 2times10‐10 mol l‐1 significantly increased insulin release; 10 ‐10 mol l‐1 of either hormone had no significant effect. The response at 10‐9 and 10‐8 mol l‐1 was similar for both; at 4times10‐10 mol l‐1 GLP‐1(7–36amide), however, was clearly more effective than GIP. At low glucose (2.8 or 5.0 mol l‐1) no sigificant differences were found. A concentration of 10‐8 mol l‐1 of both hormones was slightly stimulatory. At 8.3 mmol l‐1 glucose, 10‐9 mol l‐1 GLP‐l(7–36amide) was 60% more effective than GIP (4.8 ± 0.4 vs. 3.0 + 0.4, n= 13, P<0.005), the response to 10‐8 mol l‐1 was similar. These data show comparable effects of high concentrations of GIP and GLP‐1 (7–36amide) on glucose‐induced insulin release; at presumably physiological concentrations, however, GLP‐l(7–36amide) was clearly more effective. The combination of the two peptides was not more than additive, suggesting that they act via the same final mechanism.
Alterations in lipoprotein density classes in infantile visceral Leishmaniasis: presence of apolipoprotein SAA
Authors: BEKAERT E. D. , DOLE E. , DUBOIS D. Y. , BOUMA M.‐E. , LONTIE J‐F. , KALLEL R. , MALMENDIER C. L. , AYRAULT‐JARRIER M.
Published: March 2008

Abstract. This study describes the alterations in the plasma lipoproteins from nine young Tunisian children with active visceral Leishmaniasis. The plasma lipid profile from affected patients was characterized by a marked hypertriglyceridaemia associated with reduced levels of total and high density lipoprotein (HDL)‐cholesterol and a significant increase in the plasma ratio of unesterified to total cholesterol. Quantitative determination of plasma apolipoproteins revealed significantly decreased levels of all measured apolipoproteins, especially of apolipoproteins A‐I and A‐II, with the exception of apolipoprotein E, the levels of which were markedly increased. Moreover, at least two isoforms of the apolipoprotein serum amyloid A (SAA), an acute phase protein, were detected in all patients' plasma using two‐dimensional electrophore‐sis. Immunochemical evidence was presented that apolipoproteins E and SAA, although both primarily associated with apolipoprotein A‐ (A‐I and A‐II) as well as with apolipoprotein B‐containing lipoproteins, could occur as LP‐E and LP‐SAA subspecies, devoid of apolipoproteins A and B. However, it should be pointed out that LP‐SAA particles were found in HDL2 from only two patients whereas the abnormal LP‐E particles were detected in LDL and HDL2 from all investigated patients. The polydispersity and heterogeneity of patients' HDL3 were assessed by electron microscopy. It was further suggested that the profound changes in the lipoprotein metabolism of these young patients may be due to the increased hepatic synthesis of apolipoprotein SAA and/or to their altered immune function during active visceral Leishmaniasis.
Effect of endothelin on normal and diseased human coronary arteries
Authors: CHESTER A. H. , O'NEIL G. S. , ALLEN S. P. , LUU T. N. , TADJKARIMI S. , YACOUB M. H.
Published: March 2008

Abstract. We have examined the action of endothelin on healthy and diseased human epicardial coronary arteries to assess its possible role in coronary vascular disorders such as vasospasm and atherosclerosis. Endothelin (10‐10 mol l‐1 10‐7 mol l‐1) produced dose‐dependent contractions in both normal and diseased vessels. The level of constriction was significantly greater in healthy vessels at 10‐8 mol l‐1 endothelin. A greater response was recorded in smaller, more distal vessel segments, irrespective of the pathology of the tissue. Endothelium denudation of disease‐free segments had no significant effect on the response to endothelin. In the presence of a threshold dose of endothelin (10‐9 mol l‐1), there was no measurable increase in the tension generated by potassium chloride, the thromboxane‐mimetic U46619, noradrenaline and histamine. However, the response to 5‐HT showed a large increase in arteries from four patients (440–147%) but slight or no increase in arteries from another three patients. We conclude that the interaction with other vasoconstrictor substances is a possible mechanism whereby endothelin may be involved in coronary artery vasospasm. In addition, endothelin may also be involved in the regulation of vascular tone of the small vessels of the heart.
The influence of erythrocyte shape on suspension viscosities
Authors: REINHART W. H. , SINGH‐MARCHETTI M. , STRAUB P. W.
Published: March 2008

Abstract. Erythrocyte shape changes are known to occur in vivo and can readily be induced in vitro. We have analysed the influence of increasing stomatocyto‐sis produced by 0–0.64 mmol 1‐1 chlorpromazine and increasing echinocytosis induced with 0–120 mmol 1‐1 salicylate or 0–8 mmol 1‐1 2,4‐dinitrophenol on suspension viscosities. The morphological index of each sample was determined and related to the suspension viscosity. It was found that the viscosity was increased by echinocytosis in dextran‐free solutions, where no aggregation occurred. The viscosity could be normalized by retransforming echinocytes into discocytes. Under conditions with erythrocyte aggregation (suspension with 4 g dl‐1 dextran 70, low shear rate:0.1 s‐1) a small degree of echinocytosis produced the highest viscosity, whereas at higher degrees of echinocytosis the ability to aggregate was reduced and the viscosity was similar to that of discocytes or stomato‐cytes. Erythrocytes incubated in hypotonic medium (constant cell number/volume) had a higher viscosity than cells in iso‐ or hypertonic medium. Severely hypotonic medium led to sphering of erythrocytes which reduced the ability of these cells to aggregate and hence decreased the viscosity of suspensions with dextran at low shear rate. The results indicate that discocytes have the lowest viscosity and thus the best oxygen transport efficiency and that iso‐ to hypertoni‐city provides a lower viscosity and better oxygen transport efficiency than hypotonicity. These results may contribute to the understanding of blood flow in health and disease.
Trichosanthin treatment of HIV‐induced immune dysregulation
Authors: MAYER R. A. , SERGIOS P. A. , COONAN K. , O'BRIEN L.
Published: March 2008

Abstract. Twenty patients with the acquired immunodeficiency syndrome (AIDS), AIDS‐related complex (ARC) or asymptomatic HIV infection (HIV +) were given 20 meg kg‐3 trichosanthin (TCS; ‘Compound Q’), a ribosome‐inactivating protein with in vitro antiviral activity against human immunodeficiency virus (HIV) once every four weeks for up to 12 weeks. With the concurrent administration of prostaglandin inhibitors, the drug was moderately well tolerated, with most subjects experiencing mild arthralgia, hives and malaise. Additionally, four patients experienced neurological complications which resolved spontaneously without intervention. Four of 20 subjects in this open label pilot study showed progressive although transient reductions in viral activity as measured by p‐24 antigen level decreases. Subjects also experienced decreases in levels of β2‐microglobulin. Ten HIV‐)‐ and healthy ARC subjects demonstrated improved immunological status as measured by significant increases in percentage of CD4+ cells and augmentations in delayed hypersensitivity reactions. Eight of 20 subjects reported improved appetites and increased energy levels. The group as a whole had a weight gain of 3.2 kg. Eight of 20 subjects who presented with persistent generalized lymphadenopathy exhibited a marked diminution in the size of their lymph nodes after the first treatment. No subject who presented with oral candidiasis experienced an improvement in that condition. We conclude that, in the short term, TCS seems to have the ability to reduce viral activity and improve certain symptoms in healthy ARC patients and HIV+ asymptomatics although it may not be able to restore immune competence in persons with advanced AIDS or poor prognosis ARC. Additionally, the drug may pose a special risk for patients with HIV‐related dementia.