bluuebunny/crossref_metadata_2025 huggingface dataset:
Pancreatic beta‐cell function and interleukin‐1β in plasma during the acute phase response in patients with major burn injuries
Authors: WOGENSEN L. , JENSEN M. , SVENSSON P. , WORSAAE H. , WELINDER B. , NERUP J.
Published: March 2008

Abstract. Animal experiments demonstrate that inter‐leukin‐lβ (IL‐1β) is beta‐cell cytotoxic in vitro and inhibits insulin secretion in vivo. However, it is unknown if IL‐Iβ affects beta‐cell function in man. Since IL‐1β and other cytokines are main mediators of the acute phase response, the objectives of the present study were to examine beta‐cell function in patients with major burn injuries, and to test if changes in beta‐cell function correlated to systemic levels of IL‐1β and tumour necrosis factor α (TNFα). We established and validated an IL‐1β assay measuring free and protein bound IL‐1β; protein bound IL‐1β was detached from the IL‐1β specific binding protein by acidification, rendering it accessible for the employed antibody. The IL‐1β specific binding protein (43–60 kDa) was found in serum and plasma from all tested patients and normal subjects. Survivors of burn injuries had a stimulated beta‐cell function, whereas non‐survivors had an impaired beta‐cell function as indicated by an increased plasma concentration of proinsulin, and an increased proinsulin/insulin ratio. In addition, non‐survivors had significantly increased plasma levels of TL‐1β. However, we could not demonstrate any correlation between C‐peptide, proinsulin, insulin or proinsulin/insulin ratio and plasma concentration of IL‐1β. In conclusion, beta‐cell function abnormalities are evident in patients with major burn injuries, and a high plasma level of IL‐1β correlates with a fatal outcome. However, the present study did not provide evidence for the hypothesis that beta‐cell function is influenced by circulating IL‐1β or TNFα during the acute phase response.
Relationship between ventilation and carbon dioxide production in normal subjects with induced changes in anatomical dead space
Authors: CLARK A. L. , COATS A. J. S.
Published: March 2008

Abstract. The aim of this study was to test the hypothesis that the increased ventilation to carbon dioxide production relationship on exercise associated with chronic cardiac failure may be due in part to changes in respiratory pattern, causing an increase in anatomical dead space ventilation. In order to assess the effect of changes in respiratory pattern on the relationship between ventilation and carbon dioxide production, normal subjects exercised at the same level at three different respiratory rates (normal, 25% slower, 25% faster). Nine healthy subjects were recruited from amongst hospital staff volunteers. Minute ventilation, carbon dioxide production and oxygen consumption were measured. There were no significant changes in ventilation, carbon dioxide production, or the correlation between ventilation and carbon dioxide production. This finding lends support to the view that changes in respiratory pattern can only be responsible for a very small proportion of the Ve/Vco2 slope difference between chronic cardiac failure and normals.
Dose‐response effects of lactate infusions on gluconeogenesis from lactate in normal man
Authors: JENSSEN T. , NURJHAN N. , CONSOLI A. , GERICH J. E.
Published: March 2008

Abstract. Lactate is the predominant gluconeogenic precursor in man. To determine the dose‐response relationships between plasma lactate concentration and rates of lactate incorporation in plasma glucose (lactate gluconeogenesis, LGN), we infused 17 normal volunteers with sodium lactate for 180 min at rates ranging from 6 to 40 γmol kg‐1 min‐1 and measured [U‐14C]lactate incorporation into plasma glucose, as well as rates of lactate and glucose appearance in plasma. With the highest lactate infusions, plasma lactate increased up to 7 mM (compared to 1.1±0.13 mM during control sodium bicarbonate infusions, n=10) and LGN averaged 4.73 ± 0.23 μmol kg‐1 min‐1 (compared to 1.57 ± 0.26 μmol kg‐1 min‐l in bicarbonate control experiments, P< 0.001). The data relating plasma lactate concentration to LGN best fit a sigmoidal curve which plateaued at plasma lactate concentrations of approximately 6 mM and yielded an ED50 of 2.04 ± 0.20 (SD) mM and a Vmax (6.25±1.2) (SD) (mUmol kg‐1 min‐1). The sum of the basal rate of lactate appearance and the rate of lactate infusion was not significantly different from the overall rates of lactate appearance during the lactate infusions (35.8±2.2 vs. 34.8±2.9 μmol kg‐1 min‐1, P = 0.23). Thus, our results support the view that infusion of exogenous lactate does not suppress endogenous lactate appearance in plasma.
Insulin induced hypoglycaemia and sugar transport across the brush border and basolateral membranes of rat jejunal enterocytes
Authors: DEBNAM E. S. , CHOWRIMOOTOO G.
Published: March 2008

Abstract. Acute hypoglycaemia enhances intestinal sugar uptake but the mechanisms involved are unknown. Results from the present study show increased galactose movement across the brush border and basolateral membranes of isolated upper, but not mid‐villus, jejunal enterocytes 45 min after intravenous administration of insulin to rats at a level which reduced by half plasma glucose concentration. Incubation of upper villus cells from uninjected animals with insulin (100 mU ml‐1) for 40 min was without effect on brush border or basolateral sugar transport. Insulin treatment of rats did not affect glucose uptake by brush border vesicles prepared from upper villus cells when the process was driven by an inwardly directed 100 mM sodium thiocyanate gradient. In contrast, glucose uptake using a 100 mM inwardly directed sodium chloride gradient was reduced by 49% following hypoglycaemia. It is concluded that the enhanced sugar uptake following insulin hypoglycaemia involves both brush border and basolateral membranes of only the most mature villus cells at the villus tip. Upregulation of Na+‐sugar cotransport at the brush border is best explained by an increased electrochemical driving force for Na +‐sugar cotransport rather than increased numbers of transporters. The transport response is not due to a direct effect of insulin on the enterocyte and the possible systemic factors involved are discussed.
Disparate effects of a triglyceride lowering diet and of bezafibrate on the HDL system: a study in patients with hypertriglyceridaemia and low HDL‐cholesterol levels
Authors: ARNON R. , SEHAYEK E. , EISENBERG S.
Published: March 2008

Abstract. The response of plasma triglyceride and of the high density lipoprotein (HDL) system to a triglyceride lowering diet and to a bezafibrate was compared in a group of 24 human subjects with mild to moderate hypertriglyceridaemia and low HDL‐cholesterol levels. Post‐heparin plasma lipoprotein (LPL) and hepatic (HL) lipase activities were determined before the initiation of the study and at the end of the diet (12 weeks) and bezafibrate (12 weeks) periods. HDL structure and composition were determined on a zonal centrifugation system at the end of the diet and bezafibrate periods. Diet caused a 9–20% reduction of plasma triglycerides but there was no change in LPL, HL or HDL levels. The individual responses between plasma triglycerides and HDL cholesterol levels however were highly correlated (r = 0.60 to 0.78). Combined diet plus bezafibrate therapy caused a further 38% decrease of plasma triglycerides with a 28% increase of HDL‐cholesterol and a 47% increase of LPL activity. HDL3 density decreased and the contribution of cholesteryl ester to the HDL mass was increased while the contribution of proteins and triglycerides decreased. In the majority of the subjects (61%) HDL cholesterol levels increased by 20% or more and in these subjects the change of HDL was highly correlated with the change of the LPL/HL ratio (r = 0.74) but not with the change of the plasma triglyceride levels. In the remaining subjects (39%), HDL cholesterol levels remained unchanged or increased by less than 20%. The change of HDL cholesterol levels in these subjects was unrelated to the decrease of plasma triglycerides or the change of post‐heparin lipase activities. It is suggested that during triglyceride‐lowering diets HDL levels change in relation to the reduction of plasma triglycerides due to a decreased cholesteryl ester transfer between lipopro‐teins (a weak effect) while during combined diet plus bezafibrate therapy, an additional strong effect on HDL due to the increased LPL activity exists at least in the majority of the subjects.
Time‐course and dose‐response of nitric oxide inhalation for systemic oxygenation and pulmonary hypertension in patients with adult respiratory distress syndrome
Authors: GERLACH H. , ROSSAINT R. , PAPPERT D. , FALKE K. J.
Published: March 2008

Abstract. Inhalation of nitric oxide (NO), an endoge‐neous vasodilator, was recently described to reduce pulmonary vascular resistance, and to improve arterial oxygenation by selective vasodilation of ventilated areas in patients with adult respiratory distress syndrome (ARDS). We describe the time‐course and dose‐response of initial short‐term NO inhalation in 12 patients with ARDS. Enhanced oxygenation was achieved within 1–2 min after starting NO inhalation; after inhalation, baseline conditions were re‐achieved within 5–8 min. Effective doses for improvement of oxygenation [baseline: PaO2= 10.2±2.5 KPa (76.4±18.7 mmHg)] were low: ED50 was about 100 ppb—a concentration similar to the atmosphere. NO doses of more than 10 ppm [10 ppm NO: PaO2=17.3 ± 3.3 KPa (129.4 ± 25.1 mmHg)] re‐worsen the arterial oxygenation. The ED50 for reduction of mean pulmonary artery pressure was 2–3 ppm. This indicates that inhalation of NO for improvement of oxygenation in severe ARDS should be performed using lower doses, with lower risk of toxic side effects.
The platelet angiotensin II receptor in type I diabetes: studies in patients with and without nephropathy
Authors: MAKARIOUS M. , PAWLAK M. , CAMPBELL L. V. , TIMMERMANS V. , DUGGAN K. , CHARLESWORTH J. A. , MACDONALD G. J.
Published: March 2008

Abstract. Experimental studies demonstrate impaired regulation of the mesangial angiotensin II (AII) receptor in diabetes. This could contribute to the disturbance of glomerular blood flow and the development of diabetic nephropathy. The aim of this study was to determine whether a similar receptor abnormality occurs in patients with type I insulin‐dependent diabetes mellitus (IDDM) and if so whether this is more prevalent in patients with micro‐ or macro‐albumi‐nuria. The platelet AII receptor was chosen because of its availability from the circulation and its comparable regulatory properties to tissue‐based receptors. The interaction between plasma All and its platelet receptor was examined in 45 patients with TDDM and 36 age‐ and sex‐matched control subjects. Seven patients had clinical nephropathy and two had persistent micro‐albuminuria. The duration of diabetes varied from 1 month to 42 years.

There was a significant inverse correlation between plasma AIT and the logarithm of receptor number in the control group (r= ‐0.555, P <0.001). This relationship was not observed in the diabetic patients irrespective of the duration of disease or the presence of nephropathy. Receptor expression in patients without nephropathy showed no correlation with either duration of disease or the degree of glycaemic control. However, a significant relationship between AII receptor number and duration of diabetes was noted in the group with nephropathy (r = 0.723, P <0.05). Patients without nephropathy had a significantly lower receptor number than control subjects (i.e. 3.9 ± 0.4 and 5.1±0.7 sites per cell respectively; P = 0.02), while comparable values to controls were observed in patients with renal disease (5.7 ±1.2 sites per cell). Plasma renin and AII levels for both groups of patients were comparable to those observed in the control subjects.

If these findings are representative of tissue‐based AII receptors, then the loss of ligand/receptor relationship in the presence of higher receptor expression in patients with nephropathy could provide an explanation for the glomerular haemodynamic abnormalities observed in human diabetes.
Heterozygous apolipoprotein C‐II deficiency: lipoprotein and apoprotein phenotype and Rsal restriction enzyme polymorphism in the Apo C'IIPadova kindred
Authors: GABELLI C. , BILATO C. , SANTAMARINA‐FOJO S. , MARTINI S. , JR H. B. BREWER , CREPALDI G. , BAGGIO G.
Published: March 2008

Abstract. Deficiency of apolipoprotein C‐II (apo C‐II), the cofactor for lipoprotein lipase, results in the familial chylomicronaemia syndrome characterized by severe hypertriglyceridaemia and fasting chylomicronaemia. To investigate the biochemical features of the heterozygous state for apo C‐II deficiency, we characterized the lipid, lipoprotein and apolipoprotein profiles in 18 relatives of two affected individuals (brother and sister) homozygous for the apo C‐IIPadova gene defect which results in the synthesis of a truncated 36 amino acid apolipoprotein. Carrier status was established in first degree relatives as well as in seven non‐obligate heterozygotes by restriction enzyme analysis of amplified apo C‐II genomic DNA using RsaI.

No significant differences in lipid, lipoprotein and apo C‐II levels were observed in heterozygotes when compared to unaffected family members. Thus, in this study, the carrier state was not associated with hypertriglyceridaemia or reduced plasma levels of apo C‐II.

However, analysis of amplified DNA from members of the apo C‐IIPsdova kindred by digestion with the enzyme RsaI, which identifies the mutant apo C‐II, permitted the identification of heterozygous family members which could not be recognized by measuring either fasting triglycerides or plasma apo C‐II levels.

This study provides further evidence that apo C‐II deficiency syndrome is a heterogeneous disease not only at the molecular level but also on the clinical ground with variable phenotypic expression in heterozygous individuals from different kindreds.
Biochemical markers of bone turnover in women with surgically treated carcinoma of the breast
Authors: LI F. , PITT P. I. , SHERWOOD R. , BARRETTT J. , HOUGHTON J. , PARSONS V. , MONIZ C.
Published: March 2008

Abstract. Biochemical markers of bone turnover were measured in fasting urine and blood samples obtained from 38 postmenopausal women with previous surgi cal treatment of breast cancer combined with adjuvant chemotherapy, tamoxifen, or placebo. Significantly elevated urinary pyridinoline as nmol mmol‐1 creatinine (47.5 and 42.5 in tamoxifen and placebo treated patients compared with 26.3 in normal controls, both P<0.001) and deoxypyridinoline (11.9 and 10.5 com pared with 6.3, P<0.001 and P=0.002 respectively) were found with unchanged urinary hydroxyproline, serum alkaline phosphatase and procollagen I carboxyterminal peptide (PICP). These findings suggest enhanced bone resorption resulting from the humoral osteoclast activating effect of the previous breast cancer or underlying carcinoma recurrence. Alternatively the raised pyridinium excretion might indicate an altered cross linking composition of bone collagen. No specific effect on bone metabolism was found with tamoxifen treatment as all measured parameters were similar in both tamoxifen ex‐users and non‐users. This confirmed the safety of tamoxifen therapy with respect to bone.
The influence of pretransplant lipoprotein abnormalities on the early results of renal transplantation
Authors: DIMÉNY E. , TUFVESON G. , LITHELL H. , LARSSON E. , SIEGBAHN A. , FELLSTRÖM B.
Published: March 2008

Abstract. Lipoprotein patterns were investigated before and after renal transplantation in a prospective study including 151 patients. Kidney graft losses during the first 6 months were associated with higher total cholesterol (P= 0.03), LDL cholesterol (P= 0.003) and LDL triglyceride levels (P= 0.01) before transplantation. Patients with serum cholesterol ±6.9 mmol l‐1 before transplantation had more acute rejections (1.7 vs. 0.9), a worse graft function and more vascular intimal hyperplasia and glomerular mesangial changes in transplant biopsies at 6 months. Patients with serum creatinine levels exceeding 160 μmol l‐1 at 6 months had more severe lipid disorders already before transplantation.

Serum creatinine at 6 months was influenced by the number of acute rejection episodes (P= 0.0001) and the age of the donor (P= 0.009) while the number of acute rejections was found to be related to pretrans plant total cholesterol levels (P= 0.0086) and the age of the recipient (P = 0.025).

In conclusion, pretransplant lipoprotein disturbances have an impact on the early outcome of renal transplantation. Since there is a progresssion of hyperlipidaemia following transplantation, this may have an influence also on the cardiovascular morbidity and late graft dysfunction.
Effect of transferrin concentration on bacterial growth in human ascitic fluid from cirrhotic and neoplastic patients
Authors: ROMERO A. , PÉREZ‐ARELLANO J. L. , GONZÁLEZ‐VILLARÓN L. , BROCK J. H. , BELLIDO J. L. MUÑOZ , CASTRO S. DE
Published: March 2008

Abstract. Cirrhotic patients with ascites have an unusually high frequency of development of spontaneous bacterial peritonitis. Iron availability is a key factor in bacterial growth and the ability of the host to limit it is associated with resistance to infection. The present study was undertaken to evaluate the influence of iron and transferrin on bacterial growth in ascitic fluid from 25 biopsy‐proven cirrhotic and nine neoplastic carcinomatous patients. No significant differences were found when comparing total ascitic fluid iron between the two groups but ascitic fluid transferrin concentration was significantly lower in cirrhotic (29.26 mg dl‐1 SD 29.58) than neoplastic (96.57 mg dl‐1 SD 76.01) patients. Moreover, a significant negative correlation was found between bacterial growth and transferrin concentration in ascitic fluid (P = 0.039). When the iron concentration in ascitic fluid was experimentally elevated (50 μg dl‐1 or 150 μg dl‐1) we observed a progressive increase in bacterial growth. If transferrin concentration is simultaneously elevated (250 mg dl‐1) this increase does not occur. These findings indicate that the transferrin level is an important factor in the regulation of bacterial growth in ascitic fluid and that the low concentration found in cirrhotic patients could facilitate spontaneous bacterial peritonitis.
The effect of porphyrins on cellular redox systems: a study on the dark effect of porphyrins on phagocytes
Authors: KONINGSBERGER J. C. , ASBECK B. S. VAN , HATTUM J. VAN , WIEGMAN L. J. J. M. , HENEGOUWEN G. P. VAN BERGE , MARX J. J. M.
Published: March 2008

Abstract. Erythropoietic protoporphyria (EPP) and porphyria cutanea tarda (PCT) are characterized by skin morbidity, induced by pro‐inflammatory reactive oxygen species generated by the photosensitizing properties of protoporphyrin IX and uroporphyrin I. How these porphyrins exert a toxic effect on the liver in the absence of light is poorly understood. We tested the hypothesis that porphyrins can interference with cellular redox systems, by studying the dark effects of protoporphyrin (PP), haematoporphyrin (HP), deu‐teroporphyrin (DP) and uroporphyrin (UP) on the cellular redox system of phagocytes, and on enzymatic oxyradical generating systems. Both in phagocytic cells and enzymatic systems, a dose‐dependent inhibition of chemiluminescence was observed by all porphyrins added. Catalase and SOD‐like activity of porphyrins was excluded by oxygraph and ferricyto‐chrome c reduction. However, ferrocytochrome c oxidation was inhibited by porphyrins indicating ferrireductase‐like activity. In a Fenton type reaction between H2O2 and PP, we could demonstrate the generation of *OH, or an electronically excited por‐phyrin species. No influence on phagocyte chemotaxis, phagocytosis and killing‐capacity was observed. We conclude that porphyrins do interfere with (cellular) redox systems and can both inhibit and enhance oxygen free radical generation, dependent on the type of redox reaction. Porphyrins can thus affect cellular metabolism. Since H2O2 and PP both readily dissolve in biological membranes, their interaction in the presence of transition metals may contribute to the toxic dark effects of porphyrins as observed in patients with EPP and PCT.
Patients with achalasia lack nitric oxide synthase in the gastro‐oesophageal junction
Authors: MEARIN F. , MOURELLE M. , GUARNER F. , SALAS A. , RTVEROS‐MORENO V. , MONCADA S. , MALAGELADA J.‐R.
Published: March 2008

Abstract. The abnormal function of the lower oesophageal sphincter in achalasia is likely to be due to impaired nonadrenergic, noncholinergic (NANC) inhibitory input. Since recent studies in animals suggest that nitric oxide (NO) is implicated physiologically in the inhibitory responses of the lower oesophageal sphincter, we have investigated whether the synthesis of NO is altered in the gastro‐oesophageal junction of patients with achalasia. NO synthase activity was investigated in samples of tissue from the gastro‐oesophageal junction obtained during surgery in eight patients with typical achalasia and six non‐achalasic controls who underwent oesophagectomy for reasons other than sphincter dysfunction. The NO synthase activity was determined by the transformation of 14C‐L‐arginine into 14C‐L‐citrulline in tissue homogenates. In addition, immunohistochemical staining of the tissues was performed using a polyclonal antibody raised against a peptide sequence of rat brain NO synthase. Furthermore, the relaxant response to an exogenous NO donor (sodium nitroprusside, SNP) was measured in vitro in muscle strips obtained from two patients with achalasia and in two non‐achalasic controls. NO synthase activity was detected in each of the samples obtained from six control patients (0.59 ±0.21 pmol mg‐1 min‐1; mean æ). By contrast, none of the samples obtained from the eight patients with achalasia had any detectable NO synthase activity. Immunohistochemical studies confirmed the presence of NO synthase in the myenteric plexus of the gastro‐oesophageal junction of control patients and its absence in achalasia. SNP relaxed muscle strips precontracted with bethanechol in both control samples and those from patients with achalasia. We suggest that the absence of NO synthase in the myenteric plexus of the gastro‐oesophageal junction explains the impaired function of the lower oesophageal sphincter in achalasia.
The impact of intermittent claudication on quality of life evaluated by the Sickness Impact Profile technique
Authors: ARFVIDSSON B. , KARLSSON J. , DAHLLÖF A.‐G. , LUNDHOLM K. , SULLIVAN M.
Published: March 2008

Abstract. Unselected patients suffering from intermittent claudication (n= 148) were invited to take part in a prospective study. Physical examination and several circulatory investigations were performed including a treadmill walking test, bicycle ergometry and a quality of life examination (Sickness Impact Profile, SIP, technique). The SIP has been reported to be sensitive enough to identify specific dysfunction profiles in several clinical conditions, but it has not been used on patients with intermittent claudication. The aim of this study was to determine to what extent quality of life was influenced by reduced walking ability in patients with intermittent claudication. If so, the SIP technique should then be a useful tool for determination of the degree of reduced exercise capacity in patients who may benefit from surgery instead of conservative treatment. A majority of the SIP categories, Sleep and rest, Emotional behaviour, Body care and movement, Home management, Mobility, Social interaction, Ambulation and Overall SIP were shown to be useful in confirming objective dysfunctions in our patients. The correlation between maximum walking ability and SIP scores indicated an approximate cut‐off limit at 70 W walking capacity. Thus, significant reductions in everyday life function were demonstrated in patients with maximum walking ability below 70 W. Patients with intermittent claudication also suffered from several other dysfunctions in addition to walking disability. These factors may, as well, impact on quality of life without walking disability.

Our results demonstrated that quality of life assessment by the SIP technique was a sensitive method for evaluation of overall dysfunction in patients with intermittent claudication. A comparison with a previous reference material from a general population showed that patients performing more than 70 W had only marginal dysfunctions in their everyday life. It may therefore be low cost‐effective to treat such patients particularly with surgery or angioplasty.
Human intestinal alkaline phosphatase—release to the blood is linked to lipid absorption, but removal from the blood is not linked to lipoprotein clearance
Authors: DOMAR U. , KARPE F. , HAMSTEN A. , STIGBRAND T. , OLIVECRONA T.
Published: March 2008

Abstract. To evaluate a possible quantitative relationship between the rise in intestinal alkaline phosphatase (IAP) activity and triglyceride‐rich lipoproteins in the blood after an oral fat intake, a specific and sensitive immunocatalytic assay was used. First, day to day variation of the basal IAP activity in the blood of eight volunteers was evaluated. One group of subjects with high basal IAP activity and great variations from one day to the other was distinguished from a group with low basal IAP activity and small day to day variations. The subjects with high basal IAP activities were all secretors of red blood cell antigens, while those with low basal IAP activities were non‐secretors. The IAP activity in the blood rose after fat rich meals but not after fat free meals. To further investigate this, IAP activities were measured in the blood of 28 men before 3, 6, 9 and 12 h after a standardized oral fat load of a mixed meal type. The activity rose in all individuals and showed a similar time course as the rise in plasma TG concentration. The elevations of the IAP activity were, however, not quantitatively correlated with the elevations in TG concentration, nor were there any relations in time to peak levels. Subjects with high basal IAP increased their IAP activity more than those with low basal IAP, but within neither group there was any correlation between the basal IAP activity and the rise in IAP activity. IAP did not float with lipoproteins on ultracentrifugation of plasma, nor did IAP bind to lipid droplets from a fat emulsion added to plasma.

It is concluded that transport of IAP from mucosal cells to the blood is greatly stimulated by fat absorption, but in the blood IAP was not bound to lipoproteins and no quantitative relationship between the rise in IAP activity and TG concentration was found. Therefore we suggest that the metabolism of TAP in the blood is not determined by intravascular lipoprotein metabolism, but by other factors, e.g. its glycosylation pattern.
Factors affecting the assay of urinary 3–hydroxy pyridiniurn crosslinks of collagen as markers of bone resorption
Authors: COLWELL A. , RUSSELL R. G. G. , EASTELL R.
Published: March 2008

Abstract. The measurement of the 3–OH pyridinium compounds, pyridinoline (Pyr) and deoxypyridinoline (Dpyr), in urine by high performance liquid chromato‐graphy is potentially useful in clinical studies, since they are specific biochemical markers of bone resorption. The aims of the present study were to improve assay performance and optimize sample collection. An isocratic high performance liquid chromatogram (HPLC) separation with baseline resolution was accomplished within 4 min using heptafluorobutyric acid as an ion‐pair. The sample preparation for HPLC, using CFl cellulose, produced uncontami‐nated samples with a recovery higher than 90% for both crosslinks. An elastin‐derived material, tentatively identified as isodesmosine (Ides), was also tested and proved to be a suitable internal standard. Use of this standard improved assay precision. The effect of an oral gelatin load on the excretion of Pyr and Dyr was investigated. The creatinine corrected excretion of Pyr and Dpyr was unchanged over a 6 h period, in contrast to the 10–fold increase in the excretion of urinary hydroxyproline with a peak 2–4 h after ingestion. In 20 postmenopausal women, 2 h fasting morning urine results correlated with results from 24–h urine collections Dpyr/Cr (r = 0.70, n= 20). There was a day‐to‐day variation of 26% in adults studied for 10 days.
Influence of platelet size before coronary angioplasty on subsequent restenosis
Authors: SMYTH D. W. , MARTIN J. F. , MICHALIS L. , BUCKNALL C. A. , JEWITT D. E.
Published: March 2008

Abstract. Platelet size has been shown to reflect platelet activity. We prospectively measured the mean platelet volume (MPV) in 47 patients undergoing single vessel angioplasty for symptomatic angina. The patients underwent repeat angiography 4–8 months later irrespective of symptomatic status. Restenosis was assessed quantitatively by hand held calliper measurements of the lesion and qualitatively by a return of angina, ST segment changes on an exercise test and visual analysis of the lesion severity by two experienced angiogra‐phers. Twenty‐four patients developed recurrent angina during the follow‐up period, the MPV in the group with chest pain was 8.54 ± 0.60 fl compared to 8.1±0.69 fl in the asymptomatic group (P = 0.04). Twenty two patients had significant ST segment changes at exercise. In this group the MPV was 8.6 ± 0.56 fl compared to 8.0 ±0.70 fl for the group with a negative test (P = 0.002). Similarly visually assessed angiographic stenosis showed a significant increase in the restenotic group (8.6 ± 0.56 vs. 8.0 ± 0.61 fl, P=0.001). The relative odds for developing clinically defined restenosis were 10.2 times greater if the pre‐procedural MPV lay in the upper compared to the lowest quartile.

There was a positive correlation between MPV and change in minimal luminal diameter between post angioplasty and follow‐up angiography, assessed quantitatively, r=+0.56, P = 0.016. There was no association between clinical or angiographic definitions of restenosis and haemoglobin, red cell count, mean corpuscular volume, white cell count or platelet count. Platelet size may influence the development of restenosis after succeesful coronary angioplasty.
Enhanced cellular metabolism of very low density lipoprotein by simvastatin. A novel mechanism of action of HMG‐CoA reductase inhibitors
Authors: SEHAYEK E. , BUTBUL E. , AVNER R. , LEVKOVITZ H. , EISENBERG S.
Published: March 2008

Abstract. To test the possibility that HMG‐CoA reductase inhibitors reduce LDL mass by an increased VLDL catabolism, we determined the effect of simvastatin therapy on cellular metabolism of VLDL in 18 patients with primary hypercholesterolaemia. Six months of simvastatin therapy was followed by 26%, 31% and 21% reduction of plasma total cholesterol, LDL‐cholesterol and plasma triglyceride levels, respectively. Before therapy, patients' VLDL metabolism in cultured human normal skin fibroblasts was similar to control VLDL. Six months after therapy was initiated, a remarkable 2–5‐fold increase in VLDL cell metabolism was found. These effects were even more marked when the VLDL was enriched with exogenous recombinant apo E‐3. A comparison of the metabolism of the patients' VLDL to control VLDL and LDL, revealed that simvastatin increased metabolic ratios of 60–70% and 45–95%, respectively. Simvastatin therapy was associated with a decrease of VLDL cholesteryl ester content of 19% and increase of the phospholipid content of 13%. The data strongly indicate that simvastatin therapy stimulates VLDL: cell interactions and catabolism, possibly reflecting alterations of the physico‐chemical properties of the particle. It is proposed that in addition to other previously described pathways, HMG‐CoA reductase inhibitors decrease LDL mass through a novel mechanism of enhanced VLDL catabolism prior to the conversion to LDL.
Acute dexfenfluramine administration normalizes glucose tolerance in rats with insulin‐deficient diabetes
Authors: ARORA R. , DRYDEN S. , McKIBBIN P. E. , WILLIAMS G.
Published: March 2008

Abstract. Dexfenfluramine has been shown to lower blood glucose concentrations independently of its effects in reducing food intake and body weight, in human and animal syndromes of non‐insulin dependent diabetes. This study aimed to determine whether dexfenfluramine could also reduce glycaemia in rats with severe insulin‐deficient diabetes induced by the β‐cell toxin, streptozotocin (55 mg kg‐1). Three weeks after diabetes induction, nine groups (each n= 10) of diabetic and non‐diabetic rats underwent oral glucose tolerance tests (1 g kg‐1, by gavage). These tests were preceded by 12–18 h of fasting to remove the confounding effects of hyperphagia in diabetic rats, and to stabilize glycaemia.

Dexfenfluramine (1·0 mg kg‐1), given 2 h before the glucose challenge, significantly reduced basal glycaemia and decreased the post‐challenge glycaemic rise (P<0·01 vs. untreated diabetics). Dexfenfluramine dosages of 2·5 and 5·0 mg kg‐1 both further flattened the post‐challenge glycaemic profiles (both P<0·01 vs. untreated diabetics) and achieved levels that did not differ significantly from those in non‐diabetics (both P> 0·05). Subsequently, the studies using dexfenfluramine dosages of 2·5 and 5·0 mg kg‐1 were repeated to determine whether the drug affected plasma insulin levels 2 h after dosing. In diabetic rats, plasma insulin concentrations were reduced to 10–20% of non‐diabetic values, and were not significantly altered by dexfenfluramine.

Acute dexfenfluramine administration therefore improves and (at dosages of 2·5 and 5·0 mg kg‐1) essentially normalizes glucose tolerance in rats with severe insulin‐deficient diabetes. As circulating insulin concentrations were not increased, dexfenfluramine probably acts by enhancing and/or mimicking insulin action. The magnitude of this effect suggests that dexfenfluramine could find application as adjunctive treatment in the management of human insulin‐dependent diabetic patients with insulin insensitivity, such as that associated with obesity.
Effect of adiposity on plasma lipid transfer protein activities: a possible link between insulin resistance and high density lipoprotein metabolism
Authors: DULLAART R. P. F. , SLUITER W. J. , DIKKESCHEI L. D. , HOOGENBERG K. , TOL A. VAN
Published: March 2008

Abstract. The mechanisms responsible for the decreased high density lipoprotein (HDL) cholesterol levels associated with obesity and insulin resistance are not well understood. Lecithin: cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein (CETP) are key factors in the esterification of cholesterol in HDL and the subsequent transfer of cholesteryl ester towards apolipoprotein B‐containing lipoproteins. Phospholipid transfer protein (PLTP) may be involved in the regulation of HDL particle size. We therefore measured the activities of LCAT, CETP and PLTP using exogenous substrate assays, as well as lipids, lipoproteins, insulin and C‐peptide in fasting plasma from eight healthy obese men (body mass index >27 kg m‐2) and 24 non‐obese subjects. The obese men had lower levels of HDL cholesterol (P<0·05) and higher levels of plasma triglycerides (P<0·05), insulin (P<0·05) and C‐peptide (P<0·01), as compared to the quartile of subjects with the lowest body mass index (BMI <22·4 kg m‐2). CETP and PLTP activities were elevated in the obese men by 35% (P<0·01) and by 15% (P<0·05), respectively. LCAT activity was comparable among the quartiles. Linear regression analysis showed that CETP activity was positively correlated with body mass index (P<0·02), fasting blood glucose (P7lt;0·05) and plasma C‐peptide (P<0·05). PLTP activity was positively related to body mass index (P<0·01), waist to hip circumference ratio (P<0·001), as well as to fasting blood glucose (P<0·05) and plasma C‐peptide (P<0·05)

It is concluded that the activities of CETP and PLTP are influenced by adiposity and possibly by insulin resistance. Elevated lipid transfer protein activities may provide a mechanism that contributes to alterations in HDL in insulin resistant states.
Enhancement of transforming growth factor β1 expression in the rat pancreas during regeneration from caerulein‐induced pancreatitis
Authors: GRESS T. , MÜLLER‐PILLASCH F. , ELSÄSSER H.‐P. , BACHEM M. , FERRARA C. , WEIDENBACH H. , LERCH M. , ADLER G.
Published: March 2008

Abstract Synthesis of extracellular matrix components is enhanced in the rat pancreas during regeneration from caerulein‐induced pancreatitis. To study the involvement of transforming growth factor β1 (TGFβ1), one of the most potent modulators of the extracellular matrix, in the process of pancreatic regeneration we examined the expression of this gene on the transcript and protein level. Pancreatic RNA was extracted from rats killed 0h, 12h, 24h, 2, 3 and 7 days after induction of caerulein pancreatitis. Transcript levels for TGFβ1 were measured by slot–blot analysis and mRNA in situ hybridization. Total amount of TGFβ1‐protein was measured using a radioligand binding assay. TGFβ1 protein was increased twofold after 24h and 48h and returned to control values 7 days after induction of pancreatitis, TGFβ1‐mRNA reached maximal values (3‐fold over controls) after 2 days. The largest amount of TGFβ1‐mRNA was found in pancreatic acinar cells and in stromal cells. In summary, expression of TGFβ1 in acinar and stromal cells of the rat pancreas is enhanced during regeneration from caerulein‐induced pancreatitis, which may indicate an involvement of TGFβ1 in the regulation of extracellular matrix regeneration in the rat pancreas after caerulein‐induced pancreatitis.
Diurnal variations in the plasma concentrations of mevalonic acid in patients with abetalipoproteinaemia
Authors: PAPPU A. S. , ILLINGWORTH D. R.
Published: March 2008

Abstract Previous studies have demonstrated that changes in the rates of cholesterol biosynthesis can be evaluated by the determination of plasma concentrations of sterol intermediates, including mevalonic acid and lathosterol and that, in normal human subjects, a diurnal rhythm exists in which the highest concentrations of sterol intermediates are observed at night. The factors responsible for this diurnal rhythm in cholesterol synthesis are, however, unknown. To test the hypothesis that the nocturnal increase in cholesterol biosynthesis is attributable to a reduced rate of hepatic uptake of chylomicron remnants at night as compared to higher rates of uptake during the daytime in response to alimentary lipaemia, we have examined the diurnal rhythm of mevalonic acid in six normal volunteers and three patients with phenotypic abetalipoproteinaemia. The latter patients do not absorb appreciable amounts of dietary cholesterol and are unable to synthesize chylomicron particles. Plasma concentrations of mevalonic acid exhibited a diurnal rhythm in the normal subjects, and the highest plasma concentrations were observed between 24.00 hours/04.00 hours. A similar rhythm was observed in the plasma of patients with abetalipoproteinaemia. These results suggest that the nocturnal increase in cholesterol biosynthesis which occurs in humans is not attributable to reduced hepatic uptake of chylomicron remnants at night; further studies are needed to better define those factors which influence the periodicity of cholesterol biosynthesis in humans.
Silicon and aluminium and their inter‐relationship in serum and urine after renal transplantation
Authors: BELLIA J. P. , NEWTON K. , DAVENPORT A. , BIRCHALL J. D. , ROBERTS N. B.
Published: March 2008

Abstract. The present study was undertaken to establish the relationship between serum and urine silicon and improve renal function and examine whether the increased urinary excretion of aluminium observed after successful renal transplantation was associated with silicon. The changes in silicon and aluminium concentrations in serum and urine were measured in 15 patients for a period of up to 17 days following a first renal transplant. Serum silicon, unlike aluminium, progressively decreased with improving renal function and was significantly positively correlated with serum aluminium but not with the silicon excretion. The urine excretion of aluminium peaked between 4–8 days post‐transplantation and was highly significantly positively correlated with urine silicon. The individual patient fractional excretion profiles of aluminium and silicon were variable but in general gave significant positive correlations suggesting that the elements may be cleared by the kidney through a common mechanism or as a chemical species, possibly an hydroxyaluminosilicate. If soluble silicon can chemically interact with aluminium in vivo it may, as in the biosphere, be important in the control of aluminium toxicity and eventual detoxification. Thus, elevated serum silicon concentrations may help to alleviate aluminium toxicity in end‐stage renal disease and assist in the rapid clearance of aluminium seen after kidney transplantation.
The HELP‐LDL‐apheresis multicentre study, an angiographically assessed trial on the role of LDL‐apheresis in the secondary prevention of coronary heart disease. II. Final evaluation of the effect of regular treatment on LDL‐cholesterol plasma concentrations and the course of coronary heart disease*
Authors: SCHUFF‐WERNER P. , GOHLKE H. , BARTMANN U. , BAGGIO G. , CORTI M. C. , DINSENBACHER A. , EISENHAUER T. , GRÜTZMACHER P. , KELLER C. , KETTNER U. , KLEOPHAS W. , KÖSTER W. , OLBRICHT C. J. , RICHTER W. O. , SEIDEL D. , GROUP THE HELP‐STUDY
Published: March 2008

Abstract The efficacy of the heparin‐induced extra‐corporeal LDL‐precipitation (HELP)‐apheresis procedure has been studied in an open prospective multicentre trial. After 2 years of regular weekly HELP‐treatment the data from 39 of 51 patients could be evaluated according to the study criteria. Twelve of the initially recruited study patients were omitted from the evaluation either because of premature termination of the treatment or because they did not fulfil the exact guidelines of the study protocol. A mean of 2·831 plasma was regularly treated on average every 7·85 days. The mean pre‐/post‐apheresis LDL‐cholesterol levels decreased from 286/121 mg dl‐1 at the first HELP treatment to 203/77 mg dl‐1 after 1 year and to 205/77 mg dl‐1 after 2 years of regular apheresis; the corresponding values for fibrinogen were 314/144, 246/98 and 250/105 mg dl‐1, respectively. In contrast, the mean pre‐/post‐apheresis HDL‐cholesterol levels rose from 41/38 through 51/44 mg dl‐1 after 1 year to 52/43 mg dl‐1 after 2 years of treatment. The overall result was a normalization of the atherogenic index (LDL‐/HDL‐cholesterol ratio) from 6·9/3·2 to 4·0/1·9. The angiographies from 33 patients obtained before and after 2 years of regular treatment could be evaluated blindly using the cardiovascular angiography analysis system. The mean degree of stenosis of all segments decreased from 32·5% (SD = 16) to 30·6% (SD ‐ 16·8) over the 2 years. A regression > 8% was observed in 50/187 (26·7%) segments, whereas 29/187 (15·5%) segments showed progression. In 108/187 (57·8%) segments the lesions were stable (< 8% deviation) over 2 years. We conclude that regular treatment with HELP‐LDL‐apheresis is able to stabilize progressive atherosclerotic disease and to induce almost twice as much regression as progression of atherosclerotic lesions.
Hormone replacement therapy may reduce high serum homocysteine in postmenopausal women
Authors: MOOREN M. J. VAN DER , WOUTERS M. G. A. J. , BLOM H. J. , SCHELLEKENS L. A. , ESKES T. K. A. B. , ROLLAND R.
Published: March 2008

Abstract In a prospective study we investigated the possible changes in fasting serum total homocysteine concentrations during continuous micronized 17β‐oestradiol, 2 mg daily, in combination with cyclic dydrogesterone, 10 mg daily during the first 14 days of each 28 day cycle, in 21 healthy non‐hysterectomized postmenopausal women. During the first six cycles mean serum homocysteine decreased by 10·9% (P= 0·013), after which no further significant changes were found during the 2 years of treatment. A 16·9% decrease (P= 0·017; n= 8) was found in women with high homocysteine concentrations, while in women with low homocysteine concentrations (n= 13) no significant changes were observed. The observed decrease in high homocysteine concentrations in postmenopausal women may in part contribute to the decreased risk of developing cardiovascular disease during hormone replacement therapy.
Systemic interleukin‐1 α and interleukin‐2 secretion in response to acute stress and to corticotropin‐releasing hormone in humans*
Authors: SCHULTE H. M. , BAMBERGER C. M. , ELSEN H. , HERRMANN G. , BAMBERGER A. M. , BARTH J.
Published: March 2008

Abstract Acute stress results in activation of the hypothalamic‐pituitary‐adrenal (HPA) axis. ACTH and cortisol secretion is stimulated by corticotropin‐releasing hormone (CRH). It has also been shown that activation of the HPA axis during stress is accompanied by changes in the immune response. However, little is known about the influence of acute stress on the release of cytokines such as inteleukin‐1 (IL‐1) or interleukin‐2 (IL‐2). In this study, we determined serum IL‐1 α and IL‐2 levels in 19 patients undergoing the acute stress of angioplasty for coronary artery disease. A second protocol was devised to determine serum IL‐1 α and IL‐2 concentrations as well as lymphocyte subpopulations in 10 normal volunteers receiving 1 μ kg‐1 human CRH intravenously. Finally, IL‐1 α concentrations were measured in CRH‐incubated mononuclear cell (MNC) and monocyte cultures.

In response to the stress of angioplasty, ACTH and cortisol as well as IL‐1 α and IL‐2 concentrations were clearly above baseline levels (IL‐1 α, mean ± SEM, baseline: 1·39 ± 0·34 ng ml‐1, after angioplasty: 2·64 ± 0·73 ng ml‐1, P < 0·05; IL‐2, baseline: 1·2 ± 0·13 ng ml‐1, after angioplasty: 2·8 ± 1·14 ng ml, P < 0·05). A similar pattern was obtained in normal subjects in response to CRH (IL‐1 α, baseline: 0·8 ± 0·2 ng ml‐1, after angioplasty: 3·7 ± 1·4 ng ml‐1, P < 0·05; IL‐2, baseline: 1·9 ± 0·4 ng ml‐1, after angioplasty: 5·4 ± 2·2 ng ml‐1, P < 0·02). The percentage of IL‐2 receptor‐positive lymphocytes rose from 3·9 ± 1·2% to 6·2 ± 1·6% (P < 0·05), the relative number of CD‐3 lymphocytes rose from 74·5 ± 1·6% to 78·3 ± 2·0% (P < 0·05). No significant changes were observed in the number of CD‐4, CD‐8, natural killer and B cells. In vitro, IL‐1 α concentrations in cultures containing CRH were not significantly different from control cultures. Our data demonstrate significant activation of the HPA axis and secretion of IL‐1 α and IL‐2 in response to both angioplasty and CRH. Furthermore, CRH administration resulted in activation of the cellular immune system (indicated by an increase in IL‐2 receptor positive lymphocytes). Our in vitro data suggest that CRH may not directly act on blood mononuclear cells to induce IL‐1 α release or, alternatively, sources other than blood mononuclear cells may account for the elevated IL‐1 α levels observed in vivo. We conclude that CRH may play a major role in neuroendocrine‐immune interactions during acute stress.