bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of metformin on food intake in obese subjects
Authors: Paolisso  , Amato  , Eccellente  , Gambardella  , Tagliamonte  , Varricchio  , Carella  , Giugliano  , D'onofrio
Published: March 2003

Background

It has been hypothesized that metformin inhibits food intake, but in humans such effect needs to be demonstrated. Our study aims at investigating the effect of metformin administration on food intake in obese, non‐diabetic, normotensive patients.

Methods

Thirty patients underwent a double‐blind, randomized study. Placebo (P; n = 15) and metformin (M; n = 15) were both given for 15 days, and food intake (FI) was recorded at baseline and in the last 4 days of each treatment period.

Results

M administration allowed a stronger decline in body weight (BW) (−2.8 ± 1.6 vs. −0.3 ± 0.4 kg P < 0.01), body fat (BF) (−1.4 ± 1.2 vs. −0.3 ± 1.1 kg P < 0.01), plasma leptin concentration (−5.2 ± 8.9 vs. −1.8 ± 10.4 ng mL−1P < 0.05) and FI (−642 ± 491 vs. −70 ± 1165 kJ per 24 h P < 0.01) than P. In M‐treated subjects, changes in FI significantly correlated with those in BW (r = 0.63, P < 0.007) and BF (r = 0.74, P < 0.001). Independently of sex and change in BF, the changes in FI and in fasting plasma leptin concentration (r = 0.58, P < 0.01) were still correlated.

Conclusion

Our study suggests that metformin administration is useful to inhibit FI and to lower BW and BF in obese non‐diabetic patients.
Lipoprotein (a) induces angiogenesis on the chick embryo chorioallantoic membrane
Authors: Ribatti  , Vacca  , Giacchetta  , Cesaretti  , Anichini  , Roncali  , Damacco
Published: March 2003

Background

Both lipoprotein (a) [Lp(a)] and angiogenesis have been shown to be associated with initiation and progression of atherosclerotic plaque. Lp(a) and two neutralizing anti‐Lp(a) antibodies were investigated for their capacity to affect the vasoproliferative processes of the chick embryo chorioallantoic membrane (CAM), a useful model for such an investigation.

Methods

Gelatin sponges loaded with Lp(a) alone or together with anti‐Lp(a) antibodies, or with vehicle alone, phosphate‐buffered saline (PBS), were implanted in vivo onto the CAM at incubation day 8. Four days later, sponges and the adjacent CAM tissues were assessed for the extent of angiogenesis in terms of microvessel counts.

Results

Lp(a)‐loaded sponges gave significantly higher counts than those loaded with the Lp(a)–anti‐Lp(a) antibodies complex, which overlapped those treated with PBS. The angiogenic response was similar to that obtained with basic fibroblast growth factor, a well‐known angiogenic molecule.

Conclusion

These data suggest that Lp(a) is capable of inducing angiogenesis in vivo, which might account for its ability to enhance and support atherosclerosis.
Regulation of iron metabolism in the acute‐phase response: interferon γ and tumour necrosis factor α induce hypoferraemia, ferritin production and a decrease in circulating transferrin receptors in cancer patients
Authors: Feelders  , Vreugdenhil  , Eggermont  , Kuiper‐Kramer  , Van Eijk  , Swaak
Published: March 2003

Background

The acute‐phase response and anaemia of chronic disease are characterized by hypoferraemia associated with an increased ferritin synthesis, which might be mediated by the activated cytokine cascade.

Methods

We examined the prolonged effects of isolated limb perfusion (ILP) with recombinant human tumour necrosis factor α (rTNF), recombinant human interferon γ (rIFN‐γ) and melphalan on interleukin (IL) 6 and acute‐phase protein levels, iron status and serum transferrin receptor (sTfR) levels in 12 patients with melanoma or sarcoma. Patients were treated with ILP during 90 min after pretreatment with rIFN‐γ during 2 days.

Results

After ILP, leakage of TNF resulted in systemic peak levels at 3 min followed by an increase in IL‐6 with maximum levels at 4 h. C‐reactive protein (CRP) rose at 4 h to peak levels at day 2, whereas α1‐antitrypsin and α1‐acid glycoprotein increased to maximum levels at day 3. Albumin and transferrin levels decreased after ILP and recovered after day 2. Serum iron and sTfR levels decreased during pretreatment and after ILP to minimum levels at 8 h and day 1 respectively. This was associated with an increase in serum ferritin levels, which paralleled CRP values.

Conclusions

Our data point to a central role for the cytokine network in the modulation of iron metabolism in the acute‐phase response and anaemia of chronic disease. TNF, possibly via induction of IL‐6, and IFN‐γ induce hypoferraemia, which may in part result from a decrease in tissue iron release based on a primary stimulation of ferritin synthesis. The fall in sTfR levels may reflect an impaired erythroid growth and/or TfR expression mediated by TNF and IFN‐γ.
Dipyridamole and dilazep suppress oxygen radicals in puromycin aminonucleoside nephrosis rats
Authors: Nakamura  , Kojima  , Arai  , Shirai  , Usutani  , Akimoto  , Masaoka  , Nagase  , Yamamoto
Published: March 2003

Background

Reactive oxygen species (ROS) are involved in the pathophysiology of puromycin aminonucleoside (PAN) nephrosis. To elucidate further the role of radicals in PAN nephrosis and the to determine the particular radical species scavenged by dipyridamole (DPM) and dilazep (DZ), we applied chemiluminescence and electron spin resonance (ESR) techniques.

Methods

Chemiluminescence of glomeruli, which were isolated on day 7 from rats injected with 100 mg kg−1 PAN, was measured with or without scavengers. The inhibitory effects of DPM and DZ on hydroxyl radical adduct formation in the Fenton's reaction were evaluated using ESR.

Results

Chemiluminescence was greater in glomeruli from rats with PAN nephrosis than in the the glomeruli of control rats. This increase was suppressed by superoxide dismutase, catalase, dimethylthiourea and also by DPM and DZ. ESR indicated that DPM and DZ inhibited hydroxyl radical adduct formation with a second‐order rate constant of 2.9 × 1010 and 1.6 × 1010 (mol L−1 s−1) respectively, similar to that of dimethylthiourea.

Conclusion

DPM and DZ scavenge hydroxyl radicals, thereby alleviating PAN nephrosis.
Sudden infant death syndrome and nitrogen metabolism: further development of a hypothesis
Authors: Wiklund  , George  , Nord  , Ronquist  , Saldeen
Published: March 2003

Background

A hypothesis suggesting an inducible inability of the enteric bacteria to metabolize urea in infants, resulting in metabolic alkalosis and subsequent respiratory insufficiency, has been proposed as the cause of sudden infant death syndrome (SIDS).

Methods

Microbiological cultivation and determination of faecal urease activity and faecal urea content were carried out in 30 cases of unexpected infant deaths out of which 22 were considered to be due to SIDS and eight from other causes. The concentration of nitric oxide (NO) in sealed test tubes was determined after incubation of faeces in normal saline.

Results

The SIDS subjects differed significantly from the control cases in two respects: they had low or no sigmoid faecal urease activity and an unmetabolized sigmoid faecal urea content, whereas the control subjects had normal faecal urease activity and none, or very little, remaining faecal urea. The NO concentration in faeces was correlated with the faecal content of urea in the SIDS cases.

Conclusion

The present findings lend support to the hypothesis of an insufficient metabolism of enteric urea in infants with SIDS.
Aspirin inhibits inducible nitric oxide synthase expression and tumour necrosis factor‐α release by cultured smooth muscle cells
Authors: Sánchez de Miguel L. , De Frutos T. , González‐Fernández F. , Del Pozo V. , Lahoz C. , Jiménez A. , Rico L. , García R. , Aceituno E. , Millás I. , Gómez J. , Farré J. , Casado S. , López‐Farré A.
Published: March 2003

Background

Inflammatory related cardiovascular disease, i.e. cardiac allograft rejection, myocarditis, septic shock, are accompanied by cytokine production, which stimulates the expression of inducible nitric oxide (iNOS).

Materials and methods

The aim of the present study was to examine whether anti‐inflammatory doses of acetylsalicylic acid (aspirin) could regulate iNOS protein expression in bovine vascular smooth muscle cells (BVSMCs) in culture.

Results

Interleukin 1β (IL‐1β, 0.03 U mL−1) induced nitric oxide release by BVSMCs. Aspirin inhibited nitric oxide release from IL‐1β‐stimulated BVSMCs in a dose‐dependent manner. In addition, aspirin significantly inhibited iNOS protein expression in BVSMCs and reduced the translocation of the nuclear factor‐κB (NF‐κB). Furthermore, aspirin and the blockade of NO generation by BVSMCs reduced the production of tumour necrosis factor α (TNF‐α) by these cells.

Conclusion

High doses of aspirin inhibited iNOS protein expression in BVSMCs and decreased NF‐κB mobilization. The inhibition of iNOS expression by aspirin was further associated with a reduced ability of BVSMCs to produce TNF‐α. This study could provide new mechanisms of action for aspirin in the treatment of the inflammation‐related cardiovascular diseases.
Determination of heparin‐induced IgG antibody in heparin‐induced thrombocytopenia type II
Authors: Wang  , Huhle  , Malsch  , Hoffmann  , Song  , Harenberg
Published: March 2003

Background

Heparin‐induced thrombocytopenia is a relatively uncommon but severe side‐effect of heparin therapy. Heparin‐induced IgG antibody has been elucidated to be the main isotype and the most pathogenic antibody in the pathophysiology. As affected patients are at high risk of developing thrombotic events, confirmation of the clinical diagnosis and avoidance of heparin re‐exposure are important and desirable.

Materials and methods

In the present study, heparin‐induced IgG was measured by the binding of neoantigens, which were prepared by incubating FITC‐heparin with platelet factor 4 present in normal serum. The cross‐reactivities of heparin‐induced IgG with low‐molecular‐weight heparin and danaparoid were analysed by competitive binding.

Results

A total of 81 clinically suspected heparin‐induced thrombocytopenia type II patients were analysed. Thirty‐seven of 38 heparin‐induced thrombocytopenia type II patients, in whom thromboembolism was confirmed by objective methods, had elevated relative fluorescence intensity ratios (patient normal control) and 36 had positive heparin‐induced platelet activation results. The prevalence of heparin‐induced IgG in heparin‐induced thrombocytopenia type II patients was 97.4%. Positive heparin‐induced IgG results were: 0/319 healthy volunteers, 0/38 other thrombo‐cytopenia and 2/56 heparin/low‐molecular‐weight heparin‐receiving patients without thrombocytopenia, 2/41 hyperbilirubinaemic patients and 2/50 hyperlipidaemic patients. A small amount of cross‐reaction assays showed similar results as obtained in heparin‐induced platelet activation.

Conclusion

Our results suggest that a very high frequency of heparin‐induced IgG in heparin‐induced thrombocytopenia type II patients can be detected using a novel antigen assay. The rapid determination of pathogenic heparin‐induced IgG may be a useful tool for the rapid diagnosis of heparin‐induced thrombocytopenia type II that could facilitate further management of the patients.
The role of glutathione in the regulation of apoptosis
Authors: Hall
Published: March 2003

Recent advances in the study of the regulation of cell death by apoptosis suggest that changes in mitochondrial permeability frequently precede the development of morphological features such as chromatin condensation, phosphatidylserine inversion of the outer cell membrane and the activation of endonucleases. There is evidence that this permeability transition is associated with, and may be regulated by, changes in the intracellular redox potential. The role of the tripeptide thiol glutathione in the regulation of apoptosis‐associated redox changes and the control of mitochondrial membrane permeability is reviewed in this article.
Serum zinc, copper, insulin and lipids in Alzheimer's disease epsilon 4 apolipoprotein E allele carriers*
Authors: González  , Martín  , Cacho  , Breñas  , Arroyo  , García‐Berrocal  , Navajo  , González‐Buitrago
Published: March 2003

Background

Copper (Cu) and zinc (Zn) have been implicated in the development of Alzheimer's disease (AD) and, in this regard, Cu and Zn serum concentrations have been analysed but with inconclusive results. Serum insulin, glucose and cholesterol concentrations have been related to the apolipoprotein E genotype in non‐AD populations.

Design

In this study, we have analysed the relationship between serum Cu, Zn, insulin, glucose and lipid parameters (cholesterol, triglycerides, apoA and apoB apolipoproteins) in AD and AD epsilon 4 apolipoprotein E carriers by multivariate analysis using logistic regression, including the variables that showed a significance of P < 0.05 in the bivariate analysis.

Results

The results obtained show that epsilon 4 apoE allele is an independent AD risk factor (OR = 6.67, 95% CI = 2.59–17.16). In AD epsilon 4 apoE allele carriers, we found significantly higher Zn, Cu and insulin serum concentrations. Non‐demented control subjects with at least one epsilon 4 apoE allele had the lowest serum insulin concentrations. There was no significant association between epsilon 4 apolipoprotein E allele and lipid parameters in the sample studied.

Conclusions

In AD we have found a significant association between higher serum Zn, Cu and insulin concentrations and the presence of an epsilon 4 apoE allele, but only greater serum Zn concentration appears to be an independent risk factor associated with the development of AD.
Echocardiographic features of primary, secondary and familial amyloidosis
Authors: Moyssakis I. , Triposkiadis F. , Rallidis L. , Hawkins P. , Kyriakidis M. , Nihoyannopoulos P.
Published: March 2003

Background

Currently recognized types of amyloidosis include primary, familial and secondary, each of which may affect the heart. There may be differences in the heart response to the deposition of amyloid fibrils in these three forms of the disease.

Materials and methods

Over a period of 10 years (1985–95), 28 consecutive patients with primary, 11 with secondary and 17 with familial amyloidosis were studied at the Departments of Cardiology of Laiko and Hammersmith Hospitals. The diagnosis of amyloidosis was confirmed by biopsies of subcutaneous fat, rectum, kidney, bone marrow, gum or sural nerve. Diagnosis of cardiac involvement was based on typical electrocardiographic and echocardiographic findings.

Results

The left ventricular fractional shortening (%) was reduced in primary compared with familial or secondary amyloidosis (29.8 ± 10.2 vs. 36.2 ± 6.5 vs. 36 ± 5.9, P < 0.05). The transmitral flow velocity pattern was compatible with abnormal relaxation in most patients in the three groups [primary 16 (57%), familial 11 (64.7%), secondary 6 (54.5%), P = NS]. Right ventricular systolic dysfunction (right ventricular dP/dt < 220 mmHg s−1 or tricuspid annulus systolic excursion < 10 mm) was present in 8 (28.6%), 2 (11.8%) and 0 patients. Patients with primary amyloidosis were followed up for 15 ± 6 months. There were 12 deaths, and repeat echocardiography in the survivors revealed a significant deterioration of left ventricular systolic function (fractional shortening = 23.6% ± 8.8%, P < 0.05 vs. baseline).

Conclusion

Primary amyloidosis is characterized by more severe cardiac involvement than the familial or secondary amyloidosis and has an ominous course.
Insulin decreases plasma cholesteryl ester transfer but not cholesterol esterification in healthy subjects as well as in normotriglyceridaemic patients with type 2 diabetes
Authors: Dullaart  , Riemens  , Scheek  , Van Tol
Published: March 2003

Background

Plasma cholesterol esterification (EST) and subsequent cholesteryl ester transfer (CET) from high‐density lipoproteins (HDLs) towards apolipoprotein (apo) B‐containing lipoproteins are key steps in HDL metabolism.

Materials and methods

The effects of exogenous hyperinsulinaemia on plasma CET and EST, measured with isotope methods, were evaluated in 10 male normotriglyceridaemic (plasma triglycerides <2.0 mmol L−1) patients with type 2 diabetes and 10 individually matched healthy subjects during a two‐step hyperinsulinaemic euglycaemic clamp over 6–7 h.

Results

No between‐group differences in baseline plasma lipid parameters were observed, but the HDL cholesteryl ester content was lower (P < 0.02) and the HDL triglyceride content was higher (P < 0.05) in diabetic patients. Baseline CET and EST were similar in the groups. In both groups, hyperinsulinaemia decreased plasma triglycerides (P < 0.01) and the HDL triglyceride content (P < 0.01) compared with saline infusion in healthy subjects, whereas the HDL cholesteryl ester content increased (P < 0.05 vs. saline infusion) in diabetic patients. CET was similarly decreased by hyperinsulinaemia in both groups (P < 0.01 vs. saline infusion). In contrast, the change in EST in either group was not different from that during saline administration. In the combined group, baseline CET was positively correlated with plasma triglycerides (Rs = 0.68, P < 0.01). The HDL cholesteryl ester content was negatively (Rs = −0.48, P < 0.05) and the HDL triglyceride content was positively (Rs = 0.64, P < 0.01) correlated with CET.

Conclusion

Insulin infusion decreases plasma CET in conjunction with a fall in triglycerides but does not decrease cholesterol esterification in healthy and type 2 diabetic subjects, indicating that acute hyperinsulinaemia has a different effect on these processes involved in HDL metabolism. Despite unaltered fasting plasma CET, HDL core lipid composition was abnormal in diabetic patients, suggesting that additional mechanisms may contribute to changes in HDL metabolism in diabetes mellitus.
High dose insulin does not increase glucose transfer across the blood–brain barrier in humans: a re‐evaluation
Authors: Knudsen  , Hasselbalch  , Hertz  , Paulson
Published: March 2003

Background

This study re‐evaluates previously published data on blood–brain barrier transfer coefficients in humans exposed to high insulin levels.

Design

In this study of seven volunteers, global blood–brain barrier permeability to glucose and phenylalanine was measured by means of the intracarotid double‐indicator method before, during, and after an insulin‐glucose clamp. Data were reanalyzed by means of a mathematical model that takes capillary heterogeneity and labelled glucose backflux from the brain into account.

Results

The permeability‐surface area product (PS) for glucose transport from the blood into the brain, PS1, was 0.145 (0.102–0.211) (median and quartiles), 0.146 (0.113–0.259), and 0.157 (0.133–0.181) ml g−1 min−1 before, during, and after insulin challenge, respectively. In six of the subjects, PS for transport from brain to blood over the brain glucose distribution volume, PS2/Ve decreased under hyperinsulinemia, from a baseline value of 6.56 (3.0–14.9) to 3.86 (1.41–5.32), and restored to a value of 3.8 (2.8–12.1) min−1 after insulin challenge. This decrease in PS2/Ve is probably due to an increase in the brain glucose distribution volume induced by an insulin induced increased intracellular glucose uptake during the experiment. For phenylalanine (n = 5), PS1 was unchanged before, during, and after insulin challenge. In hyperinsulinemia, PS3/Ve for phenylalanine decreased in all subjects.

Conclusion

We conclude that acutely elevated high plasma insulin levels in humans does not alter the brain uptake of glucose or phenylalanine from the blood. It seems, however, that high plasma insulin levels induce an increase in the movement of d‐glucose and
l‐phenylalanine from the brain interstitial fluid into the intracellular compartment.
Acute methylprednisolone administration induces a transient alteration of glucose tolerance and pyruvate dehydrogenase in humans
Authors: Pellacani  , Fornengo  , Bruno  , Ceruti  , Mioletti  , Curto  , Rinaudo  , Pagano  , Cavallo‐Perin
Published: March 2003

Background

Glucocorticoid administration induces alteration of glucose tolerance, and impairment of glucose oxidation may contribute to glucocorticoid‐induced derangement of glucose metabolism. We investigated glucose tolerance following methylprednisolone administration in humans. In the same model, we evaluated pyruvate dehydrogenase (PDH), the rate limiting enzyme of glucose oxidation, in peripheral blood mononuclear cells.

Materials and methods

Methylprednisolone (2 × 40 mg, iv, one dose every 12 h) was administered to six healthy volunteers. Glucose tolerance was evaluated through an oral glucose tolerance test (oGTT, 75 g glucose) at least a week before and after drug administration (2 and 24 h post‐drug). To assess modifications of lipid metabolism circulating free fatty acids (FFA) and glycerol were measured, during fasting and oGTT. The active form of PDH (PDHa) was evaluated in peripheral blood mononuclear cells, both as ex vivo activity and as in vitro response to insulin (30pmol l−1).

Results

Methylprednisolone induced an alteration of glucose tolerance 2 h after its administration. Such alteration was completely reversed at 24 h. Alteration of glucose tolerance was accompanied by decreased ex vivo PDHa activity. PDH responsiveness to insulin in vitro was also impaired. Circulating FFA were unmodified, but decreased glycerol levels suggested a slight inhibition of lipolysis.

Conclusions

Acute methylprednisolone administration in humans induced a transient decrease of glucose tolerance 2 h after drug administration, accompanied by hyperinsulinaemia, inhibition of ex vivo PDH activity and its response to insulin in vitro. These alterations were completely abolished at 24 h, suggesting that methylprednisolone can be safely administered acutely. Furthermore, methylprednisolone induced only minor modifications of circulating FFA and glycerol, indicating minimal impact on lipid metabolism.
Creatine corrects muscle 31P spectrum in gyrate atrophy with hyperornithinaemia
Authors: Heinänen  , Näntö‐Salonen  , Komu  , Erkintalo  , Alanen  , Heinonen  , Pulkki  , Nikoskelainen  , Sipilä  , Simell
Published: March 2003

Background

Eye fundus destruction and type II muscle fiber atrophy in gyrate atrophy of the choroid and retina with hyperornithinaemia (GA) may be mediated by elevated ornithine concentrations which strongly inhibit creatine biosynthesis. This results in deficiency of creatine phosphate (PCr), a key intracellular energy source, as we have demonstrated in skeletal muscle of the patients by 31P magnetic resonance spectroscopy (31P MRS).

Materials and methods

Possible correction of the relative PCr deficiency by long‐term daily exogenous supplementation of creatine or its precursors was investigated in four GA patients receiving creatine and in five patients treated with guanidinoacetic acid‐methionine combination. The relative PCr concentration, expressed as PCr/Pi (Pi; inorganic phosphate) or as PCr/ATP ratios, was compared with the values of untreated GA patients, and matched healthy volunteers.

Results

Muscle PCr/Pi ratios (mean ± SD) of the untreated and creatine supplemented GA patients and controls were 4.9 ± 1.4, 7.9 ± 0.4 and 8.4 ± 1.3. Guanidinoacetate‐methionine combination was similarly effective (respective PCr/Pi ratios: 4.9 ± 0.7, 6.3 ± 1.1 and 10.7 ± 2.8).

Conclusion

Supplementation with creatine or creatine precursors almost normalised low muscle PCr/Pi ratios of patients with GA.
The p22 phox polymorphism C242T is not associated with CHD risk in Asian Indians and Chinese
Authors: Saha  , Sanghera  , Kamboh
Published: March 2003

Background

Oxygen free radicals such as superoxide anion have been implicated in the pathogenesis of atherosclerosis and coronary heart disease (CHD). The nonglycosylated 22 kDa α‐subunit of the NADH/NADPH oxidase (p22 phox) of the vasculature acts as the final electron transporter in the generation of superoxide anion. Recently, a common polymorphism (C242T) at codon 72 in the p22 phox gene has been reported to be associated with CHD risk.

Study design

We examined the role of the C242T polymorphism with the risk of CHD in a biracial sample of Asian Indians and Chinese from Singapore. The sample comprised angiographically confirmed CHD patients (126 Asian Indians and 151 Chinese) and age‐ and sex‐matched healthy control subjects (154 Asian Indians and 167 Chinese).

Results

The frequency of the T allele was significantly higher in Asian Indian control subjects than in Chinese control subjects (0.38 vs. 0.09; P < 0.0001). However, there was no difference in the frequency of this allele between case patients and control subjects either in Chinese (0.10 vs. 0.09) or Asian Indians (0.38 vs. 0.40). This polymorphism was also not associated with plasma lipid and apolipoprotein levels in any group.

Conclusions

The p22 phox codon 72 polymorphism is not associated with the risk of CHD in the present samples of Asian Indians and Chinese.
Influence of physical exercise on polyamine synthesis in the rat skeletal muscle
Authors: Turchanowa  , Rogozkin  , Milovic  , Feldkoren  , Caspary  , Stein
Published: March 2003

Background

Physical exercise and testosterone administration result in a series of adaptive anabolic phenomena in the skeletal muscle. The role of polyamines in these processes has been poorly explored.

Design

We measured the activities of polyamine‐synthesising enzymes, ornithine decarboxylase (ODC) and S‐adenosylmethionine decarboxylase (SAMDC) and polyamine content in skeletal muscle of male rats exposed to endurance or resistance exercise, or a single testosterone treatment. Soleus muscle (consisting mainly of slow‐twitching oxidative fibres—STO) and extensor digitorum longus (mainly fast‐twitching glycolytic muscle fibres—FTG) were analysed for polyamine content by HPLC, and ODC and SAMDC activity.

Results

Both endurance and resistance exercise induced a threefold increase in endogenous testosterone production. Two hours after exercise, ODC was increased in STO fibres, returning to baseline after 24 h; in FTG fibres the increase was less prominent. An increase in SAMDC activity occurred in a more sustained manner, with its peak 8 h after exercise. Polyamines were subsequently accumulated in both skeletal muscle fibres, with a rise in putrescine concentration after 2 h, and a fall corresponding to conversion of putrescine to spermidine and spermine by SAMDC. Single dose of 17α‐methyltestosterone resulted in a similar increase in polyamine‐synthesising enzyme activities and polyamine concentrations in the skeletal muscle.

Conclusion

Polyamine accumulation in the skeletal muscle after physical exercise is likely to occur secondary to testosterone production. Polyamines are apparently involved in the oxidative, but not in glycolytic processes related to muscle adaptation to exercise.
Effectiveness of recombinant erythropoietin and iron sucrose vs. iron therapy only, in patients with postpartum anaemia and blunted erythropoiesis
Authors: Breymann  , Richter  , Hüttner  , Huch  , Huch
Published: March 2003

Background

To compare efficacy between recombinant human erythropoietin (rhEPO) plus parenteral iron vs. iron alone (parenteral vs. oral) in postpartum anaemia.

Methods

Sixty patients (haemoglobin 8.6 ± 1.1 g dL−1) were randomized to rhEPO plus intravenous (i.v.) iron sucrose (group 1), rhEPO placebo plus i.v. iron sucrose (group 2), or oral iron alone (group 3), daily for 4 days beginning 48–72 h postpartum. Erythropoiesis and iron status were assessed before, and on 4, 7 and 14 days after, starting therapy.

Results

On day 7 the group 1 haematocrit increase was 7.7 ± 3.1% vs. 5.3 ± 1.9% (group 2, P < 0.01) and 4.4 ± 3.2% (group 3, P < 0.01), and on day 14, 11.3 ± 2.9% vs. 9.2 ± 3.4% (group 2, P < 0.05) and 8 ± 2.8% (group 3, P < 0.01). The odds of achieving a target haematocrit > 32% on day 7 and > 35% on day 14 were higher on rhEPO (1.5–2.7) than on either iron regimen alone. Group 1 reticulocyte counts were also higher on days 4 (P < 0.05 vs. oral iron) and 7 (P < 0.01 vs. oral and parenteral iron).

Conclusion

All three regimens were effective in postpartum anaemia, but the haematocrit and reticulocyte responses to rhEPO plus parenteral iron were significantly greater than to iron alone. Benefit was greatest in the blunted erythropoiesis subgroup with elevated post‐Caesarean section C‐reactive protein levels.
Evaluation of CD14 in host defence
Authors: Antal‐Szalmás
Published: March 2003

An extensive search for the cell membrane targets for lipopolysaccharide (LPS), the major causative agent of Gram‐negative septic shock, resulted in the identification of CD14 as the major endotoxin ‘receptor’. Besides recognition of LPS, several new aspects of its biological functions have been described recently. In this review the different CD14 forms, their most important biological and biochemical features, signalling properties, cellular and subcellular distribution and association with different diseases are discussed in detail, showing that these molecules posses several unique biological functions and further proving their central role in innate immunity.
Decreased antioxidant defence in individuals infected by the human immunodeficiency virus
Authors: Treitinger  , Spada  , Verdi  , Miranda  , Oliveira  , Silveira  , Moriel  , Abdalla
Published: March 2003

Background

The oxidative stress associated with HIV infection may be important for the progression of the disease because reactive oxygen species activate the nuclear transcription factor NF‐κB, which is obligatory for HIV replication.

Patients and methods

The activities of the antioxidant enzymes superoxide dismutase (SOD, EC 1.15.1.1) and glutathione peroxidase (GPx, EC 1.11.1.9) of blood plasma and peripheral blood mononuclear cells, as well as the plasma levels of ascorbate, α‐tocopherol and β‐carotene, were measured in 75 subjects with HIV infection and in 26 controls. The HIV‐infected patients were classified according to the Walter Reed Army Institute criteria.

Results

The extracellular SOD (EC‐SOD) of blood plasma activity was decreased in HIV‐infected patients compared to controls, while the SOD activity of mononuclear cells decreased with the HIV‐associated disease progression. GPx activities and α‐tocopherol concentration of HIV‐infected patients neither differed as compared to controls nor in relation to disease progression. Lower concentrations of ascorbate and β‐carotene were found in HIV‐infected patients than in controls. A positive correlation between CD4 lymphocyte counts and the SOD activities of plasma and mononuclear cells was found.

Conclusion

These results suggest that abnormalities of antioxidant defence, mainly of SOD activity, are related to the progression of the HIV infection.
Mutation analysis of the human adipocyte‐specific apM‐1 gene
Authors: Schäffler A. , Barth N. , Palitzsch K‐D. , Drobnik W. , Schölmerich J. , Schmitz G.
Published: March 2003

Background

The aim of this study was to analyse the human adipocyte‐specific apM‐1 gene for sequence variations.

Methods

Sequence analysis was performed in 344 randomly chosen blood samples using a capillary sequencer.

Results

Whereas no mutations were detected in intronic regions and in 2.7 kb of the promoter, two sequence variations were found within the coding sequence of apM‐1. For both mutations, a polymerase chain reaction‐(PCR) based restriction fragment length polymorphism (RFLP) analysis was developed, which provided a rapid screening method. A conservative T → G transition at nucleotide + 45 within exon‐2 [Gly15Gly] was detected with an allelic frequency of 0.9 for the wild‐type allele and 0.1 for the mutated allele. In addition, a missense point mutation at nucleotide + 331 within exon‐3 [Tyr111His] was detected with an allelic frequency of 0.97 for the wild‐type allele and 0.03 for the mutated allele. This mutation replaces a tyrosine by an histidine within the carboxyterminal globular domain of apM‐1. Concerning the Gly15Gly polymorphism, the TT genotype was found in 275 subjects (79.9%), the TG genotype in 67 subjects (19.5%) and the GG genotype in 2 subjects (0.6%): one with maturity onset diabetes of young age (MODY‐diabetes) and one with Lipoatrophic Diabetes Syndrome (LPDS). Concerning the Tyr111His polymorphism, the TT genotype was found in 328 subjects (95.4%), the TC genotype in 15 subjects (4.3%) and the CC genotype in 1 subject (0.3%).

Conclusion

The existence of two yet unknown mutations within the apM‐1 gene was demonstrated and RFLP analysis was established for rapid screening. Well defined cohorts of patients are necessary to determine the putative role of apM‐1 gene mutations in the pathogenesis of metabolic disorders.
Circulating concentrations of C‐reactive protein and total sialic acid in tobacco smokers remain unchanged following one year of validated smoking cessation
Authors: Crook M. A. , Scott D. A. , Stapleton J. A. , Palmer R. M. , Wilson R. F. , Sutherland G.
Published: March 2003

Background

Elevated plasma concentrations of C‐reactive protein (CRP) and total sialic acid (TSA) have been associated with increased cardiovascular risk. Additionally, levels of both CRP and TSA have been reported to be significantly elevated in smokers. However, it is not clear if the raised TSA and CRP levels noted in smokers are directly attributable to the smoking experience, or if they may be elevated due to a secondary mechanism(s), such as smoking‐induced tissue inflammation.

Subjects and methods

We measured the plasma concentration of CRP and TSA in a group of smokers at baseline and following one year of validated smoking cessation (n = 30) and in a control group of tobacco users who continued to smoke over the year (n = 30).

Results

The baseline concentration of TSA and CRP was 67.2 mg dL−1 and 1.91 mg L−1, respectively (n = 60). No significant dose‐dependent relationship was noted between baseline CRP or TSA concentration and either plasma cotinine, expired‐air CO or daily cigarette consumption. There was no difference in the mean change in CRP level in the quitters over one year (− 0.2 mg L−1) compared to the continuing smokers (+ 0.5 mg L−1), P = 0.80, or in the change in concentration of TSA in the quitters (− 2.7 mg dL−1) compared to the continuing smokers (+ 0.4 mg dL−1), P = 0.26.

Conclusions

As the circulating concentrations of both CRP and TSA remain unchanged following one year of smoking cessation, these results would suggest that the elevated levels noted in smokers are not directly attributable to tobacco use and are more likely to be elevated due to a secondary process that is yet to be established.
Ibuprofen inhibits adhesiveness of monocytes to endothelium and reduces cellular oxidative stress in smokers and non‐smokers
Authors: Zapolska‐Downar D. , Naruszewicz M. , Zapolski‐Downar A. , Markiewski M. , Bukowska H. , Millo B.
Published: March 2003

Cigarette smoking is a major risk factor in atherosclerosis and a useful model from which to study chronic inflammation. We compared monocyte function, lipid profiles and inflammatory markers in smokers and non‐smokers, before and after oral ibuprofen intake. The adhesion of freshly isolated monocytes to native and tumour necrosis factor α (TNFα) stimulated human umbilical vein endothelial cells (HUVEC), as well as superoxide anion (O2−) levels and hydrogen peroxide (H2O2) production in resting and phorbol myristate acetate (PMA) stimulated monocytes were determined.

A group of nine smokers without any other coronary risk factor was compared with an age‐matched group of 9 non‐smokers. Tests were performed before and after a two‐week course of oral ibuprofen (600 mg day−1).

In smokers before ibuprofen, monocyte adhesion to native and TNFα‐stimulated HUVEC was increased (P < 0001 and P < 0·01, respectively), and so were O2− levels in native and PMA‐stimulated monocytes (P < 0·01 and P < 0·001, respectively). Ibuprofen reduced the adhesion of monocytes to native and stimulated HUVEC (P < 0·001) and O2− generation by resting and PMA‐stimulated cells (P < 0·01) in both groups. H2O2 production by resting and PMA‐stimulated monocytes was reduced in smokers and non‐smokers (P < 0·01). Interestingly, ibuprofen increased HDL cholesterol levels in smokers (P < 0·01) and non‐smokers (P < 0·001), and reduced the level of triglycerides in smokers (P < 0·05).

Oral administration of ibuprofen reduced the adhesion of monocytes to HUVEC, suppressed oxidative stress and increased HDL cholesterol levels in smokers and non‐smokers.
New mechanisms of adrenostatic compounds in a human adrenocortical cancer cell line
Authors: Fassnacht M. , Hahner S. , Beuschlein F. , Klink A. , Reincke M. , Allolio B.
Published: March 2003

Background

Adrenostatic compounds are frequently used in the treatment of patients with Cushing's syndrome and act via direct inhibition of steroidogenic enzymes. However, additional mechanisms may be involved in the blockade of adrenal steroid secretion. We therefore investigated the effects of aminoglutethimide (AG), metyrapone (MTP) and etomidate (ETO) in the human NCI‐h295 adrenocortical carcinoma cell line.

Materials and methods

Cells were incubated with increasing doses of the adrenostatic compounds. Steroid hormone secretion (cortisol, 17‐OH‐progesterone, DHEA‐S) and cAMP synthesis were determined and Northern blot analysis and cell proliferation experiments were performed.

Results

ETO was the most potent adrenostatic compound inhibiting P450c11 hydroxylase at low concentrations (IC50 15 nM), and also blocking P450 side‐chain cleavage (scc) enzyme (IC50 400 nM) at higher concentrations. The pattern of enzyme inhibition was similar for MTP with an IC50 of 3á5 μM for P450c11 and 17 μM for P450scc, while AG blocked P450scc with an IC50 of 10 μM. AG significantly suppressed the baseline ACTH‐R mRNA expression in a dose‐dependent fashion (300 μM AG: 5% ± 1%; 30 μM AG: 64% ± 1%; 3 μM AG: 108% ± 19% compared with control cells: 100% ± 11%) but increased glucocorticoid receptor mRNA. The reduced ACTH‐R mRNA was paralleled by low ACTH‐induced cAMP accumulation indicating reduced expression of ACTH‐R protein. The simultaneous incubation of hydrocortisone together with AG reversed the inhibitory effect of AG on the ACTH‐R expression. AG and ETO inhibited cell proliferation in the NCI‐h295 cells, but ETO was much more potent and showed antiproliferative effects at concentrations of 6 μM. The growth inhibition was not reversed by administration of hydrocortisone.

Conclusions

Our data demonstrate that adrenostatic compounds not only act by suppression of steroidogenic enzymes but can also influence both ACTH‐R expression and cell proliferation in adrenal cells. As these effects occur in vitro at concentrations that are reached during treatment with theses drugs in patients, they are probably also of clinical relevance. Particularly the antiproliferative activity of ETO may be useful in Cushing's syndrome due to adrenocortical cancer. The interaction of steroidogenesis, ACTH‐R and glucocorticoid receptor expression as well as cell proliferation provides a new concept of the intra‐adrenal response to stress in humans.
Reduction of hepatitis C virus load by H.E.L.P.–LDL apheresis
Authors: Schettler V. , Monazahian M. , Wieland E. , Ramadori G. , Grunewald R. W. , Thomssen R. , Müller G. A.
Published: March 2003

The association of HCV with apolipoprotein B containing lipoproteins has been observed and this led to the assumption that the LDL receptor may also serve as a candidate receptor for HCV. H.E.L.P.–LDL apheresis is suggested to be an effective and rapid tool to safely eliminate apolipoprotein B containing lipoproteins.

In this pilot study, we have investigated whether H.E.L.P. treatment would reduce HCV load in five patients, all infected for more than 4 years with HCV and resistant against established anti‐HCV therapy (interferon, ribaverin). HCV–RNA was determined by RT–PCR in plasma immediately before the start of apheresis (SA) and after treatment of 2500 mL plasma (AA).

H.E.L.P. apheresis led to a mean decrease of 77·3%(16th percentile 36·5%, 84th percentile 89·6%) of HCV–RNA when AA values were compared to SA values. This decline was reproducible during nine treatment procedures, but was not correlated to the decrease in LDL cholesterol.

This investigation shows for the first time that HCV load can be reduced by H.E.L.P. apheresis, which is an established and approved therapy for hypercholesterolemia. Even though the efficiency of viral load reduction varied between single procedures and did not correlate to LDL removal, this extracorporeal therapy opens the possibility to treat patients with established immune modulatory and antiviral therapy in the interval between two apheresis procedures.
Inhibition of prostacyclin by indomethacin ameliorates the splanchnic hyposensitivity to glypressin in haemorrhage‐transfused common bile duct‐ligated rats
Authors: Lee F.‐Y. , Chu C.‐J. , Wang S.‐S. , Chang F.‐Y. , Lin H.‐C. , Hou M.‐C. , Chan C.‐C. , Wu S.‐L. , Chen C.‐T. , Huang H.‐C. , Lee S.‐D.
Published: March 2003

Prostacyclin (PGI2) is an important contributor to the mediation of hyporeactivity to vasoconstrictors and the development of hyperdynamic circulation in portal hypertensive states. Inhibition of PGI2 synthesis in haemorrhage‐transfused partially portal vein‐ligated rats could ameliorate the splanchnic hyposensitivity to glypressin, a long‐acting vasopressin analogue. This study investigated whether the hyposensitivity to glypressin also exists in rats with common bile duct ligation (BDL) and whether the inhibition of PGI2 synthesis by indomethacin could potentiate the portal‐hypotensive effect of glypressin in bleeding BDL rats.

Two series of BDL rats were used. Series 1 investigated the haemodynamic effects of low dose glypressin (0·07 mg kg−1) in BDL rats with or without bleeding by catheterization. In series 2, haemodynamic parameters were measured in stable or bleeding BDL rats that were receiving intravenously high dose glypressin (0·2 mg kg−1) or indomethacin (5 mg kg−1) followed by high dose glypressin. In rats with a hypotensive haemorrhage, 4·5 mL of blood was withdrawn and 50% of the withdrawn blood was reinfused before the administration of glypressin or indomethacin.

Splanchnic hyposensitivity to glypressin was demonstrated in haemorrhage‐transfused BDL rats receiving high, but not low, doses of glypressin. Indomethacin infusion did not cause significant systemic and portal haemodynamic changes in bleeding BDL rats (P > 0·05). The addition of indomethacin significantly enhanced the portal‐hypotensive effects of glypressin (P < 0·05) and potentiated the increases in mean arterial pressure induced by glypressin infusion (P < 0·001) in bleeding BDL rats.

Splanchnic hyposensitivity to glypressin observed in haemorrhage‐transfused BDL rats could be ameliorated by the addition of indomethacin, suggesting a role of endogenous PGI2 in its pathophysiology.
Influence of D‐ and L‐glucose on erythrocytes and blood viscosity
Authors: Bühler I. , Walter R. , Reinhart W. H.
Published: March 2003

Background Elevated blood glucose levels are associated with substantial morbidity and mortality. The pathomechanism behind it is not well understood. The aim of the present study was to investigate the effect of glucose on blood rheology.

Materials and methods Blood from healthy volunteers was incubated with various concentrations of D‐ and L‐glucose for 1 h at 37 °C. Whole blood viscosity at haematocrit 45% was measured at high and low shear rate (94·5 and 0·1 s−1). Erythrocyte shape and volume were assessed. Haemoglobin solutions were incubated with
D‐glucose for up to 96 h and the viscosity was measured.

Results D‐glucose dissolved in H2O and diluted with isotonic NaCl, added to whole blood (additional D‐glucose concentrations 0–80 m
m), led to a red cell swelling and an increase in blood viscosity at low shear rate (0·1 s−1). This process was reversible upon removal of D‐glucose. L‐glucose, which is not transported into the red cell by the D‐glucose‐specific transport protein GLUT‐1, had no effect. When D‐glucose was dissolved and diluted in autologous plasma, haematocrit and viscosity remained unaffected, but L‐glucose decreased both values. Incubation of a haemoglobin solution with D‐glucose at 37 °C led to a time‐dependent increase in glycosylated haemoglobin (HbA1C) up to 8%, but left the viscosity unchanged.

Conclusion Blood glucose tested in a wide range of concentrations did not affect blood viscosity and morphological or biophysical properties of erythrocytes.
Role of various tissues in apo(a) fragmentation and excretion of fragments by the kidney
Authors: Frank S. , Hrzenjak A. , Blaschitz A. , Dohr G. , Kostner G. M.
Published: March 2003

Background Lipoprotein(a) [Lp(a)] is an atherothrombotic plasma lipoprotein with unknown function. Little is known about the catabolism of this lipoprotein, in particular the steps related to apolipoprotein(a) [apo(a)] fragmentation and excretion by the kidney.

Material and methods High plasma levels (up to 9 mg dL−1) of the N‐terminal fragment of apo(a) were expressed in mice by adenovirus mediated gene transfer. Plasma of such N‐apo(a) mice was injected into acceptor mice and the fragmentation and urinary secretion of N‐apo(a) were followed by immunochemical techniques.

Results Mice transduced with N‐Ad expressed apo(a)‐fragments with 3–11 kringle‐IV (KIV) repeats. Injection of N‐apo(a)‐plasma from donor mice into acceptor mice resulted in fragmentation of N‐apo(a)s with 3–11 KIVs yielding smaller peptides down to 2 KIVs. Secretion of N‐apo(a)‐fragments with 2 to maximally 6 KIVs into urine occurred as early as 2 min after injection. Immunohistochemical studies of kidney suggested filtration as a mechanism of apo(a)‐fragment excretion.

When N‐apo(a) was incubated in vitro with various tissues from perfused mice, skeletal muscle and kidney followed by liver and spleen contributed to fragmentation. Tissues from unperfused organs, or the addition of normal mouse plasma, caused marked reduction in N‐apo(a) fragmentation. EDTA, and not aprotinin or leupeptin, prevented apo(a) cleavage.

Conclusion Here we provide evidence that apo(a) is cleaved by metalloproteinases located on skeletal muscle, kidney and other organs. Small apo(a)‐fragments up to a size of 6 KIVs are excreted into urine, yet a major portion of apo(a) fragments is removed from circulation extrarenally.