bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteolytic destruction of functional proteins by phagocytes in human peritonitis
Authors: Jochum  , Billing  , Fröhlich  , Schildberg  , Machleidt  , Cheronis  , Gippner‐Steppert  , Fritz  
Published: March 2003

BackgroundBesides phagocyte‐derived oxidative autoaggression, proteolytic destruction of functional proteins in the peritoneal cavity may also be involved in the pathomechanism of secondary peritonitis. To evaluate the pattern of proteolysis, 43 patients undergoing initial operation for acute peritonitis (n = 30) or scheduled abdominal lavages (Etappenlavage) for resolution of persistent peritonitis (n = 13) and 16 surgical patients with abdominal exudation without peritonitis were enrolled in our study.Materials and methodsThirty blood samples and purulent exudates were taken simultaneously in each peritonitis group at the surgical interventions. Sixteen clear exudates were obtained from patients with post‐operative non‐infectious irritations. The following parameters were measured: (a) elastase (from neutrophils) and cathepsin B (from monocytes/macrophages); (b) α1‐proteinase inhibitor (α1PI) and overall cysteine proteinase inhibitor capacity; and (c) opsonic activity and degradation products of fibrinogen, complement C3 and immunoglobulin IgG.ResultsCirculating levels of phagocyte proteinases and of α1PI were significantly elevated, whereas antigen concentrations and opsonic activity of C3 and IgG were slightly reduced in peritonitis patients compared to healthy volunteers. No degradation products were detectable in patients’ blood. Discharge of phagocyte proteinases was even more pronounced in both types of peritonitis exudates. Although most of the elastase was complexed with α1PI, active elastase and its specific fibrinogen split product was found along with significantly reduced inhibitory capacity for elastase and cysteine proteinases. Local opsonic activity was dramatically diminished because of proteolytic degradation of C3 and IgG. Despite some phagocyte proteinase release, no destruction of functional proteins was seen in clear exudates.ConclusionsHigher values of extracellularly released phagocyte proteinases concomitant with lower opsonin activity in exudates from patients with persistent peritonitis can be taken as a further hint of the involvement of local proteolysis‐induced pathomechanisms in the development of lethal multiple organ failure, which occurred more frequently in patients with persistent peritonitis (54%) than in those with acute peritonitis (27%).
Effects of tumour necrosis factor α and melphalan on the cytokine production of circulating T cells in patients with cancer
Authors: Stam  , M. Eggermont  , G. Swaak  
Published: March 2003

BackgroundThe objective of the present study was to investigate the effects of isolated limb perfusion (ILP) with tumour necrosis factor α (TNF‐α) and melphalan on circulating T cells from cancer patients using two different methods.DesignEight patients undergoing an ILP entered the study. At first, the number of T cells at several time points was determined using FACScan. Subsequently, production of interferon gamma (IFN‐γ) (T‐helper 1) and interleukin (IL) 4 (T‐helper 2) was measured at the intracytoplasmic level after stimulation with phorbol 12‐myristate 13‐acetate (PMA) and ionomycin. IFN‐γ, IL‐4 and IL‐2 (also T‐helper 1) production in the whole‐blood cell culture system was then determined after stimulation with a combination of anti‐CD3/anti‐CD28 monoclonal antibodies.ResultsAn enormous decrease in the number of circulating T cells was observed. In the remaining T‐cell population cytokine production (IL‐2, IL‐4, IFN‐γ) was depressed, showing the same pattern in both methods. No difference could be detected between the effect of TNF‐α and melphalan on Th1 cells and Th2 cells.ConclusionsThe results demonstrate that TNF‐α and melphalan reduce the number of circulating T cells and at the single‐cell level decrease cytokine production in the remaining circulating T cells. No selective effect of TNF‐α on Th1 or Th2 cells could be detected. If the impaired T‐cell function is representative of all T cells remaining in the systemic circulation, this could help to explain the tolerability of high TNF concentrations after ILP, perhaps by decreasing the synthesis and production of T‐cell‐derived cytokines.
Effect of inhibiting HMG‐CoA reductase on 7α‐hydroxy‐4‐cholesten‐3‐one, a marker of bile acid synthesis: contrasting findings in patients with and without prior up‐regulation of the latter pathway
Authors: Naoumova  , O'Neill  , Dunn  , Neuwirth  , Taylor  , Axelson  , Thompson  
Published: March 2003

BackgroundAtorvastatin is a potent inhibitor of 3‐hydroxy‐3‐methyl‐glutaryl coenzyme A reductase, but its effect on bile acid synthesis is unknown. The objectives of the study were to determine the effect of atorvastatin on bile acid synthesis in patients in whom this process had not been or had been previously up‐regulated by pharmacological or surgical means.Materials and methodsFour patients with heterozygous familial hypercholesterolaemia (FH) and partial ileal bypass (PIB) and 19 FH heterozygotes without PIB were treated with placebo, atorvastatin 10 mg and atorvastatin 40 mg daily, each regimen for 4 weeks. The non‐PIB group was subsequently treated with bile acid (BA) sequestrant 8–16 g daily followed by co‐administration of atorvastatin 10 mg, each for 4 weeks. Plasma 7α‐hydroxy‐4‐cholesten‐3‐one (7α‐HCO), a well‐validated marker of BA synthesis was measured using high‐performance liquid chromatography with UV detection.ResultsThe plasma 7α‐HCO concentration was tenfold higher with placebo in the PIB than in the non‐PIB group (418.5 ng mL−1 vs. 39.6 ng mL−1P = 0.0001). Levels decreased in PIB patients treated with atorvastatin 10 mg and 40 mg daily (350.1 ng mL−1 and 174.0 ng mL−1, P = 0.007 respectively) but did not change significantly in the non‐PIB group (44.7 ng mL−1 and 28.3 ng mL− respectively). Administration of BA sequestrant to non‐PIB patients increased 7α‐HCO to 197.4 ng mL−1; this decreased to 106.0 ng mL−1 during co‐administration of atorvastatin 10 mg daily (P = 0.0001).ConclusionAtorvastatin decreases the rate of BA synthesis only if the latter is up‐regulated by PIB or BA sequestrants, presumably by limiting the supply of newly synthesized free cholesterol.
Impaired antiplatelet effects of aspirin associated with hypoxia and ATP release from erythrocytes. Studies in a system with flowing human blood
Authors: Bozzo  , Hernández  , Galán  , Heras  , Ordinas  , Escolar  
Published: March 2003

BackgroundWe have explored how hypoxic conditions may affect the antiplatelet effects of aspirin.Materials and methodsFor this purpose, a perfusion system containing a damaged vessel segment was modified in order to induce hypoxia (low Po2) in flowing blood. Blood samples were incubated with 50 μmol L−1 aspirin and divided into two aliquots, one being perfused under standard conditions (normoxic) and the other under hypoxic conditions. The interaction of platelets with the subendothelium was morphometrically evaluated.ResultsIn studies with untreated blood under normoxic conditions, platelet interaction with the subendothelium was 0.3 ± 0.1% of contact, 5.3 ± 1.6% of adhesion, 24.3 ± 3.3% of thrombus and 29.9 ± 2.7% of total covered surface. Aspirin‐treated blood perfused under normoxic conditions showed a marked decrease in thrombus with a concomitant increase in both platelet adhesion and covered surface percentages. However, when aspirin‐treated blood was perfused under hypoxic conditions, platelet interaction was not significantly different from that observed in untreated blood. Hypoxia induced a 10‐fold increase in ATP release from erythrocytes in the perfusates. If apyrase was added to the perfusates, ATP release was prevented and aspirin effects were evident again.ConclusionOur results suggest that, under hypoxic conditions, the presence of aspirin would not help to inhibit further platelet activation.
Differences between men and women in the response of serum cholesterol to dietary changes
Authors: Weggemans  , Zock  , Urgert  , Katan  
Published: March 2003

BackgroundHypercholesterolaemia is initially treated by diet. However, most studies of diet and cholesterol response have been carried out in men, and it is not known whether women react to diet to the same extent as men do. We therefore studied sex differences in the response of serum cholesterol and lipoproteins to diet.Materials and methodsWe measured the responses of serum cholesterol to a decrease in dietary saturated fat in seven trials involving 126 men and 147 women, to a decrease in dietary trans fat in two trials (48 men and 57 women) and to a decrease in dietary cholesterol in eight trials (74 men and 70 women). We also measured responses to the coffee diterpene cafestol, which occurs in unfiltered coffee, in nine trials (72 men and 61 women). All subjects were lean and healthy.ResultsThe response of total cholesterol (± standard deviation) to a decrease in the intake of saturated fat was greater in men (−0.62 ± 0.39 mmol L−1) than in women (−0.48 ± 0.39 mmol L−1; 95% confidence interval, 0.04–0.23 mmol L−1). The response of total cholesterol to a decrease in the intake of cafestol was also larger in men (−1.01 ± 0.49 mmol L−1) than in women (−0.80 ± 0.49 mmol L−1; 95% confidence interval, 0.04–0.39 mmol L−1). Responses to trans fat and to dietary cholesterol did not differ between men and women.ConclusionMen have larger responses of total and low‐density lipoprotein cholesterol to saturated fat and cafestol than women do.
Nef protein induces differential effects in CD8+ cells from HIV‐1‐infected patients
Authors: Silvestris  , Camarda  , Del Prete  , Tucci  , Dammacco  
Published: March 2003

BackgroundThe Nef protein of HIV‐1 is suspected to play a role in the depletion of uninfected CD4+ lymphocytes that leads to AIDS. By contrast its effect on CD8+ cells, whose functions are also deregulated during HIV‐1 infection, is presently unclear. Here we describe a number of derangements induced in vitro by Nef in CD8+ cells from HIV‐1‐infected patients.DesignPeripheral lymphocytes from 16 HIV‐1+ subjects and 9 uninfected individuals were cultivated on a Nef‐transfected mouse fibroblast layer exposing the carboxyl‐terminal region of the viral protein on cell membrane. The cultures were then measured for both apoptosis and proliferation by subdiploid DNA content and Ki67 expression, respectively, whereas the molecular analysis of purified CD8+ cells investigated the Fas‐L mRNA levels in Nef‐treated CTLs. In addition, we evaluated the Nef‐induced variation in the extent of CD8+/HLA‐DR+ subset, which includes non cytotoxic cells secreting T‐cell antiviral factor (CAF) and a soluble factor inhibiting the HIV‐1 replication.ResultsThe viral protein induced in peripheral blood lymphocytes (PBL) a moderate tendency to proliferate, as measured by the increment of Ki67 antigen, particularly on the CD8+ subset of HIV‐1 infected individuals (P < 0.05). This profile was particularly evident in cultures from patients with severe CD4+ lymphopenia and paralleled an apparent expansion of the CD8+/CD57+ suppressor cell subset. Molecular analysis of purified CD8+ cells revealed a defective expression of Fas‐L mRNA in Nef‐cultured CTLs, whereas the viral protein exerted a down modulatory effect on the CD8+/HLA‐DR+ subset (P < 0.05), thus suggesting a potential inhibition of CAF.ConclusionsThese results support a potential role of Nef in the progression of HIV‐1 infection as a number of cellular functions are affected in the CD8+ subset. In particular, the defective functions of CD8+ cells induced by the viral protein could contribute, at least partly, to the escape of HIV‐1 from the immune control of these cells.
Renal hemodynamic changes during smoking: effects of adrenoreceptor blockade
Authors: Benck  , Clorius  , Zuna  , Ritz  
Published: March 2003

BackgroundCigarette smoking accelerates progression of renal failure in diabetic and nondiabetic renal disease. Renal hemodynamics during smoking are characterised by a reversible decrease in glomerular filtration rate (GFR) and filtration fraction (FF) accompanied by increased renovascular resistance (RVR), systemic blood pressure, heart rate and plasma catecholamine concentrations.Materials and methodsTo further assess the role of sympathetic overactivity we compared the effects of different pharmacological interventions on smoking‐induced changes of renal hemodynamics in occasional smokers. In a first series, placebo pretreatment plus smoking was compared to Prazosin pretreatment (3 mg) plus smoking. In a second study, placebo pretreatment plus smoking was compared to Atenolol pretreatment (50 mg) plus smoking.ResultsBasal blood pressure was significantly lower with Prazosin and Atenolol. On placebo, GFR and FF decreased significantly during smoking and RVR increased. With Prazosin pretreatment compared to placebo pretreatment no statistically significant differences for the changes of GFR, FF, RPF and RVR were seen. In contrast, with Atenolol pretreatment compared to placebo pretreatment, the smoking‐induced changes in active renin, GFR and RVR were significantly smaller.ConclusionIt is suggested that the acute renal hemodynamic effects of smoking are mediated, at least in part, via increased sympathetic activity operating mainly through beta‐1 adrenergic mechanisms.
Vitamin E supplementation in hyperlipidaemic patients: effect of increasing doses on in vitro and in vivo low‐density lipoprotein oxidation
Authors: Wen  , Killalea  , Norris  , Cooke  , Feely  
Published: March 2003

BackgroundVitamin E supplementation is associated with a reduced risk of developing atherosclerotic events; probably because it inhibits low‐density lipoprotein (LDL) oxidation, an initial step in atherosclerosis. Metal ion‐dependent LDL oxidation is a commonly used method to estimate oxidizability of LDL, but the effect of antioxidant supplementation on the levels of autoantibodies to oxidised LDL (ox‐LDL), an in vivo indicator of LDL oxidation, is unknown.DesignThis double‐blind, placebo‐controlled study investigated the susceptibility of LDL to copper induced oxidation and malondialdehyde (MDA) derivatized‐LDL (MDA‐LDL) in hyperlipidaemic patients on supplements of vitamin E. The vitamin E group (n = 20) took vitamin E 100 IU daily and the dose was doubled at six‐weekly intervals to 1600 IU daily. The control group (n = 17) received placebo in the same fashion. Blood samples were obtained at baseline and each subsequent visit to measure vitamin E status and oxidation of LDL.ResultsA significant increase in both α‐tocopherol levels and the lengths of lag phase was seen in the vitamin E group after first week of supplementation (100 IU day−1). This continued to rise in a dose‐dependent fashion with a doubling of the lag phase on 1600 IU daily. However, the titre of antibodies to MDA‐LDL was not altered.ConclusionsThe results suggest that although regarded as an in vivo marker of LDL oxidation, antibodies to MDA‐LDL may not be a suitable measure to evaluate the effect of short‐term antioxidant supplementation. The failure of autoantibody titres to fall despite reduced oxidizability of LDL may possibly be attributable to a long half‐life of the antibody or, once initiated, a continuous immunological response to ox‐LDL contained in atherosclerotic lesions of the arterial wall.
rhIGF‐I/IGFBP‐3 complex, but not free rhIGF‐I, supports muscle protein biosynthesis in rats during semistarvation
Authors: Svanberg  , Ohlsson  , Kimball  , Lundholm  
Published: March 2003

BackgroundThe aim of this study was to evaluate the effect of insulin like growth factor‐I (rhIGF‐I) in complex with binding protein 3 (IGFBP 3) compared to the effect of free IGF‐I on muscle protein biosynthesis in undernourished animals.MethodsThree groups of female Sprague–Dawley rats (200 g) were initially semi‐starved for 3 days and then treated with saline (controls), rhIGF‐I (1 μg g−1) or equimolar amounts of rhIGF‐I/rhIGFBP‐3 complex (5 μg g−1) i.v. twice daily for 3 days during continuous semistarvation. Protein metabolism in hind limb skeletal muscle was studied by incorporation of L‐[14C‐U]phenylalanine into proteins, western blot determination of translation initiation factors involved in the binding of the 40S ribosomal subunit to mRNA, and quantification of mRNA content for IGF‐I, IGF‐IR and GH‐R. Plasma measurements of insulin, IGF‐I and amino acids were also performed.ResultsrhIGF‐I/rhIGFBP‐3, but not rhIGF‐I alone, stimulated protein synthesis by 177 ± 26% (P ≤ 0.05) in semi‐starved rats. This stimulation was associated with dissociation of the 4E‐BP1.eIF‐4E complex, implicating increased binding of the 40S ribosomal subunit to mRNA, and hence increased initiation of protein synthesis in these animals. Muscle content of IGF‐I mRNA was reduced in semi‐starved animals, whereas IGF‐I receptor mRNA was unaltered despite food restriction. Plasma concentration of IGF‐I was 20% (P ≤ 0.05) higher in rhIGF‐I/rhIGFBP‐3 treated animals as compared to rats treated with saline or free IGF‐I. Plasma concentrations of amino acids were increased in rhIGF‐I/rhIGFBP‐3 treated animals (P ≤ 0.05 vs. semi‐starved controls).ConclusionrhIGF‐I/rhIGFBP‐3 (SomatoKine) was a significant stimulator of muscle protein synthesis in chronically semi‐starved animals whereas IGF‐I alone failed to increase protein synthesis during the same experimental conditions. This stimulation was because of increased initiation of translation, likely induced by more physiologic concentrations/kinetics of plasma IGF‐I and amino acids following rhIGF‐I/rhIGFBP‐3 treatment, compared to IGF‐I in its free form.
Serum homocysteine is weakly associated with von Willebrand factor and soluble vascular cell adhesion molecule 1, but not with C‐reactive protein in type 2 diabetic and non‐diabetic subjects — The Hoorn Study
Authors: Becker  , Van Hinsbergh  , Kostense  , Jager  , Dekker  , Nijpels  , Heine  , Bouter  , Stehouwer  
Published: March 2003

BackgroundHyperhomocysteinaemia may constitute an independent risk factor for cardiovascular disease, but it is still unclear by which pathophysiological mechanisms homocysteine (tHcy) may promote atherothrombosis. The aim of this study was firstly to examine whether tHcy is associated with endothelial dysfunction, increased adherence of leukocytes, and/or chronic low‐grade inflammation, as estimated from plasma levels of von Willebrand factor (vWf), soluble vascular cell adhesion molecule 1 (sVCAM‐1) and C‐reactive protein (CRP), respectively. Secondly we investigated whether the presence of type 2 diabetes modifies these associations.Materials and MethodsSix hundred and ten subjects of a general population of middle‐aged and elderly subjects, 170 of whom had type 2 diabetes, participated in this cross‐sectional study. Linear regression analyses were used to study whether tHcy was associated with vWf, sVCAM‐1 and CRP, and whether the presence of diabetes modified these associations.ResultsAfter adjustment for confounders, tHcy was significantly but weakly associated with vWf (β = 0.15, P = 0.05) and sVCAM‐1 (β = 0.082, P = 0.04). tHcy was not significantly associated with CRP (β = 0.02, P = 0.91). The presence of diabetes did not significantly modify these associations.ConclusionsThis study provides evidence that tHcy is, at most, weakly associated with endothelial dysfunction as estimated from plasma vWf, and with leukocyte adhesion as estimated from plasma sVCAM‐1. tHcy was not significantly associated with chronic low‐grade inflammation as estimated from plasma CRP. Our data thus suggest that the link between tHcy and atherothrombosis cannot be explained by associations of tHcy with vWf, sVCAM‐1 or CRP.
Apolipoproteins A–I, A–II and B, lipoprotein(a) and the risk of ischaemic heart disease: the Caerphilly Study
Authors: Sweetnam P. M. , Bolton C. H. , Downs L. G. , Durrington P. N. , Mackness M. I. , Elwood P. C. , Yarnell J. W. G. 
Published: March 2003

Apolipoproteins B, A–I and Lp(a) have been proposed as independent predictors of subsequent ischaemic heart disease (IHD) improving on the prediction obtained by routine lipid measurements. In this report we have investigated the relative predictive ability of apolipoproteins and plasma lipids in a prospective study of middle aged men.2398 men aged 49–65 years from the general population of Caerphilly, South Wales, UK were screened for evidence of IHD. After an overnight fast 2225 men each provided a venous blood sample on which plasma lipids, apolipoproteins B, A–I, A–II, and lipoprotein (a) (Lp(a)) were measured.Over a follow‐up period of nearly 9 years, 282 (12%) men developed major IHD. Multiple logistic regression analysis showed that after adjusting for standard cardiovascular risk factors other than lipids there was a strong trend (standardised relative odds (SRO) = 1·20; P = 0·009) for incidence of IHD to increase with apolipoprotein B. However, on further adjusting for total cholesterol this trend largely disappeared (SRO = 1·05; P = 0·57). Similarly, a trend for incidence of IHD to increase with decreasing apolipoprotein A–I (SRO = 1·18; P = 0·02) disappeared when HDL cholesterol was added to the model. Levels of apolipoprotein A–II were not related to risk of subsequent IHD. Incidence of IHD was effectively constant over nearly 90% of the range of Lp(a). Only among the 5% of men with Lp(a) greater than 70 mg dL−1 was the risk of IHD significantly (P = 0·04) greater than among men with Lp(a) less than 10 mg dL−1.Apolipoproteins B and A–I do not improve on the prediction of risk of IHD provided by total and HDL cholesterol, respectively. Apolipoprotein A–II was not related to risk of IHD. Lp(a) may be independently associated with incident IHD among the 5–10% of men with the highest levels.
Hepatic damage in C282Y homozygotes relates to low numbers of CD8+ cells in the liver lobuli
Authors: Cardoso E. M. P. , Hagen K. , De Sousa M. , Hultcrantz R. 
Published: March 2003

Background Although most Caucasian patients with hereditary haemochromatosis (HH) show the same mutation in the HFE gene, the phenotypic expression of the disease varies greatly. We have previously shown that patients with HH who have high iron stores have low numbers of circulating CD8+ T lymphocytes. Patients and methods Liver and peripheral blood were studied in 37 C282Y homozygous HH patients; nine normal livers and 11 livers from patients with cirrhosis due to hepatitis C virus or alcoholic liver disease were also investigated. Eleven jejunal biopsies from HH patients and 17 normal biopsies were studied. The numbers of CD8+ cells were determined in peripheral blood by fluorescence‐activated cell sorting analysis, and in the liver or small intestine by immunohistochemistry. Results In HH patients the number of CD8+ T lymphocytes in peripheral blood correlated significantly with the number of CD8+ cells in the liver lobuli but not with that in the small intestine. Body iron stores correlated negatively with the number of CD8+ T lymphocytes in peripheral blood and in the liver, but not with the number in the small intestine. HH patients with cirrhosis had the lowest CD8+ cell count in liver sections, in contrast with other forms of cirrhosis. Conclusion The results indicate that HH patients with the HFE C282Y mutation and low numbers of CD8+ cells in the liver lobuli have higher iron stores and are more prone to develop liver cirrhosis.