bluuebunny/crossref_metadata_2025_split huggingface dataset:
CCK‐B/gastrin receptors in human colorectal cancer
Authors: Schmitz F. , Otte J.‐M. , Stechele H. U. , Reimann B. , Banasiewicz T. , Fölsch U. R. , Schmidt W. E. , Herzig K.‐H. 
Published: March 2003

Background Mature amidated gastrin (G17 amide) mediates its effects in the gastrointestinal tract by activating G protein‐coupled CCK‐B/gastrin receptors. Although trophic actions of gastrin on the gastric mucosa have been well‐established, the effect of G17 amide, progastrin and intermediates to colon neoplasia in humans is controversial. While epidemiological evidence from patients with elevated serum gastrin levels related to pernicious anaemia does not support an increased risk for colon cancer [1], a recent study suggests that prolonged hypergastrinaemia is associated with an increased risk for colon cancer [2]. The extent to which trophic actions of gastrin in colorectal cancer are mediated by functional gastrin receptors remains to be defined. The aim of the present study was to determine CCK‐B/gastrin receptor expression, structure, and function in 79 patients with colon cancer.Materials and methods CCK‐B/gastrin receptor cDNAs were isolated from 79 human colorectal cancer specimens and 15 control tissues, subcloned into the eukaryotic expression vector pCR3.1 and subjected to DNA sequence analysis. Wild‐type and mutant cDNAs were transiently expressed in COS‐7 cells to determine ligand affinities by 125I‐labelled CCK‐8S competition binding. Activation of the MAP kinase signalling cascade by G17 amide was determined in transfected Colo 320 cells expressing the wild‐type or mutant CCK‐B/gastrin receptors. Clonal expansion of single cells was quantified in transfected Colo 320 cells.Results Gastrin mRNA is expressed in 44% of colorectal cancers and in 13% of control tissues. CCK‐B/gastrin receptor mRNA is expressed in 38% of colorectal cancers and 13% of normal colonic tissue. Co‐expression of gastrin and CCK‐B/gastrin receptor message is significantly increased in colorectal cancer specimens (32% vs. 0%). There is no correlation between CCK‐B/gastrin receptor expression and disease stage or histological grading. DNA sequence analysis revealed one spontaneous CCK‐B/gastrin receptor mutation within the third intracellular loop with an exchange of valine‐287 for phenylalanine. Pharmacological characterisation of the 287V → F CCK‐B/gastrin receptor reveals wild‐type affinities for G17 amide, glycine‐extended gastrin, CCK‐8S and L‐365,260. Mutation 287V → F is associated with a loss of gastrin‐induced MAPK p44/p42 signalling in Colo 320 cells while clonal expansion from single cells is increased by 53·1 ± 15·9% when compared to Colo 320 cells expressing wild‐type CCK‐B/gastrin receptors.Conclusions Structural alterations of CCK‐B/gastrin receptors may account for increased growth‐promoting effects of amidated gastrins in colorectal cancer.
Heterogeneity of smooth muscle cells in advanced human atherosclerotic plaques: intimal smooth muscle cells expressing a fibroblast surface protein are highly activated by platelet‐released products
Authors: Martínez‐González J. , Berrozpe M. , Varela O. , Badimon L. 
Published: March 2003

In vascular disease, smooth muscle cells (SMC) undergo phenotypic modulation and may acquire properties resembling those of fibroblasts in tissue wound healing.We aimed to show the differential expression of a fibroblast surface protein (FSP) by SMC in atherosclerotic lesions.In early human coronary atherosclerotic lesions the expression of FSP in the intima was absent. In contrast, 29 of 29 middle/advanced lesions contained intimal SMC expressing high levels of FSP. Fibroblast surface protein positive SMC were negative for desmin but expressed variable levels of α‐SM actin, SM caldesmon, SM myosin heavy chain and vimentin. Explants from advanced atherosclerotic lesions yielded two main SMC subpopulations. SMC over‐expressing FSP exhibited higher in vitro mitogenic response (premitotic DNA synthesis) to sera (2‐ to 8‐fold) and platelet‐released products (8‐ to 26‐fold), especially from thrombin‐activated platelets, than FSP‐negative SMC.Our results suggest that the expression of FSP in SMC could indicate an activated phenotype, and the presence of highly positive FSP cells in the atherosclerotic lesions might be indicative of an increased SMC responsiveness to processes that locally generate thrombin and activate platelets.
Mixed cryoglobulinemia is associated with increased risk for death, or neoplasia in HIV‐1 infection
Authors: Kordossis T. , Sipsas N. V. , Kontos A. , Dafni U. , Moutsopoulos H. M. 
Published: March 2003

Backround Cryoglobulinemia has been reported in several chronic infectious and autoimmune diseases, and in patients with HIV‐1 infection. Cryoglobulinemia associated with hepatitis C virus infection is considered a risk factor for the development of neoplasia, especially B‐cell non‐Hodgkin lymphoma. This study was undertaken to investigate whether the presence of circulating cryoglobulins is associated with survival or development of neoplastic disease in HIV‐1 infection.Design We evaluated 87 unselected consecutive HIV‐1 infected patients for the presence of cryoglobulinemia and they were prospectively followed up for a median of 34 months, with clinic visits at 4‐month intervals. None of the patients had neoplasia at study entry. Time‐to‐event analysis for death, neoplasm and B‐cell lymphoproliferative disorder were performed with Cox proportional hazards models.Results Mixed cryoglobulinemia (types II and III) was detected in 24 (28%) of the 87 patients. During the follow up, 12 patients died and 8 developed neoplastic disease. Multivariate analysis showed that circulating cryoglobulins were an independent predictor of death [relative risk (RR), 4·97; 95% confidence intervals (CI), 1·26–19·63] and development of neoplasia (RR, 5·18; 95% CI, 1·23–21·83). In addition, cryoglobulinemia reached borderline significance as a predictor of lymphoproliferative disorder of B‐cell origin (P = 0·08; RR, 4·53; 95% CI, 0·83–24·75).Conclusions Our results suggest that cryoglobulinemia is associated with an increased risk for death, neoplasia or development of lymphoproliferative disorder of B‐cell origin, in HIV‐1 infected patients.
Procion orange tracer dye technique vs. identification of intrafibrillar fibronectin in the assessment of sarcolemmal damage
Authors: Palacio J. , Gāldiz J. B. , Alvarez F. J. , Orozco‐Levi M. , Lloreta J. , Gea J. 
Published: March 2003

AbstractBackground The use of Procion orange dye (POD) is one of the most widely accepted techniques to assess sarcolemmal damage. This phenomenon has been related to functional adaptation in skeletal muscles. The POD method includes intravenous injection of this colorant in vivo, enabling its identification inside those fibres with membrane leaks (fluorescence). However, the safety of the use of POD has not been proven.Aim This study was designed to compare POD with a safer alternative, involving the identification of intracellular fibronectin using specific antibodies.Method Eight Swiss mice were submitted to electrical stimulation of the lower limbs at different frequencies (10–80 Hz). Subsequently, the POD solution was infused, and samples from the vastus medialis muscle were obtained 24 h later. Samples were processed and serial sections were analysed using immunohistochemistry (monoclonal antibodies against fibronectin) and epifluorescence microscopy.Results Ninety‐eight per cent of the fibres were equally classified by both techniques, which in addition showed good correlation (percentages of damaged fibres, r = 0·998, P < 0·001) and concordance (R1 = 0·82) in quantitative terms.Conclusions Although the two techniques compared here are based on different principles, both are comparable in assessing sarcolemmal damage. This would facilitate comparisons between human and experimental studies. In addition, the fibronectin technique appears to be a suitable alternative for long‐term studies including repeated biopsies.
Growth hormone replacement therapy induces codeine clearance
Authors: Gil Berglund E. , Johannsson G. , Beck O. , Bengtsson B‐Å. , Rane A. 
Published: March 2003

AbstractBackground The increasing clinical use of growth hormone (GH) has raised questions about other than growth‐related metabolic effects of this treatment. GH regulates the expression of several hepatic drug metabolising enzymes in the rat, but it is not known whether GH treatment alters the expression of such liver enzymes in man. We have investigated the effects of GH on codeine clearance and two enzymes of the cytochrome P450 (CYP) family, CYP3A and CYP2D6, and UDP‐glucuronosyl transferase (UDPGT). These enzymes have a superior importance in hepatic biotransformation of numerous drugs. In addition, CYP3A and UDPGT are catalysts of many reactions with endobiotics such as steroid hormones.Methods We used codeine as a probe drug for assessment of the enzyme activities. Codeine was administered as a single‐dose prior to, and after 3 months of GH substitution in GH‐deficient patients. Total clearance, and clearance along each of the three primary metabolic pathways of codeine, was assessed.Results Three months of GH substitution increased the total clearance of codeine (21%, P < 0·01) and clearance catalysed by UDPGT significantly (31%, P < 0·05). The treatment tended to increase the clearance via the CYP3A pathway (83%, P = 0·05).Conclusions The effects of GH replacement therapy on drug metabolism may have clinical implications when combined with drugs that are substrates of UDPGT and CYP3A. Effects on steroid hormone metabolism with endocrine consequences can not be ruled out.
Nitric oxide attenuates platelet‐activating factor‐induced nasal airway plasma extravasation in healthy subjects
Authors: Maniscalco M. , Ferrara G. , Carratù L. , Sofia M. 
Published: March 2003

AbstractBackground Paranasal sinuses and the nose are important sources of nitric oxide (NO) in humans but the relevance of NO production to the control of nasal airway plasma exudation and its response to inflammatory mediators such as platelet‐activating factor (PAF) in healthy subjects is not well known.Design In this study we aimed to evaluate the effect of the nitric oxide synthase (NOS) inhibitor NGl‐arginine methyl ester (l‐NAME) on nasal airway plasma extravasation at baseline and after an acute challenge with PAF that induces most symptoms of rhinitis. Eleven healthy subjects were enrolled in the study. Plasma extravasation in the nasal airway was assessed by measuring the albumin content of nasal lavage.Results PAF challenge caused a significant increase in concentrations of albumin in the nasal lavage fluid (from 0·59 ± 0·13 mg dL−1 to 2·46 ± 0·45 mg dL−1) after placebo. Pretreatment with l‐NAME significantly prevented the increase of albumin in the nasal lavage fluid induced by PAF as compared to placebo (from 0·53 ± 0·11 mg dL−1 to 1·70 ± 0·28 mg dL−1; P < 0·005).Conclusion Topical administration of a NO inhibitor is able to attenuate the nasal airway plasma extravasation induced by PAF, suggesting that NO release in vivo is involved in the nasal response to PAF.
Methylenetetrahydrofolate reductase gene C677T mutation is related to the defects in the internal elastic lamina of the artery wall
Authors: Hämelahti P. , Järvinen O. , Sisto T. , Wirta V. , Ilveskoski E. , Koivula T. , Lehtimäki T. 
Published: March 2003

AbstractBackground The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene leads to C/C, C/T and T/T genotypes, which affect the plasma homocysteine concentration in humans. In mini‐pigs, high serum homocysteine levels are associated with defects in the internal elastic lamina (IEL) of the artery wall, which are apparently related to the migration of smooth muscle cells into the intima during atherogenesis. We studied the association between the MTHFR genotypes and the number of gaps in the IEL in the wall of the five major abdominal arteries.Materials and methods The autopsy study included 123 subjects (90 males and 33 females) aged 18–93. For the light microscopy, a 0·5 cm circular segment of the coeliac, the superior mesenteric, the inferior mesenteric and the renal arteries were cut and embedded in paraffin blocks. The circumference of the IEL, the thickness of the intima and the number of the gaps per millimetre in the IEL were measured by MOP 3 image analysis.Results The T‐allele carriers (C/T and T/T) of the MTHFR gene had significantly less gaps in the IEL than the subjects with the C/C genotype in the superior mesenteric and in the left renal arteries (2·02 ± 2·25 vs. 2·53 ± 1·89, P < 0·04 and 0·56 ± 1·09 vs. 1·82 ± 2·66, P < 0·02, respectively). The trend was similar for the coeliac and the right renal arteries.Conclusions Our result suggests that MTHFR polymorphism may be involved in the fragmentation of the IEL.
G‐455A polymorphism of the fibrinogen beta gene and deep vein thrombosis
Authors: Renner W. , Cichocki L. , Forjanics A. , Köppel H. , Gasser R. , Pilger E. 
Published: March 2003

AbstractBackground Elevated fibrinogen levels have been linked to increased risk for deep venous thrombosis, although it is not clear whether fibrinogen is causal or rather a marker for the presence of other risk factors. A common G/A polymorphism in the gene for the fibrinogen beta‐chain (FGB G‐455A) is associated with elevated fibrinogen levels. The present study was designed to analyze the role of this genetic marker for deep venous thrombosis.Materials and Methods We performed a case–control study including 307 patients with documented deep venous thrombosis and 316 control subjects. β‐fibrinogen genotypes were determined by allele‐specific polymerase chain reaction.Results GG, GA and AA genotype frequencies were similar among the patients (53·1%, 41·0, 5·9) and controls (51·6%, 42·1, 6·3; P = 0·92). Fibrinogen levels of the patients (median 3·72 g l−1; range 1·93–11·6) did not differ significantly from those of the controls (3·76; 2·17–9·99). Carriers of the homozygous AA genotype had significantly higher fibrinogen levels than noncarriers (patients: 5·32 vs. 3·59; P = 0·024; controls: 6·29 vs. 3·72; P = 0·048).Conclusion Our data suggest that the fibrinogen‐elevating FGB G‐455A gene polymorphism is not linked to an increased risk for deep venous thrombosis.
Is the gender difference in LDL size explained by the metabolic complications of visceral obesity?
Authors: Lemieux I. , Pascot A. , Lamarche B. , Prud’homme D. , Nadeau A. , Bergeron J. , Després J.‐P. 
Published: March 2003

AbstractBackground Several studies have reported a significant gender difference in low‐denstiy lipoprotein (LDL) size, with men being characterized by smaller, denser LDL particles than women, and it has been suggested that the contribution of the greater accumulation of visceral adipose tissue in men compared with women may be a factor potentially contributing to the gender difference in LDL heterogeneity.Materials and methods We measured LDL particle size by 2–16% nondenaturing polyacrylamide gradient gel electrophoresis in 299 men and 231 women in whom visceral adipose tissue accumulation was measured by computed tomography. A fasting plasma lipoprotein‐lipid profile was also obtained in all subjects.Results Overall, the men were characterized by a more deteriorated metabolic risk factor profile, which included higher plasma insulin and triglyceride levels, a greater visceral adipose tissue accumulation (P < 0·001) and smaller LDL particles (251·7 ± 5·2 vs. 254·4 ± 4·2 Å, P < 0·0001). This gender difference in LDL peak particle diameter remained significant (252·4 ± 4·3 vs. 253·5 ± 4·3 Å, P < 0·01) after adjustment for sex‐specific differences in plasma triglyceride levels by covariance analysis. Significant negative correlations were noted between the LDL particle diameter and the triglyceride concentrations in both genders (r = −0·52 and r = −0·36, P < 0·0001 for the men and women, respectively), with no gender difference in this relationship being found. However, viscerally obese women (visceral adipose tissue levels > 100 cm2) with increased plasma triglyceride concentrations (> 2·0 mmol L−1) still had larger LDL particles than viscerally obese men with a similar elevation in their triglyceride levels (251·6 ± 4·9 vs. 248·7 ± 4·5 Å, P < 0·01).Conclusions Results of the present study suggest that the reduced LDL particle size observed in men compared with women cannot be entirely explained by their higher visceral adipose tissue accumulation and increased plasma triglyceride levels. Moreover, the gender difference in LDL size could be influenced, at least in part, by the severity of the hypertriglyceridaemic state.
Differential expression of α‐ and β‐defensins in human peripheral blood
Authors: Fang X.‐M. , Shu Q. , Chen Q.‐X. , Book M. , Sahl H.‐G. , Hoeft A. , Stuber F. 
Published: March 2003

AbstractBackground  Human defensin peptides with broad‐spectrum antimicrobial activity have been implicated in the human defence response towards microbial invasion. Two families of defensins designated α‐ and β‐defensins, respectively, have been identified. Little is known about the expression of both defensin families in human peripheral blood. The purpose of this study was to examine the expression of α‐ and β‐defensin genes in human peripheral blood.Material and methods  Fifty‐one healthy blood donors were screened for defensin expression. Blood from defensin responders was stimulated by lipopolysaccharide or heat‐inactivated Pseudomonas aeruginosa ex vivo. Levels of mRNA were assessed by semiquantitative RT‐PCR. Southern blot analysis and sequencing were used to confirm the identity of defensin gene transcripts. Western blotting analysis was used to detect the expression of defensin peptides.Results  β‐defensin was undetected in human peripheral blood without stimulation. Following stimulation by lipopolysaccharide or heat‐inactivated bacterial cells, the majority (88·2%) of healthy individuals had a detectable expression for β‐defensin‐1 gene and 39·2% for β‐defensin‐2 gene, compared with none for β‐defensin‐3. β‐defensin‐1 and ‐2 mRNAs in the stimulated human peripheral blood of responders became detectable at 3 h and showed a maximum at 6 h following induction by 100 ng mL−1 of lipopolysaccharide or bacterial cells. In contrast, human α‐defensins 1–3 mRNA are constitutively expressed in peripheral leukocytes but not up‐regulated by lipopolysaccharide or bacterial cells.Conclusions  In human peripheral blood, β‐defensin‐1 and ‐2 genes were transiently transcribed and translated following the induction of lipopolysaccharide or heat‐inactivated bacterial cells, whereas α‐defensins 1–3 genes were constitutively transcribed, and β‐defensin‐3 gene was not expressed. The inducible expression of β‐defensin‐1 and ‐2 genes showed interindividual variability.
Lipopolysaccharide represses cholesterol 7‐alpha hydroxylase and induces binding activity to the bile acid response element II
Authors: Dikopoulos N. , Weidenbach H. , Adler G. , Schmid R. M. 
Published: March 2003

AbstractBackground Inflammatory states such as hepatitis and sepsis are frequently associated with alterations of bile acid synthesis. These conditions are mediated by bacterial wall products like lipopolysaccharide (LPS). Cholesterol 7‐alpha hydroxylase is the rate‐limiting enzyme of bile acid synthesis. Hydrophobic bile acids repress cholesterol 7‐alpha hydroxylase transcription via binding to the farnesoid X receptor and interaction with the bile acid response element II in the cholesterol 7‐alpha hydroxylase promoter.Methods We tested the effect of LPS on hepatic expression of cholesterol 7‐alpha hydroxylase in C57BL/6 mice and Wistar rats. Further, we analyzed the binding activity of hepatic nuclear extracts to the bile acid response element II and the binding site for farnesoid X receptor heterodimers (ecdysone response element).Result Lipopolysaccharide caused a 100‐fold reduction of cholesterol 7‐alpha hydroxylase mRNA levels in mice and a 10‐fold reduction in rats. Protein levels of cholesterol 7‐alpha hydroxylase also decreased in both species. These changes inversely correlated with the increased binding activity of nuclear proteins to the bile acid response element II and the ecdysone response element.Conclusion Lipopolysaccharide‐induced repression of cholesterol 7‐alpha hydroxylase occurs at the transcriptional level. The underlying mechanism involves an increased binding activity of nuclear proteins to the bile acid response element II and the ecdysone response element. In conclusion, the farnesoid and retinoid X receptors participate in LPS‐induced cholesterol 7‐alpha hydroxylase repression.
No acute impact of lipid apheresis treatment on free radical scavenging enzyme gene expression in white blood cells
Authors: Schettler V. , Krontal J. , Scheel A. , Wieland E. 
Published: March 2003

AbstractBackground Lipid apheresis (LA) treatment has been suggested to cause oxidative stress. Defense against oxygen‐radical‐mediated damage is provided by nonenzymatic and enzymatic antioxidants. In the present investigation we have investigated whether gene expression of free radical scavenging enzymes (FRSE) is affected in leukocytes of patients undergoing LDL‐apheresis.Materials and methods For this purpose cellular glutathione peroxidase (GPx‐1), phospholipid glutathione peroxidase (GPx‐4), glutathione reductase (GSSG‐R), glutathione synthetase (GSH‐S), Cu/Zn‐superoxide dismutase (SOD‐1) and catalase (CAT) mRNA expression were followed at the start (SA) and immediately after (EA) LA treatment (n = 25). Gene expression was determined by quantitative RT‐PCR with the LightCycler® instrument (Roche Diagnostics, Mannheim, Germany) and transcription elongation factor‐2 as reference gene.Results The expression of GPx‐1, GPx‐4, GSSG‐R, GSH‐S, SOD‐1, CAT mRNA was not affected by a single LA treatment. Free radical scavenging enzymes mRNAs were significantly (P < 0·05) increased in the LA patients (GPx‐1: 2·00 ± 1·37; GPx‐4: 0·52 ± 0·46; GSSG‐R: 0·07 ± 0·03; GSH‐S: 0·04 ± 0·03; SOD‐1: 1·12 ± 0·74; CAT: 0·15 ± 0·07) when compared with 26 healthy blood donors (GPx‐1: 1·1 ± 0·6; GPx‐4: 0·35 ± 0·19; GSSG‐R: 0·02 ± 0·01; GSH‐S: 0·03 ± 0·01; SOD‐1: 0·16 ± 0·08; CAT: 0·09 ± 0·05; mean ± SD).Conclusions These results show that the LA procedure does not acutely affect the antioxidant defense system on the gene level but suggests that the chronic stress resulting from hyperlipidaemia and/or LA may cause FRSE gene induction.
Molecular insights into insulin action and secretion
Authors: Rhodes C. J. , White M. F. 
Published: March 2003

AbstractTightly co‐ordinated control of both insulin action and secretion is required in order to maintain glucose homeostasis. Gene knockout experiments have helped to define key signalling molecules that affect insulin action, including insulin and insulin‐like growth factor‐1 (IGF‐1) receptors, insulin receptor substrate (IRS) proteins and various downstream effector proteins. β‐cell function is also a tightly regulated process, with numerous factors (including certain signalling molecules) having an impact on insulin production, insulin secretion and β‐cell mass. While signalling molecules play important roles in insulin action and secretion under normal circumstances, abnormal insulin signalling in muscle, adipose tissue, liver and pancreas leads to insulin resistance and β‐cell dysfunction. In particular, the signalling protein IRS‐2 may have a central role in linking these abnormalities, although other factors are likely to be involved.