bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myocardial fibrosis in transforming growth factor‐β1 (TGF‐β1) transgenic mice is associated with inhibition of interstitial collagenase
Authors: Seeland U. , Haeuseler C. , Hinrichs R. , Rosenkranz S. , Pfitzner T. , Scharffetter‐Kochanek K. , Böhm M. 
Published: March 2003

AbstractBackground TGF‐β1 mediates effects on fibroblast proliferation and collagen synthesis in the myocardium. The extracellular matrix remodeling depends on the fibrillar collagen degrading matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). The in vivo effects of TGF‐β1 on the MMP/TIMP system in TGF‐β1 overexpressing transgenic mice were studied.Methods Male Alb/TGF‐β1(cys223,225ser) transgenic mice (TG) and nontransgenic controls (C; 8 weeks) were examined. Protein expression of collagen type I, ‐III, interstitial collagenase (Int Coll), MMP‐2, ‐9, TIMP‐1, ‐2, ‐4 and TGF‐β1 as well as enzyme activity (MMP‐2, ‐9) were measured (Western blots, zymographic assays). mRNA expression of the interstitial collagenase and MMP‐9 was studied with the Light‐Cycler based real‐time PCR.Results Overexpression of TGF‐β1 resulted in a 10‐fold increase in plasma and a seven‐fold increase in myocardial TGF‐β1 concentrations. Relative heart weights increased (mg g−1: 7·8 ± 0·4 vs. 4·8 ± 0·6, n= 6; P < 0·01) in TG compared to C. Collagen type I and III increased in TG (1·9‐fold and 1·7‐fold) compared to controls. Interstitial collagenase protein activity (− 91%) and mRNA expression (−75%) in TG were reduced (P < 0·05–P < 0·001). Gelatinase (MMP‐2, MMP‐9) expression and activity were not significantly alterated. MMP‐inhibitors were increased 2·5‐fold (TIMP‐1, ‐4) and 6‐fold (TIMP‐2) in TG.Conclusions TGF‐β1 produces myocardial fibrosis in vivo. This effect is not only produced by a stimulation of matrix protein formation: a complex regulation of MMP and TIMP interaction, namely decrease of expression and activity of interstitial collagenase and an enhanced inhibition by increased levels of TIMPs, are involved. These mechanisms are optional targets for therapeutic interventions in myocardial diseases.
Relevance of apoptosis and cell proliferation for survival of patients with dilated cardiomyopathy undergoing partial left ventriculectomy
Authors: Metzger M. , Higuchi M. L. , Moreira L. F. , Chaves M. J. F. , Castelli J. B. , Silvestre J. M. L. , Bocchi E. , Stolf N. , Ramires J. A. 
Published: March 2003

AbstractBackground Cardiomyocyte apoptosis as well as proliferation have been described in congestive heart failure, but their clinical relevance remains unclear. In order to clarify whether apoptosis and cell proliferation occur in patients with idiopathic dilated cardiomyopathy and whether their degree in left ventricle fragments resected during partial left ventriculectomy has any influence on the outcome after this surgery, we compared their occurrence in four groups of patients: group A, short‐term survivors (n = 18); group B, deaths within 6 months of the surgery (n = 13); group C, long‐term survivors (n = 12); and Group D, deaths within 60 months (n = 19).Design Apoptotic cardiomyocytes and interstitial cells were quantified in left ventricle fragments from 31 patients with idiopathic‐dilated cardiomyopathy using the TUNEL assay. Cell proliferation was quantified in parallel sections by KI‐67 immunohistochemistry.Results Apoptotic cells were present in the majority of cases (n = 24) and proliferative cells in all cases. Whereas there was no significant difference regarding all parameters examined between Groups A and B, there was a highly significant difference between Groups C and D in the number of apoptotic cardiomyocytes (P = 0·012) and apoptotic interstitial cells (P = 0·006). There was no significant relationship between apoptotic cardiomyocytes and KI‐67‐positive cardiomyocytes, but a negative correlation between apoptotic interstitial cells and KI‐67‐positive interstitial cells (r = −0·383; P = 0·028).Conclusion Cardiomyocyte apoptosis and proliferation occur in the majority of patients with idiopathic‐dilated cardiomyopathy. High numbers of apoptotic cardiomyocytes and apoptotic interstitial cells are significantly related to a bad late outcome after partial left ventriculectomy.
Inhibition of human primary melanoma cell proliferation by histamine is enhanced by interleukin‐6
Authors: Lázár‐Molnár E. , Hegyesi H. , Pállinger É. , Kovács P. , Tóth S. , Fitzsimons C. , Cricco G. , Martin G. , Bergoc R. , Darvas Z. , Rivera E. S. , Falus A. 
Published: March 2003

AbstractBackground Interleukin‐6 (IL‐6) is a bifunctional growth factor in malignant melanoma; its expression increases during the malignant progression of the disease. Histamine, detected in large amounts in normal and pathological proliferating tissues, is an important paracrine and autocrine regulator of normal and tumour cell proliferation as well.Materials and methods We investigated the presence and function of IL‐6 and histamine in the WM35 primary human melanoma cell line with respect to their direct role in cell proliferation and their regulatory interactions.Results IL‐6 inhibited the proliferation of WM35 melanoma cells and increased significantly the expression of histidine decarboxylase as well as histamine production. It had dose‐dependent effects on the proliferation: high concentration (10−5 M) was inhibitory through H1 histamine receptors while low histamine concentration acting on H2 receptors, with a simultaneous increase of cAMP, enhanced colony formation in the monolayer. Furthermore, IL‐6 increased the H1‐ but decreased the H2‐histamine receptor expression of the melanoma cells. On the other hand, histamine was locally synthesized by the WM35 melanoma cells.Conclusion We suggest that the growth arrest induced by IL‐6 is in part mediated by its dual action on histamine: a shift toward H1 receptor predominance and an elevation of locally produced histamine with prevalent action on the inhibitory response triggered through the H1 receptor. These findings suggest a local cross‐talk between histamine and IL‐6 in the regulation of melanoma growth.
Basal TSH levels compared with TRH‐stimulated TSH levels to diagnose different degrees of TSH suppression: diagnostic and therapeutic impact of assay performance
Authors: Christ‐Crain M. , Meier C. , Roth C.‐B. , Huber P. , Staub J.‐J. , Müller B. 
Published: March 2003

AbstractBackground The estimated prevalence of endogenous subclinical hyperthyroidism varies from 4% to 6% and a basal thyroid stimulating hormone (TSH) level < 0·5 mU L−1 may be associated with increased mortality in subjects over 60 years of age who are not on thyroid medication. Exogenous TSH suppression is a mainstay in the treatment of thyroid cancer. Because of recent concerns about potential adverse effects, especially of endogenous TSH suppression on bone, the cardiovascular system and cognitive functions, subclinical hyperthyroidism obtained new clinical importance. We therefore re‐evaluated the diagnostic value of basal and thyrotrop in TRH‐stimulated serum TSH measurements using TSH assays with different sensitivities.Materials and methods A total of 805 oral and nasal TRH stimulation tests were performed on 409 ambulatory subjects with low basal serum TSH concentrations of less than 0·1 mIU L−1. Basal serum TSH was measured either using a second generation assay (functional sensitivity > 0·03 mIU L−1) or two third generation assays (functional sensitivity 0·01 mIU L−1 and 0·007 mU L−1, respectively). Serum TSH concentration was determined before and 3 h after oral administration of 40 mg of TRH and before and 30 min after nasal administration of 2 mg of TRH.Results In the oral testing group, the basal TSH levels measured by the different TSH assays were 0·06 ± 0·03, 0·04 ± 0·02 and 0·03 ± 0·02, respectively, whereas the peak TSH levels were 0·4 ± 0·6, 0·4 ± 0·6 and 0·3 ± 0·5 in the patients with subclinical hyperthyroidism. In overt hyperthyroidism, the basal TSH levels were 0·06 ± 0·02, 0·03 ± 0·02 and 0·03 ± 0·02, whereas the peak TSH levels were 0·19 ± 0·3, 0·16 ± 0·3 and 0·15 ± 0·2, respectively. Basal TSH values could discriminate between different degrees of TSH suppression if measured with a third generation assay (P < 0·001), but not with a second generation assay. There was only a weak correlation between basal TSH and peak TSH when measured by a second generation assay (n = 126; r = 0·3; P < 0·001) in contrast to the strong correlation found using the third generation assays (n = 128; r = 0·7; P < 0·001 and n = 69; r = 0·8; P < 0·001, respectively).Conclusions In view of the recent concerns about potential adverse effects in TSH suppression and based on our data, it is mandatory to select a TSH assay with a functional sensitivity of ≤ 0·01 mIU L−1 for optimal titration of L‐T4 suppressive therapy, especially in patients with thyroid cancer. If, however, only a second generation TSH assay is available, additional TRH testing allows a more careful titration of suppressive thyroxine therapy.
S‐adenosylhomocysteine and the ratio of S‐adenosylmethionine to S‐adenosylhomocysteine are not related to folate, cobalamin and vitamin B6 concentrations
Authors: Becker A. , Smulders Y. M. , Teerlink T. , Struys E. A. , De Meer K. , Kostense P. J. , Jakobs C. , Dekker J. M. , Nijpels G. , Heine R. J. , Bouter L. M. , Stehouwer C. D. A. 
Published: March 2003

AbstractBackground It is unclear whether homocysteine itself is causal in the pathogenesis of cardiovascular disease. Alternatively or additionally, the association between homocysteine and cardiovascular disease may be because of its metabolic precursor, S‐adenosylhomocysteine, or of the ratio of S‐adenosylmethionine to S‐adenosylhomocysteine. Therefore, it is relevant to know how these moieties are interrelated, and whether, as is the case for homocysteine, they are influenced by blood levels of folate, cobalamin or vitamin B6.Design We cross‐sectionally studied a population‐based cohort of 97 Caucasian subjects aged 60–85 years. Concentrations of homocysteine, S‐adenosylhomocysteine, S‐adenosylmethionine, folate, cobalamin and vitamin B6 were measured in fasting blood samples.Results In multiple regression analysis, homocysteine was associated with vitamin B12 (per 50 pmol L−1 increase of cobalamin, change in homocysteine, –0·70 mmol L−1; 95% CI, −1·30 to −0·10 mmol L−1) and folate (per 100 nmol L−1 increase in erythrocyte folate, change in homocysteine, –0·68 mmol L−1; 95% CI −1·28 to −0·08 mmol L−1). S‐adenosylhomocysteine, S‐adenosylmethionine and the ratio of S‐adenosylmethionine to S‐adenosylhomocysteine were not associated with serum folate, cobalamin or vitamin B6, nor with erythrocyte folate. Furthermore, plasma homocysteine showed a negative correlation with the ratio of S‐adenosylmethionine to S‐adenosylhomocysteine in plasma (r = −0·27; P < 0·01) but not in erythrocytes.Conclusions In contrast to homocysteine, the plasma concentrations of S‐adenosylhomocysteine and the ratio of S‐adenosylmethionine to S‐adenosylhomocysteine were not associated with the folate, cobalamin and vitamin B6 concentrations in the present study. If these precursors in part explain why homocysteine is associated with cardiovascular disease, homocysteine‐lowering treatment with B vitamins may be less effective than currently expected, at least in an elderly population.
Alternatively spliced mRNA molecules of the thrombospondin receptor (CD36) in human PBMC
Authors: Kern P. , Kolowos W. , Hagenhofer M. , Frank C. , Kalden J. R. , Herrmann M. 
Published: March 2003

AbstractWe employed reverse transcription polymerase chain reaction (RT‐PCR) to detect alternatively spliced CD36 mRNA in human peripheral blood mononuclear cells (PBMC). Sequencing of cloned cDNA revealed alternatively spliced mRNA molecules in 13 out of 39 clones. We observed exon skipping of up to 10 out of 12 coding exons in eight alternative transcripts. Additionally, in five of the transcripts, alternative splice donor or acceptor sites were used during mRNA maturation. Considering the CD36 molecule serves many functions in coagulation, host defence, lipid metabolism, and scavenging, we speculate that the proteins encoded by the alternatively spliced mRNA molecules may be involved in regulation of both CD36 gene expression and function.
Intercellular adhesion molecule‐1 gene polymorphisms in Behçet’s disease
Authors: Verity D. H. , Vaughan R. W. , Kondeatis E. , Madanat W. , Zureikat H. , Fayyad F. , Marr J. E. , Kanawati C. A. , Wallace G. R. , Stanford M. R. 
Published: March 2003

AbstractIntercellular adhesion molecule‐1 (ICAM‐1) gene polymorphisms have been implicated in the susceptibility to inflammatory diseases, including multiple sclerosis and inflammatory bowel disease. The expression of both soluble and tissue ICAM‐1 is increased in Behçet’s disease (BD) but the contribution of ICAM‐1 gene polymorphisms to this disease remains unknown. Associations with BD have been reported for genes within the MHC, including HLA‐B51, TNF and MICA, but the role of non‐MHC genes in BD remains largely unexplored. We have investigated the frequency of the R/G 241 and K/E 469 ICAM‐1 gene polymorphisms in 83 patients with BD disease and 103 healthy controls, all of Palestinian and Jordanian descent, and demonstrated an association between BD and the ICAM‐1 E469 allele (Pc = 0.046, OR = 2.1). Among patients, no association was found between the presence of ocular disease and ICAM‐1 polymorphisms. While the functional correlate of this polymorphism remains unclear, this finding indicates that a genetic polymorphism in the ICAM‐1 gene domain, which is independent of the MHC, may contribute to disease.
Analysis of a CD40 ligand dinucleotide microsatellite in multiple sclerosis
Authors: Dai Y. , Masterman T. , Huang W. , Hillert J. 
Published: March 2003

SummaryIn recent years, numerous reports have described the diverse roles of the CD40–CD40 ligand receptor–ligand pair. The interaction of these two cell‐surface molecules regulates both humoral and cell‐mediated immune functions. Because the CD40 ligand is known to be highly expressed on the peripheral blood mononuclear cells (PBMC) of multiple sclerosis (MS) patients, and because activated helper T cells expressing CD40 ligand have been found in the brain sections of MS patients, but not in those of normal controls, the protein is believed to be involved in MS development. We studied the influence of a polymorphic dinucleotide‐repeat marker located in the 3′ untranslated region of the X‐linked gene encoding CD40 ligand (CD40LG) on susceptibility to and disease severity in MS. From a total cohort of 771 Nordic definite‐MS patients, the most (n = 92) and least (n = 90) disabled octiles, as well as random samples of intermediately disabled males (n = 119) and females (n = 121), were genotyped; 135 ethnically matched healthy subjects were used as controls. In addition, the effect of the polymorphism on CD40 ligand mRNA expression was assessed using PBMC from 54 MS patients and 22 controls. The phenotype frequencies for the CD40LG marker did not differ significantly between gender‐conditioned intermediate‐MS subgroups and controls, or between gender‐conditioned disability octiles. Nor did the polymorphism appear to exert any significant effect on mRNA expression in either patients or controls.
Association between two tumour necrosis factor intronic polymorphisms and HLA alleles
Authors: Low A. S. , Azmy I. , Sharaf N. , Cannings C. , Wilson A. G. 
Published: March 2003

SummaryThe gene for tumour necrosis factor (TNF) lies at the telomeric end of the class III region of the major histocompatibility complex (MHC). Polymorphisms within this gene have been implicated in the genetic background of a large number of common human diseases. Recently two polymorphisms, TNF +489 and +691, have been described in the first intron of TNF (+489, G to A transition; +691, G deletion) and disease associations have been reported; however, the pattern of linkage disequilibrium with other MHC alleles has not been studied. We have therefore studied the association of TNF alleles with HLA‐DR, ‐DQ and ‐B alleles in 216 healthy individuals from the north of England. The frequencies of the uncommon alleles were 0.08 (+489A) and 0.05 (+691Gdel). The +489A allele is associated with carriage of DRB1*1104, DQB1*0301, B18 and B35. The +691Gdel allele is associated with carriage of DRB1*13 *11, DQB1*0301 and B44. Knowledge of the pattern of association, indicating probable linkage disequilibrium, between these TNF alleles may be useful in studies aimed at determining the role of this locus in the genetic background of the large number of diseases which show genetic associations with MHC haplotypes.
CTLA‐4 49 A/G dimorphism and type 1 diabetes susceptibility: a French case–control study and segregation analysis. Evidence of a maternal effect
Authors: Fajardy I. , Vambergue A. , Stuckens C. , Weill J. , Danze P. M. , Fontaine P. 
Published: March 2003

SummarySeveral studies have demonstrated an association of cytotoxic T lymphocyte‐associated molecule 4 (CTLA‐4) (IDDM 12) alanine 17 with type 1 diabetes, but we wished to study the parental effect of CTLA‐4 49 A/G dimorphism in diabetic families. The CTLA‐4 exon 1 polymorphism (49 A/G), HLA‐DRB1 and insulin gene (INS) variable number tandem repeats (VNTR) were analysed in 134 type 1 diabetic patients vs. 273 control subjects. The segregation analysis for transmission was carried out in 70 informative diabetic families using the transmission distortion test (TDT). All genotyping was performed by PCR‐RFLP. CTLA‐4 49 G allele frequency was not increased in diabetic patients compared to controls (41 vs. 38%, not significant). The distribution of GG, AG and AA CTLA‐4 genotypes was similar in the two groups (13, 57 and 30% vs. 11, 54 and 35%, respectively) and was independent of HLA‐DRB1 or INS VNTR polymorphism. The CTLA‐4 49 G allele showed weak distorted transmission to the diabetic offspring, whereas random transmission was observed in unaffected offspring. This distortion is attributable to a maternal effect (71% compared to the 50% expected ratio; tdt = 4.8; P < 0.03). The combined transmission of maternal CTLA‐4 G with HLA‐DRB1*03 (90%; tdt = 6.4; P < 0.01) and VNTR class I (80%; tdt = 5.4; P < 0.02) enhanced the susceptibility effect of each marker separately. We noted a slight CTLA‐4 49 G and HLA‐DRB1*04 distortion of transmission shared in paternal and maternal diabetic meiosis. In non‐diabetic offspring, the CTLA‐4 49 A allele confers a protective effect in the presence of maternal HLA‐DRB1*03 and paternal HLA‐DRB1*04 alleles. Despite the absence of a positive association of the CTLA‐4 49 G allele with type 1 diabetes, our segregation analysis supports the hypothesis of a modulation by CTLA‐4 49 G/A dimorphism of the susceptibility conferred by maternal HLA‐DRB1*03 inheritance. This potential parental effect needs to be confirmed in a larger data set.
Proficiency testing for HLA‐DRB high‐resolution typing: a 4‐year experience in Italy
Authors: Borelli I. , Fasano M. E. , Curtoni E. S. 
Published: March 2003

SummaryTwenty‐one Italian laboratories participated for four consecutive years in the collaborative Italian proficiency testing of HLA class II (DRB1, DRB3, DRB4 and DRB5) high‐resolution typing. In this paper the results are analysed. Seven different kinds of errors are described and discussed. The errors were divided into technical errors and errors of allele reporting. Each year, a list of errors made was prepared by our laboratory and discussed collegially with all laboratories. The allele reporting errors diminished over time, as a result of the common discussions. The technical performance of the laboratories did not improve overall for the 21 laboratories participating: for 16 of them results were good or improved in quality, but for the remaining five results deteriorated over time. From this experience, some recommendations for the future emerged. A relevant conclusion was that, to improve the performance of a group of laboratories, the proficiency test is not effective alone, but should be integrated within a framework of continuous collaboration and mutual technical help.
Molecular cloning of agonistic and antagonistic monoclonal antibodies against human 4‐1BB
Authors: Lee U.‐H. , Kwack K. B. , Park J.‐W. , Kwon B. S. 
Published: March 2003

SummaryPreviously, we prepared two different monoclonal antibodies (mAbs) against human 4‐1BB (CD137): an agonistic mAb BBK‐1 and an antagonistic mAb BBK‐2. In this paper, we describe the molecular cloning of these two mAbs and present comparisons of their amino acid sequences. cDNAs encoding the heavy (H) and light (L) chains of the two mAbs were cloned by screening of cDNA libraries constructed from hybridomas secreting these mAbs. Comparisons of amino acid sequences of the two mAbs showed that, while the constant regions of the H and L chains were identical between the two mAbs, the variable region showed 45% identity in H chains and 48% identity in L chains. This suggests that these two mAbs recognize different epitopes of 4‐1BB and may have different effects on the activity of 4‐1BB.
Complementary DNA sequence of the HLA‐B*3924 allele1
Authors: Estefanía E. , Gómez‐Lozano N. , De Pablo R. , Moreno M. E. , Vilches C. 
Published: March 2003

SummaryWe have isolated the complete coding region of HLA‐B*39 from a Spanish Caucasoid, using a new PCR primer for its 5′ untranslated region. The cDNA matched partial genomic sequences of B*3924, an allele whose distribution appears to be restricted to Mediterranean and Arabian Caucasoids. A single amino acid change exclusive to B*3924 (threonine‐98) distinguishes it from B*3903.
β‐glucosidase activity in the presence of copper and goethite
Authors: Geiger G. , Livingston M. P. , Funk F. , Schulin R. 
Published: March 2003

SummaryWe investigated the effect of goethite and copper on almond β‐glucosidase activity. The activity of β‐glucosidase was found to be inhibited at dissolved copper concentrations exceeding 0.2 mm. Copper was most influential in the pH range 5–5.5, at which the enzyme activity was reduced by 50% or more at total copper concentrations of 0.2 mm compared with copper‐free assays. At pH 4, the presence of 0.2 mm copper reduced the activity by 15% at most. Copper caused a shift of the pH optimum towards lower pH. Goethite did not influence β‐glucosidase activity significantly, although up to 95% of the enzyme was adsorbed on its surface. The adsorption seemed to be caused principally by non‐electrostatic forces which were too weak to affect the structure of the enzyme. Goethite reduced the inhibitory effect of copper because of the strong affinity of copper for goethite, as observed in batch adsorption experiments. The sorption of the enzyme on goethite was not competitive with copper at concentrations less than 0.2 mm; at larger concentrations, however, the presence of the enzyme reduced copper adsorption. The influence of copper on enzyme activity as well as the influence of copper in combination with goethite could be described with a model combining Michaelis–Menten enzyme kinetics with a simple conditionally first‐order reaction law for the binding of copper by the enzyme.