bluuebunny/crossref_metadata_2025_split huggingface dataset:
Total cholesterol and mortality in the elderly
Authors: Casiglia E. , Mazza A. , Tikhonoff V. , Scarpa R. , Schiavon L. , Pessina A. C. 
Published: September 2003

Abstract Casiglia E, Mazza A, Tikhonoff V, Scarpa R, Schiavon L, Pessina AC (Department of Clinical and Experimental Medicine, University of Padova, Italy). Total cholesterol and mortality in the elderly. J Intern Med 2003; 254: 353–362.Objective. To evaluate, at a population level, whether total cholesterol (TC) is a risk factor of mortality. To verify whether or not this is true for both genders.Design. Population‐based, long‐lasting, prospective study.Setting. Institutional epidemiology in primary care.Subjects. A total of 3257 subjects aged 65–95 years, recruited from Italian general population.Intervention. None.Main outcome measures.Total cholesterol was measured, analysed as a continuous variable and then divided into quintiles and re‐analysed. For each quintile, the multivariate relative risk (RR) of mortality adjusted for confounders was calculated in both genders. Stratification of mortality risk by TC quintiles, body mass index and cigarette smoking was also performed in both genders.Results. Total cholesterol levels directly predicted coronary mortality in men [RR being in the fifth rather than in the first quintile: 2.40 (1.40–4.14)] and any other mortality in women. It also inversely predicted miscellaneous mortality in both genders. This trend was more evident when low cholesterol was associated with malnutrition or smoking.Conclusions. High TC remains a strong risk factor for coronary mortality in elderly men. On the other hand, having a very low cholesterol level does not prolong survival in the elderly; on the contrary, low cholesterol predicts neoplastic mortality in women and any other noncardiovascular mortality in both genders.
A 5‐year follow‐up study of disease incidence in men with an abnormal hormone pattern
Authors: Rosmond R. , Wallerius S. , Wanger P. , Martin L. , Holm G. , Björntorp P. 
Published: September 2003

Abstract Rosmond R, Wallerius S, Wanger P, Martin L, Holm G, Björntorp P (The Cardiovascular Institute, Sahlgrenska University Hospital, Göteborg; and Huddinge University Hospital, Huddinge; Sweden). A 5‐year follow‐up study of disease incidence in men with an abnormal hormone pattern. J Intern Med 2003; 254: 386–390.Objectives. Previous studies have suggested that abnormal levels of cortisol and testosterone might increase the risk of serious somatic diseases. To test this hypothesis, we conducted a 5‐year follow‐up study in middle‐aged men.Methods. A population‐based cohort study conducted in 1995 amongst 141 Swedish men born in 1944, in whom a clinical examination supplemented by medical history aimed to disclose the presence of cardiovascular disease (CVD) (myocardial infarction, angina pectoris, stroke), type 2 diabetes and hypertension were performed at baseline and at follow‐up in the year 2000. In addition, salivary cortisol levels were measured repeatedly over the day. Serum testosterone concentrations were also determined. Using the baseline data, an algorithm was constructed, which classified the secretion pattern of cortisol and testosterone from each individual as being normal or abnormal.Results. By the end of follow‐up, men with an abnormal hormone secretion pattern (n = 73) had elevated mean arterial pressure (P = 0.003), fasting insulin (P = 0.009) and insulin : glucose ratio (P = 0.005) compared with men with a normal secretion pattern (n = 68). Body mass index, waist circumference, and waist : hip ratio were significantly elevated in both groups. However, the 5‐year incidence of CVD, type 2 diabetes, and hypertension were significantly higher (P < 0.001) in men with an abnormal neuroendocrine secretory pattern compared to men with a normal pattern.Conclusions. These data suggest that an abnormal neuroendocrine secretory pattern is prospectively associated with an increased incidence of cardiovascular‐related events and type 2 diabetes.
Preproghrelin Leu72Met polymorphism in patients with type 2 diabetes mellitus
Authors: Ukkola O. , Kesäniemi Y. A. 
Published: September 2003

Abstract Ukkola O, Kesäniemi YA (University of Oulu, Oulu, Finland). Preproghrelin Leu72Met polymorphism in patients with type 2 diabetes mellitus. J Intern Med 2003; 254: 391–394.Objectives. The association between the Leu72Met polymorphism of the preproghrelin gene and diabetic complications was examined in patients with type 2 diabetes mellitus.Subjects and methods. A total of 258 patients with type 2 diabetes mellitus and 522 control subjects were screened. Genotypes were determined by polymerase chain reaction technique. The diagnosis of coronary heart disease was based on clinical and ECG criteria. Laboratory analyses were carried out in the hospital laboratory.Results. No differences in the genotype distributions and allele frequencies of the preproghrelin Leu72Met polymorphism were found between type 2 diabetes mellitus patients and controls. The polymorphism was not associated with macro‐ or micro‐angiopathy or hypertension. However, Leu72Met polymorphism was associated with serum creatinine (P = 0.006) and lipoprotein(a) [Lp(a)] levels (P = 0.006) with Leu72Leu subjects showing the highest values. This association was observed only amongst diabetic group.Conclusions. The Leu72Met polymorphism of the preproghrelin gene was not related to cardiovascular disease in type 2 diabetes mellitus patients. Leu72Met polymorphism was, however, associated with serum creatinine and Lp(a) levels in diabetic patients. The mechanism might be associated with a possible change in ghrelin product and its somatotropic effect.
Novel anticoagulant agents: introduction
Authors: Schulman S. 
Published: September 2003

Abstract Schulman S (Karolinska Hospital, Stockholm, Sweden). Novel anticoagulant agents: introduction (Minisymposium). J Intern Med 2003; 254: 308–312.In this Minisymposium three principles for anticoagulant therapy are discussed and examples of novel, selective coagulation inhibitors at the stage of advanced clinical trials are given.This introduction attempts to explain the different mechanisms of action on a broad scale, and also includes a brief look at effects on inflammation and cancer.
Recombinant nematode anticoagulant protein c2 and other inhibitors targeting blood coagulation factor VIIa/tissue factor
Authors: Lee A. Y. Y. , Vlasuk G. P. 
Published: September 2003

Abstract Lee AYY, Vlasuk GP (McMaster University, Hamilton, ON, Canada; and Corvas International, Inc., San Diego, CA, USA). Recombinant nematode anticoagulant protein c2 and other inhibitors targeting blood coagulation factor VIIa/tissue factor (Minisymposium). J Intern Med 2003; 254: 313–321.Originally isolated from a haematophagous hookworm, recombinant nematode anticoagulant protein c2 (rNAPc2) is an 85‐amino acid protein with potent anticoagulant properties. Unlike conventional anticoagulants that attenuate blood coagulation via inhibition of thrombin or activated factor X (FXa) at the downstream portion of the cascade, rNAPc2 is a potent inhibitor of the activated factor VII/tissue factor complex (FVIIa/TF), the key physiological initiator of blood coagulation. Its mechanism of action requires prerequisite binding to circulating FXa or zymogen factor X (FX) to form a binary complex prior to its interaction and inhibition of membrane‐bound FVIIa/TF. The binding of rNAPc2 to FX results in an elimination half‐life of longer than 50 h following either subcutaneous or intravenous administration. Recombinant NAPc2, like other inhibitors of FVIIa/TF including tissue factor pathway inhibitor (TFPI) and active site‐blocked FVIIa (ASIS, FFR‐rFVIIa or FVIIai), may have a promising role in the prevention and treatment of venous and arterial thrombosis, as well as potential efficacy in the management of disseminated intravascular coagulopathies because of their potent and selective inhibition of FVIIa/TF.
Oral direct thrombin inhibitors in clinical development
Authors: Gustafsson D. 
Published: September 2003

Abstract Gustafsson D (AstraZeneca R&D, Mölndal, Sweden). Oral direct thrombin inhibitors in clinical development (Minisymposium). J Intern Med 2003; 254: 322–334.Thrombin has long been a target for development of oral anticoagulants but it has been difficult to find synthetic inhibitors with a desirable combination of pharmacodynamic and pharmacokinetic properties. However, there are now two oral direct thrombin inhibitors (DTIs) in clinical development, ximelagatran (ExantaTM) and BIBR 1048. Both are prodrugs with two protecting groups that are eliminated after absorption from the gastrointestinal tract. Their main active substances, melagatran and BIBR 953, are both potent and selective DTIs. In experimental models of thrombosis, melagatran has been shown to have a shallower dose–response curve than warfarin and, therefore, a better separation between efficacy and bleeding. Oral bioavailability, measured as the plasma concentration of the active metabolite, seems to be higher for ximelagatran (20%) than for BIBR 1048 (estimated to 5%). BIBR 953 has a longer half‐life (about 12 h) than does melagatran (3–5 h) after oral administration of BIBR 1048 and ximelagatran, respectively. Both melagatran and BIBR 953 are mainly eliminated via the renal route. The variability of the plasma concentration of melagatran after oral administration of ximelagatran is low. There are no clinically relevant interactions with food or cytochrome P450 metabolized drugs and ximelagatran. In clinical studies, ximelagatran has been administered in a twice‐daily fixed‐dose regimen without coagulation monitoring. Results of published clinical studies are encouraging, both with regard to efficacy and bleeding. Major indications in Phase III studies with ximelagatran are the prevention of venous thromboembolism (VTE) in hip and knee replacement surgery, treatment and long‐term secondary prevention of VTE and prevention of stroke in patients with nonvalvular atrial fibrillation. It is anticipated that with a favourable outcome of the Phase III clinical studies new oral DTIs, with the oral fixed‐dose regimen without routine coagulation monitoring, will ease the use of today's anticoagulant therapy.
Short‐ and long‐acting synthetic pentasaccharides
Authors: Koopman M. M. W. , Büller H. R. 
Published: September 2003

Abstract Koopman MMW, Büller HR (Academic Medical Centre, Amsterdam, The Netherlands). Short‐ and long‐acting synthetic pentasaccharides (Minisymposium). J Intern Med 2003; 254: 335–342.Inhibition of activated coagulation factor X (FXa) is an attractive target for antithrombotic treatment strategies, because of the central position of FXa in the coagulation cascade. Most of the now available anticoagulant drugs have inhibitory effects not only on FXa, but also on thrombin. With the development of pentasaccharides, a new class of antithrombotic agents has emerged that acts by specific inhibition of FXa and lacks activity against FIIa. Fondaparinux, the first synthetic short‐acting pentasaccharide, has been evaluated, in a large phase II and III clinical programme concerning prophylaxis and treatment of venous thromboembolism and also in phase II studies in patients with acute coronary syndromes. Idraparinux, the long‐acting pentasaccharide, has been studied in a dose‐finding study in patients with established deep‐vein thrombosis and phase III studies are now planned in patients with venous thromboembolism and in patients with atrial fibrillation.
Resin‐bonded fixed partial denture retention: a retrospective 13‐year follow‐up
Authors: Zalkind M. , Ever‐Hadani P. , Hochman N. 
Published: September 2003

summary  A total of 51 resin‐bonded fixed partial dentures (RBFPDs) were inserted under controlled clinical conditions and evaluated over a period of 13 years.Three levels of survival were defined: complete survival (no debonding); functional survival (loss of retention on one occasion with rebonding of the original RBFPD); and multiple survival (loss of retention on several occasions with rebonding of the original RBFPD).The effect of the aetiology, location (anterior/posterior or maxillary/mandibulary) and number of units of the missing tooth on RBFPD survival rates were investigated. The mean survival times and confidence levels were determined for each survival category, using the Kaplan–Meier procedure. The relative risks were calculated by the Cox regression procedure.The overall complete survival level of the study population at the end of the follow‐up period was 85 months ± 13%. Rebonding the RBFPDs once increased the overall functional survival rate to 112 months ± 10% and multiple rebonding led to a further increase to 131 months ± 8%. The RBFPD placement under conditions of good periodontal support in which orthodontic treatment was not required, such as trauma among other factors, showed significantly higher survival rates than those placed after periodontal or orthodontic treatment. This indicates that, under both these conditions, RBFPDs may serve as long‐term or semi‐permanent restorations.
AHP2 is required for bivalent formation and for segregation of homologous chromosomes in Arabidopsis meiosis
Authors: Schommer Carla , Beven Ali , Lawrenson Tom , Shaw Peter , Sablowski Robert 
Published: September 2003

SummaryA new Arabidopsis meiotic mutant has been isolated. Homozygous ahp2‐1 (Arabidopsis homologue pairing 2) plants were sterile because of failure of both male and female gametophyte development. Fluorescent in situ hybridisation showed that in ahp2‐1 male meiocytes, chromosomes did not form bivalents during prophase I and instead seemed to associate indiscriminately. Chromosome fragmentation, chromatin bridges and unbalanced segregation were seen in anaphase I and anaphase II. The ahp2‐1 mutation was caused by a T‐DNA insertion in an Arabidopsis homologue of meu13+, which has been implicated in homologous chromosome pairing during meiosis in Schizosaccharomyces pombe. Our results suggest that meu13+ function is conserved in higher eukaryotes and support the idea that Arabidopsis, yeast and mouse share a pairing pathway that is not present in Drosophila melanogaster and Caenorhabditis elegans.
Co‐expression of N‐terminal truncated 3‐hydroxy‐3‐methylglutaryl CoA reductase and C24‐sterol methyltransferase type 1 in transgenic tobacco enhances carbon flux towards end‐product sterols
Authors: Holmberg Niklas , Harker Mark , Wallace Andrew D. , Clayton John C. , Gibbard Carl L. , Safford Richard 
Published: September 2003

SummaryThe enzymes 3‐hydroxy‐3‐methylglutaryl CoA reductase (HMGR) and C24‐sterol methyltransferase type 1 (SMT1) have been proposed to be key steps regulating carbon flux through the sterol biosynthesis pathway. To further examine this hypothesis, we co‐expressed the catalytic domain of Hevea brasiliensis HMGR (tHMGR) and Nicotiana tabacum SMT1 in tobacco, under control of both constitutive and seed‐specific promoters, resulting in increased accumulation of total sterol in seed tissue by 2.5‐ and 2.1‐fold, respectively. This enhancement is greater than when tHMGR and SMT1 were expressed singularly where, for example, seed‐specific expression enhanced total sterols by 1.6‐fold. Significantly, the relative level of 4‐desmethyl sterols (end‐product sterols) was higher in seed co‐expressing tHMGR and SMT1 from seed‐specific promoters (79% of total sterols) than when co‐expressed from constitutive promoters (59% of total sterols) and similar to wild‐type seed (80% of total sterols). These results demonstrate that HMGR and SMT1 work in concert to control carbon flux into end‐product sterols and that the sterol composition can be controlled by the temporal activity of the promoters driving transgene expression. In addition, constitutive expression of the transgenes resulted in elevated accumulation of substrates for C4‐demethylation reactions, which indicates that one or several enzymes catalysing such reactions limit carbon flow to end‐product sterols, at least in a physiological situation when the carbon flow is upregulated.
Genome‐wide mRNA profiling reveals heterochronic allelic variation and a new imprinted gene in hybrid maize endosperm
Authors: Guo Mei , Rupe Mary A. , Danilevskaya Olga N. , Yang Xiaofeng , Hu Zihua 
Published: September 2003

SummaryWe have taken a genomic approach to examine global gene expression in the maize endosperm in relation to dosage and parental effects. Endosperm of eight hybrids generated by reciprocal crosses and their seven inbred parents were sampled at three developmental stages: 10, 14, and 21 days after pollination (DAP). These samples were subjected to GeneCalling, an open‐ended mRNA‐profiling technology, which simultaneously analyzes thousands of genes. Results indicated that the overall level of gene expression in the maize endosperm was dosage‐dependent, that is, the gene expression was proportional to the parental genome contribution of 2n maternal : 1n paternal. However, approximately 8% of the genes deviated from such allelic additive expression and exhibited differential expression in hybrids of reciprocal crosses, resembling either maternally or paternally expressed genes. There were more genes with maternal‐like expression (MLE) than those with paternal‐like expression (PLE). Allele‐specific expression analysis of four selected genes using the WAVE denaturing HPLC (dHPLC) system revealed several mechanisms responsible for the deviation from the allelic additive expression in the hybrid endosperm: heterochronic allelic variation, allelic variation in the level of expression, and genomic imprinting. We discovered a novel imprinted gene no‐apical‐meristem (NAM) related protein1 (nrp1) that was expressed only in the endosperm and regulated by gene‐specific imprinting. The nrp1 gene, a putative transcriptional factor, may play an important role in endosperm development.
Chromosomes form into seven groups in hexaploid and tetraploid wheat as a prelude to meiosis
Authors: Martinez‐Perez Enrique , Shaw Peter , Aragon‐Alcaide Luis , Moore Graham 
Published: September 2003

SummaryHexaploid wheat possesses 42 chromosomes derived from its three ancestral genomes. The 21 pairs of chromosomes can be further divided into seven groups of six chromosomes (one chromosome pair being derived from each of the three ancestral genomes), based on the similarity of their gene order. Previous studies have revealed that, during anther development, the chromosomes associate in 21 pairs via their centromeres. The present study reveals that, as a prelude to meiosis, these 21 chromosome pairs in hexaploid (and tetraploid) wheat associate via the centromeres into seven groups as the telomeres begin to cluster. This results in the association of multiple chromosomes, which then need to be resolved as meiosis progresses. The formation of the seven chromosome clusters now explains the occasional occurrence of remnants of multiple associations, which have been reported at later stages of meiosis in hexaploid (and tetraploid) wheat. Importantly, the chromosomes have the opportunity to be resorted via these multiple interactions. As meiosis progresses, such interactions are resolved through the action of loci such as Ph1, leaving chromosomes as homologous pairs.
The YORE‐YORE gene regulates multiple aspects of epidermal cell differentiation in Arabidopsis
Authors: Kurata Tetsuya , Kawabata‐Awai Chie , Sakuradani Eiji , Shimizu Sakayu , Okada Kiyotaka , Wada Takuji 
Published: September 2003

SummaryWe have identified a new Arabidopsis mutant, yore‐yore (yre), which has small trichomes and glossy stems. Adhesion between epidermal cells was observed in the organs of the yre shoot. The cloned YRE had high homology to plant genes involved in epicuticular wax synthesis, such as ECERIFERUM1 (CER1) and maize GLOSSY1. The phenotype of transgenic plants harboring double‐stranded RNA interference (dsRNAi) YRE was quite similar to that of the yre mutant. The amount of epicuticular wax extracted from leaves and stems of yre‐1 was approximately one‐sixth of that from the wild type. YRE promoter::GUS and in situ hybridization revealed that YRE was specifically expressed in cells of the L1 layer of the shoot apical meristem and young leaves, stems, siliques, and lateral root primordia. Strong expression was detected in developing trichomes. The trichome structure of cer1 was normal, whereas that of the yre cer1 double mutant was heavily deformed, indicating that epicuticular wax is required for normal growth of trichomes. Double mutants of yre and trichome‐morphology mutants, glabra 2 (gl2) and transparent testa glabra1 (ttg1), showed that the phenotype of the trichome structure was additive, suggesting that the wax‐requiring pathway is distinct from the trichome development pathway controlled by GL2 and TTG1.
Towards deciphering phloem: a transcriptome analysis of the phloem of Apium graveolens
Authors: Vilaine F. , Palauqui J.‐C. , Amselem J. , Kusiak C. , Lemoine R. , Dinant S. 
Published: September 2003

SummaryEvents occurring in the phloem tissue are key to understanding a wide range of developmental and physiological processes in vascular plants. While a considerable amount of molecular information on phloem proteins has emerged in the past decade, a unified picture of the molecular mechanisms involved in phloem differentiation and function is still lacking. New models to increase our understanding of this complex tissue can be created by the development of global approaches such as genomic analysis. In order to obtain a comprehensive overview of the molecular biology of the phloem tissue, we developed a genomic approach using Apium graveolens as a model. cDNA libraries were constructed from mRNAs extracted from isolated phloem of petioles. Expression data obtained from the analysis of 989 expressed sequence tags (ESTs) and the transcript profile deduced from a cDNA macroarray of 1326 clones were combined to identify genes showing distinct expression patterns in the vascular tissues. Comparisons of expression profiles obtained from the phloem, xylem and storage parenchyma tissues uncovered tissue‐specific differential expression patterns for given sets of genes. The major classes of mRNAs predominantly found in the phloem encode proteins related to phloem structure, metal homeostasis or distribution, stress responses and degradation or turnover of proteins. Of great interest for future studies are the genes we found to be specifically expressed in the phloem but for which the function is still unknown, and also those genes described in previous reports to be up or downregulated by specific interactions. From a broader prospective, our results also clearly demonstrate that cDNA macroarray technology can be used to identify the key genes involved in various physiological and developmental processes in the phloem.
Transgene‐induced RNA interference: a strategy for overcoming gene redundancy in polyploids to generate loss‐of‐function mutations
Authors: Lawrence Richard J. , Pikaard Craig S. 
Published: September 2003

SummaryGene redundancy in polyploid species complicates genetic analyses by making the generation of recessive, loss‐of‐function alleles impractical. We show that this problem can be circumvented using RNA interference (RNAi) to achieve dominant loss of function of targeted genes. Arabidopsis suecica is an allotetraploid (amphidiploid) hybrid of A. thaliana and A. arenosa. We demonstrate that A. suecica can be genetically transformed using the floral dip method for Agrobacterium‐mediated transformation. Transgenes segregate as in a diploid, indicating that chromosome pairing occurs exclusively (or almost so) among homologs and not among homeologs. Expressing a double‐stranded (ds) RNA corresponding to the A. thaliana gene, decrease in DNA methylation 1 (DDM1) caused the elimination of DDM1 mRNAs and the loss of methylation at both A. thaliana‐ and A. arenosa‐derived centromere repeats. These results indicate that a single RNAi‐inducing transgene can dominantly repress multiple orthologs.