bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low‐grade inflammation, endothelial activation and carotid intima‐media thickness in type 2 diabetes
Authors: Leinonen E. S. , Hiukka A. , Hurt‐Camejo E. , Wiklund O. , Sarna S. S. , Mattson Hultén L. , Westerbacka J. , Salonen R. M. , Salonen J. T. , Taskinen M.‐R. 
Published: July 2004

Abstract.Objectives.  The objective of this study was to assess the relationship between inflammation, endothelial activation and incipient atherosclerosis in type 2 diabetes.Design.  Cross‐sectional study.Setting and subjects.  We studied 239 type 2 diabetic patients [71 with clinical cardiovascular disease (CVD)] and 78 healthy control subjects, aged 50–75 in a single research centre.Methods.  Carotid intima‐media thickness (IMT) was determined by ultrasound. Circulating intracellular adhesion molecule‐1, vascular cell adhesion molecule‐1, E‐selectin, ultra‐sensitive C‐reactive protein, human serum amyloid A, interleukin‐6, monocyte colony‐stimulating factor, secretory nonpancreatic phospholipase A2 type IIA, glucose, HbA1c, and lipid/lipoprotein variables were measured.Results.  Carotid IMT was significantly thicker in diabetic patients than healthy controls across the whole age range. IMT was also thicker in diabetic patients with, than without, CVD, but this difference disappeared after controlling for confounding factors. Concentrations of the inflammatory and endothelial markers except IL‐6 were significantly higher in the diabetic patients than in healthy controls, but comparable in diabetic patients with and without CVD. The main determinants of IMT in the diabetic patients were blood pressure, age and diabetes duration.Conclusions.  Low‐grade inflammation and endothelial activation are increased in diabetic patients but do not associate with IMT or clinical CVD. The inflammatory reaction seems to be rather a feature of the metabolic syndrome than a direct determinant of atherosclerosis.
Leptin, but not adiponectin, predicts stroke in males
Authors: Söderberg S. , Stegmayr B. , Stenlund H. , Sjöström L.‐G. , Ågren Å. , Johansson L. , Weinehall L. , Olsson T. 
Published: July 2004

Abstract.Objective.  To test whether leptin and adiponectin are risk markers for a first‐ever stroke.Research design, methods and subjects.  A nested case‐referent study identified 276 cases with first‐ever stroke (234 cases with ischaemic and 42 with haemorrhagic stroke). Prior to the stroke, they had participated in population‐based health surveys in northern Sweden (median time between survey and stroke was 4.9 years). Referents were matched for sex, age, date and type of health survey, and geographical region. Putative risk markers for first‐ever stroke, including blood pressure (BP), diabetes, smoking, body mass index (BMI), cholesterol, leptin, and adiponectin, were analysed by conditional logistic regression analysis.Results.  Increased BMI, high cholesterol and fasting glucose levels, diabetes mellitus and hypertension were found in future stroke patients. Whereas leptin levels were higher in male subjects (P = 0.004), adiponectin did not differ between groups. A high leptin level independently predicted stroke in men (OR = 2.46; 95% CI 1.08–5.62) but not in women. Adiponectin levels did not predict stroke. Males with high leptin levels developed stroke faster than males with low leptin levels (P = 0.0009), independently of traditional risk factors.Conclusions.  Leptin may be an important link to the development of cerebrovascular disease in men, whereas adiponectin does not associate with future stroke.
Improving the outcomes of anticoagulation: an evaluation of home follow‐up of warfarin initiation
Authors: Jackson S. L. , Peterson G. M. , Vial J. H. , Jupe D. M. L. 
Published: July 2004

Abstract.Objectives.  A number of studies have reported that the risk of bleeding associated with warfarin is highest early in the course of therapy. This study examined the effect of a programme focused on the transition of newly anticoagulated patients from hospital to the community.Design.  Open‐label randomized controlled trial.Setting.  Home‐based follow‐up of patients discharged from acute care hospital in southern Tasmania, Australia.Subjects.  A total of 128 patients initiated on warfarin in hospital and subsequently discharged to general practitioner (GP) care were enrolled in the study. Sixty were randomized to home monitoring (HM) and 68 received usual care (UC).Interventions.  HM patients received a home‐visit by the project pharmacist and point‐of‐care international normalized ratio (INR) testing on alternate days on 4 occasions, with the initial visit two days after discharge. The UC group was solely managed by the GP and only received a visit 8 days after discharge to determine anticoagulant control.Results.  At discharge, 42% of the HM group and 45% of the UC group had a therapeutic INR. At day 8, 67% of the HM patients had a therapeutic INR, compared with 42% of UC patients (P < 0.002). In addition, 26% of UC patients had a high INR, compared with only 4% of HM patients. Bleeding events were assessed 3 months after discharge and occurred in 15% of HM patients, compared with 36% of the UC group (P < 0.01).Conclusions.  This programme improved the initiation of warfarin therapy and resulted in a significant decrease in haemorrhagic complications in the first 3 months of therapy.
Is the placebo powerless? Update of a systematic review with 52 new randomized trials comparing placebo with no treatment
Authors: Hróbjartsson A. , Gøtzsche P. C. 
Published: July 2004

Abstract.Background.  It is widely believed that placebo interventions induce powerful effects. We could not confirm this in a systematic review of 114 randomized trials that compared placebo‐treated with untreated patients.Aim.  To study whether a new sample of trials would reproduce our earlier findings, and to update the review.Methods.  Systematic review of trials that were published since our last search (or not previously identified), and of all available trials.Results.  Data was available in 42 out of 52 new trials (3212 patients). The results were similar to our previous findings. The updated review summarizes data from 156 trials (11 737 patients). We found no statistically significant pooled effect in 38 trials with binary outcomes, relative risk 0.95 (95% confidence interval 0.89–1.01). The effect on continuous outcomes decreased with increasing sample size, and there was considerable variation in effect also between large trials; the effect estimates should therefore be interpreted cautiously. If this bias is disregarded, the pooled standardized mean difference in 118 trials with continuous outcomes was −0.24 (−0.31 to −0.17). For trials with patient‐reported outcomes the effect was −0.30 (−0.38 to −0.21), but only −0.10 (−0.20 to 0.01) for trials with observer‐reported outcomes. Of 10 clinical conditions investigated in three trials or more, placebo had a statistically significant pooled effect only on pain or phobia on continuous scales.Conclusion.  We found no evidence of a generally large effect of placebo interventions. A possible small effect on patient‐reported continuous outcomes, especially pain, could not be clearly distinguished from bias.
A patient withTSC1germline mutation whose clinical phenotype was limited to lymphangioleiomyomatosis
Authors: Sato T. , Seyama K. , Kumasaka T. , Fujii H. , Setoguchi Y. , Shirai T. , Tomino Y. , Hino O. , Fukuchi Y. 
Published: July 2004

Abstract.Background: Lymphangioleiomyomatosis (LAM) can occur as in isolated form (sporadic LAM) or as a pulmonary manifestation of tuberous sclerosis complex (TSC) (TSC‐associated LAM). Recent studies, however, revealed that both forms of LAM are genetically related but that sporadic LAM is a distinct clinical entity caused by somatic mutations ofTSC2(notTSC1) rather than a forme fruste of TSC carrying either of theTSC1orTSC2germline mutations.Method: Case presentation and in‐depth molecular and histopathological examinations. A 34‐year‐old Japanese woman was diagnosed as having pulmonary lymphangioleiomyomatosis (LAM) when bilateral pneumothoraces were surgically treated in 1992. Although slowly progressive renal disfunction was observed due to bilateral multiple renal cysts during the past 4 years, she had no other clinical features of TSC and was diagnosed as having sporadic LAM with multiple renal cysts of undetermined aetiology. Her subsequent clinical course was complicated by an endobrochial carcinoid tumour, which eventually resulted in her death in June 1999 due to massive haemoptysis.Results: Postmortem examination revealed the presence of LAM lesions in the lungs, mediastinal lymph nodes, kidneys and uterus. Diffuse renal LAM lesions are presumed to generate multiple renal cysts by constricting the nephron rather than epithelial hyperplasia obstructing lumina, which is analysis of theTSCgenes demonstrated that she did not haveTSC2/PKD1contiguous gene syndrome but had aTSC1 germline mutation (Sato Tet al. J Hum Genet 2002;47: 20–8) that had occuredde novo.Conclusion: This patient therefore illustrates that clinical manifestations of TSC are sufficiently diverse as to allow a forme fruste of TSC that mimics sporadic LAM and thatTSC1 mutation can cause multiple renal cysts resulting in renal failure.
Trends in the incidence of chronic Philadelphia chromosome negative (Ph‐) myeloproliferative disorders in the city of Göteborg, Sweden, during 1983–99
Authors: Johansson P. , Kutti J. , Andréasson B. , Safai‐Kutti S. , Vilén L. , Wedel H. , Ridell B. 
Published: July 2004

Abstract.Objective.  In the literature the incidence rates for the chronic Philadelphia chromosome negative (Ph‐) myeloproliferative disorders (MPD) are known to vary extensively; only a few studies have, however, been concerned with incidence trends over time. Therefore, the aim of the present work was to investigate possible trends as regards incidence rates over time for Ph‐MPD.Design.  Herein, we carried out a retrospective population‐based survey on the incidence of polycythaemia vera (PV), essential thrombocythae‐mia (ET) and chronic idiopathic myelofibrosis (IMF), in the city of Göteborg (Sweden), covering the years 1983–99.Results.  The study comprised 416 patients with Ph‐MPD. There were 205 patients with PV, 153 patients with ET, 34 with IMF and 24 with unclassified MPD. The annual incidence for PV was 1.97 per 105 inhabitants; the corresponding figures for ET and IMF were 1.55 per 105 and 0.30 per 105 inhabitants, respectively. There was a significant increase in the annual incidence rate for ET (P = 0.008); this increase was significant for male subjects (P = 0.015) but did not reach significance for females (P = 0.118). No such increase over time was recorded as regards PV and IMF.Conclusions.  The increasing annual incidence rate for ET is most possibly explained by the more frequent use of automated platelet counts whenever a patient consults a doctor. Thereby, an increasing number of patients with overt thrombocytosis of unknown origin are discovered and will be referred to specialists within the field of haematology for a correct diagnosis.
Activity reversal of Tet repressor caused by single amino acid exchanges
Authors: Scholz Oliver , Henßler Eva‐Maria , Bail Johannes , Schubert Peter , Bogdanska‐Urbaniak Joanna , Sopp Sabine , Reich Marco , Wisshak Stefanie , Köstner Martin , Bertram Ralph , Hillen Wolfgang 
Published: July 2004

SummaryWe explore by extensive mutagenesis regions in the sequence allowing reversal of the allosteric response of Tet repressor. The wild type requires anhydrotetracycline for induction. About 100 mutants are presented, which, in contrast, require the drug for repression. Their mutations are clustered at the interface of the DNA‐ and inducer‐binding domains. This interface consists of a central hydrophobic region surrounded by several hydrogen bonds. While most of the mutants described here contain two to five mutations, we found five positions in this region of TetR, at which single amino acid exchanges lead to activity reversal. They may disrupt the hydrogen‐bonding network bordering the domain interface. We assume that the mutations cause a repositioning of the DNA reading head with respect to the effector binding core so that the same conformational change can result in opposite activities.
RovA is autoregulated and antagonizes H‐NS‐mediated silencing of invasin and rovA expression in Yersinia pseudotuberculosis
Authors: Heroven Ann Kathrin , Nagel Geraldine , Tran Hien J. , Parr Susanne , Dersch Petra 
Published: July 2004

SummaryThe transcriptional activator RovA of Yersinia pseudotuberculosis, a member of the SlyA/Hor family, activates its own expression and that of the virulence factor invasin in response to moderate growth temperature, but not at 37°C. In this work, we analysed the mechanism of RovA‐dependent transcription of the rovA and inv genes. We found that rovA is transcribed by two different promoters. Sequences located upstream and downstream of the promoters were involved in rovA autoregulation and interacted specifically with the RovA protein. To define the nucleotides recognized by the RovA protein, we determined the RovA binding sites in the rovA and the inv regulatory region and revealed related AT‐rich sequence motifs at diverse positions relative to the transcriptional start sites. We also showed that rovA and the RovA‐dependent inv gene were both subject to silencing by the nucleoid‐associated H‐NS protein of Y. pseudotuberculosis. The binding sites of the H‐NS and RovA proteins in the rovA and inv regulatory sequences were superimposed, and the presence of the RovA protein alleviated H‐NS‐mediated repression of the rovA and inv promoter. Moreover, loss of H‐NS function led to a significant increase in rovA and inv transcription nearly independently of RovA, indicating that RovA acts mainly as an antirepressor. We therefore hypothesize that the transcription level of RovA‐dependent genes reflects the outcome of the RovA/H‐NS competition and the rovA autoregulatory mechanism.
Tailoring modification of deoxysugars during biosynthesis of the antitumour drug chromomycin A3 by Streptomyces griseus ssp. griseus
Authors: Menéndez Nuria , Nur‐e‐Alam Mohammad , Braña Alfredo F. , Rohr Jürgen , Salas José A. , Méndez Carmen 
Published: July 2004

SummaryChromomycin A3 is a member of the aureolic acid group family of antitumour drugs. Three tailoring modification steps occur during its biosynthesis affecting the sugar moieties: two O‐acetylations and one O‐methylation. The 4‐O‐methylation in the 4‐O‐methyl‐D‐oliose moiety of the disaccharide chain is catalysed by the cmmMIII gene product. Inactivation of this gene generated a chromomycin‐non‐producing mutant that accumulated three unmethylated derivatives containing all sugars but differing in the acylation pattern. Two of these compounds were shown to be substrates of the methyltransferase as determined by their bioconversion into chromomycin A2 and A3 after feeding these compounds to a Streptomyces albus strain expressing the cmmMIII gene. The same single membrane‐bound enzyme, encoded by the cmmA gene, is responsible for both acetyl transfer reactions, which convert a relatively inactive compound into the bioactive chromomycin A3. Insertional inactivation of this gene resulted in a mutant accumulating a dideacetylated chromomycin A3 derivative. This compound, lacking both acetyl groups, was converted in a two‐step reaction via the 4E‐monoacetylated intermediate into chromomycin A3 when fed to cultures of S. albus expressing the cmmA gene. This acetylation step would occur as the last step in chromomycin biosynthesis, being a very important event for self‐protection of the producing organism. It would convert a molecule with low biological activity into an active one, in a reaction catalysed by an enzyme that is predicted to be located in the cell membrane.
Dimer‐induced signal propagation in Spo0A
Authors: Muchová K. , Lewis R. J. , Perečko D. , Brannigan J. A. , Ladds J. C. , Leech A. , Wilkinson A. J. , Barák I. 
Published: July 2004

SummarySpo0A, the response regulator protein controlling the initiation of sporulation in Bacillus, has two distinct domains, an N‐terminal phosphoacceptor (or receiver) domain and a C‐terminal DNA‐binding (or effector) domain. The phosphoacceptor domain mediates dimerization of Spo0A on phosphorylation. A comparison of the crystal structures of phosphorylated and unphosphorylated response regulators suggests a mechanism of activation in which structural changes originating at the phosphorylatable aspartate extend to the α4β5α5 surface of the protein. In particular, the data show an important role in downstream signalling for a conserved aromatic residue (Phe‐105 in Spo0A), the conformation of which alters upon phosphorylation. In this study, we have prepared a Phe‐105 to Ala mutant to probe the contribution of this residue to Spo0A function. We have also made an alanine substitution of the neighbouring residue Tyr‐104 that is absolutely conserved in the Spo0As of spore‐forming Bacilli. The spo0A(Y104A) and spo0A(F105A) alleles severely impair sporulation in vivo. In vitro phosphorylation of the purified proteins by phosphoramidate is unaffected, but dimerization and DNA binding are abolished by the mutations. We have identified intragenic suppressor mutations of spo0A(F105A) and shown that these second‐site mutations in the purified proteins restore phosphorylation‐dependent dimer formation. Our data support a model in which dimerization and signal transduction between the two domains of Spo0A are mediated principally by the α4β5α5 signalling surface in the receiver domain.
A role forcreD, a carbon catabolite repression gene fromAspergillus nidulans, in ubiquitination
Authors: Boase Natasha A. , Kelly Joan M. 
Published: July 2004

SummaryInAspergillus nidulans, it is known thatcreBencodes a deubiquitinating enzyme that forms a complex with the WD40 motif containing protein encoded bycreC, that mutations in these genes lead to altered carbon source utilization and that thecreD34mutation suppresses the phenotypic effects of mutations increCandcreB. Therefore,creDwas characterized in order to dissect the regulatory network that involves the CreB–CreC deubiquitination complex. CreD contains arrestin domains and PY motifs and is highly similar to the Rod1p and Rog3p proteins fromSaccharomyces cerevisiae. An additional gene was identified in theA. nidulansgenome that also encodes anarrestin andPYmotif‐containing protein, which we have designatedapyA, and thus two similar proteins also exist inA. nidulans. InS. cerevisiae, Rod1p and Rog3p interact with the ubiquitin ligase Rsp5p, and so theA. nidulanshomologue of Rsp5p was identified, and the gene encoding thisHECTubiquitinligase was designatedhulA. CreD and ApyA were tested for protein–protein interactions with HulA via the bacterial two‐hybrid system, and ApyA showed strong interaction, and CreD showed weak interaction, with HulA in this system.
Membrane localization itself but not binding to IICBGlc is directly responsible for the inactivation of the global repressor Mlc in Escherichia coli
Authors: Tanaka Yuya , Itoh Fumie , Kimata Keiko , Aiba Hiroji 
Published: July 2004

SummaryMlc is a global transcriptional repressor involved in the regulation of genes linked to glucose metabolism. The activity of Mlc is modulated through the interaction with a major glucose transporter, IICBGlc, in response to external glucose. To understand how IICBGlc–Mlc interaction controls the repressor activity of Mlc, we attempted to isolate Mlc mutants that retain the ability to repress target genes even in the presence of glucose. The Mlc mutants were tested for their ability to interact with IICBGlc. Mutants in which a single amino acid substitution occurs in the N‐terminal portion were no longer able to bind to IICBGlc, suggesting that the N‐terminal region of Mlc is primarily responsible for the interaction with IICBGlc. To examine whether the Mlc–IICBGlc interaction and/or the membrane localization of Mlc per se are essential for the inactivation of Mlc, the properties of several hybrid proteins in which either IIBGlc or Mlc is fused to membrane proteins were analysed. The cytoplasmic IIBGlc domain failed to inhibit the Mlc action although it retains the ability to bind Mlc in cells. However, it gained the ability to inhibit the Mlc activity when it was fused to a membrane protein LacY. In addition, we showed that Mlc is inactivated when fused to membrane proteins but not when fused to cytoplasmic proteins. We conclude that the IICBGlc–Mlc interaction is dispensable for the inactivation of Mlc, and that membrane localization is directly responsible for the inactivation of Mlc.
The Candida albicans CaACE2 gene affects morphogenesis, adherence and virulence
Authors: Kelly Mary T. , MacCallum Donna M. , Clancy Susanne D. , Odds Frank C. , Brown Alistair J. P. , Butler Geraldine 
Published: July 2004

SummaryMorphogenesis between yeast and hyphal growth is a characteristic associated with virulence in Candida albicans and involves changes in the cell wall. In Saccharomyces cerevisiae, the transcription factor pair Ace2p and Swi5p are key regulators of cell wall metabolism. Here, we have characterized the CaACE2 gene, which encodes the only C. albicans homologue of S. cerevisiae ACE2 and SWI5. Deleting CaACE2 results in a defect in cell separation, increased invasion of solid agar medium and inappropriate pseudohyphal growth, even in the absence of external inducers. The mutant cells have reduced adherence to plastic surfaces and generate biofilms with distinctly different morphology from wild‐type cells. They are also avirulent in a mouse model. Deleting CaACE2 has no effect on expression of the chitinase gene CHT2, but expression of CHT3 and the putative cell wall genes CaDSE1 and CaSCW11 is reduced in both yeast and hyphal forms. The CaAce2 protein is localized to the daughter nucleus of large budded cells at the end of mitosis. C. albicans Ace2p therefore plays a major role in morphogenesis and adherence and resembles S. cerevisiae Ace2p in function.
Transcription of the sporulation gene ssgA is activated by the IclR‐type regulator SsgR in a whi‐independent manner in Streptomyces coelicolor A3(2)
Authors: Traag Bjørn A. , Kelemen Gabriella H. , Van Wezel Gilles P. 
Published: July 2004

SummarySsgA plays an important role in the control of sporulation‐specific cell division and morphogenesis of streptomycetes, and ssgA null mutants have a rare conditionally non‐sporulating phenotype. In this paper we show that transcription of ssgA and of the upstream‐located ssgR, an iclR‐type regulatory gene, is developmentally regulated in Streptomyces coelicolor and activated towards the onset of sporulation. A constructed ssgR null mutant was phenotypically very similar to the ssgA mutant. The absence of ssgA transcription in this mutant is probably the sole cause of its sporulation deficiency, as wild‐type levels of sporulation could be restored by the SsgR‐independent expression of ssgA from the ermE promoter. Binding of a truncated version of SsgR to the ssgA promoter region showed that ssgA transcription is directly activated by SsgR; such a dependence of ssgA on SsgR in S. coelicolor is in clear contrast to the situation in S. griseus, where ssgA transcription is activated by A‐factor, and its control by the SsgR orthologue, SsfR, is far less important. Our failure to complement the ssgR mutant with S. griseus ssfR suggests functional differences between the genes. These observations may explain some of the major differences in developmental control between the phylogenetically divergent species S. coelicolor and S. griseus, highlighted in a recent microreview (Chater and Horinouchi (2003) Mol Microbiol 48: 9–15). Surprisingly, transcription of ssgA and ssgR is not dependent on the early whi genes (whiA, whiB, whiG, whiH, whiI and whiJ ).