bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of host connective tissue growth factor expression: a novel Trypanosoma cruzi‐mediated response
Authors: Unnikrishnan Meera , A. Burleigh Barbara
Published: November 2004

Connective tissue growth factor (CTGF) is a secreted cytokine that plays a fundamental role in the development of tissue fibrosis by mediating many of the profibrotic effects of TGF‐β. We present the novel finding that the intracellular pathogen Trypanosoma cruzi elicits immediate and sustained repression of basal CTGF expression in dermal fibroblasts, followed by down‐regulation of the extracellular matrix proteins, fibronectin, and collagen I α1. To address mechanisms underlying this response, the major CTGF‐regulating pathways were investigated. We report that both T. cruzi trypomastigotes and secreted parasite factor(s) antagonize TGF‐β‐dependent induction of CTGF in fibroblasts. Of the TGF‐β‐dependent signaling pathways required for CTGF expression, we demonstrate that T. cruzi interferes with cellular Erk1/2 phosphorylation but not Smad3 signaling. While increased stimulation of Erk phosphorylation alone was insufficient to override the parasite‐mediated repression of CTGF, stimulation of fibroblasts with increased concentrations of TGF‐β, which activates both Smad3 and Erk1/2, completely abrogated this inhibition. Together with the finding that T. cruzi‐mediated down‐regulation of CTGF expression requires de novo host cell protein synthesis, our data indicate that the unique ability of T. cruzi to interfere with the host fibrogenic response is a complex process requiring input from multiple host cell signaling pathways.—Unnikrishnan, M., Burleigh, B. A. Inhibition of host connective tissue growth factor expression: a novel Trypanosoma cruzi‐mediated response. FASEB J. 18, 1625–1635 (2004)
Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart
Authors: Sharma Saumya , Adrogue Julia V. , Golfman Leonard , Uray Ivan , Lemm John , Youker Keith , Noon George P. , Frazier O. H. , Taegtmeyer Heinrich
Published: November 2004

In animal models of lipotoxicity, accumulation of triglycerides within cardiomyocytes is associated with contractile dysfunction. However, whether intramyocardial lipid deposition is a feature of human heart failure remains to be established. We hypothesized that intramyocardial lipid accumulation is a common feature of non‐ischemic heart failure and is associated with changes in gene expression similar to those found in an animal model of lipotoxicity. Intramyocardial lipid staining with oil red O and gene expression analysis was performed on heart tissue from 27 patients (9 female) with non‐ischemic heart failure. We determined intramyocardial lipid, gene expression, and contractile function in hearts from 6 Zucker diabetic fatty (ZDF) and 6 Zucker lean (ZL) rats. Intramyocardial lipid overload was present in 30% of non‐ischemic failing hearts. The highest levels of lipid staining were observed in patients with diabetes and obesity (BMI>30). Intramyocardial lipid deposition was associated with an up‐regulation of peroxisome proliferator‐activated receptor a (PPARα) ‐regulated genes, myosin heavy chain β (MHC‐β), and tumor necrosis factor α (TNF‐α). Intramyocardial lipid overload in the hearts of ZDF rats was associated with contractile dysfunction and changes in gene expression similar to changes found in failing human hearts with lipid overload. Our findings identify a subgroup of patients with heart failure and severe metabolic dysregulation characterized by intramyocardial triglyceride overload and changes in gene expression that are associated with contractile dysfunction.—Sharma, S., Adrogue, J. V., Golfman, L., Uray, I., Lemm, J., Youker, K., Noon, G. P., Frazier, O. H., Taegtmeyer, H. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J. 18, 1692–1700 (2004)
Linearity and time-scale invariance of the creep function in living cells
Authors: Lenormand Guillaume , Millet Emil , Fabry Ben , Butler James P. , Fredberg Jeffrey J.
Published: November 2004

We report here the creep function measured in three cell types, after a variety of interventions, and over three time decades (from 3ms to 3.2 s). In each case the response conformed to a power law, implying that no distinct molecular relaxation times or time constants could characterize the response. These results add to a growing body of evidence that stands in contrast to widely used viscoelastic models featuring at most a few time constants. We show instead that the ability of the matrix to deform is time-scale invariant and characterized by only one parameter: the power law exponent that controls the transition between solid-like and liquid-like behaviour. Moreover, we validate linearity by comparison of measurements in the time and frequency domains.
Rapid accumulation of mutations during seed-to-seed propagation of mismatch-repair-defective Arabidopsis
Authors: Hoffman Peter D. , Leonard Jeffrey M. , Lindberg Gerrick E. , Bollmann Stephanie R. , Hays John B.
Published: November 2004

During the many cell divisions that precede formation of plant gametes, their apical-meristem and floral antecedents are continually exposed to endogenous and environmental mutagenic threats. Although some deleterious recessive mutations may be eliminated during growth of haploid gametophytes and functionally haploid early embryos (“haplosufficiency quality-checking”), the multiplicity of plant genome-maintenance systems suggests aggressive quality control during prior diploid growth. To test in Arabidopsis a hypothesis that prior mismatch repair (MMR) is paramount in defense of plant genetic fidelity, we propagated in parallel 36 MMR-defective (Atmsh2-1) and 36 wild-type lines. The Atmsh2-1 lines rapidly accumulated a wide variety of mutations: fifth-generation (G5) plants showed abnormalities in morphology and development, fertility, germination efficiency, seed/silique development, and seed set. Only two Atmsh2-1, but all 36 wild-type lines, appeared normal at G5. Analyses of insertion/deletion mutation at six repeat-sequence (microsatellite) loci showed each Atmsh2-1 line to have evolved its own “fingerprint,” the results of as many as 10 microsatellite mutations in a single line. Thus, MMR during diploid growth is essential for plant genomic integrity.
Fine-tuning of the Escherichia coli σE envelope stress response relies on multiple mechanisms to inhibit signal-independent proteolysis of the transmembrane anti-sigma factor, RseA
Authors: Grigorova Irina L. , Chaba Rachna , Zhong Hong Ji , Alba Benjamin M. , Rhodius Virgil , Herman Christophe , Gross Carol A.
Published: November 2004

Proteolytic cascades are widely implicated in signaling between cellular compartments. In Escherichia coli, accumulation of unassembled outer membrane porins (OMPs) in the envelope leads to expression of σE-dependent genes in the cytoplasmic cellular compartment. A proteolytic cascade conveys the OMP signal by regulated proteolysis of RseA, a membrane-spanning anti-sigma factor whose cytoplasmic domain inhibits σE-dependent transcription. Upon activation by OMP C termini, the membrane localized DegS protease cleaves RseA in its periplasmic domain, the membrane-embedded protease RseP (YaeL) cleaves RseA near the inner membrane, and the released cytoplasmic RseA fragment is further degraded. Initiation of RseA degradation by activated DegS makes the system sensitive to a wide range of OMP concentrations and unresponsive to variations in the levels of DegS and RseP proteases. These features rely on the inability of RseP to cleave intact RseA. In the present report, we demonstrate that RseB, which binds to the periplasmic face of RseA, and DegS each independently inhibits RseP cleavage of intact RseA. Thus, the function of RseB, widely conserved among bacteria using the σE pathway, and the second role of DegS (in addition to RseA proteolysis initiation) is to improve the performance characteristics of this signal transduction system.
The Polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation
Authors: Caretti Giuseppina , Di Padova Monica , Micales Bruce , Lyons Gary E. , Sartorelli Vittorio
Published: November 2004

The Ezh2 protein endows the Polycomb PRC2 and PRC3 complexes with histone lysine methyltransferase (HKMT) activity that is associated with transcriptional repression. We report that Ezh2 expression was developmentally regulated in the myotome compartment of mouse somites and that its down-regulation coincided with activation of muscle gene expression and differentiation of satellite-cell-derived myoblasts. Increased Ezh2 expression inhibited muscle differentiation, and this property was conferred by its SET domain, required for the HKMT activity. In undifferentiated myoblasts, endogenous Ezh2 was associated with the transcriptional regulator YY1. Both Ezh2 and YY1 were detected, with the deacetylase HDAC1, at genomic regions of silent muscle-specific genes. Their presence correlated with methylation of K27 of histone H3. YY1 was required for Ezh2 binding because RNA interference of YY1 abrogated chromatin recruitment of Ezh2 and prevented H3-K27 methylation. Upon gene activation, Ezh2, HDAC1, and YY1 dissociated from muscle loci, H3-K27 became hypomethylated and MyoD and SRF were recruited to the chromatin. These findings suggest the existence of a two-step activation mechanism whereby removal of H3-K27 methylation, conferred by an active Ezh2-containing protein complex, followed by recruitment of positive transcriptional regulators at discrete genomic loci are required to promote muscle gene expression and cell differentiation.
Properties of overlapping genes are conserved across microbial genomes
Authors: Johnson Zackary I. , Chisholm Sallie W.
Published: November 2004

There are numerous examples from the genomes of viruses, mitochondria, and chromosomes that adjacent genes can overlap, sharing at least one nucleotide. Overlaps have been hypothesized to be involved in genome size minimization and as a regulatory mechanism of gene expression. Here we show that overlapping genes are a consistent feature (approximately one-third of all genes) across all microbial genomes sequenced to date, have homologs in more microbes than do non-overlapping genes, and are therefore likely more conserved. In addition, the size, phase (reading frame offset), and distribution, among other characteristics, of overlapping genes are most consistent with the hypothesis that overlaps function in the regulation of gene expression. The upstream sequences and conservation of overlapping orthologs of two model organisms from the genus Prochlorococcus that have significantly different GC-content, and therefore different nucleotide sequences for orthologs, are also consistent with small overlapping sequence regions and programmed shifts in reading frame as a common mechanism in the regulation of microbial gene expression.
A novel method for multiple alignment of sequences with repeated and shuffled elements
Authors: Raphael Benjamin , Zhi Degui , Tang Haixu , Pevzner Pavel
Published: November 2004

We describe ABA (A-Bruijnalignment), a new method for multiple alignment of biological sequences. The major difference between ABA and existing multiple alignment methods is that ABA represents an alignment as a directed graph, possibly containing cycles. This representation provides more flexibility than does a traditional alignment matrix or the recently introduced partial order alignment (POA) graph by allowing a larger class of evolutionary relationships between the aligned sequences. Our graph representation is particularly well-suited to the alignment of protein sequences with shuffled and/or repeated domain structure, and allows one to construct multiple alignments of proteins containing (1) domains that are not present in all proteins, (2) domains that are present in different orders in different proteins, and (3) domains that are present in multiple copies in some proteins. In addition, ABA is useful in the alignment of genomic sequences that contain duplications and inversions. We provide several examples illustrating the applications of ABA.
Whole-genome analysis ofAlurepeat elements reveals complex evolutionary history
Authors: Price Alkes L. , Eskin Eleazar , Pevzner Pavel A.
Published: November 2004

Alurepeats are the most abundant family of repeats in the human genome, with over 1 million copies comprising 10% of the genome. They have been implicated in human genetic disease and in the enrichment of gene-rich segmental duplications in the human genome, and they form a rich fossil record of primate and human history.Alurepeat elements are believed to have arisen from the replication of a small number ofsourceelements, whose evolution over time gives rise to the 31Alusubfamilies currently reported in Repbase Update. We apply a novel method to identify and statistically validate 213Alusubfamilies. We build an evolutionary tree of these subfamilies and conclude that the history ofAluevolution is more complex than previous studies had indicated.
Genome sequence of Haloarcula marismortui: A halophilic archaeon from the Dead Sea
Authors: Baliga Nitin S. , Bonneau Richard , Facciotti Marc T. , Pan Min , Glusman Gustavo , Deutsch Eric W. , Shannon Paul , Chiu Yulun , Weng Rueyhung Sting , Gan Rueichi Richie , Hung Pingliang , Date Shailesh V. , Marcotte Edward , Hood Leroy , Ng Wailap Victor
Published: November 2004

We report the complete sequence of the 4,274,642-bp genome of Haloarcula marismortui, a halophilic archaeal isolate from the Dead Sea. The genome is organized into nine circular replicons of varying G+C compositions ranging from 54% to 62%. Comparison of the genome architectures of Halobacterium sp. NRC-1 and H. marismortui suggests a common ancestor for the two organisms and a genome of significantly reduced size in the former. Both of these halophilic archaea use the same strategy of high surface negative charge of folded proteins as means to circumvent the salting-out phenomenon in a hypersaline cytoplasm. A multitiered annotation approach, including primary sequence similarities, protein family signatures, structure prediction, and a protein function association network, has assigned putative functions for at least 58% of the 4242 predicted proteins, a far larger number than is usually achieved in most newly sequenced microorganisms. Among these assigned functions were genes encoding six opsins, 19 MCP and/or HAMP domain signal transducers, and an unusually large number of environmental response regulators—nearly five times as many as those encoded in Halobacterium sp. NRC-1—suggesting H. marismortui is significantly more physiologically capable of exploiting diverse environments. In comparing the physiologies of the two halophilic archaea, in addition to the expected extensive similarity, we discovered several differences in their metabolic strategies and physiological responses such as distinct pathways for arginine breakdown in each halophile. Finally, as expected from the larger genome, H. marismortui encodes many more functions and seems to have fewer nutritional requirements for survival than does Halobacterium sp. NRC-1.
The molecular structure of the DNA fragments eliminated during chromatin diminution in Cyclops kolensis
Authors: Degtyarev Sergei , Boykova Tatiana , Grishanin Andrei , Belyakin Stepan , Rubtsov Nikolai , Karamysheva Tatiana , Makarevich Grigory , Akifyev Alexei , Zhimulev Igor
Published: November 2004

Presumptive somatic cells of the copepod Cyclops kolensis specifically eliminate a large fraction of their genome by the process of chromatin diminution. The eliminated DNA (eDNA) remains only in the germline cells. Very little is known about the nature of the sequences eliminated from somatic cells. We cloned a fraction of the eDNA and sequenced 90 clones that total 32 kb. The following organizational patterns were demonstrated for the eDNA sequences. All do not contain open reading frames. Each fragment contains 1–3 families of short repeats (10–30 bp) highly homologous within families (87%–100%). Most repeats are separated by spacers up to 50 bp long. Homologous regions were found between fragments, motifs from 15–300 bp in length. Among fragments there occur groups in which the same motifs are ordered in the same fashion. However, spacers between the motifs differ in length and nucleotide composition. Ubiquitous motifs (those occurring in all fragments) were identified. Analysis of motifs revealed submotifs, each occurring within several motifs. Thus, motifs may be regarded as mosaic structures composed of submotifs (short repeats). Taken together, the results provide evidence of a high organizational ordering of the DNA sequences restricted to the germline. With this in mind, it appears incorrect to refer to this part of the genome as junk. Moreover, eDNA is redundant for only the somatic cells—its function is to be sought in germline cells.
DNA amplification method tolerant to sample degradation
Authors: Wang Gang , Maher Elizabeth , Brennan Cameron , Chin Lynda , Leo Christopher , Kaur Manjit , Zhu Penny , Rook Martha , Wolfe Jia Liu , Makrigiorgos G. Mike
Published: November 2004

Despite recent advances in linear whole genome amplification of intact DNA/RNA, amplification of degraded nucleic acids in an unbiased fashion remains a serious challenge for genetic diagnosis. We describe a new whole genome amplification procedure, RCA–RCA (Restriction and Circularization-Aided Rolling Circle Amplification), which retains the allelic differences among degraded amplified genomes while achieving almost complete genome coverage. RCA–RCA utilizes restriction digestion and whole genome circularization to generate genomic sequences amenable to rolling circle amplification. When intact genomic DNA is used, RCA–RCA retains gene-amplification differences (twofold or higher) between complex genomes on a genome-wide scale providing highly improved concordance with unamplified material as compared with other amplification methodologies including multiple displacement amplification. Using RCA–RCA, formalin-fixed samples of modest or substantial DNA degradation were successfully amplified and screened via array-CGH or Taqman PCR that displayed retention of the principal gene amplification features of the original material. Microsatellite analysis revealed that RCA–RCA amplified genomic DNA is representative of the original material at the nucleotide level. Amplification of cDNA is successfully performed via RCA–RCA and results to unbiased gene expression analysis (R2 = 0.99). The simplicity and universal applicability of RCA–RCA make it a powerful new tool for genome analysis with unique advantages over previous amplification technologies.
OptStrain: A computational framework for redesign of microbial production systems
Authors: Pharkya Priti , Burgard Anthony P. , Maranas Costas D.
Published: November 2004

This paper introduces the hierarchical computational framework OptStrain aimed at guiding pathway modifications, through reaction additions and deletions, of microbial networks for the overproduction of targeted compounds. These compounds may range from electrons or hydrogen in biofuel cell and environmental applications to complex drug precursor molecules. A comprehensive database of biotransformations, referred to as the Universal database (with >5700 reactions), is compiled and regularly updated by downloading and curating reactions from multiple biopathway database sources. Combinatorial optimization is then used to elucidate the set(s) of non-native functionalities, extracted from this Universal database, to add to the examined production host for enabling the desired product formation. Subsequently, competing functionalities that divert flux away from the targeted product are identified and removed to ensure higher product yields coupled with growth. This work represents an advancement over earlier efforts by establishing an integrated computational framework capable of constructing stoichiometrically balanced pathways, imposing maximum product yield requirements, pinpointing the optimal substrate(s), and evaluating different microbial hosts. The range and utility of OptStrain are demonstrated by addressing two very different product molecules. The hydrogen case study pinpoints reaction elimination strategies for improving hydrogen yields using two different substrates for three separate production hosts. In contrast, the vanillin study primarily showcases which non-native pathways need to be added intoEscherichia coli. In summary, OptStrain provides a useful tool to aid microbial strain design and, more importantly, it establishes an integrated framework to accommodate future modeling developments.
Isolation of the repertoire of VSG expression site containing telomeres of Trypanosoma brucei 427 using transformation-associated recombination in yeast
Authors: Becker Marion , Aitcheson Niall , Byles Elaine , Wickstead Bill , Louis Edward , Rudenko Gloria
Published: November 2004

Trypanosoma brucei switches between variant surface glycoproteins (VSGs) allowing immune escape. The active VSG is in one of many telomeric bloodstream form VSG expression sites (BESs), also containing expression site-associated genes (ESAGs) involved in host adaptation. The role of BES sequence diversity in parasite virulence can best be understood through analysis of the full repertoire of BESs from a given T. brucei strain. However, few BESs have been cloned, as telomeres are highly underrepresented in standard libraries. We devised a strategy for isolating the repertoire of T. brucei 427 BES-containing telomeres in Saccaromyces cerevisiae by using transformation-associated recombination (TAR). We isolated 182 T. brucei 427 BES TAR clones, 167 of which could be subdivided into minimally 17 BES groups. This set gives us the first view of the breadth and diversity of BESs from one T. brucei strain. Most BESs ranged between 40 and 70 kb (average, 57 ± 17 kb) and contained most identified ESAGs. Phylogenetic comparison of the cohort of BES promoter and ESAG6 sequences did not show similar trees, indicating rapid evolution most likely mediated by sequence exchange between BESs. This cloning strategy could be used for any T. brucei strain, facilitating research on the biodiversity of telomeric gene families and host-pathogen interactions.
PIL5, a Phytochrome-Interacting Basic Helix-Loop-Helix Protein, Is a Key Negative Regulator of Seed Germination inArabidopsis thaliana [W]
Authors: Oh Eunkyoo , Kim Jonghyun , Park Eunae , Kim Jeong-Il , Kang Changwon , Choi Giltsu
Published: November 2004

The first decision made by an angiosperm seed, whether to germinate or not, is based on integration of various environmental signals such as water and light. The phytochromes (Phys) act as red and far-red light (Pfr) photoreceptors to mediate light signaling through yet uncharacterized pathways. We report here that the PIF3-like 5 (PIL5) protein, a basic helix-loop-helix transcription factor, is a key negative regulator of phytochrome-mediated seed germination. PIL5 preferentially interacts with the Pfr forms of Phytochrome A (PhyA) and Phytochrome B (PhyB). Analyses of a pil5 mutant in conjunction with phyA and phyB mutants, a pif3 pil5 double mutant, and PIL5 overexpression lines indicate that PIL5 is a negative factor in Phy-mediated promotion of seed germination, inhibition of hypocotyl negative gravitropism, and inhibition of hypocotyl elongation. Our data identify PIL5 as the first Phy-interacting protein that regulates seed germination.
A Novel Molecular Recognition Motif Necessary for Targeting Photoactivated Phytochrome Signaling to Specific Basic Helix-Loop-Helix Transcription Factors[W]
Authors: Khanna Rajnish , Huq Enamul , Kikis Elise A. , Al-Sady Bassem , Lanzatella Christina , Quail Peter H.
Published: November 2004

The phytochrome (phy) family of sensory photoreceptors (phyA to phyE) in Arabidopsis thaliana control plant developmental transitions in response to informational light signals throughout the life cycle. The photoactivated conformer of the photoreceptor Pfr has been shown to translocate into the nucleus where it induces changes in gene expression by an unknown mechanism. Here, we have identified two basic helix-loop-helix (bHLH) transcription factors, designated PHYTOCHROME-INTERACTING FACTOR5 (PIF5) and PIF6, which interact specifically with the Pfr form of phyB. These two factors cluster tightly with PIF3 and two other phy-interacting bHLH proteins in a phylogenetic subfamily within the large Arabidopsis bHLH (AtbHLH) family. We have identified a novel sequence motif (designated the active phytochrome binding [APB] motif) that is conserved in these phy-interacting AtbHLHs but not in other noninteractors. Using the isolated domain and site-directed mutagenesis, we have shown that this motif is both necessary and sufficient for binding to phyB. Transgenic expression of the native APB-containing AtbHLH protein, PIF4, in a pif4 null mutant, rescued the photoresponse defect in this mutant, whereas mutated PIF4 constructs with site-directed substitutions in conserved APB residues did not. These data indicate that the APB motif is necessary for PIF4 function in light-regulated seedling development and suggest that conformer-specific binding of phyB to PIF4 via the APB motif is necessary for this function in vivo. Binding assays with the isolated APB domain detected interaction with phyB, but none of the other four Arabidopsis phys. Collectively, the data suggest that the APB domain provides a phyB-specific recognition module within the AtbHLH family, thereby conferring photoreceptor target specificity on a subset of these transcription factors and, thus, the potential for selective signal channeling to segments of the transcriptional network.
A Conserved Transcript Pattern in Response to a Specialist and a Generalist Herbivorew⃞
Authors: Reymond Philippe , Bodenhausen Natacha , Van Poecke Remco M.P. , Krishnamurthy Venkatesh , Dicke Marcel , Farmer Edward E.
Published: November 2004

Transcript patterns elicited in response to attack reveal, at the molecular level, how plants respond to aggressors. These patterns are fashioned both by inflicted physical damage as well as by biological components displayed or released by the attacker. Different types of attacking organisms might therefore be expected to elicit different transcription programs in the host. Using a large-scale DNA microarray, we characterized gene expression in damaged as well as in distal Arabidopsis thaliana leaves in response to the specialist insect, Pieris rapae. More than 100 insect-responsive genes potentially involved in defense were identified, including genes involved in pathogenesis, indole glucosinolate metabolism, detoxification and cell survival, and signal transduction. Of these 114 genes, 111 were induced in Pieris feeding, and only three were repressed. Expression patterns in distal leaves were markedly similar to those of local leaves. Analysis of wild-type and jasmonate mutant plants, coupled with jasmonate treatment, showed that between 67 and 84% of Pieris-regulated gene expression was controlled, totally or in part, by the jasmonate pathway. This was correlated with increased larval performance on the coronatine insensitive1 glabrous1 (coi1-1 gl1) mutant. Independent mutations in COI1 and GL1 led to a faster larval weight gain, but the gl1 mutation had relatively little effect on the expression of the insect-responsive genes examined. Finally, we compared transcript patterns in Arabidopis in response to larvae of the specialist P. rapae and to a generalist insect, Spodoptera littoralis. Surprisingly, given the complex nature of insect salivary components and reported differences between species, almost identical transcript profiles were observed. This study also provides a robustly characterized gene set for the further investigation of plant–insect interaction.
Do extra‐pair paternities provide genetic benefits for female blue tits Parus caeruleus?
Authors: Charmantier Anne , Blondel Jacques , Perret Philippe , Lambrechts Marcel M.
Published: November 2004

A large body of theories on extra‐pair paternity (EPP) in birds has proposed four main “genetic” hypotheses to explain this behaviour: the “good genes” hypothesis, the genetic diversity hypothesis, the genetic compatibility hypothesis and the fertility insurance hypothesis. Empirical tests have been scarce, mainly because high sample sizes are difficult to collect. We have tested these hypotheses in three Mediterranean populations of blue tits Parus caeruleus in which 50–68% of the broods contained extra‐pair young. Results showed that the distribution of extra‐pair young among broods was not random, and that survival to fledging of extra‐pair young was higher than that of their within‐pair sibs. These results support the idea of genetic effects benefiting extra‐pair young. However, comparison of cuckolded and cuckolding males showed no significant difference in their body size, age, survival or relatedness with their paired females, and offspring morphometrics did not differ between extra‐pair and within‐pair young. We conclude that none of the genetic hypotheses can explain fully the high level of extra‐pair paternity, at least in our populations of Mediterranean blue tits. We suggest that direct ecological benefits of EPP for females should be tested more often in correlative as well as experimental approaches.
Factors influencing fecundity in migratory songbirds: is nest predation the most important?
Authors: Nagy Laura R. , Holmes Richard T.
Published: November 2004

Nest predation often is reported to be the major cause of nest failure in birds and by extension the predominant influence on annual fecundity. However, other factors such as the ability of some individuals to renest after a failed nest or to lay additional clutches after successful ones, both of which may in turn be influenced by food availability, can also contribute to individual fecundity. We evaluated the relative importance of nest predation, multiple brooding, renesting, and food availability on mean annual fecundity of a migratory songbird population, using AICcfrom multiple regression models. In a 16‐yr study of black‐throated blue warblersDendroica caerulescens, these four variables combined explained 87% of the annual variance in fecundity. Individually, however, food abundance explained more of the variability (35%) than did predation (29%), double‐brooding (19%), or renesting (15%). These results suggest that measuring food availability may be essential to understanding annual differences in reproductive output. They also demonstrate that failing to account for the contribution of food availability, renesting, and multiple brooding in studies of avian demography can result in serious underestimates of mean annual fecundity, potentially biasing calculations of population growth rate, source‐sink dynamics, habitat quality, or population viability.
An integrated competency‐based approach to management education: an Italian MBA case study
Authors: Camuffo Arnaldo , Gerli Fabrizio
Published: November 2004

Several studies have analysed the impact of competency‐based methodologies on human resource management, with special emphasis on their applications to management education and development. As concerns management education, however, these studies have usually focused on one or few separate aspects, never proposing a consistent application of competency‐based methodologies throughout the entire educational process. This paper shows how it is possible to design, deliver and monitor a management education programme that uses, in an integrated manner, a multiplicity of competency‐based tools in all the stages of the process, and discusses the application of such an integrated approach to an Italian MBA programme. This study provides a multiple constituency framework that integrates educational institutions, students and the companies that hire them in the design, implementation and control of effective, competency‐based, management education.
Learning organization in mainland China: empirical research on its application to Chinese state‐owned enterprises
Authors: Zhang De , Zhang Zhen , Yang Baiyin
Published: November 2004

This paper examines the applicability of the learning organization concept and its measurement in a Chinese context. Based on the theoretical framework proposed by Watkins and Marsick (1993, 1996, 1997), this paper identifies the differences in seven of the Dimensions of Learning Organization Questionnaire (DLOQ) between traditional state‐owned enterprises (SOEs) versus independent listed companies and companies in service versus manufacturing industries in China. Results indicate that the Chinese version of the DLOQ demonstrated acceptable psychometric properties. Service companies exhibit better learning practices than manufacturing companies; however, the independently listed companies failed to show better learning practices than their unlisted counterparts. Implications for practice and future research are discussed.
Book reviews
Authors: Stewart Jim
Published: November 2004

Books reviewed

Jim Stewart and Graham Beaver. HRD in Small Organisations, Research and Practice.
Are patients’ sedation preferences at gastroscopy influenced by preceding patients’ decisions?
Authors: Olithselvan A. , McIntyre A. S. , Gorard D. A.
Published: November 2004

Background : When patients choose sedation or no sedation for gastroscopy, it is unknown whether the decision and experience of preceding patients on the same endoscopy list influence such decisions.

Aim : To address this question in an endoscopy unit, where pre‐ and postprocedure patients are free to communicate.

Methods : The order and sedation decisions of 503 out‐patients attending diagnostic gastroscopy lists were analysed. One hundred patients completed a preprocedural questionnaire about sedation preferences.

Results : Three hundred and fifteen (63%) patients chose no sedation. Men were more likely to be unsedated, 170 (72%), than women 158 (59%) (χ2 = 9.1, P < 0.01). Age did not influence decisions. If the first patient on an endoscopy list requested sedation, 36% of subsequent patients were also sedated. This was similar to 38% of subsequently sedated patients on lists where the first patient was unsedated. Similar proportions of subsequent patients requested sedation when comparing lists where the first two patients were both sedated or both unsedated and when comparing lists where the first three patients were all sedated or all unsedated. Ninety per cent of the patients completing preprocedural questionnaires had made sedation choices before arrival; the remaining undecided patients had unsedated endoscopies.

Conclusions : Patients’ sedation decisions are not influenced by preceding patients’ decisions. Most patients attending for out‐patient gastroscopy have already decided about sedation.
Meta‐analysis: a randomized trial of peginterferon plus ribavirin for the initial treatment of chronic hepatitis C genotype 4
Authors: Khuroo Mohammad S. , Khuroo Mehnaaz S. , Dahab Salim T.
Published: November 2004

Background: Guidelines for treatment of patients infected with hepatitis C virus genotype 4 are not available.

Aim: To perform a meta‐analysis of randomized controlled trials comparing peginterferon plus ribavirin with interferon plus ribavirin treatment in treatment‐naïve patients infected with chronic hepatitis C virus genotype 4.

Methods: The outcome measure was sustained virologic response. The measure of association employed was relative risk calculated by the random‐effect model, with heterogeneity, sensitivity and subgroup analyses.

Results: Of the 565 studies screened, six randomized controlled trials including 424 patients (peginterferon plus ribavirin 219, interferon plus ribavirin 205) were analysed. Duration of therapy was 1 year in all trials. Sustained virological response obtained with peginterferon plus ribavirin (55%) was significantly higher than with interferon plus ribavirin (30%) [relative risk, 1.71 (95% confidence interval, 1.15–2.56);P = 0.0088]. In the subgroup analyses, sustained virological response in trials using standard‐dose ribavirin (1000 or 1200 mg/day) was 72% as against 45.8% in trials using low‐dose ribavirin (800 mg/day) (P = 0.01). Further sub‐group analyses for treatment duration, body weight, viral load and cirrhosis could not be performed because of lack of relevant data.

Conclusion: Treatment‐naïve patients infected with hepatitis C virus genotype 4 should be treated with peginterferon plus standard‐dose ribavirin for 1 year, with an expected sustained virological response rate of 72%.
Personal view: cost and benefit of medical rituals in gastroenterology
Authors: Sonnenberg A.
Published: November 2004

Background : Unable to resolve a medical problem, gastroenterologists occasionally choose an ineffectual intervention instead. The elusive path to effectual management becomes substituted with an ineffectual but readily available medical ritual. The term ‘ritual’ refers to the utilization of an ineffectual intervention with little chances of achieving a medically relevant goal.

Aim : The aim of the article is to analyse the cost–benefit relationship of rituals in gastroenterology and the reasons why gastroenterologists utilize them.

Methods : Ritualistic disease management is described in terms of medical decision and threshold analysis.

Results : If the perceived benefit of a ritual exceeds its cost, the ineffectual path becomes more attractive than expectant management or doing nothing. To engage in an ineffectual intervention, the threshold probability for success needs to exceed its cost–benefit difference divided by the benefit associated with success. In choosing an ineffectual intervention, doctors tend to underestimate the true costs of a ritual and overestimate its probability of success. The availability of an effectual path leads to more stringent conditions for the benefit associated with an ineffectual path.

Conclusions : A better understanding of their economical underpinnings should lead to more restricted utilization of rituals in gastroenterology, especially, in situations where they drain scarce resources disproportionately to their perceived benefit.
Influence of socioeconomic status on the quality of prescribing in the elderly – a population based study
Authors: Odubanjo Enitan , Bennett Kathleen , Feely John
Published: November 2004

Aims

To compare the quantity and quality of prescribing, using prescribing indicators, between the relatively deprived and the relatively affluent patients over 70 years old in primary care.

Methods

We examined the General Medical Services (GMS) scheme prescribing data for the Eastern region in Ireland for all patients aged 70 years or more (n = 95 055) during July 2001–December 2002. Prescribing indicators applied to the prescription data to evaluate drugs prescribed to each patient were classified as: (1) descriptive, e.g. number of drug items/patient; (2) indicators assessing potentially harmful prescribing; (3) evidence‐based indicators, e.g. secondary prevention therapy in those with ischaemic heart disease (IHD). Results are expressed as odds ratio (OR) and 95% confidence intervals for comparison of prescribing between the relatively deprived and affluent cohorts, adjusted for age and gender (CI) using logistic regression analysis.

Results

The relatively deprived cohort was more likely to receive a greater number of drugs (5.2 vs. 4.5, P < 0.0001), more generic products (P = 0.01) and be exposed to major polypharmacy (≥ five drugs) compared with monotherapy (OR = 1.58; 95% CI = 1.52,1.64, P < 0.0001). They were more likely to receive potentially harmful drugs such as cerebral vasodilators (OR = 1.52; 1.38,1.69), long‐acting sulphonylurea (OR = 1.43; 1.20,1.72), potentially interacting agents such as angiotensin converting enzyme (ACE) inhibitor and potassium sparing diuretic (OR = 1.78; 1.48,2.15). In terms of evidence‐based prescribing, the relatively deprived cohort with IHD was less likely to receive secondary prevention therapies such as statins (OR = 0.82; 0.74, 0.90) and beta blockers (OR = 0.85; 0.77,0.93).

Conclusions

These results show that suboptimal prescribing is more prevalent among the relatively deprived cohort and suggests the differences observed in the quality of prescribing between these patient groups may be related to their socioeconomic status.
MDR1 haplotypes derived from exons 21 and 26 do not affect the steady‐state pharmacokinetics of tacrolimus in renal transplant patients
Authors: Mai Ingrid , Perloff Elke S. , Bauer Steffen , Goldammer Mark , Johne Andreas , Filler Guido , Budde Klemens , Roots Ivar
Published: November 2004

Aim

This retrospective study investigated the influence of MDR1 haplotypes derived from the polymorphisms 2677G > T (exon 21) and 3435C > T (exon 26) on the pharmacokinetics of the immunosuppressant drug tacrolimus in 73 renal transplant patients.

Methods

Based on both variants of SNPs 2677 and 3435, four different haplotypes and eight different genotypes were identified in the study sample. Tacrolimus trough concentrations (C0) were compared between different SNP variants and genotypes, as well as between carriers and noncarriers of each haplotype. Additionally, CYP3A5 genotype (6956G > A) was determined.

Results

No significant differences were observed between groups. Differences in mean tacrolimus C0 values between carriers and noncarriers of each haplotype ranged from −0.04 µg/litre (95% confidence interval: −0.53 to 0.60) to −23 µg/litre (−1.07 to 1.53). No association was found between CYP3A5*1/*3 genotype and tacrolimus Co concentractions.

Conclusion

MDR1 haplotypes derived from the SNPs 2677G > T (exon 21) and 3435C > T (exon 26) do not influence the pharmacokinetics of tacrolimus in renal transplant patients.
Comparison of gentamicin dose estimates derived from manual calculations, the Australian ‘Therapeutic Guidelines: Antibiotic’ nomogram and the SeBA‐GEN and DoseCalc software programs
Authors: Mohan Mitali , Batty Kevin T. , Cooper Jennifer A. , Wojnar‐Horton Richard E. , Ilett Kenneth F.
Published: November 2004

Aim

To compare gentamicin dose estimates from four predictive methods.

Methods

A retrospective study was conducted, comprising patients at Fremantle Hospital who received gentamicin therapy and had at least one gentamicin serum concentration reported. A manual calculation method, the Australian ‘Therapeutic Guidelines: Antibiotic’ (TGA) nomogram and the SeBA‐GEN and DoseCalc software packages were compared. SeBA‐GEN dose estimates were regarded as the reference standard.

Results

There were 64 males and 30 females with mean age of 58 ± 16 years. In patients with moderate renal impairment (CLCr = 30–60 ml min−1; n = 21), mean dose estimates using DoseCalc and the manual calculation method were comparable to SeBA‐GEN but the mean TGA nomogram dose (230 mg; 95% confidence interval 179, 281) was significantly lower than SeBA‐GEN (286 mg; 261, 311; P = 0.002; one‐way RM anova). In patients with mild renal impairment (CLCr = 60–90 ml min−1; n = 48), DoseCalc (392 mg; 367, 427) was comparable to SeBA‐GEN (377 mg; 362, 392). Although the manual method (341 mg; 306, 376; P = 0.007) and the TGA nomogram (335 mg; 302, 368; P < 0.001) estimates were significantly lower than SeBA‐GEN, the practical difference was modest.

Conclusions

SeBA‐GEN and DoseCalc are generally comparable for estimation of gentamicin doses in patients with renal impairment. The ‘Therapeutic Guidelines: Antibiotic’ nomogram is a valid approach to dosage estimation, but only when used in patients with normal renal function. Simple manual calculations are a suitable alternative in patients with renal impairment.
Adsorption of oxacalcitriol by polysulphone haemodialyser in patients with secondary hyperparathyroidism
Authors: Tsuruoka Shuichi , Yamamoto Hisashi , Ioka Takashi , Ando Hitoshi , Saito Tetsuo , Fujimura Akio
Published: November 2004

Aims

This study was undertaken to evaluate removal of 22‐oxacalcitriol (OCT), an active and intravenously used vitamin D3 analogue with less calcaemic activity, by polysulphone haemodialyser in vivo and in vitro. We further compared the pharmacodynamic efficacy [suppression of intact parathyroid hormone (iPTH)] when given intravenously either during or at the end of the haemodialysis.

Methods

(i) Drug clearance by the polysulphone dialyser was measured during a single continuous infusion (5 µg) for 30 min into the arterial side of the dialyser in end‐stage renal failure patients with secondary hyperparathyroidism (n = 7). (ii) The drug adsorption by the hollowfibre membrane during incubation for 30 min was measured in vitro. (iii) To evaluate efficacy, the drug was given (i.v. bolus) during or at the end of haemodialysis for 4 weeks in a cross‐over fashion with a washout period of 8 weeks (n = 9). Serum Ca2+, phosphate (P) and iPTH concentrations just before the initiation of the dialysis were monitored every week.

Results

(i) OCT was significantly cleared by the polysulphone haemodialyser, but the clearance declined in a time‐dependent manner to approach zero at 30 min. Arterial (at the place between the drug infusion site and the haemodialyser column) drug concentrations did not change during the infusion (mean = 2064 ± 233 pg ml−1). Venous (just after the dialyser) drug concentrations at 10 min after the infusion were significantly lower than those of the arterial side (mean = 784 ± 84 pg ml−1); however, they increased with time and reached those of the arterial side at 30 min. (ii) In vitro, OCT was adsorbed by the membrane. The amount of adsorption was concentration‐dependent and was lower in the presence of human serum (55 ± 4% without and 23 ± 4% with serum at 600 pg ml−1 of OCT). (iii) Although serum Ca2+ and P increased and iPTH decreased by both treatment regimens (i.e. OCT administered either during or at the end of haemodialysis), these changes did not significantly differ. Mean differences (and 95% confidence interval) of Ca2+, P, and iPTH at the end of the trial were 0.03 (−0.04, 0.09) mm, 0.41 (−0.43, 1.26) mg dl−1 and 38 (−42, 88) pg ml−1, respectively.

Conclusion

OCT is adsorbed by polysulphone dialyser in vitro and in vivo. However, the pharmacodynamic effectiveness was largely independent of the administration regimen of OCT given either during or at the end of haemodialysis.
Comparison of tincture of opium and methadone to control opioid withdrawal in a Thai treatment centre
Authors: Jittiwutikarn Jaroon , Ali Robert , White Jason M. , Bochner Felix , Somogyi Andrew A. , Foster David J. R.
Published: November 2004

Aims

To evaluate the effectiveness of oral tincture of opium (TOP) and methadone to control opioid withdrawal in patients in northern Thailand.

Methods

Open label, parallel group study in an inpatient facility compared 15 former heroin users receiving methadone 5–20 mg 12 hourly with 15 former opium smokers receiving TOP (3.33–10 mg morphine equivalents 12 hourly). At 0, 1, 3 and 8 h, blood, withdrawal scores and subjective opioid effects were collected.

Results

There was a reciprocal association between withdrawal scores/direct subjective opioid effects and plasma (R)‐methadone, but not plasma morphine, concentrations. Withdrawal scores at the time of dosing were higher in the TOP patients (9.1 ± 3) than in the methadone patients (4.5 ± 4.6) and in the TOP patients were significantly (P = 0.001) attenuated at 3 and 8 h.

Conclusions

At the doses used, TOP was inferior to methadone in suppressing withdrawal. It could prove to be a cost effective and valuable drug, but only after dose size and frequency are further investigated.